Edited by R
L
Souhami
MD FRCP FMedSci
Emeritus Professor of Medicine, University College London, UK J Moxham MD FRCP Professor of Respiratory Medicine and Vice-Dean, Guy's King's and St Thomas' School of Medicine, King's College Hospital, London, UK
CHURCHILL LIVINGSTONE
EDINBURGH LONDON NEW YORK OXFORD PHILADELPHIA ST LOUIS SYDNEY TORONTO 2002
CHURCHILL LIVINGSTONE An imprint of Elsevier Limited © Pearson Professional Limited 1996 Assigned to Harcourt Brace and Company 1998 © 2002, Elsevier Science Limited. All rights reserved. © 2004, Elsevier Limited. All rights reserved.
Commissioning Editor: Laurence Hunter Project Development Manager: Barbara Simmons Project Manager: Nancy Arnott Designer: Erik Bigland
The right of Robert Souhami and John Moxham to be identified as editors of this work has been asserted by them in accordance with the Copyright, Designs and Patents Act 1988. No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, without either the prior permission of the publishers or a licence permitting restricted copying in the United Kingdom issued by the Copyright Licensing Agency, 90 Tottenham Court Road, London WIT 4LP. Permissions may be sought directly from Elsevier's Health Sciences Rights Department in Philadelphia, USA: phone: (+1) 215 238 7869, fax: (+1) 215 238 2239, e-mail:
[email protected]. You may also complete your request on-line via the Elsevier Science homepage (http://www.elsevier.com), by selecting 'Customer Support' and then 'Obtaining Permission First edition 1990 Second edition 1994 Third edition 1997 Fourth edition 2002 Reprinted 2004 ISBN 0-443-06464-4
British Library Cataloguing in Publication Data A catalogue record for this book is available from the British Library
Library of Congress Cataloging in Publication Data A catalog record for this book is available from the Library of Congress
Note Medical knowledge is constantly changing. As new information becomes available, changes in treatment, procedures, equipment and the use of drugs become necessary. The authors and the publishers have taken care to ensure that the information given in this text is accurate and up to date. However, readers are strongly advised to confirm that the information, especially with regard to drug usage, complies with the latest legislation and standards of practice. your source for books, journals and multimedia in the health sciences www.elsevier hea lth.com
ELSEVIER
The publisher's policy is to use paper manufactured from sustainable forest!
Printed in China
Preface The Fourth Edition of this textbook continues the approach, first begun fifteen years ago, to provide a comprehensive account of internal medicine that incorporates the ideas of modern medical science. The intervening years have strengthened our belief that an understanding of cellular and physiological processes makes medicine more exciting and less arbitrary. The emphasis of the book is clinical, giving a full description of the presentation, investigation and treatment of disease. We have attempted to interpret these clinical aspects by reference to the underlying mechanisms whenever possible. Modern integrated curricula demand this approach. The textbook is primarily intended for students of medicine, but we hope and anticipate that it will continue to be of value to trainee doctors and health care professionals in many fields. The Fourth Edition has been completely revised to incorporate all major developments and advances, leading to an expansion of many sections especially in the areas of infectious disease including AIDS, and cardiovascular disease. Many of the illustrations have been replaced or extended to include the most up-to-date epidemiological data. We hope that these will give the reader a sense of the way medicine is developing and where future advances in practice may lead. The most important innovation, however, affects the entire book. By linking the book to an easily-accessed internet site we
have been able to incorporate case problems, multiple choice questions and clinical images throughout the text. The illustrative case problems, some of which are in the textbook itself, are designed to allow the reader to test his or her knowledge by practical application in clinical problem solving. Knowledge and understanding can also be assessed by multiple choice questions, formerly in a companion volume but which are now located on the associated internet site. In addition the website contains 500 supplementary clinical images. This extra information, all of which is clearly cross-referenced in the text, represents for the reader an important additional compendium of knowledge, which expands the versatility of the book as a learning aid. The range and depth of specialised medical knowledge necessary for a major textbook has led us to select our authors from a wide range of medical schools. They have been chosen for their acknowledged reputation in clinical and scientific medicine. In this Fourth Edition we have again expanded the team of authors. All of us would be pleased to receive suggestions which will help the book change and develop for future editions. London 2002
RLS JM
V
Acknowledgements As in previous editions we are greatly indebted to Laurence Hunter for his help in the planning and realisation of the new edition. He has a very effective production team that have made our task much easier. Our editor Barbara Simmons has, as usual, been helpful, efficient and outstandingly courteous even in the face of occasionally rather provoking circumstances. We owe her a lot and are very grateful.
vi
The multiple choice questions and answers for the website have been developed by Dr Andrew Freedman, Dr Richard Watts and Dr Richard Evans. We are very grateful to them for their painstaking work, which has added greatly to the educational value of the book. We are also grateful to Dr Donncha O'Gradaigh for writing the rheumatology case studies.
Contributors Geoffrey J Bellingan PhD MRCP Senior Lecturer, Department of Medicine, University College London Medical School; Consultant, Department of Intensive Care Medicine, University College London Hospitals, London, UK Brian T Cooper BSC MD FRCP Consultant Gastroenterologist, City Hospital, Birmingham; Senior Clinical Lecturer in Medicine, University of Birmingham, UK John Costello MD FRCP FRCPI Consultant Physician and Clinical Director of Medicine, King's College Hospital, London, UK
Jeremy Holmes MD MRCP FRCPsych Consultant Psychotherapist, Devon Partnership Trust; Senior Lecturer, University of Exeter, Exeter, UK Cameron T C Kennedy MA MB BChir FRCP Consultant Dermatologist and Clinical Senior Lecturer, Bristol Dermatology Centre, Bristol, UK Michael E J Lean MA MD FRCP Professor of Human Nutrition, University of Glasgow; Consultant Physician, Glasgow Royal Infirmary; Non-executive Director, Health Education Board for Scotland, Glasgow, UK David C Linch BA MB BChir FRCP FRCPath FMedSci
John Cunningham MD FRCP Professor of Renal and Metabolic Medicine, Barts and the London, Queen Mary's School of Medicine and Dentistry, University of London, UK J David M Edgar BSc(Hons) FRCP MRCPath Consultant Immunologist, Regional Immunology Service, The Royal Hospitals Belfast, N Ireland
Professor of Haematology, Royal Free and University College London Medical School, London, UK Richard G Long MD(Lond) FRCP (Lond) Consultant Gastroenterologist, City Hospital and Queen's Medical Centre, Nottingham; Clinical Teacher, Nottingham University Medical School, Nottingham, UK
Jeremy M Gibbs MD FRCP Consultant Neurologist and Honorary Senior Lecturer, Royal Free Hospital, London, UK
John P Monson MD FRCP Professor of Endocrinology, Department of Endocrinology, Barts and the London, Queen Mary's School of Medicine and Dentistry, London, UK
John Goldstone MD FRCA Consultant in Intensive Care Medicine and Consultant Anaesthetist, University College London Hospitals, London, UK
John Moxham MD FRCP Professor of Respiratory Medicine and Vice-Dean, Guy's King's and St Thomas' School of Medicine, King's College Hospital, London, UK
Robin A C Graham-Brown BSc MB FRCP Consultant and Honorary Senior Lecturer in Dermatology, University Hospital of Leicester NHS Trust and Leicester Royal Infirmary, Leicester, UK
John O'Grady MD FRCPI Consultant Hepatologist, King's College Hospital, London, UK
Brian Hazleman MA FRCP Consultant Rheumatologist, Addenbrooke's Hospital, Cambridge; Director Rheumatology Research Unit; Fellow, Corpus Christi College, Cambridge, UK
Peter W Overstall FRCP Consultant in Geriatric Medicine, Hereford Hospital, Hereford, UK
VII
Philip A Routledge MD FRCP FRCPE Professor of Clinical Pharmacology, University of Wales College of Medicine, Cardiff; Honorary Consultant Physician, Cardiff and Vale NHS Trust, Cardiff, UK
John Wilding DM FRCP Reader in Medicine and Honorary Consultant Physician, University of Liverpool and University Hospital Aintree, Liverpool, UK
John W Scadding MD FRCP Consultant Neurologist, The National Hospital for Neurology and Neurosurgery and Whittington Hospital, London, UK
Gareth Williams MA MD FRCP Professor of Medicine and Honorary Consultant Physician, Clinical Sciences Centre, University Hospital Aintree, Liverpool, UK
Herb F Sewell MB ChB MSC PHD FRCP FRCPath FMedSci Professor and Consultant Immunologist, University of Nottingham, Queen's Medical Centre, Nottingham, UK Martin Smith MBBS FRCA Consultant Neuroanaesthetist, Department of Neuroanaesthesia and Intensive Care, The National Hospital for Neurology and Neurosurgery, London, UK Robert L Souhami MD FRCP FMedSci Emeritus Professor of Medicine, University College London, UK L B Tan DPM FRCP FESC Consultant Cardiologist, Leeds General Infirmary, Leeds, UK J Malcolm Walker MD FRCP Consultant Cardiologist and Clinical Director of the Hatter Institute of Cardiovascular Studies, University College Hospitals, London, UK Mark H Wansbrough-Jones MSC FRCP Consultant Physician and Senior Lecturer in Infectious Diseases, St George's Hospital and Medical School, London, UK Antony P Weetman MD DSC FRCP Professor of Medicine, University of Sheffield; Honorary Consultant Physician, Sheffield Teaching Hospitals Trust, Sheffield, UK
viii
Ian G Williams BSC MRCP Senior Lecturer, Department of Sexually Transmitted Diseases, University College London Medical School, London, UK Robin M Winter FRCP FMedSci Professor of Dysmorphology and Clinical Genetics, Institute of Child Health, London, UK Stephen G Wright MB FRCP Consultant Physician, Hospital for Tropical Diseases, London; Honorary Senior Lecturer, London School of Hygiene and Tropical Medicine, London, UK
MULTIPLE CHOICE QUESTIONS Richard H Evans MRCP Specialist Registrar in Infectious Diseases and General (Internal) Medicine, University Hospital of Wales, Cardiff, UK Andrew Freedman MA MD FRCP Senior Lecturer in Infectious Diseases, University of Wales College of Medicine; Consultant Physician, University Hospital of Wales, Cardiff, UK Richard A Watts MA DM FRCP Consultant Rheumatologist Ipswich Hospital NHS Trust, Ipswich, UK
Contents 1. Therapeutics and toxicology
14. Critical care medicine
1
725
J Goldstone, G J Bellingan, M Smith
P A Routledge
2. Acute physical and environmental disorders 45
15. Gastrointestinal disease 751 R G Long, B T Cooper
J Moxham, R L Souhami
16. Liver and biliary tract disease 835 3. The genetic basis of disease
57
J O'Grady
R M Winter
17. Endocrine disease 4. Immunological disorders
79
883
A P Weetman
J D M Edgar, H F Sewell
5. Nutrition in clinical medicine
105
18. Metabolic bone disease and mineral metabolism 953 J Cunningham, J P Monson
M E J Lean
6. Cancer medicine
19. Diabetes mellitus and lipid metabolism
145
979 J Wilding, G Williams
R L Souhami
7. Ageing and disease 171 20. Renal and urinary disease 1031 J Cunningham
P W Overstall
8. Psychological medicine
205 21. Salt and water homeostasis and acidbase balance 1099
J Holmes
9. Infectious, tropical and parasitic disease 259 M H Wansbrough-Jones, S G Wright
10. Skin disease
J P Monson
22. Musculoskeletal and connective tissue disease 1119
379
B Hazleman
C T C Kennedy, RAG Graham-Brown
23. Haematological disorders 1201 11. AIDS and genitourinary disease
439
D C Linch
I G Williams
24. Neurological disease 12. Cardiovascular disease
463
1283
J W Scadding, J Gibbs
J M Walker, L B Tan
Index 13. Respiratory disease J Moxham, J Costello
1443
605 ix
This page intentionally left blank
n Therapeutics andToxicology Philip A Routledge
Pharmacodynamic variability refers to differences in response to the same drug concentration at its effector site. This is sometimes related to differences in the number and/or activity of specific receptors or other effector sites (e.g. ion channels). The very young and the elderly appear to have an increased sensitivity to several drugs, particularly those affecting the central nervous system. An increased sensitivity to drugs acting on the central nervous system is also seen in patients with chronic renal and liver disease. The elderly appear also to have less adaptable homeostatic mechanisms and are therefore more prone to drug-induced postural hypotension or hypothermia. Hyperthyroid patients are more sensitive to the effects of oral anticoagulants and less sensitive to digoxin.
Causes of variability in drug response 1
Poisoning with gases and volatile solvents 33
PHARMACOKINETIC VARIABILITY
Adverse drug reactions 5
Overdose with alcohols 35
Drug interactions 7
Poisoning with corrosive agents 36
This occurs when the handling of a drug is altered in disease or in different physiological states. The causes of variability are shown in Summary 1 (p. 4).
Therapeutic drug monitoring 11 Specific drugs 12 Drug regulation and development 13
Drug overdose 15
Poisoning with insecticides, herbicides, fungicides and rodenticides 37 Poisonous plants and fungi 39 Poisonous animals 41
Diagnosis of poisoning 16 Principles of management of poisoning 18
Poisoning by metals 43
Management of specific drug overdose 23
Therapeutics is the branch of medicine that deals with the treatment and cure of disease and ill health. Medicines are the most important tool in therapeutics, and an understanding of their pharmacology in normal dose and excess dose (toxicology) is essential in ensuring their safe and effective use. Therapeutics developed as a specialty because of the need to understand the causes of biological variability in drug response in humans, particularly in disease states.
CAUSES OF VARIABILITY IN DRUG RESPONSE PHARMACODYNAMIC VARIABILITY There are three major ways in which a drug can produce pharmacological effects: • By combination with specific receptors; • By alteration of physiological enzyme processes; • By direct physical or chemical action.
Absorption Drugs are usually given by mouth and must therefore pass through the bowel wall in order to enter the bloodstream. This occurs via four different mechanisms: • Passive diffusion, which involves diffusion down a concentration gradient from the gut into the bloodstream. For this to occur the drug must dissolve in the gastrointestinal fluids, traverse the cell membrane and enter the bloodstream. The rate at which it does so depends on both the concentration gradient and the lipid solubility of the drug. This is the most important mechanism of absorption for most drugs. • Active transport, a less important mechanism by which some drugs, because of their resemblance to naturally occurring substances, use existing transport systems. Thus, levodopa is absorbed by the active process responsible for absorption of the amino acid tyrosine. • Filtration through pores, a route generally limited to molecules of molecular weight less than 100 (e.g. urea). Most drugs are too large to traverse the pores between cells. • Endocytosis, by which drugs or particles are engulfed by cells in the bowel wall. This is of relatively little importance to drug absorption. Factors affecting absorption Absorption is affected by the chemical nature and formulation of the drug, as well as the physiological characteristics of the absorption site. Thus, some drugs cannot be administered orally because they are broken down by gastrointestinal enzymes (e.g. the polypeptide insulin) or are unstable at extremes of pH (e.g. benzyl penicillin at gastric pH). Most drugs are either weak acids or weak bases and thus exist in two forms in solution - as ions or as undis-
1
sociated molecules. At the low pH encountered in the stomach, a weakly acidic drug exists mainly in its undissociated form; it is thus more lipid soluble and will tend to be more easily absorbed. Basic drugs, on the other hand, are largely ionized at low pH and exist predominantly in the undissociated form only in the alkaline medicine of the small bowel. Despite these considerations, both acidic and basic drugs tend to be absorbed predominantly in the small intestine, because they are there for longer and because the inner surface of the intestine provides a much greater absorptive area than the stomach. Formulation factors are important in determining the rate and extent of drug absorption. Most drugs consist not only of an active agent but also of diluents, granulating and binding agents, lubricants and disintegrating agents, any of which may have a marked effect on absorption. Particle size of the active constituent may also be important, and sustained- or delayed-release preparations will also delay absorption rate. Gastrointestinal motility affects the rate of absorption. Delays in gastric emptying will result in delayed drug absorption, although the extent of absorption is normally unchanged. Food has a variable effect. Some drugs (e.g. propranolol) have greater bioavailability in the presence of food because of reduced presystemic elimination, whereas others (e.g. rifampicin) are more poorly absorbed. Such factors may be important in determining the times of administration of drugs. The route of administration is also important. Alternatives to the oral route are:
2
• Intramuscular injection, either to speed the onset of effects or to enhance bioavailability when the oral route is suboptimal. Use of the intramuscular route can, however, cause local pain, and some drugs (e.g. phenytoin and diazepam) are poorly and variably absorbed when administered in this way, because of poor solubility at tissue pH. Absorption rate varies with the muscle group used and may be slow in situations of poor tissue perfusion. • Rectal administration can sometimes be used, but because the haemorrhoidal veins drain partly into the portal tract, presystemic elimination is not completely avoided. The suppository may also be variably retained or have poor and erratic absorption. • Buccal administration can completely avoid presystemic elimination and is used for drugs (e.g. glyceryl trinitrate) that are rapidly metabolized after the oral route. Unfortunately, not all such drugs can rapidly penetrate the buccal mucosa and enter the systemic circulation. • Transdermal administration is an alternative to the buccal route for drugs such as glyceryl trinitrate or the antihistamine hyoscine. The rate of absorption varies with the skin site used and the extent of absorption is limited, so that only very potent drugs (effective dose <10mg) can be usefully administered by this route. Absorption is normally rapid, but membranes are being developed to control the rate.
• Intrapulmonary route. Some drugs, and all anaesthetic gases, are administered by the intrapulmonary route. Non-gaseous compounds are difficult to introduce into the lungs. Only 10% of a drug administered by pressurized aerosol actually enters the lungs: the remainder is deposited in the buccal cavity and subsequently swallowed. Absorption of drugs is normally so efficient that it is unusual to see differences in the extent of absorption of most modern drugs, even in the presence of extensive bowel resection. However, reduced absorption may occur in severe malabsorption syndromes or in severe diarrhoea, or in severe congestive cardiac failure because of oedema of the small intestine. Differences in bowel motility may affect the rate (often more than the extent) of absorption. Gastric emptying is slow and erratic in the very young and in adults who are shocked or in pain. In such circumstances (e.g. myocardial infarction) threshold concentrations for drug effect may not be achieved rapidly, or at all, and the drug (e.g. analgesic treatment) may be more effective when given by an alternative, non-alimentary route.
Distribution If drug distribution did not occur, only those drugs with an action within the vascular compartment would provoke biological effects. Like absorption, distribution is dependent on the physicochemical characteristics of the drug as well as upon biological factors. The major physicochemical properties determining drug distribution are lipid solubility and (if the drug is a weak electrolyte) the degree of dissociation (ionization) in tissues. Highly lipid-soluble drugs are generally distributed throughout all fluid compartments and, because they can cross lipid membranes readily, can reach most organs, including the brain. Poorly lipid-soluble drugs are normally able to enter the interstitial fluid, but if they are weak electrolytes only the undissociated form can penetrate the cells, and then only to a limited extent, depending on the lipid-water partition coefficient. Biological factors determining the distribution of drugs in the body include the degree of both plasma protein binding and of uptake by tissue, either by binding or by active transport mechanisms. The blood contains approximately 180 g of protein, half of which is albumin. Albumin is thus the most abundant single protein in the plasma and, because of its structure, is able to reversibly bind many drugs by Van der Waals forces, hydrogen bonds or hydrophobic bonds. However, its binding capacity is relatively limited and it has been estimated that only 200 mg of drug of average molecular weight (300) would be bound to albumin in plasma if there were only one binding site available on each albumin molecule. For some drugs there may be more than one binding site and the binding capacity will be relatively greater. Major sites of binding are the so-called site 1 (warfarin site), which also binds the endogenous compound bilirubin, and site 2 (diazepam
1
FIG. 1.1 Relationship between the percentage of diazepam and theophylline free in plasma and plasma albumin concentration in different disorders See text for details.
FIG. 1.2 Relationship between the percentage of lidocaine (lignocaine) free in plasma and plasma AAG concentration in several disease states and in neonates
site), the site at which the endogenous amino acid tryptophan also binds. Drugs may bind to either or both of these sites and can competitively displace each other. The relationship between the serum albumin concentration and the proportion of two drugs in the free (unbound) form is shown in Figure 1.1. It can be seen that the differences in protein binding are likely to be relatively, small over the range of serum albumin concentrations seen in health. In situations of hypoalbuminaemia, however, even small further decreases in serum albumin concentration may cause marked increases in the proportion of drug free in the plasma. Another plasma protein, a,-acid glycoprotein (AAG) also binds drugs, particularly those of a basic nature. Although its plasma concentration is much lower (c. 2%) than that of albumin, its affinity for drugs is high and some drugs (e.g. lidocaine (lignocaine), erythromycin and disopyramide) may bind appreciably more to this protein than to albumin. Because of its low concentration, however, its binding capacity is relatively limited and, for several drugs, protein binding falls with increasing drug concentration. The tissues also contain proteins which combine with drugs (60% of the total exchangeable body albumin is outside the vascular compartment), whereas body fat can serve as an important reservoir for lipid-soluble agents such as thiopentone. Finally, active transport mechanisms - such as the uptake of adrenergic neuron-blocking drugs by the adrenergic neuron - may also contribute to high tissue concentrations of a drug. Extensive tissue binding tends to result in the drug having a large apparent volume of distribution (Vci), as most of the drug is outside the intravascular space. Distribution of drugs may be altered by changes in regional blood flow in disease. The volume of distribution of lidocaine (lignocaine), for example, appears to be lower in patients with cardiac failure. Protein binding also determines drug distribution. Albumin concentrations are low in the neonate, begin to decline over the age of 40, and are reduced during pregnancy. Severe hypoalbuminaemia also
occurs in nephrotic syndrome and chronic liver disease. In patients with chronic renal failure the proportion of drug in the free form is greater than would be expected from the reduction in serum albumin alone, indicating either structural changes in albumin or the presence of endogenous inhibitors of binding. AAG is reduced in neonates and in pregnancy but tends to be normal in healthy elderly individuals. It is markedly increased in patients with rheumatoid arthritis and other inflammatory diseases, including chronic renal disease, after myocardial infarction, and in cancer. As with albumin, it may be reduced in patients with nephrotic syndrome or chronic liver disease. Concomitant changes in plasma protein binding of drugs also occur, the effects depending on the relative strength of binding of the drug to these two proteins and on the disease state in question (Fig. 1.2), which may alter the amount bound to free drug. Thus the total plasma concentration of drug (free + bound), which is generally measured in clinical practice, may not always reflect the free (active) concentration. Therapeutic ranges for total drug may therefore need to be altered in diseases where plasma protein binding is affected (see Therapeutic drug monitoring).
Metabolism The liver is the main organ of drug metabolism, although some may also occur in the gastrointestinal tract, lung, blood or kidney. Metabolism is particularly important for lipid-soluble drugs, which more readily enter cells and are also prevented by their lipid solubility from being excreted unchanged by the kidney. The routes of metabolism are relatively non-specific and are shared by a variety of drugs. In most instances, more water-soluble metabolites (which are more easily excreted by the kidney) are produced. There are two groups of metabolic reaction: phase I and phase II. Phase I reactions involve the enzyme mono-oxygenase, situated in the smooth endoplasmic reticulum of cells with metabolic function, especially the liver. These are called
3
cytochrome P450 enzymes and are responsible for oxidation, reduction, hydrolysis and dealkylation of drugs with the relevant molecular structure. A given drug may be metabolized by one or more of these routes to produce more water-soluble (and thus biologically active) metabolites. Phase II reactions are conjugation reactions of more water-soluble molecules to the drug or metabolite. Conjugation with glucuronide (glucuronidation) is the commonest pathway, but conjugation can also occur with sulphate, amino acids such as glutathione, or acetylCoA (acetylation). Most of these conjugated metabolites (except for some acetylated compounds) are biologically inactive. Although most metabolic processes are controlled by environmental factors, acetylation is under genetic control: 45% of the UK population are slow acetylators and the remainder either intermediate or fast acetylators. Approximately 7% of the British population have a reduced ability to hydroxylate several drugs (e.g. debrisoquine, nortriptyline and phenformin), which may lead to an increased risk of adverse reactions to drugs metabolized by this route. Metabolism of drugs may be diminished at the extremes of age. Neonates have a reduced capacity for phase I, and most phase II reactions. Thus the effect of caffeine (a phase I pathway) is markedly reduced. Reaction of phase II pathways such as the glucuronidation of chloramphenicol, for example, may lead to grey baby syndrome in the neonate. Immaturity of these processes is greatest in the premature neonate, who is therefore at greatest risk of adverse drug reactions. In the healthy elderly, impairment of drug metabolism is only slight and tends to be overshadowed by changes in pharmacodynamic response. However, marked reductions in drug metabolism may be seen in the frail elderly. Dietary and environmental factors, such as smoking, may affect the rate of metabolism of some drugs; and chronic liver disease is often associated with an impairment of metabolism, particularly of phase I pathways. In liver disease the serum albumin concentration correlates roughly with the degree of impairment of drug metabolism (i.e. the lower the albumin the more severe the impairment). The effect of impairment of metabolism in liver disease will be greater for those drugs with extensive presystemic metabolism. The bioavailability of propranolol is much greater in patients with chronic liver disease, not because of better absorption (absorption is virtually complete in health) but because it cannot be efficiently metabolized on its first passage through the liver. This is due not only to the reduced hepatocyte metabolic activity, but also to intra- and extrahepatic shunting of blood past the liver cells and a consequent reduction in effective liver blood flow.
A MCQ1.1-1.5
4
SUMMARY 1 Pharmacokinetic causes of variability in drug response Absorption Extent of drug absorption reduced only in rare circumstances Distribution Altered in disease by changes in regional blood flow, altered plasma protein binding (e.g. hypoalbuminaemia in hepatic cirrhosis), or changes in activity of energy dependent transporter systems (e.g. P-glycoprotein) Metabolism Diminished in neonates (particular if premature) and the elderly (especially if frail). Affected by genetic factors (e.g. genetic polymorphisms), environmental factors (e.g. smoking) and liver disease Excretion Immature in neonates (particularly if premature) Impaired in renal disease and declines with advancing age over 40 years
In cardiac failure and shock, cardiac output is reduced and a disproportionately greater reduction in hepatic blood flow (normally around 1.5L/min) may result in a marked reduction in the systemic clearance of normally efficiently cleared compounds (e.g. lidocaine (lignocaine)), for which hepatic blood flow is the major determinant of delivery of drug to and clearance by the liver. In addition, the liver can be affected by the increased venous backpressure caused by failure of the right side of the heart in biventricular (congestive) cardiac failure. This results in increased size and congestion of the liver and derangement of liver function, with reduced hepatocyte clearance of several drugs. Genetic factors play a major role in determining drug response and handling, and susceptibility to adverse drug reactions. Allelic variations affecting pharmacokinetics with a frequency of at least 1% in the population are often termed genetic polymorphisms (e.g. acetylation) and are associated with a bimodal or trimodal (rather than the normal unimodal) distribution of clearance values. Some clinically important pathways of drug metabolism showing such polymorphisms are ./V-acetylation, oxidation (hydroxylation) via the cytochrome (CYP) P450 isoform, CYP2D6, succinylcholine hydrolysis (de-esterification) and thiopurine s-methylation. More are being recognized as detection techniques improve.
Excretion The vast majority of drugs must first be metabolized to more water-soluble compounds before they can be excreted in the urine. Those drugs (e.g. cimetidine, digoxin, aminoglycosides, lithium, cephalosporins, penicillins, atenolol and chlorpropamide) that are largely excreted unchanged tend to be relatively water-soluble and are not appreciably bound to plasma proteins and so can enter the glomerular filtrate. Lipid-soluble drugs may also enter the glomerular filtrate, provided they are not extensively plasma protein bound, but they then readily pass back
through the proximal tubular cells into the bloodstream by passive diffusion down a concentration gradient. Only when they have been metabolized to more water-soluble compounds will they have difficulty in passing back through the renal tubular cells and therefore be excreted in the urine. Weak electrolytes can also be actively secreted in the proximal renal tubules - weak bases sharing one mechanism and weak acids another - and there is some evidence for an active transport system promoting the excretion of digoxin in the distal renal tubule. Drugs may also be excreted in the bile, normally as conjugates and particularly if they have a high molecular weight. The drug may, however, be reabsorbed from the intestine, either directly or after deconjugation by intestinal microflora, to create an enterohepatic cycle. This may reduce the clearance of the drug and thus prolong its effect. Excretion of drugs is reduced in neonates (particularly if premature) because of a reduced glomerular filtration rate (GFR) relative to their body surface area, and also because their active renal tubular secretory mechanisms are not fully developed. These processes mature relatively rapidly and are fully functional after 6-12 months, but GFR begins to fall again over the age of 40 (the renal tubular secretory mechanisms appear to be less affected by age). Thus, the dose of digoxin or gentamicin (drugs excreted predominantly by glomerular filtration) may need to be reduced in the elderly or the very young. Renal disease is associated predominantly with a fall in GFR, with active renal tubular secretion mechanisms being less affected. Measurement of serum creatinine or creatinine clearance is therefore useful in calculating the optimum dose of drugs excreted predominantly by glomerular filtration, but it is of less value for drugs such as penicillins, which are actively secreted at the proximal renal tubule. 1
ADVERSE DRUG REACTIONS It has been estimated that approximately 5 % of all hospital admissions are because of adverse reactions to a drug; 1 in 10 patients admitted for other reasons will develop an adverse reaction to a drug while in hospital; and perhaps 1 in 1000 deaths in hospital are due to an adverse reaction to a drug, making adverse reactions between the fourth and sixth most common cause of death in the USA, for example. Adverse reactions are also common in general practice. The drug groups most commonly associated with adverse reactions are antihypertensives, anticoagulants, antirheumatics (particularly the non-steroidal antiinflammatories), cytotoxic agents, corticosteroids and digoxin. Although adverse reactions can affect all systems of the body, they are most often described in the skin and central nervous system, perhaps because detection tends to be easier. The very young (i.e. under 1 year of age) and the elderly are particularly at risk, and women appear to be at greater risk than men, although the reason for this is
unknown. Patients with a history of atopy, or who have had a drug reaction in the past, are more likely to develop further reactions, even to a drug in some other therapeutic group. The presence of disease, particularly heart failure or liver or renal disease, predisposes to a risk of adverse reactions, as may genetic factors, such as enzyme deficiencies.
1
TYPES OF ADVERSE DRUG REACTION Adverse reactions have been classified into two major types.
Type A The most common type is the dose-dependent adverse reaction (type A), which is an 'augmentation' or 'accentuation' of a known pharmacological effect of the drug not necessarily always the wanted effect. Thus, fisympathomimetic agents can cause increased tremor, a recognized pharmacological effect of the drug but one that may limit their use in bronchodilator therapy. Type A reactions account for about 75% of all adverse reactions and, because they are often insidious in onset, may go unrecognized for some time. They may therefore produce considerable morbidity, but the mortality from type A reactions is generally low. They may occur because of altered pharmacokinetic or pharmacodynamic factors and are therefore commonest in diseases (e.g. renal and liver disease) where these are most affected.
Type B The occurrence of type B reactions is not dependent on the dose given. They are unpredictable or 'bizarre' reactions to a drug that may be present only in tiny concentrations, although the severity of the reaction may be greater if a larger dose is administered rapidly (e.g. after intravenous administration). Because of their lack of predictability and their often acute onset they have a proportionally higher mortality than type A reactions, but associated morbidity is relatively low if the patient survives the initial event. Like type A reactions, type B reactions can be related to pharmacokinetic or pharmacodynamic factors. There are many ingredients in medications other than the active
SUMMARY 2 Types of adverse drug reaction (ADR) Type A Dose-dependent 'accentuation' of known pharmacological effect. Account for 75% of ADRs. Cause considerable morbidity but mortality is low. Can sometimes be treated by dose reduction rather than cessation of treatment Type B Non-dose dependent, 'bizarre' and unpredictable. Higher mortality. Type B reactions can be related to hereditary enzyme deficiencies or allergic mechanisms. Usually treated by discontinuing treatment immediately
5
compound: reactions may occur to the preservative, filler, dye, binder or solubilizing agent in the tablet or injection. Type B reactions may occur because individual subjects metabolize the drug through a novel pathway that produces a toxic metabolite. In other cases the presence of hereditary enzyme deficiencies may predispose the patient to the toxic effects of drugs or their metabolites. Thus, haemolysis caused by dapsone and other oxidizing agents is commoner in patients with glucose 6-phosphate dehydrogenase (G6PD) deficiency. Similarly, many agents can precipitate an attack of acute intermittent porphyria (p. 1027) in those carrying a gene for this disorder. Type B reactions are also often related to allergic mechanisms, and may involve any or all forms of antibody- or cellmediated tissue damage. Thus, anaphylaxis may occur as a result of immediate (type I) hypersensitivity associated with cell-bound IgE, after the administration of drugs such as penicillin. Cell surface (type II hypersensitivity) damage may occur as a result of the combination of methyldopa with red cell (or quinine with platelet) membranes and subsequent haemolysis or thrombocytopenia, 1 respectively. Toxic immune complexes may be formed in patients receiving gold or penicillamine, resulting in skin toxicity by a type III hypersensitivity mechanism. Cell-mediated (type IV) tissue damage is thought to be the mechanism of the relatively common (but usually mild) rash associated with ampicillin therapy 2 or the more serious erythroderma sometimes associated with drugs such as gold. 34
DIAGNOSIS AND MANAGEMENT OF ADVERSE DRUG REACTIONS Diagnosis It is rarely possible to make a diagnosis of drug-induced adverse reaction with complete certainty. Either an infective agent or the antibiotic with which the patient was being treated, for example, may cause erythema multiforme. It is therefore necessary to weigh up all circumstantial evidence carefully before making the diagnosis. This includes taking a full drug history, remembering that patients may not consider over-the-counter and herbal remedies, or even the oral contraceptive pill, as medicines or drugs. The brand names of the agents may also be important, as different pharmaceutical formulations may contain different dyes, binders, fillers, preservatives or lubricants, and reactions may occur only with certain formulations. Physical examination provides only limited information. Some physical signs may be directly attributable to drug therapy, e.g. the blue discoloration of the skin
1
Fig. 1.1
4
Case 1.1 Case 1.2
2 Fig. 1.2
3
© Fig. 1.3 6
MCQ1.6
Fig. 1.4
associated with amiodarone therapy 0 is rarely caused by disease. Similarly, an eruption occurring at a fixed site on the skin may suggest a drug-induced fixed drug eruption. 6 However, in most cases the organs affected have a limited number of responses to noxious stimuli. Biochemical tests are also of limited value, but measurement of plasma drug concentration may help to confirm the suspicion of a dose-dependent (type A) adverse reaction. In some cases measurement of metabolic phenotype may also be helpful. It is extremely rare, for example, for patients who are fast acetylators to develop drug-induced lupus erythematosus after hydralazine therapy. Probably the most helpful indication of the drug responsible for the adverse reaction is the time course relative to drug treatment, particularly the rate of resolution of symptoms on stopping a specific drug (dechallenge). Subsequent re-exposure (rechallenge) associated with a recurrence of the symptoms or signs gives the strongest evidence of causation, but it is rarely ethically justifiable unless the patient's need for the drug outweighs the potential risk of the adverse reaction.
Management The only choice with most type B reactions is to stop the suspected drug completely. With type A reactions it is sometimes possible to reduce the dose to prevent the unwanted effects while still obtaining therapeutic benefit. If an adverse reaction does occur, the patient's medical notes and prescription chart should be clearly marked with an eye-catching label to indicate the nature and date of the reaction. Any serious adverse reaction should also be reported to the Committee on Safety of Medicines using a yellow card. In addition, even minor adverse reactions to drugs that have been recently introduced (marked with an inverted black triangle in the British National Formulary) should be reported.
PREVENTION OF ADVERSE REACTIONS It must be remembered that although drugs provide enormous benefit to patients, all are potentially toxic and should be used selectively, particularly in those at greatest risk of adverse reactions, i.e. the very young, the very old and those with severe disease. The risk of developing an adverse reaction appears to increase disproportionately with increasing number of drugs prescribed concomitantly. Prescriptions should therefore be reviewed and, whenever possible, drug therapy rationalized at frequent intervals. When a drug is prescribed, the prescription should be written legibly, in block letters, and preferably using the approved name. Failure to do so may lead to errors in prescribing. In some cases the risk of adverse reactions to certain drugs is such that they should be avoided if at all possible. There are particular dangers during pregnancy or breastfeeding, when certain drugs may cause an adverse reaction in the fetus or breastfed child (Table 1.1).
TABLE 1.1 Some drugs to avoid during pregnancy or breastfeeding Pregnancy
Breastfeeding
Antibiotics
Tetracyclines Sulphonamides Aminoglycosides Chloramphenicol Trimethoprim Nitrofurantoin Quinolones
Tetracyclines Sulphonamides Isoniazid Chloramphenicol Metronidazole Nitrofurantoin Vancomycin
Antithyroids
All, including radioiodine
All, including radioiodine
Analgesics
Opiates NSAIDs
Aspirin NSAIDs (several)
Anticoagulants
Warfarin Acenocoumarol (nicoumalone)
Phenindione
Antidepressants Antihypertensives
SSRIs (several) Lithium ACE inhibitors Angiotensin receptor antagonists Thiazide, loop and potassium-sparing diuretics Hydralazine Minoxidil
Angiotensin receptor antagonists Calcium channel blocker (some)
Antineoplastics
Most
Most
Antidiabetics
Biguanides Sulphonylureas
Use with caution
Antirheumatics
Gold Penicillamine
Antiulcer drugs
Misoprostol Most proton pump inhibitors
DRUG INTERACTIONS
1
Drug interactions have been recognized for over 100 years and were described under the classic headings of antagonism, synergism or potentiation. Many of these interactions are beneficial and have been used to therapeutic advantage, but unwanted or adverse interactions also account for 10-20% of all adverse reactions to drugs. There are around 2000 potentially interacting drug pairs, but the number of clinically significant adverse interactions is much lower, largely involving drugs with a relatively low margin between safety and toxicity (i.e. a narrow 'therapeutic ratio'). Thus, they are most often described with oral anticoagulants, some antidiabetic drugs, anticonvulsants, antiarrhythmics (especially digoxin), tricyclic antidepressants, antihypertensive drugs, NSAIDs, neuroleptic drugs, lithium, anticancer/immunosuppressive agents and theophylline (Tables 1.2-1.4). The elderly, particularly if frail and suffering from multiple medical conditions, are more likely to experience an interaction and more likely to have serious adverse consequences. As with adverse reactions in general, the risk of developing an adverse interaction increases disproportionately with the number of drugs being prescribed concomitantly; the mechanisms of interaction are also similar, in that both pharmacodynamic and pharmacokinetic interactions may occur. Interactions may also take place, however, before the drugs even enter the body, and these have been termed 'pharmaceutical' interactions. 7
PHARMACEUTICAL INTERACTIONS Misoprostol Proton pump inhibitors
Antivirals
Most
Anxiolytics
Benzodiazepines Chloral derivatives
Sex hormones
Androgens, oestrogens and high-dose progestogens
Androgens, oestrogens and high-dose progestogens
Hypolipidaemics
Fibrates Statins
Fibrates
Miscellaneous
Vitamin D and its analogues Live vaccines Podophyllum resin and podophyllotoxin Tamoxifen Thrombolytics
Anthraquinone laxatives and phenolphthalein Amiodarone
NB Absence of a drug from this list does not imply safety. Further information can be obtained by consulting the manufacturer's datasheet, the British National Formulary, or by contacting the National Teratology Centre (0191-232-1525).
Interactions may occur prior to the drug entering the body when drugs are mixed together for infusion, or when a drug interacts with the infusion material itself. Guides to intravenous mixtures are available and should be consulted before compounds are given by intravenous infusion or mixed together. In general terms, it is advisable to avoid adding drugs to infusion fluids unless absolutely necessary, and certainly to avoid adding more than one drug if at all possible. Infusion fluids particularly likely to be associated with pharmaceutical incompatibilities include blood and blood products, amino acids and lipid solutions, mannitol and sodium bicarbonate.
PHARMACODYNAMIC INTERACTIONS Pharmacodynamic interaction occurs where one drug alters the response to another by interacting either at the receptor site or at a different site to enhance or diminish the primary drug effect. Partial agonists initiate a minor response but, by occupying a significant fraction of the receptors, they antagonize the action of more potent agonists. Nalorphine, for example, is a partial antagonist
7
TABLE 1.2 Some drug interactions of clinical importance resulting in increased drug effect Drug (A)
May interact with B
Effect of interaction
Mechanism of interaction
ACE inhibitors Antidepressants (tricyclic) Antihypertensive agents
NSAIDs Enzyme inhibitors Vasodilators (e.g. nitrates for angina) neuroleptics and some antidepressants NSAIDs
Hyperkalaemia, reduced renal function Increased effect of A Postural hypotension
Additive nephrotoxic effects Reduced clearance of A Combined hypotensive effects
Peptic ulceration
Enzyme inhibitors Verapamil NSAIDs (including aspirin) Enzyme inhibitors Amiodarone Diltiazem Verapamil Diuretics (loop and thiazide) ACE inhibitors Potassium supplements NSAIDs Thiazide diuretics Anticholinergic drugs (e.g. some antihistamines/tricyclic antidepressants) Enzyme inhibitors NSAIDs
Increased effect of A
Increased risk of peptic ulceration Reduced clearance of A
Increased risk of peptic ulceration Increased effect of A Increased effect of A
Corticosteroid prevents healing? Reduced clearance of A Reduced clearance of A
Increased effect of A (e.g. arrhythmias) Hyperkalaemia, impaired renal function
Diuretic-induced hypokalaemia Combined potassium-elevating effects
Increased effect of A
Reduced clearance of A
Excessive anticholinergic effects
Combined anticholinergic effects
Increased effect of A Seizures
Reduced clearance of A Pharmacodynamic interaction at CNS effector site Pharmacodynamic interaction Reduced clearance of A Reduced clearance of A
Aspirin (low-dose) Carbamazepine Corticosteroids (oral) Ciclosporin Digoxin Digoxin Diuretics (potassium-sparing) Lithium Phenothiazines and butyrophenones Phenytoin Quinolones Sildenafil (Viagra) Theophylline Warfarin
Nitrates Saquinavir Enzyme inhibitors (e.g. macrolides and 4-quinolones) See Table 1.4
Increased hypotensive effect of A Increased hypotensive effect of A Increased effect of A
TABLE 1.3 Some drug Interactions resulting in reduced drug effect Drug (A)
May interact with B
Effect of interaction
Mechanism of interaction
Antidepressants Antihypertensives (e.g. ACE inhibitors, thiazides and p-blockers) Calcium channel blockers Corticosteroids (oral) Ciclosporin Digoxin
Enzyme inducers NSAIDs
Reduced effect of A Reduced effect of A
Enzyme inducers Enzyme inducers Enzyme inducers Colestyramine (cholestyramine) Colestipol Enzyme inducers Broad spectrum antibiotics Enzyme inducers Colestyramine (cholestyramine) Colestipol Antacids Enzyme inducers Enzyme inducers Colestyramine (cholestyramine) and colestipol See Table 1.4
Reduced effect of A Reduced effect of A Reduced effect of A Reduced effect of A
Increased clearance of A Pharmacodynamic antagonism of anti hypertensive effect of A Increased clearance of A Increased clearance of A Increased clearance of A Reduced absorption of A
Reduced effect of A Reduced effect of A Reduced effect of A Reduced effect of A
ncreased clearance of A nterruption of enterohepatic recycling of A? ncreased clearance of A Reduced absorption of A
Reduced effect of A Reduced effect of A Reduced effect of A
ncreased clearance of A ncreased clearance of A Reduced absorption of A
Oral contraceptives Phenytoin Quinolone antibiotics
Theophylline Thyroxine
8
Warfarin
TABLE 1.4 Important drug interactions involving warfarin
Interacting drug
Effect of interaction on anticoagulant effect
Colestyramine (cholestyramine) Colestipol
Reduced anticoagulant effect
Impaired absorption and increased elimination of warfarin. Long-term treatment may cause impaired vitamin K absorption and enhance anticoagulant effect
Barbiturates Carbamazepine Griseofulvin Phenytoin (see also below) Primidone Rifampicin Ritabutin St John's wort
Reduced anticoagulant effect
Induction of warfarin metabolism
Amiodarone Azapropazone Chloramphenicol Cimetidine Ciprofloxacin Clarithromycin Dextropopoxyphene Erythromycin Fluconazole Itraconazole Ketoconazole Mefenamic acid Metronidazole Miconazole Nalidixic acid Norfloxacin Ofloxacin Phenylbutazone Sulfinpyrazone Sulphonamides (e.g. in co-trimoxazole)
Increased anticoagulant effect
Inhibition of warfarin metabolism
Anabolic steroids Bezafibrate Clofibrate Danazol D-thyroxine Gemfibrozil L-thyroxine Phenytoin (see also above) Salicylates/aspirin (high-dose) Stanozolol Tamoxifen
Increased anticoagulant effect
Pharmacodynamic potentiation of anticoagulant effect
NSAIDs (including aspirin at all doses) clopidogrel and ticlopidine
Increased risk of bleeding
Additive effects on coagulation and haemostasis
Oral contraceptives, oestrogens and progestogens Vitamin K (e.g. in some enteral feeds)
Reduced anticoagulant effect
Pharmacodynamic antagonism of anticoagulant effect
Probable mechanism(s)
but may add to the respiratory depression produced by opioids, whereas naloxone, despite having no opioidlike effects itself, antagonizes the pharmacological effects of most opioids. Many pharmacodynamic interactions occur when the physician forgets that a drug known to be acting at one receptor may also act at another. Thus, antihistamines, phenothiazines and tricyclic antidepressants may have muscarinic anticholinergic activity in addition to their desired pharmacological effects: administration of two or more of these agents (particularly in the elderly) may lead to pronounced anticholinergic symptoms and signs. Pharmacodynamic interaction may also occur when two drugs act at different sites, e.g. the interaction of digoxin and diuretics. Here, hypokalaemia caused by diureticinduced reduction of potassium reabsorption in the kidney may potentiate the effects of digoxin on the heart.
1
PHARMACOKINETIC INTERACTIONS Absorption Drugs may interact with each other to prevent either the rate or the extent of absorption of another compound. Drugs that increase gastric emptying (e.g. metoclopramide) will increase the rate of absorption of many other drugs, so that the peak concentration of that drug will tend to be higher. The opposite effect is achieved by agents - such as the anticholinergic compounds atropine, trihexyphenidyl (benzhexol) and propantheline - that diminish gastric emptying. These changes are likely to be more important after single-dose administration in a situation where a threshold concentration for drug effect exists, e.g. for analgesics. Under these circumstances (particularly if the rate of elimination of the drug is high), a delay in absorption may result in an inability to reach therapeutic drug concentrations. The extent of absorption of the drug may be impaired by the presence of another through the formation of chelates, ion pairs or complexes. Ion exchange resins such as colestyramine (cholestyramine) and colestipol combine with warfarin, levothyroxine (thyroxine) and digitalis glycosides to im-pair absorption. Similarly, the calcium, magnesium or aluminium ions in antacids or milk may interact with 4-quinolones such as ciprofloxacin. In most cases these interactions can be prevented by ensuring a time interval of at least 2 hours between administrations of the two compounds. In the case of warfarin and digitoxin, however, colestyramine (cholestyramine) or colestipol may also affect enterohepatic recirculation and reduce concentrations of these drugs, even if they are administered after absorption has been completed.
Distribution Drugs may compete for both plasma protein-binding sites and active transport processes in the body. The importance of plasma protein-binding displacement interactions has
9
TABLE 1.5 Some drugs causing induction of drug metabolism Barbiturates and primidone Carbamazepine Cigarette smoking* Phenytoin Rifampicin and rifabutin St John's wort * Selective induction (e.g. of theophylline metabolism).
FIG. 1.3 Factors determining the distribution of drugs in the body
been much exaggerated (Fig. 1.3). For most drugs, only the free form in plasma is available for metabolism. Thus, an increase in the percentage of free drug will result in a concomitant increase in total clearance and the rapid return of the free (biologically active) drug concentration to its original value. (The net result is a lower total drug concentration, but a larger percentage of this is in the free form.) The temporary increase in free drug concentration is only likely to be important if the drug is normally highly protein bound (e.g. >90%) and has a low apparent volume of distribution. If the displacing agent is given by a rapid intravenous injection, the temporary increase in free drug concentration of the displaced agent may also be important, but clinically significant examples of this interaction are difficult to find. At present, whenever significant clinical interactions have been shown to be associated with protein-binding displacement, other mechanisms (e.g. competition for metabolism) have been shown to be the major causes of the interaction. It is therefore possible that plasma protein-binding displacement merely reflects the physicochemical similarities of the two compounds, which leads to their competing for transport or metabolic processes. Inhibition of active transport of one drug by another can result in significant interactions. P-glycoprotein is a surface phosphoglycoprotein that functions as an energydependent efflux. It is coded by the human MDR1 (multidrug resistance) gene and is present in a wide variety of tissues, including the gut, kidney, liver, brain, testes, placenta and adrenals. Human P-glycoprotein has been shown to transport a wide range of structurally unrelated drugs such as digoxin, quinidine, ciclosporin and HIV-1 protease inhibitors. Competition for this pump between quinidine and digoxin, for example, can result in increased concen-
O MCQ 1.7-1.11
10
trations of digoxin entering the CNS and corresponding toxicity. If potent and safe inhibitors of P-glycoprotein and other similar transporters (multidrug resistance-associated proteins or MRPs) can be found, the interaction could possibly be used to therapeutic effect in overcoming the intrinsic or acquired multidrug resistance of human cancers.
Metabolism Compounds in cigarette smoke and a variety of other drugs (Table 1.5) can stimulate drug metabolism by the hepatic mono-oxygenase system. Enzyme induction is related to an increase in the amount of cytochromes present, and may therefore take 7-14 days to develop fully and a similar lag period to wear off after the inducing agent is discontinued. This time lag tends to disguise any causal relationship between the drug interaction and administration of the inducing agent. Furthermore, if the dose of the active drug has been increased to maintain adequate effects, marked increases in drug concentration and toxic effects may be seen when induction wears off. Other agents can impair the metabolism of concomitantly administered drugs, either by competing for metabolism or in a non-competitive manner (Table 1.6). Cimetidine is an interesting example in that, although not itself metabolized (it is excreted largely unchanged in the urine), it inhibits the metabolism of drugs by the liver. As the effect of enzyme inhibitors is generally direct, the lag time for this effect to occur is shorter than with enzyme inducers and the effects disappear more quickly after discontinuation. The effects also tend to be more selective than with enzyme induction. Thus, allopurinol has little effect on drugs metabolized by the mono-oxygenase pathway but, by inhibiting the enzyme xanthine oxidase, can impair the metabolism of azathioprine and 6mercaptopurine and potentiate their toxicity. If a drug has a carbon atom with four different substituents, it exists as two optical isomers or enantiomers, which are mirror images of each other. Most chemical syntheses will result in equal amounts of the two steroisomers, and this is termed a racemic mixture. One isomer may be much more potent than the other (e.g. S-warfarin is at least five times more potent than R-warfarin), or the toxicity
1
TABLE 1.6 Some drugs causing inhibition of metabolism Allopurinol Amiodarone Cimetidine Metronidazole Monoamine oxidase inhibitors Sulphonamides Macrolides (e.g. erythromycin, clarithromycin, azithromycin) Some antifungals (e.g. ketaconazole, fluconazole, itraconazole, miconazole) Some quinolones (e.g. ciprofloxacin, norfloxacin, ofloxacin, nalidixic acid) Some HIV-protease inhibitors (e.g. saquinavir, indinavir, nelfinavir, ritonavir) Some SSRIs (e.g. fluoxetine, fluvoxamine, nefazodone, paroxetine, sertraline)
of the two isomers may differ. The enantiomers may also differ in metabolic route or interact differently with other compounds. Cimetidine inhibits the metabolism of Rwarfarin, metronidazole inhibits the S enantiomer, and amiodarone inhibits the metabolism of both enantiomers.
Excretion It is unlikely that drug-induced changes in GFR will markedly alter the excretion of other drugs by the kidney. However, drugs that alter urinary pH may have a marked effect on the renal clearance of weak bases or acids, because of the effects on passive reabsorption in the proximal tubule. The administration of bicarbonate, for example, may enhance the removal of weak acids (such as phenobarbital and aspirin) by increasing the proportion of drug in the ionized form in the urine, thus preventing passive reabsorption. Similarly, acidification of the urine (using ammonium chloride) reduces tubular reabsorption of weak bases such as amphetamine, an effect that was once used in overdose to enhance renal excretion. Acidic drugs may compete with each other for the active renal tubular secretory pathway. Salicylates and thiazides may potentiate the toxicity of methotrexate in this way. No clinically important interactions involving basic drugs at this site have been reported. Quinidine and verapamil may compete with digoxin for an active tubular secretory mechanism in the distal convoluted tubule. This mechanism is now thought to be P-glycoprotein (see earlier), so that the digoxin-quinidine interaction results in reduced renal clearance of digoxin (as well as the increased CNS penetration of digoxin described earlier), thus causing increased plasma and CNS digoxin concentrations and increased risk of toxicity. P-glycoprotein may also be a factor in the excretion of some drugs into the gut via the intestinal wall and the bile, and may thus determine the apparent bioavailability of certain drugs such as ciclosporin. Like CYP450 enzymes, P-glycoprotein activity can be enhanced by enzyme induction, and this may well be an important determinant of rifampicin-induced reduction in ciclosporin bioavailability, for example (Fig. 1.4). 1
FIG. 1.4 Schematic representation of the effect of P-glycoprotein activity on the disposition and bioavailability of drugs
AVOIDANCE OF DRUG INTERACTIONS There are a number of strategies that can be adopted to decrease the risk of potential clinical problems. The number of drugs prescribed for an individual should be limited to as few as is necessary. The drug list (including over-the-counter and herbal preparations) should be reviewed on a regular basis, potentially unnecessary medicines withdrawn and the patient's progress monitored subsequently. Patients should be encouraged into a 'prescribing partnership', alerting doctors, pharmacists and other healthcare professionals to symptoms that occur when new drugs are introduced. The prescriber should be alert for the presence of medicines (e.g. particularly likely to be associated with interaction (e.g. enzyme inducers and inhibitors)) and avoid such combinations. He or she should also be prepared to check (there are excellent tables in the British National Formulary} before prescribing any new or unfamiliar drug, particularly in those already receiving drugs with a low therapeutic ratio. Clinicians should also report via the appropriate postmarketing surveillance scheme any drug-drug interactions they feel they have encountered.
THERAPEUTIC DRUG MONITORING Therapeutic drug monitoring refers to the measurement of drug concentrations in plasma to aid in optimizing drug efficacy and reducing the risk of toxicity.
11
TABLE 1.7 Drug concentration associated with optimal efficacy in most patients Usual half-life (hours) Carbamazepine Ciclosporin Digoxin Gentamicin
2-10 30-40 2-3
Lithium Phenytoin
7-20 20-60
Theophylline
4-15
Usual therapeutic plasma concentrations
Toxic concentrations
Principal route of elimination
4-1 2 mg/L 1 00-200 ^g/L 0.8-2 ng/L Trough <2mg/L Peak 4-8 mg/L 0.4-1 .0 mmol/L Plasma 10-20 mg/L Saliva 1-2 mg/L Plasma 10-20 mg/L Saliva 6-1 2 mg/L
>12mg/L >200^g/L >2 g/L Trough >2 mg/L Peak >12 mg/L >1.5mmol/L >20mg/L >2mg/L >20mg/L >12mg/L
Hepatic metabolism Hepatic metabolism Renal excretion Renal excretion
The ideal way to monitor drug therapy is, of course, to measure wanted and unwanted effects directly: where good measures of these exist (e.g. in anticoagulant therapy), measurement of plasma drug concentrations has a very limited role. There are, however, situations in which drug efficacy or toxicity is more difficult to measure and, both here and where the drug is being given prophylactically to prevent serious events (e.g. antiepileptic and antiarrhythmic drugs), therapeutic drug monitoring may have a role to play (Table 1.7). Measurement of plasma (or urine) drug concentration is also of value in detecting overdose (either deliberate or accidental) and in monitoring compliance with therapy in patients who may not be responding normally to the drug. For therapeutic drug monitoring to be of value in optimizing therapeutic benefit, the drug should work by a reversible mechanism without the development of tolerance. The possibility of accumulation of active metabolites that are not detected by the drug assay must also be considered. Procainamide, for example, is metabolized to Nacetylprocainamide, which also has antiarrhythmic activity and, ideally, should also be measured.
Renal excretion Hepatic metabolism Hepatic metabolism
tration taken just before the next dose will correlate most closely with the steady-state concentration. As it takes approximately five half-lives before steady state is achieved, sampling before this time will tend to underestimate the subsequent steady-state concentration and is only indicated if toxicity due to drug accumulation is possible. Details of sampling time, time and extent of last change in dose, and time of administration of the most recent dose should always be given on the assay request form to enable the plasma concentration to be interpreted correctly. Total drug concentrations are normally measured and these generally mirror the free plasma concentration. This may not be true in diseases where changes in plasma protein binding of drugs is likely, such as hepatic and renal disease. For some drugs (e.g. phenytoin and theophylline) the concentration in saliva may be a closer reflection of the free plasma concentration: in young children, saliva collection (stimulated by a drop of citric acid solution on the tongue) may avoid venepuncture.
SPECIFIC DRUGS
Sample collection
12
Unlike many endogenous compounds, such as creatinine, which are produced at a continuous rate, drugs are normally administered at fixed intervals and the plasma concentration will therefore vary markedly with time after administration. Early after administration the plasma concentration may be affected by the rate of gastric emptying. However, if there is extensive distribution of the drug early samples may be higher than the average, or steady-state, concentration during the dosing interval, and may not accurately reflect the concentration at the site of action of the drug. It is therefore preferable to wait at least 8 hours after administration of an oral dose of digoxin, or 12 hours after lithium, before sampling. If peak levels are important, samples should be taken 2-3 hours after a conventional tablet, or later if a sustained-release formulation has been administered, or 30-60 minutes after intramuscular injection. In most cases, however, a trough concen-
Anticonvulsants Phenytoin metabolism shows saturation rather than firstorder kinetics, so that clearance falls with increasing dose and the risk of toxicity increases. Half-life also increases with increasing dose, and so it will take longer for steady state to be achieved. Most patients tend to be given too small a dose of phenytoin, but therapeutic monitoring has reduced the tendency to prescribe a second antiepileptic drug in many patients who initially received subtherapeutic doses. Therapeutic monitoring of other anticonvulsants except carbamazepine is of limited value except in the identification of poor compliance.
Antiarrhythmics Because of their serious toxicity and the narrow margin between therapeutic and toxic doses, monitoring of several
antiarrhythmic drugs may help to reduce adverse effects and improve response. The half-life of most antiarrhythmics is short, but that of amiodarone is around 30-45 days. A loading dose is therefore necessary to achieve early therapeutic concentrations of this drug, and prolonged monitoring will help to detect the accumulation of amiodarone and its major (and possibly toxic) metabolite desethylamiodarone.
and regular monitoring of plasma concentration and renal function may be helpful in reducing the risks of nephrotoxicity.
Digoxin
The importance of drug regulation has grown with the rapid increase in the number of therapeutic agents developed over the last 50 years. Increased efficacy of new compounds is often associated with a risk of serious adverse effects.
The plasma digoxin concentration is one of the determinants of toxicity of the drug, particularly noncardiovascular toxicity, causing lassitude, depression and anorexia. Monitoring is particularly important in patients with reduced renal function (e.g. in the elderly), whose digoxin clearance is reduced, and will also help to identify poor compliance.
Theophylline Patients vary greatly in metabolic clearance of this potentially toxic bronchodilator, and dose adjustment is facilitated by the measurement of plasma theophylline concentrations.
Antibiotics The aminoglycosides (gentamicin in particular, but also amikacin, kanamycin, netilmicin and tobramycin) are the most frequently monitored antibiotics. The risk of ototoxicity can be reduced by preventing excessive plasma drug concentrations, but the nephrotoxic effects of the drugs are less closely related to the plasma concentration, so that renal function must also be carefully monitored during therapy. The antibiotic vancomycin is used systemically in the prophylaxis and treatment of endocarditis and other serious infections caused by Gram-positive cocci, including multiresistant staphylococci. Vancomycin (added to dialysis fluid) is also used in the treatment of peritoneal dialysis-associated peritonitis. After parenteral administration, vancomycin may be associated with renal damage and ototoxicity, and plasma concentrations are of help in minimizing toxicity.
Lithium Lithium is used in the treatment of hypomania, and because toxicity may develop insidiously (p. 27) therapeutic monitoring is essential.
Ciclosporin Ciclosporin is an immunosuppressant used in organ transplantation to prevent graft rejection and for the prophylaxis of graft-versus-host disease. It is also used in the treatment of severe atopic dermatitis, psoriasis and rheumatoid arthritis. It may cause renal damage,
1
DRUG REGULATION AND DEVELOPMENT
THE UNITED KINGDOM MEDICINES ACT (1968) AND THE MEDICINES FOR HUMAN USE REGULATIONS (1994) In the late 1950s thalidomide was introduced as a new hypnotic drug and was widely used in Europe, including in pregnant women. In 1961 an epidemic of appalling proportions occurred in which hundreds of the babies were born with limb abnormalities (phocomelia). The connection with thalidomide administration was soon realized and the drug was soon withdrawn. The nature of this adverse reaction and the public pressure it provoked resulted in the formation, in the UK, of the Committee on Safety of Drugs (the Dunlop Committee) in 1965, and the subsequent development of strict legislation concerning all aspects of drug manufacture, testing and selling. This legislation is contained in the United Kingdom Medicines Act (1968). In 1994, the European Union regulations were implemented in the UK by statutory instrument (the Medicines for Human Use Regulations) and the European Medicines Evaluation Agency (EMEA) was set up in London in 1995 to develop a centralized European procedure for drug evaluation. Each EU member state is required to have a national system for drug safety surveillance (pharmacovigilance) in place. In the UK this system is administered by the Medicines Control Agency (MCA), an executive agency of the
SUMMARY 3 Drug development Synthesis/isolation of new chemical entity Animal studies Pharmacological/toxicological studies Clinical trials Phase 1 Dose-finding tests in healthy volunteers (c 50) Phase 2 Tested in carefully selected patients (c 200) Phase 3 Formal, larger-scale trials (normally up to 2000) Efficacy, safety and comparison with other established therapies Phase 4 Post-marketing studies on a much larger population of patients
13
Department of Health, which is tasked to safeguard public health by ensuring that all medicines on the UK market meet appropriate standards of safety, quality and efficacy. It is advised by an independent Committee, the Committee on Safety of Medicines (CSM), which gives advice to the Licensing Authority (in this case the UK government) on whether new products (new active substances) submitted to the MCA should be granted a marketing authorization. It also helps to monitor the safety of marketed medicines.
DEVELOPING NEW DRUGS
14
Virtually all new drugs are developed within the pharmaceutical industry, because of the enormous financial investment (about £560 million for a new product in 2001) and the huge amount of work involved. Because a patent taken out on a new compound lasts for only 17 years, the 10-12 years (or longer) required for most drugs to reach the stage of a product licence erodes the patent life alarmingly. The industry therefore has to look very carefully at the likely returns on its investment over the short period that it alone can market the drug under patent. Developing drugs for less common diseases becomes commercially unattractive under these circumstances. Apart from the basic chemistry and pharmacology required to develop a new drug, a large amount of toxicological data from animal testing is also required from the pharmaceutical company to satisfy the licensing authority that the drug is unlikely to cause serious adverse reactions in humans. If it is so satisfied, the authority will grant a Clinical Trials Exemption (CTX) or Clinical Trials Certificate (CTC), both of which allow the drug to be tested in patients before an application for marketing authorization is made. In Europe, authorization for a marketing (product) licence can be sought by either a centralized or a decentralized procedure. The former process gives approval throughout Europe and is compulsory for medicinal products derived from biotechnology. The decentralized procedure (or mutual recognition procedure) applies to the majority of conventional medicines and is based upon the principle of mutual recognition by member states. The EMEA provides any arbitration between the member states before the final decision is made, normally by the European Commission. Member states can still, if they wish, give authorization for medicines to be marketed only in their own country. Clinical trials are usually divided into four phases. In phase 1 a small number of healthy volunteers (usually around 50) are given the drug for the first time. The initial doses are very low, and are titrated up to doses likely to show activity, with very careful monitoring for possible toxicity. In the UK, a CTX or CTC is not required for studies in healthy volunteers. If the results are satisfactory, around 200 or so carefully selected but clinically stable patients are given the drug to discover whether pharmacological and therapeutic effects occur in humans (phase
2). In the third phase, formal and larger-scale clinical trials are performed in order to confirm the drug's therapeutic benefit in a broader range of patients (around 2000 on average) with other concomitant conditions, to evaluate its adverse effects and compare it with alternative established therapies. At this point, assuming that the results are satisfactory, an application will be made for a product licence so that marketing and promotion of the drug can begin. It is thus unusual for more than 2500 individuals to have received the drug up to this point in time. Therefore, postmarketing surveillance is crucial to detect any rare (incidence <1 in 1000) ADRs that are unlikely to have been detected during the drug development process. Companies may institute formal (phase 4) prospective cohort studies at this stage, particularly if they wish to examine any potential drug safety issues on a much larger population of patients.
NATIONAL INSTITUTE FOR CLINICAL EXCELLENCE (NICE) This body was set up in 1999 to assess the cost-effectiveness and clinical effectiveness of new and existing technologies, including certain drugs, and to provide patients, health professionals and the public in England and Wales with authoritative, robust and reliable guidance on current 'best practice'. When a cost-effective treatment already exists, this is used as a benchmark against which any existing or newly marketed treatment is appraised, as to whether it is a clinically effective and cost-effective use of NHS resources. Details of the appraisals can be found at http://www.nice.org.uk.
MONITORING ADVERSE DRUG REACTIONS One of the MCA/CSM's most important tools in monitoring safety of marketed medicines is the yellow card system. Set up in 1964 in the wake of the thalidomide tragedy, it now has more than 480000 reports of suspected ADRs that have been submitted on a voluntary basis by doctors, dentists, pharmacists and coroners, and (under statutory obligation) by pharmaceutical companies. If a serious reaction is suspected, or any possible reaction to a newly marketed drug (marked with an inverted triangle in the British National Formulary), a card should be sent to the Medicines Control Agency (MCA), in certain areas via the appropriate Regional Monitoring Centre. A substantial data bank is thereby accumulated and analysed regularly for associations between suspected adverse reactions and individual drugs. Data from the UK scheme and from more than 40 other countries is shared with the WHO Collaborating Centre for International Drug Monitoring in Uppsala, Sweden. Each year more than 150000 such reports are received and the cumulative database now contains over 1.4 million records, so that potential ADR
1
FIG. 1.5 Drugs involved in self-poisoning Number and percentage of admission to the Cardiff Poisons Treatment Unit in 1999 involving the seven most frequently taken drugs/drug groups. (Some patients take more than one drug).
FIG. 1.6 The relationship between age and the incidence of poisoning in children Figures are based on enquiries concerning accidental poisoning made to the National Poisons Information Service (Cardiff Centre) in 1999.
signals can be detected more sensitively. Such spontaneous reporting schemes are relatively inexpensive and extremely cost-effective. Unfortunately, less than 10% of even serious suspected ADRs are reported via these schemes, and they could be even more effective if more health professionals regularly reported their drug-safety concerns.
Whereas death from carbon monoxide poisoning predominates in adults, there are approximately 20 accidental deaths per year from all other agents, particularly tricyclic antidepressants, iron, aspirin and barbiturates in young children. The incidence of accidental poisoning in childhood is partly determined by availability.
DELIBERATE SELF-POISONING DRUG OVERDOSE Approximately 4000 people die each year of poisoning in England and Wales, a quarter of them of carbon monoxide poisoning. Approximately two-thirds of the remaining deaths occur outside hospital. Nevertheless, more than 100000 patients are admitted to hospital in England and Wales each year with poisoning, accounting for 10% of all acute admissions. The unadjusted admission rates in the USA range from 80 per 100000 in patients aged 65-74 years to 400 per 100000 in patients aged between 15 and 24 years. Toxic compounds may be ingested or inhaled either accidentally or deliberately, or may be administered accidentally or deliberately. This forms the basis for a classification of poisoning incidents, separating them into broad epidemiological categories. The major causes of admission due to poisoning are shown in Figure 1.5.
ACCIDENTAL POISONING Accidental poisoning can occur at any age but is much more likely to occur in children under 5 years of age (Fig. 1.6). Peak incidence is around 2 years, when children have become independently mobile, and boys appear to be more at risk. This contrasts with other categories of poisoning, in which women are involved more than men. Fortunately, the mortality from accidental poisoning is relatively small.
Deliberate self-poisoning is commoner in adults who, unlike children, ingest medicinal agents more readily than they do household chemicals and other non-medicinal compounds. Women are more often involved than men, and the vast majority of instances are not intended to be ultimately fatal. Generally they represent a response to an apparently insoluble personal predicament (Ch. 8), but some have a definite suicidal intent. Patients who successfully commit suicide tend to be older and may have been recently divorced or bereaved, may be living alone, suffering from a physical illness, unemployed or abusers of alcohol.
NON-ACCIDENTAL POISONING Non-accidental poisoning usually involves children and is a form of abuse. The parents of such children may have suffered child abuse or deprivation themselves, and often have marital or financial problems or difficulties in managing the child at the time of the poisoning episode.
HOMICIDAL POISONING Although often featured in novels and plays, homicidal poisoning is uncommon. When it does happen, it is often
15
caused by a close relative or friend and generally involves the use of poisons producing chronic, rather than acute, symptoms.
DIAGNOSIS OF POISONING Laboratory tests cannot identify every agent to which an individual might be exposed. A full history and clinical examination is therefore an integral part of the diagnosis. As the patient may be unwilling or unable to give a history on presentation, it is important to talk to relatives or friends, the GP or the ambulance personnel who brought the patient into hospital. Particular difficulties are encountered with the patient who is found alone and unconscious and in whom poisoning is just one of the differential diagnoses. The first priority in the unconscious patient is maintenance of the airway, ventilation and cardiovascular function. When this has been assured, the question arises as to whether the patient is poisoned. Other causes of unconsciousness are discussed in Chapter 24. In deep coma due to drug overdose the pupillary reflexes are often preserved, but the oculovestibular responses (e.g. 'doll's eye response') are absent. Focal neurological signs are rare in overdose and, unless they can be accounted for by previous pathology, these should alert the clinician to the possibility of another cause. Papilloedema due to drug overdose is rare, unless the overdose has been associated with cerebral hypoxia and oedema. If the patient shows no improvement in level of consciousness by 12 hours after admission, another pathology should be suspected.
TABLE 1,8 Physical signs suggestive of overdose or poisoning: head and neck Sign
Possible cause
Dilated pupils
Anticholinergics Tricyclic antidepressants Amphetamines Ecstasy Carbamazepine Sympathomimetics Cocaine LSD Glutethimide Methanol
Constricted pupils
Opiates Organophosphates and carbamates
Strabismus
Carbamazepine
Nystagmus
Barbiturates Carbamazepine Phenytoin Phencyclidine
Perforated nasal septum
Cocaine abuse
Acneiform rash
Solvent abuse
Erythema/burns
Corrosives Paraquat
Mouth dryness
Anticholinergics
Hypersalivation
Parasympathomimetics Organophosphates and carbamates Arsenic Strychnine Clormethiazole Clozapine
CLINICAL EXAMINATION It is sometimes possible to identify the poison by the clinical signs on examination, although it may be more difficult if the patient has taken several agents. The most helpful clinical signs are shown in Tables 1.8 and 1.9.
Mouth
Eyes Pupillary dilatation occurs in poisoning with anticholinergic drugs, such as the tricyclic antidepressants, antiparkinsonian agents, antihistamines and phenothiazines. It also occurs with agents that stimulate the sympathetic nervous system, such as amphetamines, LSD and theophyllines. Unequal pupils are occasionally seen in poisoning. Strabismus is not uncommon, particularly in carbamazepine poisoning. Papilloedema, however, is rare, except as a
1
16
result of methanol, carbon monoxide or glutethimide poisoning. Agents affecting the central nervous system (CNS), particularly phenytoin, may cause nystagmus.
Fig. 1.5
2
Fig. 1.6
Acneiform lesions around the buccal cavity may suggest solvent abuse, O and the characteristic odour of solvent or alcohol may be present on the breath. Examination of the oral cavity may reveal ulceration due to corrosion by acids or alkalis. The mouth may be abnormally dry because of anticholinergic compounds, and increased salivation may be seen in subjects who have taken agents that stimulate the parasympathetic nervous system, e.g. carbamate insecticides and anticholinesterases.
Cardiorespiratory Chest wheeze may be caused by inhalation of irritant compounds: pulmonary oedema can also be caused by these
TABLE 1.9 Physical signs suggestive of overdose or poisoning: trunk and limbs Sign
Possible cause
Bronchospasm
Irritant gases NSAIDs (rare) Arthropod envenomation Scombroid fish
Pulmonary oedema
Irritant gases Paraquat Opioid analgesics Aspirin
Tachycardia
Anticholinergics Sympathomimetics Cocaine Phencyclidine Theophylline Amphetamines Aspirin
Bradycardia
Cardiac glycosides p-Blockers Verapamil Organophosphates and carbamates
Hypertension
Sympathomimetics Amphetamines Phencyclidine MAOIs Clonidine Cocaine SSRIs (rare)
Needle tracks
Drugs of addiction
Absent bowel sounds
Anticholinergics Tricyclic antidepressants Opioids
Bladder distension
Anticholinergics Tricyclic antidepressants
Hypothermia
Phenothiazines Tricyclic antidepressants MAOIs (rare)
Hyperthermia
MAOIs Sympathomimetics Anticholinergics MAOIs SSRIs (rare) Amphetamines Ecstasy Aspirin
Hyperreflexia
Anticholinergics Sympathomimetics Opioids
Blisters
Barbiturates Carbon monoxide Opioids Tricyclic antidepressants
Extensor plantar responses
Anticholinergics Tricyclic antidepressants
agents, or by ingestion of drugs such as opioids or aspirin. There may be tachycardia with poisoning due to anticholinergics, salicylates or drugs that stimulate the sympathetic nervous system. Verapamil, (3-blockers or drugs that stimulate the parasympathetic nervous system, on the other hand, may cause bradycardia. Cardiac arrhythmias may be associated with hypoxia, but are particularly troublesome in patients who have taken tricyclic antidepressants, drugs stimulating the sympathetic nervous system, phenothiazines or quinine. Many agents can cause hypotension, but hypertension is rarer and usually associated with monoamine oxidase inhibitors or clonidine, which in overdose may act like a-adrenoceptor agonists.
1
Abdomen Absent bowel sounds or bladder enlargement suggest the possibility of anticholinergic poisoning. Rectal examination should be performed and may reveal melaena due to poisoning by iron, non-steroidal anti-inflammatories or other agents that damage the gut mucosa. The rectal temperature should be recorded using a low-reading thermometer. This may reveal hypothermia (e.g. with phenothiazine poisoning) or hyperthermia (in poisoning by salicylates, anticholinergic compounds or drugs that stimulate the sympathetic nervous system).
Skin and nails The hands, arms and legs may show needle tracks indicating drug abuse. Blisters over the bony prominences, commoner on the lower limbs, are seen in patients who have taken a barbiturate, opioid or tricyclic antidepressant overdose, 2 or are suffering from carbon monoxide poisoning (Fig. 1.7). Their presence reflects the combination of severe hypoxia and pressure, and they often occur where the patient has been lying against a hard surface. They should alert the physician to the possibility of hypoxic damage of other organs such as muscle, since there is sometimes associated rhabdomyolysis. The nails may show transverse white (Mee's) lines in poisoning with the heavy metals, arsenic and thallium (Fig. 1.8).
Neuromuscular Examination of the limbs normally reveals hypotonia and hyporeflexia in poisoning, but anticholinergic drugs, some opioids and drugs that stimulate the sympathetic nervous system may cause hypertonia, hyperreflexia and, occasionally, myoclonus. Anticholinergic compounds may also produce an extensor plantar response that is usually bilateral. Convulsions may be caused directly by a variety of compounds, including the anticholinergic agents and drugs stimulating the sympathetic nervous system, opioids, mefenamic acid and isoniazid, or may be secondary to hypoxia or hypoglycaemia associated with overdose. Dystonic reactions are much less commonly seen, and are generally
17
FIG. 1.7 Poison blister Blister on the knee of a 25-year-old male who took an overdose of the opiate drug, dextropropoxyphene. He subsequently developed signs of rhabdomyolysis.
FIG. 1.8 Mee's lines in the nails of a patient with thallium poisoning These dystrophic changes causing a white line distal to the cuticle are also seen in poisoning with arsenic.
related to poisoning with drugs with antidopaminergic activity, such as metoclopromide, the phenothiazines and butyrophenones.
The urea and electrolytes are rarely of diagnostic value. Hypokalaemia can be caused by theophylline and drugs stimulating the sympathetic nervous system, or may indicate potassium loss owing to diuretic or purgative overdose. Hyperkalaemia is sometimes seen in severe digoxin overdose. Reduction in the serum bicarbonate may indicate metabolic acidosis and should be investigated by arterial blood gas analysis. The alcohols and glycols, as well as aspirin, may cause a metabolic acidosis, often with a high anion gap (see p. 1114). The presence of both a high anion and an osmolal gap in the absence of detectable ethanol is suggestive of methanol or ethylene glycol poisoning. Profound hypoglycaemia may indicate overdose with oral hypoglycaemic agents or be secondary to overdose with alcohols, salicylates or paracetamol. Clinical judgment must be used in deciding which test will give useful diagnostic or prognostic information. It is useful to store blood for future reference.
LABORATORY INVESTIGATIONS Routine laboratory investigations are sometimes helpful in identifying the drug ingested.
Urine The urine should be examined both macroscopically and microscopically. A specimen should also be stored for possible future analysis even if this is not indicated initially. Red discoloration may be caused by rifampicin or phenindione, 1and haematuria by drugs affecting haemostasis or clotting, or by drugs causing haemolysis, such as chlorates. Drugs that contain methylene blue (e.g. some commercial analgesics) may colour the urine blue or green; a greyish discoloration may indicate poisoning with phenols or cresols. Microscopic haematuria or albuminuria may be the first sign of renal damage. Crystalluria can occur with primidone and some of the sulphonamides, and calcium oxalate crystals may be present in ethylene glycol poisoning.
Blood Brown discoloration of venous blood may indicate methaemoglobinaemia, which can be caused by oxidizing agents such as dapsone. Pink discoloration of the plasma indicates haemolysis, which may be drug induced.
O Fig. 1.7
18
Specific tests An increasing number of compounds can now be detected specifically in either urine (which tends to be more useful as it concentrates the drugs or its metabolites) or blood. Toxicological analyses are not a substitute for clinical judgment and the physician should consider whether the result would alter his or her management.
PRINCIPLES OF MANAGEMENT OF POISONING General supportive measures to prevent complications are usually more important than specific therapies to treat the particular poison, since the latter are not always available.
SUMMARY 4 Principles of management of poisoning • General supportive management, particularly of airway, breathing and circulation (ABC), is of prime importance • Identification of the cause of poisoning can be made by history and clinical and toxicological examination • Decontamination procedures should then be considered to prevent further adsorption of drug remaining in the gastrointestinal tract • Elimination of some drugs can be enhanced. Procedures can produce complications and should only be considered when clearly indicated • General supportive care. Prevention and treatment of complications remains the mainstay of management
SUPPORTIVE MANAGEMENT
• Increased capillary permeability, resulting in a reduced circulating blood volume. In hypotensive patients a central venous pressure line should be inserted. If the venous pressure is low the blood volume should be increased using a plasma expander, such as Haemaccell. If the hypotension does not respond, intravenous (i.v.) dopamine or dobutamine may restore the blood pressure: low-dose dopamine may prevent subsequent acute renal failure (see Ch. 14). Cardiac arrhythmias, which may be a direct effect of the drug or a result of hypoxia and acidosis, may also contribute to hypotension by reducing cardiac output. It is important to correct the predisposing causes if possible before considering specific antiarrhythmic therapy, as many antiarrhythmics may further reduce cardiac output. The choice of an antiarrhythmic agent is usually based on the arrhythmia rather than the specific toxin.
Maintenance of respiratory function
Prevention of complications
Maintenance of an adequate airway and respiration is the first priority in an unconscious patient, as many early deaths from poisoning are due to airway obstruction. Dentures should be removed, the tongue pulled forward and the mouth and pharynx cleared of saliva and vomitus. If the patient has no cough reflex, a cuffed endotracheal tube is necessary to protect the lungs; in other cases a short oropharyngeal tube should be inserted. The patients is then moved into a semiprone position and, if there is any suspicion of inadequate ventilation, oxygen should be administered. Assisted ventilation may be necessary. In less urgent circumstances arterial blood gas analysis is the best guide to assessing the adequacy of ventilation. Drugs that stimulate respiration (e.g. doxapram) should be used cautiously in poisoned patients as they may provoke convulsions or cardiac arrhythmias. The shock lung syndrome (acute respiratory distress syndrome, ARDS; see p. 697) may appear at about 24 hours. The patient begins to hyperventilate but remains hypoxic, and develops a respiratory and metabolic acidosis. A chest radiography may show changes similar to pulmonary oedema and, in severe cases, the lung fields may be completely obscured. Assisted ventilation using positive endexpiratory pressure (PEEP) may help to support the patient through this severe complication. The treatment of aspiration pneumonia is discussed on page 635.
Good nursing care of the unconscious patient is essential. Skin and muscle compression injuries associated with prolonged immobility and hypoxia are a particular problem. The bladder can sometimes be emptied by firm suprapubic pressure, but if it is markedly distended catheterization may be necessary, particularly when measurement of urine production is required. The level of consciousness should be measured using a scale such as the Glasgow Coma Scale (GCS) (Table 1.10). If the conscious level does not improve after 12 hours, this may indicate neurological complications of the overdose or that there is an alternative cause of the
TABLE 1.10 Assessment of consciousness (Glasgow Coma Scale) Score Eyes open
Best motor response To verbal command To painful stimulus
Maintenance of circulatory function Maintenance of circulatory function is essential. Hypotension and reduced peripheral perfusion may be caused by several mechanisms, including: • Depression of the vasomotor centre; • A direct cardiodepressant action; • Increased venous capacitance, leading to reduced venous return to the heart and a consequent fall in cardiac output;
1
Spontaneously To verbal command To pain No response
4 3 2 1
Obeys Localizes pain Flexion-withdrawal Flexion-abnormal (decorticate rigidity) Extension (decerebrate rigidity) No response
6
Orientated and converses Disorientated and converses Inappropriate words Incomprehensible sounds No response
5 4 3 2 1
5 4 3 2 1
Best verbal response
Total
3-15
19
coma. Cerebral oedema is the most life-threatening complication of overdose, and may be caused by hypoxia, hypoglycaemia, hypercapnia or hypotension. It is particularly likely to occur after cardiorespiratory arrest and may respond to dexamethasone or mannitol. Convulsions may also be secondary to hypoxia or cerebral oedema, but otherwise are generally short-lived and do not always require specific therapy. If necessary, intravenous diazepam may be used, but if the patient is vomiting, temporary intubation and mechanical ventilation may be necessary to prevent aspiration pneumonia. Gastrointestinal bleeding or paralytic ileus may be seen in patients with drug overdose. Insertion of a nasogastric tube and regular emptying of the stomach help to reveal bleeding early and prevent the aspiration pneumonia or acute gastric dilatation sometimes seen with paralytic ileus.
MEASURES TO PREVENT FURTHER DRUG ABSORPTION Emptying the stomach can sometimes reduce further absorption of the drug from the gut. Such measures are only indicated if the amount of poison taken is likely to cause serious symptoms, and are of little value if the material ingested has already left the stomach. They should therefore generally only be considered when less than 1 hour has elapsed since ingestion of the toxin, although they may sometimes still be worthwhile if the time of ingestion is unknown.
Gastric lavage Gastric lavage has been the most widely used method of emptying the stomach in adults. It is contraindicated in patients who have taken corrosive agents, unless the danger of systemic toxicity associated with a corrosive agent is greater than the risk of local damage. It is also usually contraindicated after oral ingestion of petroleum distillates, because of the risk of aspiration pneumonia. In the unconscious patient, a cuffed endotracheal tube must always be inserted first. Lavage should be carried out in the left lateral position in a bed or trolley raised at the foot. A large-bore Jaques stomach tube (external diameter
SUMMARY 5 Prevention of further drug absorption
20
• Activated charcoal prevents further absorption of many drugs, if administered sufficiently early, and is the safest and most effective method if the substance is adsorbed by charcoal • Gastric lavage may prevent absorption of the drug if performed within 1 hour of drug ingestion • Emptying the stomach by lavage should not be attempted if the airway cannot be protected • Emesis induced by syrup of ipecacuanha is no longer recommended in children or adults
TABLE 1.11 Substances not effectively adsorbed to charcoal Boric acid Cyanide Ethanol Ethylene glycol Iron salts Lithium salts Malathion Methanol Petroleum distillates Strong acids and alkalis
c 14mm) is introduced into the stomach and the contents removed. Aliquots of water warmed to body temperature are then introduced and removed until the returned fluid is clear of particles. However, gastric emptying by lavage is often relatively inefficient and may be difficult or even dangerous in some individuals (e.g. small children and patients with tricyclic antidepressant poisoning, who may become hypoxic).
Emesis There is little benefit from inducing vomiting. Although syrup of ipecacuanha produces emesis, its effect is delayed for 20-30 minutes and there is no good evidence that it reduces drug absorption significantly in poisoned patients. In addition it has side-effects (e.g. persistent vomiting) which may increase morbidity and make diagnosis more difficult. Salt and water should never be used to produce emesis, as death may occur from hypernatraemia, particularly in small children.
Oral adsorbents Activated charcoal is increasingly being used as it may reduce the absorption of many drugs. Drugs not adsorbed effectively to charcoal are listed in Table 1.11. Charcoal is most effective for agents with high-toxicity taken at low total dose, as 10 times as much charcoal as drug is required to provide optimum adsorption. The charcoal must be given soon after the overdose (normally within 1 hour) to achieve maximum efficacy. A dose of 50-100 g (lg/kg in children) can be administered orally or, in an adult, by nasogastric tube. It is of particular value in accidental poisoning in children, as these cases normally present early enough for the adsorbent to be effective.
ANTIDOTES There are direct antidotes only to about 5% of poisons, so supportive therapy remains the mainstay of treatment for
1
CASE STUDY 1.1 DOSULEPIN (DOTHIEPIN) OVERDOSE A 50-year-old man was admitted to hospital 2 hours after taking 750 mg dosulepin (dothiepin) (conventionalrelease form) and, possibly, 100 mg diazepam. He was very drowsy (Glasgow Coma Scale 9) and tachycardic (pulse 120 bpm, regular). He had dilated pupils (responding slightly to light), exaggerated limb reflexes and bilateral extensor plantar responses. His respiratory rate was 15 per minute. Bowel sounds were present but quiet, and percussion revealed a distended bladder. His blood pressure was 100/70 mmHg. His ECG confirmed sinus tachycardia but showed marked widening of the QRS complex. Questions 1. What other investigations would you ordef ? 2. What treatment would you consider? <
Discussion
Dosulepin (dothiepin) is a tricyclic antidepressant with marked anticholinergic activity in overdose. The clinical features in this patient are consistent with anticholinergic poisoning due to tricyclic antidepressants, although diazepam (a benzodiazepine tranquillizer) could also be contributing to his reduced conscious state. Tricyclic antidepressants can produce cardiac and respiratory depression, with metabolic and respiratory acidosis. Blood gases should be measured urgently and any hypoxia corrected. His temperature should also be checked to exclude hypothermia (which can be caused by a variety of drugs in overdose, including tricyclic antidepressants). Finally, urea and electrolytes should be measured. The presence of significant ECG abnormalities is an indication for intravenous sodium bicarbonate
the vast majority of patients, including those where an antidote exists. Antidotes work in several different ways: • They may speed the metabolism of a toxin, e.g. thiosulphate speeds the metabolism of cyanide by providing sulphur to form non-toxic thiocyanate, which is then excreted in the urine. • If a compound is only toxic when metabolized, antidotes may reduce the rate of metabolism. Ethanol is used in poisoning by methanol and ethylene glycol to reduce the rate of production of toxic aldehydes and acids. • For receptor-mediated toxins, an antagonist that competes for a receptor may be useful, e.g. the use of (3agonists in the treatment of (3-adrenoceptor blocking drugs overdose. • If the toxin competes with a natural substrate, an antidote may increase the natural substrate's concentration, competitively displacing the poison from the receptor site. Inhibitors of acetylcholinesterase reverse some of the features of anticholinergic poisoning in this way. • Antidotes may combine with the poison to form an inactive compound. Thus, specific antidigoxin antibody (Fab) fragments combine with digoxin to produce an inert complex, which can be excreted more rapidly via the kidney. The availability of a specific antidote does not necessarily justify its routine use. Some antidotes are toxic in their
(50mmol), even in the absence of acidosis. Further doses may be necessary, depending on clinical response. Charcoal is of limited value at this stage and may be dangerous if he cannot protect his airway, so it should not be given. Convulsions are normally controlled by diazepam. Flumazenil (a benzodiazepine antagonist) may reverse the effects of any diazepam this patient may have taken, and thus precipitate convulsions and arrhythmias. It should not be given to patients who have taken tricyclic antidepressants. Because of the large volume of distribution of tricyclic antidepressants, forced diuresis, haemodialysis and haemoperfusion are of no proven value in enhancing their elimination. If this patient were to have a cardiac arrest, there is evidence that prolonged resuscitation might be successful.
own right and should only be used if the severity of the poisoning merits their administration. In general, they are most useful early on in the course of poisoning.
ENHANCEMENT OF DRUG ELIMINATION Methods to enhance drug elimination (Table 1.12) are of limited value in the treatment of overdose and are generally only effective when the volume of distribution of the drug is relatively small. This is because drug removal can only occur from the central (intravascular) compartment, which must therefore contain a reasonable proportion of the total body burden of the compound.
Forced diuresis Forced diuresis has been used to enhance the elimination of drugs (such as aspirin) that are excreted predominantly in an unchanged form by the kidney. It acts by increasing the glomerular filtration rate and by reducing the tubular reabsorption of unchanged drug. This is dependent on renal tubular flow, and on the degree of ionization of the drug in the tubular fluid. For weak acids, alkalinization of the tubular fluid by administration of bicarbonate will result in a greater proportion of the drug existing in the
21
TABLE 1.12 Techniques used to enhance drug elimination Enteral adsorbents Activated charcoal Carbamazepine Dapsone Phenobarbitone Quinine Theophylline
Dialysis Barbitone Ethanol Ethylene glycol Isopropanol Lithium Methanol Phenobarbitone Salicylates Haemoperfusion Barbiturates Carbamazepine Glutethimide Meprobamate Phenytoin
Colestyramine (cholestyramine) Digitoxin Phenprocoumon Warfarin
ionized, poorly lipid-soluble form. It is then unable to diffuse back across the lipid membrane of the tubular cell and be reabsorbed. Conversely, acidification of the urine by administration of ammonium chloride, arginine or lysine hydrochloride will increase the ionization of some basic drugs, thereby reducing reabsorption from the tubular fluid. Owing to the risks of fluid overload and electrolyte imbalance, and its relatively limited efficacy, forced diuresis is falling out of favour and is being largely replaced by other, safer, methods of enhancement of elimination.
Dialysis Peritoneal or haemodialysis is useful to remove drugs with low plasma protein binding, poor lipid solubility and relatively low volume of distribution. It is generally reserved for cases where other methods of removal are contraindicated. This process effectively removes salicylates, phenobarbital and barbitone, methanol, isopropanol, ethylene glycol and lithium. Haemodialysis is normally the more effective of the two approaches.
Haemoperfusion Haemoperfusion involves the passage of arterial blood through an extracorporeal column of activated charcoal or ion exchange resin. This effectively removes a number of drugs where the lipid solubility or plasma protein binding reduces the efficacy of removal by dialysis techniques,
1 22
MCQ 1.12-1.14
but a low volume of distribution of the drug is still required. Haemoperfusion is therefore sometimes considered in severe poisoning with barbiturates (including the shortacting barbiturates not removed effectively by haemodialysis) and non-barbiturate hypnotics such as glutethimide, ethcholorvynol, meprobamate, methaqualone and chloral derivatives (e.g. chloral hydrate). Fortunately, these agents are now used less frequently as hypnotics. Haemoperfusion using resin columns is particularly effective in removing theophylline and, to a lesser extent, salicylates. Complications of the procedure include thrombocytopenia, bleeding and possible infection, so haemoperfusion should only be used in patients with severe poisoning who fail to improve despite supportive management and who have developed, or are at high risk of developing, complications of the overdose. Enteral removal Enteral removal is the most recent approach to the enhancement of drug elimination. It relies on the ability of some non-absorbed agents either to remove drugs that have been excreted in the bile but would have been reabsorbed in the gut, or to remove them by 'dialysis' of the splanchnic circulation. Charcoal is the most widely used enteral adsorbent, and markedly enhances the rate of removal of phenobarbitone, digitoxin, quinine, theophylline and dapsone. It is given as an initial loading dose of 50-100 g, followed by repeated doses of 50 g every 4 hours, sometimes with a single dose of a laxative at the beginning to prevent constipation. Oral colestyramine (an anion-binding resin) increases the rate of removal of digitoxin, warfarin and some other coumarin anticoagulants. This non-invasive procedure usually has no major adverse effects, although an antiemetic may be needed in patients who are vomiting as a result of the toxin (e.g. theophylline). 1 SUPPORT SERVICES It is impossible for a clinician to be familiar with all the details of the recommended current management of all toxins. As in other countries, in the UK and Eire Poisons Information Services have therefore been established in several major cities to serve their region(s) (Fig. 1.9). They also contribute to the editing of a database system (TOXBASE), accessible via the Internet, and soon via the NHS Intranet. Its role is to provide health professionals with up-to-date relevant first-line information on the management of poisoning. It can be found on the Internet at http://www.spib.axl.co.uk. TOXBASE also contains advice on holding centres for antidotes, analytical facilities for toxins, slang terms for drugs of abuse, and references on the most important aspects of toxicology. In cases where further advice is necessary, the nearest Poisons Unit in the UK can be contacted via a single national telephone number: 0870 600 6266, or, in Eire, Dublin 837 9964.
National Poisons Information Service Toxbase: http://www.spib.axl.co.uk UK national number 08706006266
SUMMARY 6 Management of benzodiazepine poisoning
1
• Benzodiazepine poisoning is common but death is rare unless other potentiating agents (e.g. alcohol) have also been taken • Flurazepam, tlunitrazepam and triazolam may cause deeper coma than the other agents • Management is generally supportive • Flumazenil, a specific short-acting benzodiazepine antagonist, has been used in the diagnosis of mixed overdose, but may precipitate benzodiazepine withdrawal in dependent individuals, convulsions in individuals with epilepsy and serious arrhythmias in patients who have also taken tricyclic antidepressants
fatal cases each year in which a benzodiazepine is the only drug identified, but they potentiate the effects of other CNS-depressant drugs such as ethanol and can thus contribute to fatal outcome.
FIG. 1.9 Areas served by the UK and Eire Poisons Information Services
On recovery from an overdose, the patient should undergo thorough psychiatric and, if necessary, social assessment (Ch. 8, p. 224). There appears to be a poor correlation between the severity of the overdose and any underlying psychiatric illness. The GP also plays an important part in supporting the patient once he or she has left hospital. Finally, voluntary services often provide useful emotional and practical support to the patient at risk, and details of these local organizations should be made available to each patient.
MANAGEMENT OF SPECIFIC DRUG OVERDOSE The drugs most commonly involved in acute poisoning are hypnotics and tranquillizers, antidepressants and analgesics.
Diagnosis The major effects are on the CNS and include drowsiness, ataxia, dysarthria and nystagmus. Coma then supervenes, although it is rarely deep unless other agents have also been ingested. Recovery is normally within 24 hours, although flurazepam and flunitrazepam may cause deeper and more prolonged coma, and clonazepam has been associated with cyclical coma. Lorazepam causes only modest CNS depression but can be associated with restlessness and hallucinations, particularly in children. Respiratory depression occurs rarely in benzodiazepine overdose, although it may occur in patients with pre-existing respiratory disease, particularly with flunitrazepam. Cardiovascular effects are also generally mild, although slight hypotension may occur. Flunitrazepam may cause more profound hypotension and a sinus bradycardia. Bullous skin lesions have been reported, but are much rarer than after barbiturate overdose. Management Management is supportive: methods to enhance elimination of the parent compound or its active metabolites are of no value. Most patients will recover with no sequelae. Antagonists of benzodiazepines (e.g. flumazenil) have been used in the diagnosis of mixed overdose, or in avoiding the need for ventilatory support in severe poisoning. However, they may precipitate benzodiazepine withdrawal (including convulsions) in benzodiazepine-dependent individuals, convulsions in those with epilepsy, and serious arrhythmias in patients who have also taken tricyclic antidepressants concomitantly. They are also short-acting, so that benzodiazepine-induced coma can recur. They are therefore seldom used.
HYPNOTICS AND TRANQUILLIZERS Barbiturates Benzodiazepines Benzodiazepines are involved in almost half of the drug overdoses in the UK. There are only a small number of
The incidence of barbiturate poisoning has declined markedly over the past 20 years, but this group of compounds is still associated with high mortality.
23
SUMMARY 7 Management of barbiturate poisoning • Barbiturate poisoning is now relatively rare but has a significant mortality • Gastric lavage should be performed within 1 hour and activated charcoal left in the stomach. The airway must be protected • Bullous lesions should alert to the possibility of underlying muscle damage (rhabdomyolysis) • Repeat-dose activated charcoal enhances the elimination of phenobarbitone already absorbed, but not of other barbiturates • Charcoal haemoperfusion should be considered only in severe poisoning with barbiturates
Diagnosis In overdose the barbiturates produce an impaired level of consciousness and, in severe cases, hypotension and respiratory depression. Approximately 5% of patients have bullous lesions on the extremities, particularly over the extensor surfaces, but these are not specific to barbiturate overdose and can occur with other agents producing profound hypoxia. Barbiturates can be detected in the urine. Although their plasma concentrations can also be measured, these correlate poorly with the severity of the overdose, partly because of other confounding drugs such as alcohol, and partly because of tolerance, particularly in those taking the drug chronically. Plasma concentrations are therefore of limited value in the management of a particular case, although very high concentrations in the presence of deep coma and other complications of overdose may indicate the need to enhance the removal of the drug. Management Gastric lavage should be performed if tablets have been taken less than an hour previously, or if the time of ingestion in an unconscious patient is unknown. General supportive management is all that is required in most cases, with particular attention to respiration and cardiovascular function. However, even with these measures the mortality in deep coma (GCS 3) is about 5% and procedures to enhance drug elimination may be considered in such subjects, particularly if complications of overdose are already present. Repeated doses of activated charcoal given by mouth through a nasogastric tube can reduce the half-life of phenobarbitone from over 100 hours to less than 20 hours. This procedure is relatively non-invasive and may replace the use of haemoperfusion for phenobarbitone poisoning. Activated charcoal has not yet been shown to enhance the elimination of any of the other barbiturates, and charcoal haemoperfusion may be necessary in such cases who are deteriorating despite intensive management or who have developed serious complications (e.g. pneu-
1
24
MCQ1.15
monia, hepatic or renal failure). The blisters should be treated in the same way as burns. 1
Non-barbiturate, non-benzodiazepine hypnotics These were once widely used but have now been largely replaced by benzodiazepines. Isolated overdoses of these agents still occur, however. Specific effects may be seen in addition to CNS depression. Glutethimide may cause fluctuating coma, convulsions and acute respiratory failure. Pulmonary oedema and cerebral oedema may also occur, and papilloedema may be a sign of severe overdose. Charcoal haemoperfusion is indicated in severe overdose, together with management of specific complications. Chloral hydrate and its relatives (e.g. dichloralphenazone) may cause gastrointestinal irritation, haematemesis and subsequent oesophageal stricture. Cardiac arrhythmias are a particular problem with this group of agents but generally respond well to (3-blockers. Haemodialysis may remove the active metabolite, trichlorethanol, but charcoal haemoperfusion is probably more effective and may be helpful in very seriously poisoned patients. Clomethiazole (chlormethiazole) is often used in alcoholic patients, although its value is not proven and it may be dangerous when taken in overdose together with alcohol. Increased salivation is a particular problem which may increase the risk of aspiration pneumonia, and regular oropharyngeal aspiration may be necessary. Meprobamate is still used in the treatment of anxiety, and particularly with muscle spasm. Signs of overdose are muscular incoordination and weakness and CNS depression. In severe cases pulmonary oedema may be seen. Haemodialysis may be useful in severe overdose, but haemoperfusion appears to be more effective.
ANTIDEPRESSANTS Antidepressants, particularly those in the tricyclic group, are still commonly taken in overdose and are particularly dangerous.
SUMMARY 8 Overdose of tricyclic antidepressants • Tricyclic antidepressant poisoning is common and life-threatening • Anticholinergic signs predominate in the early stages but coma may supervene • Direct cardiotoxicity may result in ventricular tachycardia or ventricular fibrillation. The ECG should me monitored until recovery • Arrhythmias and hypotension may respond to correction of acidosis, hypoxia, hypothermia and hypovolaemia. Persistent arrhythmias may respond to sodium bicarbonate, even in the absence of acidosis • Prolonged cardiopulmonary resuscitation has been reported to be successful after cardiac arrest
1
CASE STUDY 1.2 BIPOLAR AFFECTIVE DISORDER A 25-year-old woman with bipolar affective disorder presented 4 hours after taking 9g (18 tablets) of paracetamol. Her parents confirmed that she had taken a package up to the bathroom and locked herself in. When she came out there were almost empty paracetamol packages, which had originally contained 20 g of paracetamol. In the emergency department she was vomiting and complained of some epigastric discomfort. She was taking carbamazepine 600 mg daily for her psychiatric condition. Examination revealed no abnormalities. She was 1.55m (5 feet 2 ins) tall and weighted 50kg (110 pounds). Her plasma paracetamol concentration at 4 hours was 150mg/L (normal treatment concentration at 4 hours is 200mg/L). Questions 1. What other investigations would you ask for? 2. What treatment (if any) 1 would you consider?
Discussion Paracetamol can damage the liver and kidney and her INR, U&Es and LFTs should be measured. In some cases the liver transaminase enzyme concentrations (AST or ALT) may rise (as early as 12 hours) before changes in the INR, and can be a useful early marker of hepatotoxicity. In this woman the y-GT and AST may already be slightly raised because of her carbamazepine therapy (this effect is seen in patients on enzyme-inducing drugs). It might also be useful to check her serum carbamazepine concentration to see whether she might have taken these in overdose. Normally, the potentially toxic dose of paracetamol is 150mg/kg or 10 g, whichever is the smaller. This patient weighs only 50kg, so any dose over 7.5 g should cause concern. In addition, carbamazepine is an enzyme inducer and may increase the risk of toxicity at any given dose. In the UK, individuals receiving enzyme-inducing drugs (carbamazepine, phenobarbitone, phenytoin, primidone, rifampicin or St John's
Tricyclic antidepressants The tricyclic antidepressants act by blocking the uptake of noradrenaline (norepinephrine) by neurons both peripherally and in the CNS. They also have an anticholinergic effect and, in overdose, may have direct actions on the heart. Diagnosis The first signs are usually due to anticholinergic effects. Dryness of the mouth and initial stimulation of the CNS are followed by depressant effects. In severe overdose muscle hypertonia, hyperreflexia and extensor plantar responses are followed by hypotonia and hyporeflexia; generalized convulsions may also occur. Other anticholinergic features are warm dry skin, pupillary dilatation, urinary retention and, in severe cases, paralytic ileus. Depression of respiration may be associated with hypoxia and respiratory and metabolic acidosis. Hypothermia may also occur, and respiratory complications such as aspiration and ARDS (p. 697) can further compromise tissue perfusion.
wort) or at increased risk for other reasons (a regular consumer of alcohol in excess, or badly nourished and thus glutathione depleted) are treated according to the 'high-risk' line, which is half the 'normal' treatment line. The timing of the overdose relative to measurement of plasma paracetamol concentration is crucial in informing such treatment decisions. In this case the parents could confirm when the overdose occurred. However, if there is doubt about the timing of the overdose, consider treating the patient anyway. The treatment of choice in the UK is intravenous N-acetylcysteine for 16 hours. Emptying of the stomach is not indicated after 1 hour. Monitor the INR and U&Es at intervals and when the N-acetylcysteine is discontinued. Subsequent psychiatric assessment is also an important part of the treatment of this patient.
The most life-threatening complication is cardiotoxicity. Tricyclic antidepressants resemble quinidine in their action on the heart, producing a decrease in myocardial contractility, prolongation of the PR interval and widening of the QRS complex. In severe cases the T wave may disappear and the ECG may resemble ventricular tachycardia. Severe ventricular arrhythmias occur in some patients (Fig. 1.10), particularly in the early stages, and the ECG should therefore be monitored preferably even before emptying the stomach.
Management If less than an hour has elapsed, activated charcoal should be given by mouth or nasogastric tube to prevent further absorption of drug in those who have ingested more than 4mg/kg, provided the airway can be protected. A second dose of charcoal (50 g) should be considered after 2 hours in patients with features of toxicity who are able to swallow, and multiple-dose activated charcoal may be useful if a modified-release preparation has been taken. Other methods to enhance elimination of tricyclic antidepressants from the body are of little or no value because
25
FIG. 1.10 Rhythm ECG in tricyclic overdose
of the large volume of distribution, with only a small proportion of the drug therefore in the blood compartment. Convulsions may be related to anoxia and will sometimes respond to adequate oxygenation, although they may require treatment with anticonvulsants such as diazepam. The anticholinesterase agent physostigmine has been used to reverse the CNS effects, but it may precipitate convulsions, ventricular tachyarrhythmias and increased salivary and bronchial secretions. It is therefore rarely used. Arrhythmias and hypotension may respond to correction of acidosis, hypoxia, hypothermia and hypovolaemia. Persistent arrhythmias may respond to bicarbonate, even in the absence of acidosis. Sodium bicarbonate (50 mmol) should be given intravenously to an adult with arrhythmias or significant ECG abnormalities. Further doses may be required depending on clinical response. Antiarrhythmic agents should be used cautiously as they may worsen already impaired myocardial contractility, but positive inotropes (e.g. dobutamine) may be necessary to correct hypotension. Prolonged cardiopulmonary resuscitation has been reported to be successful in patients with tricyclic antidepressant poisoning. 1
Monoamine oxidase inhibitors The monoamine oxidase inhibitors (MAOIs) are much less frequently taken in overdose than tricyclic antidepressants. The onset of symptoms may be delayed for up to 12 hours or more after overdose, so observation for this period at least is necessary in those who have taken a potentially toxic dose. They produce features of increased sympathetic activity, with hyperexcitability and hyperreflexia followed by coma and convulsions. Peripheral muscular effects include myoclonus and rigidity leading to hyperpyrexia and rhabdomyolysis. A sinus tachycardia is often present, but the patient may be either hypertensive or, more rarely, hypotensive. Hyperthermia, or more rarely hypothermia, has been reported. Management The agitation, convulsions and hyperthermia may respond to diazepam, and dantrolene may also be useful in controlling muscle rigidity and hyperthermia. Sympathomimetic agents (e.g. dopamine and dobutamine) should be avoided if possible, as they may lead to a severe hyper-
1MCQ1.16 2MCQ 1.17 26
tensive crisis. Severe hypertension should be treated with an a-blocker such as phentolamine.
Selective serotonin reuptake inhibitors (SSRIs) and other antidepressants These agents appear to be safer in overdose than tricyclic antidepressants and their increasing prescription in depression is reflected in an increased use in self-poisoning. Fluoxetine, fluvoxamine, citalopram, paroxetine and sertraline are the agents available in the UK. There is sometimes a latent period of hours before features occur, and alcohol may potentiate toxicity. Drowsiness, nausea, vomiting (particularly with fluvoxamine), abdominal pain, diarrhoea and sinus tachycardia have been reported. Agitation, tremor, dizziness and sweating are also sometimes seen. Rarely, junctional bradycardia, seizures and hypertension have occurred, and influenza-like symptoms may develop after a day or two. In rare instances a condition known as serotonin syndrome has recently been described. Agitation, myoclonus and sweating, shivering tremor and hyperthermia may occur, followed in some cases by rhabdomyolysis, renal failure, disseminated intravascular coagulation and, rarely, death. This condition is similar to, although normally less severe than, neuroleptic malignant syndrome (NMS), which is sometimes seen after therapeutic doses of some antipsychotic agents. Although both syndromes present with varying degrees of mental status changes and autonomic instability, high fever and muscle rigidity predominate in NMS, whereas gastrointestinal dysfunction and myoclonus are more pronounced in the serotonin syndrome. Venlafaxine potentiates neurotransmitter activity in the central nervous system, probably by inhibiting reuptake of serotonin and noradrenaline (norepinephrine). Although probably less toxic in overdose than tricyclic antidepressants, case reports involving seizures, arrhythmias, the serotonin syndrome (alone or in combination with other drugs), rhabdomyolysis and death have been reported in overdose. Nefazodone inhibits reuptake of serotonin and also selectively blocks serotonin receptors. Nausea, vomiting and drowsiness and, on occasion, convulsions have been reported after overdose. Mirtazapine, a presynaptic a2-antagonist, increases central noradrenergic and serotonergic neurotransmission. It may cause sedation in overdose. Reboxetine is a selective inhibitor of noradrenaline (norepinephrine) reuptake. Overdose may be associated with postural hypotension, anxiety and hypertension.
Management Supportive measures are normally sufficient, although activated charcoal will reduce absorption if given in the first hour. Convulsions should be treated with intravenous diazepam if they are frequent or prolonged. Treatment for all these agents is symptomatic and supportive. Management of the serotonin syndrome is also symptomatic and supportive, although drugs with antiserotonin activity, e.g. cyproheptadine, have been advocated in severe cases.
Lithium carbonate Lithium carbonate is widely used in the prophylaxis of manic depressive psychosis. It has a low therapeutic ratio, and signs of toxicity are most often due to excessive therapeutic doses. Diagnosis Nausea, vomiting and diarrhoea are often the first signs of overdose, followed by more severe signs of toxicity, including dysarthria, ataxia, drowsiness, confusion, coma and convulsions. Renal impairment and nephrogenic diabetes insipidus may occur, and liver damage has also been reported. Cardiotoxicity may be first indicated by ECG findings of non-specific ST segment depression, T-wave inversion, atrioventricular block, and prolongation of the QRS and QT intervals. Symptoms and signs may be delayed, particularly in those who have taken a sustainedrelease preparation, so observation for at least 24 hours, with ECG monitoring and 6-12-hourly plasma lithium measurements, is recommended.
Managemenf Consider gastric lavage for non-sustained release preparations if an adult has ingested more than 4g within 1 hour. Sustained-release preparations (the majority) are unlikely to be able to be removed via a lavage tube, however, and activated charcoal does not adsorb lithium. Rehydration is important, but hypernatraemia (which may indicate nephrogenic diabetes insipidus) may require i.v. dextrose until the serum sodium and osmolality become normal. Hypokalaemia should also be corrected. Toxicity correlates relatively well with the plasma lithium level, although there are differences between those who have taken an acute overdose in the naive state and those on long-term lithium therapy. Haemodialysis should be considered in the former situation in patients with signs of severe toxicity, if the plasma concentration exceeds 7.5 mmol/L, but for those with acute-on-chronic overdose or who have chronic accumulation, plasma concentrations above 4.0 mmol/L in patients with severe toxicity indicate consideration of haemodialysis. Because of the relatively large volume of distribution of lithium, plasma concentrations may increase by up to twofold shortly after the end of the dialysis. Repeated dialyses may therefore be necessary to maintain the serum lithium level at concentrations less likely to cause toxicity. 2
ANALGESICS
1
The dangers of analgesics are not widely appreciated. They are the commonest group of drugs involved in overdose in adults, and in children are associated with serious and sometimes fatal poisoning.
Salicylates Salicylate overdose is responsible for approximately 200 deaths each year in the UK. In addition to being acids themselves, salicylates also increase circulating lactic and pyruvic acid concentrations by interfering with normal carbohydrate metabolism. Stimulation of fat metabolism causes increased production of (3-hydroxybutyric and acetoacetic acids, and increased protein metabolism results in increased circulating amino acids. Impairment of reabsorption of these amino acids, by competition with the salicylate for active tubular reabsorption, produces aminoaciduria and increased fluid loss owing to the effect of this solute load. Fluid loss is worsened by the vomiting associated with salicylate overdose, and by the uncoupling of oxidative phosphorylation, which causes hyperpyrexia and increased sweating. Stimulation of the respiratory centre by salicylates causes a respiratory alkalosis, which partly offsets the metabolic acidosis but causes further bicarbonate depletion, electrolyte loss and dehydration. Diagnosis The clinical features of salicylate overdose are agitation, tinnitus and deafness, increased sweating and hyperventilation; nausea and vomiting and epigastric pain may also be present. Respiratory alkalosis may occur initially but is quickly followed, particularly in children, by a metabolic acidosis associated with increased production of lactate, pyruvate and ketones. There may be hypokalaemia and hypo- or, more rarely, hyperglycaemia. Impaired clotting factor and platelet function are sometimes seen, but bleeding is rare. Confusion and coma may occur before death. Patients older than 70 years or younger than 10 are at the greatest risk from salicylate poisoning, and CNS features, the presence of acidosis, hyperpyrexia, pulmonary oedema and salicylate levels greater than 700mg/L, as well as late presentation, are associated with increased mortality. Management Activated charcoal should be administered at the appropriate dose (50 g for an adult, 10-15 g for a child) in adults or children who have ingested more than 250mg/kg body weight of aspirin within the previous hour. Arterial blood gas measurement (in children, capillary gases or venous blood gases would be a suitable alternative) should be performed, and correction of any acid-base abnormalities and rehydration should be sufficient in mild or moderate cases of salicylate poisoning. Urea and electrolytes, international normalized ratio (INR) and blood glucose and plasma salicylate concentration should be measured, and once
27
SUMMARY 9 Salicylate poisoning • Salicylate poisoning is very serious because of the derangement of acid-base and electrolyte balance (metabolic acidosis, respiratory alkalosis and dehydration) • Coma is rare except as a terminal event, and agitation and restlessness, tinnitus, deafness and hyperventilation are characteristic • The very old and young, those with metabolic acidosis, hyperpyrexia, pulmonary oedema, coma or high salicylate concentrations, and those who present late are at greatest risk of a fatal outcome. • Correction of acid-base abnormalities and dehydration is usually sufficient in mild to moderate poisoning, but haemodialysis may be necessary in severe poisoning
the serum potassium concentration is within the normal range, sodium bicarbonate may be given intravenously to enhance the urinary salicylate excretion (optimum urine pH 7.5-8.5). This entails giving 225 mL 8.4% sodium bicarbonate over 2 hours (or 1.5 L of 1.26%) if the salicylate level is greater than 500mg/L in an adult, or 1 mL/kg 8.4% bicarbonate diluted in 0.5% dextrose or saline at 23 mL/kg/h if the plasma salicylate concentration is greater than 350mg/L in a child. Potassium supplements may be necessary to achieve adequate urinary alkalinization, but if this cannot be attained without increasing the blood pH to greater than 7.5, haemodialysis is treatment of choice. It is indicated for severely poisoned patients (generally with salicylate concentrations greater than 700mg/L, although the threshold may be lower in children under 10 years or the elderly, or those with severe acidosis or impaired renal function). Pulmonary oedema may occur as a result of fluid overload or as a direct effect of the drug on capillary permeability. In the former case the pulmonary artery pressure will be raised, but not in the latter. Ventilation with positive end-expiratory pressure may be helpful. 12
Other non-steroidal anti-inflammatory drugs Salicylates form one group of non-steroidal antiinflammatory drugs (NSAIDs) but there are five other groups that can be classified according to chemical structure. These are: • The arylalkanoic acids, which include phenyl propionic acid derivatives such as ibuprofen, naphthyl propionic acid derivatives such as naproxen, and phenyl acetic acid derivatives such as fenclofenac; • The anthranilic acids, which include the fenamates (mefenamic acid and flufenamic acid);
O Case 1.3 O MCQ1.18
28
QMCQ1.19
• The pyrazalone group of compounds, e.g. azapropazone and phenylbutazone; • The cyclic acetic acids, which include indomethacin, sulindac and tolmetin; • The oxicams, at present represented by piroxicam. Diagnosis The arylalkanoic acids, like all NSAIDs, cause headache, nausea and epigastric discomfort, but coma is rare. Gastrointestinal bleeding may occur and, rarely, bronchospasm. Poisoning with anthranilic acids (e.g. mefenamic acid) is more serious and severe haemorrhagic enterocolitis may occur. CNS effects are also commoner and may include convulsions. Overdose with pyrazolones can produce gastrointestinal and CNS toxicity and hepatic and renal damage. The cyclic acetic acids also produce coma, and piroxicam has been associated with coma and convulsions. Management The stomach should be emptied if appropriate. Early administration of charcoal will reduce the absorption of some of the anthranilic and cyclic acetic acids, and may also be of benefit in poisoning with other groups of NSAIDs. Although there is no definite evidence that histamine2-receptor antagonists (e.g. ranitidine) protect against gastrointestinal haemorrhage, they are often administered prophylactically. Convulsions are generally short-lived but can be treated with diazepam. Blood pressure should be measured regularly and hypotension corrected to prevent subsequent acute renal failure.
Paracetamol Paracetamol is a remarkably safe drug in therapeutic doses but in overdose may cause fatal hepatic necrosis and is responsible for approximately 200 deaths per year in the UK. The toxicity of paracetamol in overdose is related to the metabolism of the drug. Approximately 90 % of the drug is conjugated with glucuronide or sulphate in the liver and gut, with only 10% oxidized by the mixed-function oxidase system to a highly reactive intermediate compound (7V-acetylaminobezoneinonimine, or NABQI), which is normally conjugated with glutathione and subsequently excreted as a mercapturate conjugate. In overdose, more NABQI may be produced than can be detoxified, as glutathione stores in the liver become exhausted, and NABQI instead binds to macromolecules in the liver (and sometimes renal tubular) cells, causing necrosis. Patients on enzyme-inducing drugs (see Table 1.5) may produce more NABQI at any given dose of paracetamol and develop liver damage at lower plasma concentrations of paracetamol, and so they are termed 'high risk' and are given antidotal treatment at half the plasma concentrations recommended for patients in general. Other high-risk patients include those with glutathione depletion (e.g. malnourished individuals, including those with HIV, those with pre-existing liver disease and those who consume excess alcohol).
Diagnosis The clinical features are initially mild and consist of nausea, vomiting and epigastric pain. Metabolic acidosis, hypoglycaemia, hypotension and cardiac arrhythmias have been described, particularly with massive overdoses. Incipient liver damage may first be detected by measuring hepatic transaminase enzymes or the one-stage prothrombin time (INR), which may be abnormal even as early as 6-12 hours after the overdose. Liver damage may occur with as little as 12 g of paracetamol and may present clinically with right subcostal pain and tenderness, recurrence of nausea, vomiting, and then jaundice. Loin pain, haematuria and proteinuria after the first 24 hours strongly suggest incipient renal failure. Acute renal failure has also been reported, usually (but not always) in association with severe liver damage. Renal function and electrolytes should be measured daily. A/lanagemenf Activated charcoal should be considered if more than 150mg/kg or 12 g (whichever is the smaller) in total has been taken within 1 hour. The plasma paracetamol concentration should also be checked after 4 hours (earlier concentrations are uninterpretable) and, if it is greater than that on the treatment line (shown in Fig. 1.11), an antidote should be administered. Antidotal therapy should also be used without waiting for the plasma paracetamol concentration if the overdose has been taken at least 8 hours previously, as the efficacy of the antidotes declines markedly with time.
Summary 10 Acetylcysteine and methionine administration
1
Acetylcysteine Dose: by intravenous infusion, in 5% glucose, initially 150mg/kg in 200 ml over 15 minutes followed by 50mg/kg in 500ml over 4 hours, then 100mg/kg in 1000mL over 16 hours. Methionine Dose: by mouth 2.5g initially, followed by three further doses of 2.5g every 4 hours.
Acetylcysteine (see Summary 10) is a glutathione precursor that is usually given intravenously in the UK because, given orally, it can exacerbate vomiting. Acetylcysteine appears to have some efficacy up to 24 hours or even longer after a large overdose. Oral methionine is also used, but is probably ineffective 8 hours or more after an overdose, and the vomiting associated with paracetamol ingestion makes it difficult to retain in the stomach. Anaphylactoid reactions have been reported in around 8% of individuals after the use of acetylcysteine, often during the initial fast infusion. The reaction is probably due to histamine release, and consists of urticaria and bronchospasm, nausea, vomiting, flushing, angioedema, tachycardia, hypotension, respiratory depression and collapse, and in severe cases renal failure and disseminated intravascular coagulation. Death has occurred in patients who have been inadvertently given an overdose (tenfold greater) of acetylcysteine, so the dose of this antidote should be checked carefully. The infusion should be stopped temporarily and an antihistamine given if necessary, with corticosteroids in addition if the reaction is severe. Nebulized salbutamol may be effective in reversing bronchospasm. Once the reaction has settled, acetylcysteine can be infused at a rate of 50mg/kg over 4 hours; further reactions are extremely rare. Blood sugar should be measured and any abnormality treated. The INR should be measured daily. An INR of 4 or more at 48 hours or >6 at 72 hours indicates the likelihood of severe liver failure, in which case the patient should be commenced on a low-protein diet and oral lactulose to help to remove nitrogenous compounds from the gut. A specialist liver unit should be contacted for advice and consideration of possible transfer for management of liver failure. Management of liver failure also includes prophylaxis against infection and peptic ulceration, and management of coagulation abnormalities. Liver transplantation has been successfully performed in some cases, but has a limited role, and patients should be identified and transferred as soon as possible. Factors associated with poor outcome are metabolic acidosis, hypoprothrombinaemia, renal failure and grade 3-4 encephalopathy. Even if acute hepatic failure does occur, the mortality is less than 50% with good supportive management (p. 854). 0
Opioids FIG. 1.11 Plasma paracetamol concentrations above which antidotal treatment is required
Opioids are used not only as narcotic analgesics but also as constituents of some cough suppressants, antidiarrhoeal
29
Summary 11 Management of opiate poisoning • Opiate poisoning is a common, serious medical emergency • Naloxone reverses the effects of all opiates (except buprenorphine if given in sufficient dose, since it is a competitive antagonist) • The short half-life of naloxone necessitates repeated doses or even constant infusion in treatment of opiates with long half-lives of elimination (e.g. dihydrocodeine and methadone) • The association between intravenous opiate abuse and infection (hepatitis B and HIV should be recognized and appropriate safeguards taken)
products (e.g. diphenoxylate) and veterinary tranquillizers. The one most often involved in poisoning is dextropropoxyphene, which is combined with paracetamol in compound preparation. Opioids are being increasingly misused in society for their effects on mood, being administered intravenously as well as orally. Diagnosis Respiratory depression is the commonest cause of death in opioid overdose. The pupils are often pinpoint. Depression of the CNS eventually leads to coma and convulsions. The muscles may be hypotonic, but muscular twitching and hyperreflexia have been described. Hypotension is common, but hypertension has been described after pentazocine overdose. Non-cardiogenic pulmonary oedema may occur, particularly in methadone overdose. Management If the opiate has been taken orally activated charcoal may be of value in the first hour, or longer if the preparation is sustained release. Naloxone is a competitive antagonist that is effective in reversing the symptoms of opiate overdose with all compounds except buprenorphine (a partial agonist and not completely antagonized). It is best given intravenously (0.8-1.2 mg for an adult, and 0.01 mg/kg body weight for children), and the dose repeated if there is no response within 2 minutes. Those who have taken very large overdoses, particularly of a long-acting agent such as dihydrocodeine or methadone, may need further doses to competitively antagonize the opioid activity, and continuous intravenous infusion of naloxone, together with intensive monitoring, may be necessary. Assisted ventilation with positive end-expiratory pressure may be required if pulmonary oedema occurs. In buprenorphine poisoning naloxone may have only limited benefit and, if doxapram fails to stimulate respiration sufficiently, assisted ventilation may be necessary. Naloxone may precipitate acute opioid withdrawal, with abdominal pain, diarrhoea and piloerection, but the dan-
1MCQ1.20 2MCQ1.21 30
gers of opioid overdose are greater and life-saving treatment should not be withheld.
RECREATIONAL DRUGS In addition to opioids such as diamorphine (heroin), other drugs are being increasingly widely abused in society and may be dangerous in overdose. Amphetamines are sympathomimetic drugs of abuse. Street amphetamine usually contains up to 5% amphetamine along with inert fillers or other stimulants, but purity varies widely. Initial CNS stimulation (agitation and dilated pupils) may be followed by marked hypertonia and hyperreflexia (>39°C) and generalized convulsions. Hyperpyrexia and rhabdomyolysis may also occur. Sinus tachycardia is usual but supraventricular and ventricular arrhythmias, including ventricular tachycardia, may subsequently occur. Hypertension may be a feature and hypokalaemia may sometimes be profound. The stomach should be emptied within 1 hour and activated charcoal given. Sedation with diazepam may be necessary. Sinus tachycardia with adequate cardiac output is best left untreated, but (3-blockers may be needed. cc-Blockers or labetalol are used to manage hypertension. Diazepam is normally effective in managing convulsions, but if they are more frequent, or if vomiting is also a problem, it may be preferable to paralyse and ventilate the patient. Ventricular arrhythmias occurring in a patient who is having convulsions may respond to disopyramide. Ecstasy (3,4-methylenedioxymethamphetamine, or MDMA) is an amphetamine-like compound with a similar spectrum of toxicity. However, there is marked inter- and intraindividual variability in susceptibility, and deaths have occurred after only a single tablet in those who have previously tolerated similar or greater doses. Signs of severe toxicity include delirium, coma, convulsions, and supraventricular and ventricular arrhythmias. Hypertonia and hyperpyrexia may result in rhabdomyolysis, metabolic acidosis and acute renal failure. Hyponatraemia, disseminated intravascular coagulation, hepatocellular necrosis, adult respiratory distress syndrome and cardiovascular collapse have also been described. Death may occur from intracerebral haemorrhage. Treatment is largely symptomatic and supportive, with correction of metabolic acidosis and dantrolene (or paralysis and ventilation) for the hyperpyrexia. 1 Cocaine may be taken by the oral or intravenous route, or by inhalation. Toxicity is characterized by agitation, tachycardia, tachypnoea, sweating, delirium and hallucinations. Hypertension, hyperpyrexia, generalized convulsions, stroke, cardiac ischaemia, myocardial infarction and arrhythmias, metabolic acidosis, rhabdomyolysis and cardiorespiratory arrest may also occur. Treatment is symptomatic and supportive. Hypertension may best respond to a-blockers or combined a- and p-blockade (e.g. with labetalol). The risk of severe toxicity is particularly high
in 'body stuffers' who, on the verge of arrest, swallow the evidence, rather than in 'body packers', who are hired specifically to smuggle drugs and who have time to wrap them carefully (e.g. in a condom). Lysergic acid diethylamide (LSD) in overdose may cause acute panic attacks, delirium, hallucinations, seizures and coma, respiratory arrest and metabolic acidosis. Treatment is symptomatic and supportive, although features of psychosis may last for several days. Panic often responds to diazepam. Phenothiazines are best avoided in treating the psychosis, as they may reduce seizure threshold. y-Hydroxybutyric acid (GHB),or liquid ecstasy, is a 'psychedelic' agent that has recently become popular. It can cause coma, sinus bradycardia and hypotension in overdose, as well as respiratory depression leading to respiratory arrest. Treatment is symptomatic. The bradycardia may respond to atropine (1.2mg intravenously for an adult, 0.02mg/kg for a child). 2
ANTICONVULSANTS The incidence of psychiatric abnormalities is higher in epileptics than in the non-epileptic population. The availability of anticonvulsants to some epileptic patients results in their being taken relatively frequently in overdose. Barbiturates and primidone, which are converted into phenobarbitone and phenylethylmalonamide in the body, are described on page 23.
Phenytoin Phenytoin is one of the most widely prescribed anticonvulsants. Acute overdosage leads to ataxia, dysarthria, horizontal nystagmus, drowsiness and, in severe cases, coma. Respiratory depression is a rare but potentially serious complication, which is generally only seen after massive overdose. The stomach should be emptied within 1-2 hours of ingestion and activated charcoal will help to prevent further absorption. Because phenytoin is highly protein bound, only charcoal haemoperfusion will effectively remove the drug from the circulation. This should, however, be reserved for patients with severe overdose. Rarely, cases of permanent cerebellar damage with persistent ataxia after phenytoin overdose have been described.
Carbamazepine Carbamazepine is widely used for the treatment of generalized and partial seizures. The drug is structurally similar to tricyclic antidepressants and overdose can be associated with anticholinergic effects, including dry mouth, hyperreflexia and generalized convulsions. Nystagmus, strabismus, diplopia, ataxia, hypotension and respiratory depression have been noted, and cardiac conduction disturbances may also occur. The stomach should be emptied if appropriate, and activated charcoal administered. Repeated doses of charcoal speed the elimination of drug in
normal volunteers and may be effective in severe overdose. Effective removal of the drug by haemoperfusion has also been reported.
1
Sodium valproate Sodium valproate poisoning is associated with coma and respiratory depression. The drug is rapidly absorbed, and supportive measures form the mainstay of treatment.
CARDIOVASCULAR DRUGS Anti hy per ten si ves The major adverse effect is hypotension. With clonidine, hypotension is often associated with bradycardia, but severe hypertension caused by the drug's partial a-agonist activity is sometimes a major problem. Bradycardia often responds to atropine, and a-adrenergic blocking drugs have been used to treat the hypertension. (3-Receptor blocking agents also cause bradycardia and hypotension, and may also cause drowsiness, coma and convulsions in overdose. In hypotension atropine is used to increase cardiac output, but large doses are often required (3mg intravenously in an adult and 0.04mg/kg for a child). Glucagon is used if atropine is ineffective. An intravenous bolus of 50-150mg/kg body weight dissolved in dextrose may be effective but may need to be followed by the same dose or an intravenous infusion of 4mg/h until the patient's condition is satisfactory. Glucagon may induce vomiting and the airway needs to be protected. Pi -Agonists such as prenalterol are also effective, although large amounts may have to be given intravenously to competitively antagonize the (3-blockade. pY Agonists (e.g. salbutamol) may be necessary if bronchospasm is present, and the blood sugar should be monitored to detect and treat hypoglycaemia. Convulsions normally respond to intravenous diazepam (0.1-0.3mg/kg body weight). Calcium antagonists (especially verapamil) may also cause severe hypotension and bradycardia and conduction abnormalities and, in severe cases, asystole. If atropine is ineffective in treating the bradycardia, calcium gluconate (10-20 mL of a 10% solution in an adult) may be required. Pacing may be necessary to treat the bradyarrhythmias, and dopamine and glucagon (and, in resistant cases, insulin and dextrose) have been used to give inotropic support.
Digitalis glycosides Poisoning with the digitalis glycosides is rare but potentially very serious. Nausea, vomiting and diarrhoea are early features, but the major life-threatening complications are hypotension and cardiac conduction disturbances, with brady- and tachyarrhythmias. Hyperkalaemia is often present and mirrors roughly the severity of the overdose. This should be treated with glucose and insulin, or a sodium resonium ion exchange resin, or by haemodialysis
31
SUMMARY 12 Digitalis glycoside poisoning • Cardiac glycosides may cause nausea, vomiting, diarrhoea and generalized malaise • Cardiac effects include bradycardia with PR and QRS prolongation. Sinus arrest and varying degrees of AV block may also occur • Hyperkalaemia and metabolic acidosis may occur in severe cases • Multiple doses of charcoal enhance elimination by interrupting enterohepatic recirculation • Prophylactic pacing should be considered if hyperkalaemia or heart block occur • Severe intoxication is often effectively treated with digoxin antibodies, the dose depending on the amount taken and the serum glycoside concentration
if necessary. Metabolic acidosis may also occur. Both digoxin and digitoxin have enterohepatic recirculation processes and repeated doses of activated charcoal (see p. 24 for dosage) will speed elimination. Continuous monitoring of cardiac rhythm is essential: bradycardia sometimes responds to intravenous atropine (1.2mg for an adult or 0.02mg/kg for a child), repeated as necessary until atropinization occurs. More severe bradyarrhythmias may require temporary cardiac pacing, particularly if heart block or hyperkalaemia are present. Ventricular tachyarrhythmias often respond to lignocaine, but phenytoin and intravenous (3-blockers have both been used in resistant cases. Digoxin-specific Fab antibody fragments may be necessary in the treatment of severe digoxin and digitoxin poisoning. The dose of antibody (Digibind) is about 60 times the estimated body load of digoxin or digitoxin (the amount of drug in milligrams ingested multiplied by 0.8) rounded up to the nearest 40 mg. This can be calculated from the amount taken, or the plasma concentration of the drug.
RESPIRATORY DRUGS Theophylline Theophylline is the respiratory drug most often taken in overdose. Nausea, persistent vomiting and epigastric pain may be followed by agitation, hallucinations and convulsions. Hypertonia may be associated with rhabdomyolysis. Supraventricular and ventricular arrhythmias with hypokalaemia (often profound) may follow a sinus tachycardia. Signs may be delayed for up to 12-24 hours in those who have taken a sustained-release preparation. The stomach should be emptied to prevent further absorption and charcoal (50 g) left in the stomach. The metabolic abnormalities should be treated appropriately, 1MCQ1.22 2MCQ1.23 32
but convulsions and hypertonia may respond to diazepam administered intravenously. Supraventricular and ventricular arrhythmias may respond to the use of adrenoceptor blockers (e.g. metoprolol),but the metabolic abnormalities may only respond to agents that also possess ( 2-antagonist activity (e.g. propranolol). However, (3blockers should not be used in asthmatic patients because of the risk of precipitating bronchospasm. Disopyramide or verapamil have been used successfully to treat arrhythmias in such patients. Repeated oral administration of charcoal has recently been shown to reduce markedly the half-life of elimination of theophylline. Persistent vomiting may mean that an antiemetic such ondansetron (8 mg slowly intravenously in an adult) will be necessary to allow the charcoal to be retained. Haemoperfusion is an efficient way of enhancing the removal of theophylline from the circulation. It should be considered in severely poisoned patients, particularly those with major arrhythmias, hypotension or convulsions, and if repeated-dose charcoal is not feasible. 1
Ephedrine, salbutamol and terbutaline Ephedrine, salbutamol and terbutaline are generally safer than theophylline in overdose, but can cause all the same features in severe cases. Treatment is broadly similar to that of theophylline overdose: again, -blockers must be avoided in asthmatic subjects.
DRUGS WITH ANTICHOLINERGIC ACTIVITY In addition to tricyclic antidepressants many drugs have anticholinergic activity, including some used to suppress gastrointestinal motility (e.g. propantheline), some antiparkinsonian drugs (e.g. amantidine and orphenadrine) and some antihistamines (e.g. chlorphenamine (chlorpheniramine) and promethazine). The effects of these drugs are similar to those caused by overdosage with tricyclic antidepressants, but they are less likely to cause arrhythmias. The anticholinesterase physostigmine is no longer recommended in anticholinergic poisoning because of severe adverse effects. Treatment is supportive and symptomatic.
ANTIDIABETIC DRUGS Poisoning with antidiabetic drugs and insulin produce all the features of hypoglycaemia. The management is described in Chapter 19, page 1020. Sulphonylureas (particularly those with long half-lives of elimination (e.g. chlorpropamide) are of particular concern, as hypoglycaemia may be a problem for several days and they are sometimes resistant to glucose and glucagon. Severe hypoglycaemia has therefore been treated with diazoxide, which
inhibits insulin release and raises circulating plasma catecholamines. At the dose used (5 mg/kg body weight/24 h by mouth in two or three divided doses), it rarely produces hypotension. Diazoxide may be the treatment of choice if there is a risk of hypoglycaemia over several days. Metabolic acidosis may occur after sulphonylurea poisoning, but is more common after poisoning with the biguanide metformin. ©
atrophy. Most patients recover some vision, although some are left with permanent visual field defects. The management of quinine poisoning is supportive. Stellate ganglion block has been advocated in the past but has no proven benefit. As quinine has a large volume of distribution and is predominantly metabolized by the liver, methods to enhance elimination are of limited value, but repeated dose of oral charcoal may be beneficial.
1
Chloroquine ANTIBIOTICS The penicillins and cephalosporins are generally safe in overdose. Sulphonamides may cause bone marrow depression and renal damage (and haemolysis in glucose 6-phosphate dehydrogenase-deficient patients). Maintenance of a high urine output and alkalinization of the urine may prevent sulphonamide-induced renal damage, by preventing crystallization of the drug in the renal tubule. Calcium folinate may help to reverse bone marrow depression induced by sulphonamide or trimethoprim. Isoniazid can cause CNS symptoms with coma and convulsions. Pyridoxine can be used to treat or prevent both convulsions and the metabolic abnormalities: it should be given in a dose of 1 g for every gram of isoniazid ingested. Rifampicin overdose may be associated with orange discoloration of the skin (although this colour can be removed by washing). Treatment is usually supportive. Although most patients recover completely, occasional sudden deaths have been reported, presumably from cardiac arrhythmias. The antileprotic drug dapsone (also used in the treatment of dermatitis herpetiformis) is dangerous in overdose, causing methaemoglobinaemia and sometimes convulsions and coma.
ANTIMALARIALS Quinine Quinine, which is also used to treat night cramps, is the antimalarial agent most often taken in overdose and also the one most likely to cause serious toxicity. Children may take tablets belonging to a family member. Early symptoms of overdose are similar to those of aspirin, with nausea, vomiting, bowel disturbances, tinnitus and deafness. Initial respiratory stimulation may be followed by respiratory depression and respiratory arrest. Quinine can cause brady- and tachyarrhythmias, with death from ventricular fibrillation. Its effect on vision is dramatic. Visual acuity is initially impaired, and this may progress to constriction of visual fields or even complete blindness. Retinal examination reveals constriction of the arterioles initially, followed by retinal oedema and sometimes optic
Chloroquine is widely used as prophylaxis against malaria and can be purchased without prescription. Its toxicity is similar to that of quinine, and visual disturbances are also sometimes seen. As little as 5g may be fatal. Ventricular arrhythmias often occur early (within the first 3 hours) and include intraventricular conduction defects with a wide QRS, and prolongation of the QT interval. Ventricular tachycardia and fibrillation are early arrhythmias, and torsade-de-pointes sometimes occurs later. Very large doses of diazepam (2 mg/kg body weight intravenously over 30 minutes) may reduce mortality, but should be considered only when facilities for assisted respiration are available. Chloroquine is also predominantly metabolized by the liver and has a high volume of distribution; thus, none of the techniques for enhancing removal appears to be effective.
ANTICOAGULANTS The major risk of oral anticoagulant poisoning is haemorrhage: this occurs several days after the overdose because of the delayed effect of these agents. In cases of large overdose, and where the INR is raised at 36-48 hours, vitamin K (10 mg twice daily by slow intravenous injection, 250 g/kg body weight for a child) should be administered and may be necessary for up to a week. Repeated oral administration of colestyramine (cholestyramine) (4 g three times daily) may enhance the removal of warfarin and phenprocoumon, and also reduce the length of time for which vitamin K is required. Rodenticides contain only small amounts of oral anticoagulant and rarely cause toxicity.
POISONING WITH GASES AND VOLATILE SOLVENTS CARBON MONOXIDE Carbon monoxide is still the most common cause of fatal gas poisoning in the UK, despite the substitution of natural gas for coal gas in general use. Deaths occur either accidentally (often by inhalation of fumes during fires) or deliberately, from inhalation of car exhaust fumes in a confined space. Methylene chloride, which is widely used in
33
paint removers, is metabolized by the body to carbon monoxide and causes symptoms identical to those of direct carbon monoxide exposure. Diagnosis The early symptoms of chronic or acute exposure are headache, mental agitation, nausea and vomiting. The characteristic cherry-pink colour of the skin is rarely present during life, but the patient is not cyanosed, despite considerable hypoxia because of the production of carboxyhaemoglobin. Cerebral oedema and myocardial ischaemia or infarction may also occur. Management Oxygen should be given in as high a concentration as possible. There is no clear evidence that hyperbaric oxygen affects outcome, and its use should be discussed with the regional poisons unit. Patients who have been unconscious after exposure, who have a carboxyhaemoglobin concentration over 20% or who have neurological or psychiatric features, are most likely to obtain any possible benefit. Hyperbaric oxygen is not always immediately available, and transfer to such a facility should not interrupt the treatment of severely poisoned patients. Oxygen should be administered until the carboxyhaemoglobin concentration in blood falls below 15%: this may take up to 2 days. Mannitol, Ig/kg intravenously over 20 minutes, may be considered if there is evidence of cerebral oedema. Most patients who die of carbon monoxide poisoning do so before they reach hospital; those who do arrive in hospital usually survive. Unfortunately, permanent neuropsychiatric sequelae may be seen, including intellectual and personality deterioration, parkinsonism and, in rare cases, akinetic mutism. These severely affected patients often show areas of low density in the area of the globus pallidus on CT brain scans. 1
IRRITANT VAPOURS AND GASES
Carbon disulphide, hydrogen sulphide, sulphur dioxide, hydrochloric acid and ammonia are all highly irritant to the eyes and respiratory tract. Cough and chest pain may be followed by dyspnoea, bronchospasm, haemoptysis and pulmonary oedema. Management
Treatment is supportive, with bronchodilators for bronchospasm, oxygen for hypoxia and, in severe cases, assisted ventilation (with PEEP if pulmonary oedema is present). Steroids, diuretics and antibiotics have been used, but because the complications are direct effects of the gas, they
SUMMARY 13 Cyanide poisoning • Cyanide is absorbed through the skin, by inhalation or oral absorption • The clinical features are those related to severe hypoxia and metabolic acidosis • Oxygen in high dose should be given and the metabolic acidosis corrected • Dicobalt edetate is the antidote of choice if the diagnosis is certain • Sodium thiosulphate, together with sodium nitrite, is also an effective antidote
are unlikely to be of benefit. The metabolic acidosis may improve with adequate oxygenation, but if this fails sodium bicarbonate may have to be administered. Ophthalmologic advice should be sought to diagnose and treat corneal abrasions.
CYANIDE Cyanide may be inhaled in the form of hydrogen cyanide, sometimes in fumes caused by burning plastic. Symptoms appear within a few minutes, first with headache, agitation, confusion leading to coma, cardiovascular collapse and respiratory arrest. Cyanide may also be taken orally, in which case symptoms may occur much later, particularly if food in the stomach delays gastric emptying. Management Oxygen in high concentrations should be administered and assisted ventilation performed if necessary. Dicobalt edetate is the most effective antidote, but it may cause hypotension and chest pain on intravenous administration (300 mg intravenously over 1 minute), and should therefore only be used if the diagnosis is certain. It acts by forming inert complexes with cyanide, thereby preventing the cyanide-induced inhibition of cellular oxidizing enzymes. Sodium thiosulphate (25 mL of 50% solution intravenously over 10 minutes for an adult; 400mg/kg for a child) acts as a sulphur donor to allow conversion of cyanide to thiocyanate via the enzyme rhodanase. Subsequent administration of sodium nitrite (10 mL of 3% solution intravenously over 5-20 minutes for an adult; 0.13-0.33mL/kg of 3% solution for a child) converts haemoglobin to methaemoglobin, which chelates the cyanide ion. The two treatments act synergistically. They are generally used if there is doubt about the diagnosis, there is no response to dicobalt edetate, or if the latter is not immediately available.
HYDROCARBONS 1
34
MCQ1.24
Poisoning with hydrocarbons is nearly always accidental, generally from industrial or domestic exposure, but also increasingly from solvent abuse.
Aliphatic hydrocarbons The aliphatic hydrocarbons appear to be less toxic than the aromatic group. The shorter-chain aliphatic hydrocarbons are volatile, so that poisoning is usually from inhalation. High concentrations may cause asphyxia, and the butane in lighter fluid has been used to produce euphoria by solvent abusers. Coma may occur, with death from respiratory depression or ventricular fibrillation. Renal and liver damage may develop if the patient survives. Pulmonary and cerebral oedema have also been reported. Inhaled hydrocarbons may also produce myopathies, neuropathies and permanent neuropsychiatric damage, although some of these effects may be related to additives to the hydrocarbon. Ingestion of liquid aliphatic hydrocarbons can produce effects similar to the above, due either to a systemic effect or, more likely, to aspiration of the low surface tension solvents. Pyrexia, cough and hyperpnoea may be followed by basal crackles in the chest, consolidation, and collapse involving predominantly the middle and lower zones of the lung. Treatment of solvent inhalation or ingestion is generally supportive. Gastric lavage or emesis should not be performed after ingestion because of the risk of chemical pneumonitis. There is no evidence that steroids and antibiotics are effective in the pulmonary complications, but in severe cases ventilatory support may enable the patient to recover.
Chlorinated aliphatic hydrocarbons Chlorinated aliphatic hydrocarbons are widely used as solvents in industry. In addition to the effects described with other hydrocarbons, the chlorinated aliphatics are also more likely to produce hepatic and renal damage (particularly carbon tetrachloride and chloroform), haemolytic anaemia and aplastic anaemia. Methylene chloride is metabolized by the body to carbon monoxide and its systemic toxicity is that of this metabolite, although it is itself locally corrosive. It has been suggested that acetylcysteine may inhibit the metabolism of chlorinated hydrocarbons to reactive intermediate metabolites and thereby reduce hepatotoxicity if given early.
Aromatic hydrocarbons Aromatic hydrocarbons are less often involved in poisoning. Benzene is the most toxic of these agents and, in acute overdose, produces effects similar to those of the aliphatic hydrocarbons. Chronic exposure may lead to aplastic anaemia and leukaemias. Toluene and xylene are similar in structure and effects to, but less toxic than, benzene: any marrow toxicity is probably related to benzene contamination. Benzene contamination is probably also responsible for the haematological problems sometimes seen with chronic petrol inhalation.
1
FIG. 1.12 Blood concentrations after oral administration of ethyl alcohol (2 ml/kg) The concentration declines in a zero-order fashion at an average rate of 190mg/L each hour.
OVERDOSE WITH ALCOHOLS ETHANOL (ETHYL ALCOHOL) (See also ch. 24 p. 1435) Ethanol, present in alcoholic drinks, is the alcohol most often taken in overdose. It is also found as a solvent in some cosmetic and antiseptic preparations. Its major toxicity is related to its central nervous depressant effects. The loss of the gag reflex max result in aspiration of stomach contents. Alcohols inhibit gluconeogenesis and may cause profound hypoglycaemia, particularly in children. Blood ethanol concentrations give a rough guide to the severity of overdose, but may be misleading because of tolerance in chronic alcohol users. Severe intoxication with stupor and marked incoordination is generally associated with blood concentrations above 3000 mg/L. The rate of metabolism is shown in Figure 1.12. Management Because alcohol is rapidly absorbed, lavage is unlikely to be of benefit and the compound is poorly adsorbed by activated charcoal. Metabolism is saturated even at low doses. The treatment is usually symptomatic and supportive, with correction of hypotension and hypoglycaemia. Protection of the airway is paramount. Although haemodialysis will remove alcohol efficiently, it is only indicated in severe and complicated cases of poisoning. Fructose accelerates the metabolism of alcohol, but it can potentiate the metabolic acidosis already caused by the alcohol and should not be used. Intravenous dextrose may be necessary to treat hypoglycaemia. The problems of alcoholism are discussed on page 247.
METHANOL Methanol is much more toxic than ethanol and is widely used as a solvent. Methylated spirit is 5% methyl alcohol
35
and 95% ethanol. The mode of toxicity is not clear, but accumulation of formaldehyde and formic acid is partly responsible. As little as 10 mL of methanol may cause serious illness. The initial features are those of mild inebriation, but 8 or more hours later the patient may develop abdominal pain and vomiting, dilated and unreactive pupils, a metabolic acidosis and, sometimes, signs of cerebral oedema. The optic disc is at first hyperaemic and then becomes oedematous; vision is progressively lost. Management The stomach should be emptied within the first hour of methanol ingestion; activated charcoal does not adsorb significant quantities. Intravenous sodium bicarbonate should be used to keep the arterial pH above 7.2, but metabolic acidosis may be resistant to treatment. Diazepam is indicated if convulsions are a problem. Ethanol competitively inhibits the metabolism of methanol to formaldehyde and formic acid, and is used in less serious poisoning. Haemodialysis may be necessary if the blood methanol concentration exceeds 500 mg/L, or if there is clinical deterioration despite other measures. Haemodialysis also removes ethanol, so that ethanol administration during this procedure has to be increased. Visual impairment is often permanent, although prompt treatment reduces its severity.
ISOPROPANOL (ISOPROPYL ALCOHOL)
Isopropanol is found in rubbing agents, sterilizing fluids and disinfectants, window cleaning fluids and some aftershave lotions. Features of poisoning resemble those of ethyl alcohol poisoning, but because some of it is metabolized to acetone, ketonuria and a characteristic smell of acetone on the breath may be observed. Management
The stomach should be emptied within an hour of ingestion, but treatment is otherwise symptomatic. Haemodialysis will remove isopropyl alcohol but is normally only indicated in severe poisoning.
overdose, but ophthalmoplegias, papilloedema and subsequent optic atrophy may also occur and the patient may become comatose and develop convulsions. After 12 hours respiratory and cardiovascular complications are seen, together with a metabolic acidosis, hypocalcaemia and hyperkalaemia. If the patient survives this phase, he or she may develop acute renal failure after approximately 24 hours. Ethylene glycol is not itself toxic but is metabolized by alcohol dehydrogenase to aldehydes, glycolates, oxalates and lactate, which are responsible for the toxic features. Management The stomach should be emptied within the first hour and arterial blood gases and serum calcium measured. Activated charcoal does not adsorb ethylene glycol. Any metabolic acidosis may respond to intravenous bicarbonate, and calcium gluconate may be necessary to treat hypocalcaemia. Ethylene glycol metabolism can be inhibited by administration of alcohol in doses sufficient to attain blood ethanol concentrations between 1000 and 2000 mg/L. In severe cases (ethylene glycol concentration >500mg/L, or clinical condition deteriorating despite other measures) haemodialysis is necessary to remove ethylene glycol metabolites. Ethanol administration may also be necessary for up to 4 days after the overdose to reduce their production. Dialysis may be required for renal failure. Fomepizole has recently been licensed for the treatment of ethylene glycol poisoning. 1 POISONING WITH CORROSIVE AGENTS
Fortunately, poisoning with corrosive agents is rare, and most incidents are accidental rather than deliberate. The majority of agents produce local tissue damage by protein denaturation, but some (e.g. paraquat) also have serious systemic toxicity. The patterns of damage with acids and alkalis are different and are therefore discussed separately.
ACIDS ETHYLENE GLYCOL
Antifreeze solutions contain ethylene glycol, a solvent that is sweet-tasting and therefore not unpleasant to drink. Death may occur after ingesting as little as 100 mL of ethylene glycol which, like alcohols, is metabolized by alcohol dehydrogenase. CNS toxicity is similar to alcohol
1
36
MCQ1.25
Acids produce severe pain on ingestion. They may cause asphyxia from epiglottal oedema and, although oesophageal damage has been described, they are more likely to cause gastric perforation, particularly in the region of the antrum. Late stricture formation is also a possibility. Lavage should not be performed unless the agents also have serious systemic toxicity. Any metabolic acidosis should be treated with intravenous bicarbonate, but weak alkalis should not be given by mouth. Endoscopy is of limited value in the acute phase and may cause perforation; in later stages, however, it may be helpful in identifying stricture formation. Corticosteroids have been used to try to prevent stricture formation, but their value is unclear.
SUMMARY 14 Acid poisoning • Acid ingestion may cause local corrosion, asphyxia due to oedema of the glottis and perforation of the stomach (less commonly of the oesophagus) • Metabolic acidosis and renal failure may also occur • Lavage should not be performed unless the agent produces severe systemic toxicity • Late stricture formation may occur but the value of corticosteroids in preventing this complication is not proven
Phenol (carbolic acid) can cause systemic toxicity as well as local corrosion, although the latter is normally less severe than with inorganic acids. The urine may be dark brown or black and the breath, urine and blood may smell strongly of carbolic. Haemolysis, renal failure, coma and convulsions, myocardial damage and metabolic acidosis may occur, and early cautious gastric lavage is indicated, provided the airway can be protected. Metabolic acidosis corrected with intravenous sodium bicarbonate and urine output and renal function carefully monitored. Cresols (methylphenols) have similar effects and treatment is therefore as for phenol poisoning. Formic acid is used in kettle descalers and destaining solutions. It too can produce a metabolic acidosis, intravascular haemolysis and renal failure, as well as local corrosion. Gastric lavage is therefore indicated early after ingestion, and any metabolic acidosis should be corrected with intravenous sodium bicarbonate. As with phenols, aspiration into the lung may cause haemorrhagic tracheobronchitis and the airway must therefore be protected during lavage.
ALKALIS Corrosion by alkalis (e.g. drain and oven cleaners) is generally more severe than by acids and is more likely to cause serious oesophageal, as well as gastric, damage. Stricture may develop weeks or months after the initial injury. Treatment is similar to that for acid ingestion; lavage should not be performed. Endoscopy by an experienced operator should be considered to assess the degree of injury and to prevent unnecessary hospitalization. The instrument should normally be passed only to the level of the first area of injury. It may also be useful in identifying alkalis in tablet form, which may adhere to the oesophagus (e.g. Clinitest tablets and some denture cleaners).
BLEACHES Most bleach contains sodium hypochlorite (up to 10%), which may produce corrosion in large or concentrated doses, and laryngeal oedema due to chlorine liberation. The stomach should be cautiously emptied within an hour if more than 300 mL has been ingested in an adult (100 mL
in a child), provided there is no evidence of oesophageal corrosion or severe gastritis. An H2-receptor blocking drug such as ranitidine should be given, and corticosteroids may be of value if laryngeal or pulmonary oedema is present. The sodium load resulting from ingestion of large amounts of bleach can cause hypernatraemia and hyperchloraemic acidosis.
1
DISINFECTANTS Although phenols and cresols (found in Jeyes fluid and some other disinfectants) have been largely replaced by dichlorometaxylenol, corrosive effects may occur after large or concentrated doses. Metabolic acidosis, coma, myocardial and renal damage and laryngeal oedema may also occur after severe overdose, and the stomach should therefore be emptied and the metabolic abnormalities corrected. Some disinfectants also contain isopropanol (discussed on p. 36).
POISONING WITH INSECTICIDES, HERBICIDES, FUNGICIDES AND RODENTICIDES INSECTICIDES The organochlorine group of insecticides (e.g. DDT) have now largely been replaced by compounds that are less persistent in the environment. These include the organophosphorus and carbamate insecticides.
Organophosphates The organophosphates act as inhibitors of cholinesterase in humans, causing symptoms of excessive cholinergic activity, with vomiting, abdominal pain, sweating, constricted pupils and hypersalivation. Muscle spasm, diarrhoea, convulsions and coma follow. Organophosphates can be absorbed from the stomach, skin or bronchial mucosa. Plasma cholinesterase activity, measured in several centres throughout the UK, is useful in the diagnosis of both organophosphate and carbamate insecticide poisoning. Severe toxicity is associated with a reduction in plasma cholinesterase activity to around 10% of normal. Treatment consists of atropine to antagonize the cholinergic (muscarinic) effects. The initial dose is 2 nig for adults and 0.02mg/kg for children, by intravenous injection. Large doses (up to 30 mg in 24 hours in an adult) may be necessary until there are signs of atropinization (dry skin, tachycardia, dilated pupils and dry mouth). Within the first 24 hours the use of an oxime (e.g. pralidoxime mesylate or P2S) will help to reactivate cholinesterase. It can be obtained from holding centres in the UK, details of which can be found on TOXBASE. The normal dose in moder-
37
ate or severe poisoning is 30mg/kg by intravenous injection over 5-10 minutes. Benefit should be seen within 30 minutes, but repeated doses at 4-6-hourly intervals may be required. Alternatively, it may be given by intravenous infusion at a rate of 8mg/kg/h. Intravenous diazepam (5-10 mg for an adult; 0.02mg/kg body weight for a child) is helpful in reducing twitching and may improve survival. A clear airway must be maintained and assisted ventilation may be necessary.
the patient presents within an hour of ingestion) with care because of the corrosive effects of the toxin. Charcoal (1 g/kg body weight) is left in the stomach as an adsorbent for paraquat. Oxygen therapy should be avoided if possible as it may enhance the toxicity of these agents. Finally, haemodialysis and haemoperfusion have been tried in an attempt to remove the body burden of drug, but there is no evidence that either has any effect on mortality, particularly when the more concentrated solutions of paraquat (e.g. Gramoxone) are ingested. 2
Carbamate insecticides
Dinitro compounds
Carbamate insecticides produce similar symptoms (CNS signs are less prominent) and atropine is again the treatment of choice. However, because these compounds have a reversible effect on cholinesterase, their duration of action is much shorter and pralidoxime has not shown clear evidence of benefit in poisoning with these agents. O
Dinitro compounds (e.g. dinitro-orthocresol) are generally used in the form of washes for fruit trees. They cause yellow staining of the skin but can be absorbed subcutaneously and produce toxicity by uncoupling oxidative phosphorylation. This results in pyrexia, hyperpnoea and tachycardia, with subsequent sweating, thirst, dehydration and collapse. Treatment consists of preventing severe pyrexia and replacement of electrolytes and fluid. Pentachlorophenol acts similarly to the dinitro compounds but does not produce yellow discoloration of the skin.
HERBICIDES The five major groups of herbicides are: chlorates, triazines, bipyridilium herbicides, dinitro compounds and phenoxyacetic acids.
Chlorates The chlorates are powerful oxidizing agents that can produce haemolysis, methaemoglobinaemia, haemorrhagic gastroenteritis and, in severe cases, renal failure. Treatment consists of emptying the stomach (if appropriate) and methylene blue to reverse methaemoglobinaemia.
Triazines Triazine herbicides (e.g. simazine) appear to be relatively non-toxic, and serious human poisoning has not been reported.
Bipyridilium herbicides (paraquat) The bipyridilium herbicides, particularly paraquat, are extremely toxic. Not only can they cause local corrosion, but systemic absorption leads to renal and liver damage and later progressive pulmonary fibrosis. Diquat, which is less well absorbed from the gut, can cause similar toxicity, although pulmonary fibrosis seems to be slightly less likely to occur. Treatment consists of immediate gastric lavage (if
Phenoxyacetic acids Phenoxyacetic acids are probably the most widely used herbicides. They are relatively non-toxic unless large doses have been ingested; signs of cholinergic hyperactivity are then evident, resulting in coma and occasionally ventricular arrhythmias. Other features in severe cases include hypoglycaemia, metabolic acidosis, convulsions, hypertonia, myoclonus, rhabdomyolysis and renal failure. The stomach should be emptied if appropriate, contaminated clothing removed and the skin washed with soap and water. With 2-4-D and mecoprop urinary alkalinization may enhance their rate of removal, but haemodialysis is more efficient and should be considered in severely poisoned patients.
FUNGICIDES Organic and inorganic mercurials, organotin derivatives and dithiocarbamates are all used as fungicides in industry and horticultural practice. Organotin compounds are poorly absorbed from the gastrointestinal tract and therefore have low toxicity; dithiocarbamates are also relatively non-toxic.
Organic mercurials 1
38
MCQ 1.26, 1.27
2
MCQ1.28
Inhalation or ingestion of organic mercurials can produce severe corrosion and irritation of the respiratory tract. CNS toxicity consists of tremor, memory and psychiatric disturbances, and visual impairment that may lead to blind-
ness. The chelating agents DMSA and DMPS may reduce the systemic toxicity, but dimercaprol is contraindicated.
Inorganic mercurials Inorganic mercurial fungicides (e.g. mercuric chloride) are also predominantly corrosive. Treatment includes gastric lavage, adequate analgesia and treatment of any complications. Mercurous chloride (calomel) and mercuric oxide (the most commonly used agents) are poorly absorbed and, although corrosive, systemic toxicity is unlikely. If albuminuria occurs, however, significant absorption may have taken place and plasma mercury concentration should be measured. Treatment involves the use of the chelating agents. Although dimercaprol is licensed for this use, it has to be given by deep, painful intramuscular injection, and two orally active chelating agents, DMSA (Succimer) and DMPS (Dimaval) have also been shown to be effective. Guidance on administration should be obtained from the regional poisons centre for each individual case.
Metallic mercury Ingestion of metallic mercury is of no major consequence. However, intramuscular injection of metallic mercury may cause systemic toxicity, and intravenous injection has resulted in pulmonary embolus. Inhalation of mercury vapour may produce cough, retrosternal discomfort and breathlessness due to an acute pneumonitis, and flu-like symptoms such as lethargy, fever, aching limbs and arthralgia. High-dose corticosteroids may be useful if signs of lung damage are present. Signs of systemic poisoning may be an indication for dimercaprol, DMPS or DMSA.
cerebral oedema, coma and convulsions and ventricular fibrillation have also been reported. The chelating agents dimercaprol, DMSA and DMPS may reduce the severity of poisoning. Strychnine is sometimes used as a rodenticide, and has been found as an adulterant in some recreational drugs. It is rapidly absorbed by mouth and gastric lavage is contraindicated, as a convulsion may supervene during the procedure or be precipitated by the lavage. The clinical picture is similar to tetanus, with increase in muscle tone in the limbs and facial muscles, with severe spasms, muscle rigidity and exaggerated tendon reflexes. Twitching of muscles precedes the onset of convulsions, which may typically last between 30 seconds and 2 minutes and occur repeatedly. Convulsions may be provoked by any stimulus, including touch, pain and noise. The patient may be conscious and lucid between the convulsions. Cyanosis and death may occur during the convulsions, and most patients do not tolerate more than five convulsive episodes. The increased muscle tone can lead to hyperthermia and muscle damage (rhabdomyolysis) in severe cases. Treatment involves urgently establishing and maintaining a clear airway and ensuring adequate ventilation. This may be difficult if muscle tone is increased or convulsions are occurring, and it may be necessary to paralyse the patient before an endotracheal tube can be inserted and the patient ventilated. The patient should be kept at absolute rest and any stimuli that may precipitate further convulsions should be avoided. Sensory stimuli should be minimized by nursing in a darkened room; convulsions should be treated with diazepam. In severe cases neuromuscular blockers may be needed to paralyse the patient while ventilation is supported mechanically.
RODENTICIDES Many rodenticides contain warfarin or related coumarin anticoagulants and, unless taken in huge amounts, generally cause few symptoms. If the INR does rise, vitamin K should be administered as for warfarin overdose. Alphachloralose is a CNS stimulant that can cause coma, convulsions and rhabdomyolysis in overdose. Treatment consists of managing the complications. Fluoride salts may be associated with severe toxicity, sometimes delayed in onset, including abdominal pain and diarrhoea, with hypotension and peripheral circulatory failure. Hypocalcaemia and hypomagnesaemia cause muscle spasms, weakness, convulsions and cardiac arrhythmias including ventricular fibrillation. Coma and respiratory failure may supervene. Treatment is symptomatic and supportive. Arsenic is sometimes used as a rodenticide as well as a component of some timber (tannalizing) preservatives. Abdominal pain and vomiting precede the onset of profound (sometimes bloody) diarrhoea. Hypotension,
1
POISONOUS PLANTS AND FUNGI Although the number of plants that have been suggested to be poisonous is very great, many of these contain only small amounts of toxins and generally do not cause severe poisoning. They can be classified into those: • • • • • • • • •
producing cholinergic (nicotinic) stimulation producing cholinergic (muscarinic) stimulation with anticholinergic activity with gastrointestinal activity with effects on the heart with convulsant activity with hallucinogenic effects with dermatological effects with toxicity on other organs.
Plants with cholinergic (nicotinic) activity Alkaloids similar to nicotine are found in hemlock (coniine) and laburnum (cytisine). Nausea and vomiting
39
may be followed in severe poisoning by confusion, hallucinations, convulsions, and finally coma and respiratory arrest. Treatment for severe poisoning is as for nicotine. The stomach should be emptied and activated charcoal administered. Monitoring of fluid and electrolytes and adequate replacement therapy, together with measures to assist the respiration and cardiovascular functions, are generally only necessary in severe poisoning (rarely caused by laburnum).
Plants with cholinergic (muscarinic) activity Plants with cholinergic activity include the clitocybe and inocybe fungi. Ingestion produces increased perspiration, abdominal pain and visual disturbances. Treatment is with atropine, 1.2mg intramuscularly, repeated if necessary.
and delphinium may cause bradycardia and muscular weakness.
Plants with convulsant activity Cicuta viirosa (cowbane) and Qenanthe crocata (hemlock water dropwort) contain potent alcohols with effects similar to picrotoxin in antagonizing the CNS inhibitory effects of y-amino butyric acid. In severe cases nausea, vomiting and hypersalivation are followed by convulsions and respiratory failure. Convulsions can be controlled with either short-acting barbiturates or diazepam; respiration may require support until the effects of the toxin wear off. Strychnine is found in the seeds of the tree Strychnos nux vomica, native to India. Features and management are described under rodenticides (page 39).
Plants with hallucinogenic effects Plants with anticholinergic activity Plants with anticholinergic activity include the deadly nightshade (Atropa belladonna}, the thorn apple and henbane. In addition to atropine these plants may contain hyoscine and hyoscyamine. The symptoms are similar to those caused by drugs with anticholinergic activity (e.g. tricyclic antidepressants) and management is supportive.
Plants with gastrointestinal toxicity Oxalates present in some plants can cause local gastrointestinal irritation and painful ulceration of the mouth if chewed by children. These include the household plants dumb cane (Dieffenbachia) and some of the Monstera and philodendron species. Other plants contain irritant resins and saponins (e.g. arum, yew, bryony and Daphne mezereum), which can cause severe vomiting and diarrhoea. The beans of the Abrus species (e.g. Ricinus and Robinia) can cause delayed gastrointestinal symptoms as they contain compounds that can impair RNA synthesis. Solanum species also produce delayed gastrointestinal symptoms: these include potatoes that have been allowed to sprout, and woody and black nightshades. Treatment is supportive, with replacement of fluids and electrolyte loss.
Plants causing cardiovascular disturbances Digitalis glycosides are found not only in the foxglove but also in lily of the valley (Convallarid). Treatment is as for digitalis poisoning. The aconitine present in the monksfoot
1
40
MCQ1.29
In addition to those anticholinergic agents with hallucinogenic effects, there are several other hallucinogens in plants and fungi. These include the psilocin and psilocybin in psilocybes (magic) mushrooms, the tetrahydrocannabinol in cannabis, and the ibotinic acid and muscimol found in Amanita muscaria. Tranquillizers may be necessary if the patient is a risk to himself or to others, and adequate supervision must be given until the hallucinations subside. Table 1.13 lists various plants and their toxicities.
Plants that cause dermatological toxic ity Plants contain substances that can cause either direct chemical irritation (e.g. histamine and oxalic acid) or delayed hypersensitivity reactions (e.g. Primula obconica and the hogweeds, that can produce photoallergic dermatitis and several other species). Treatment is symptomatic.
Plants with toxic ity on other organs The lectins present in the seeds of Ricinus communis cause delayed gastrointestinal tract symptoms. Haemolytic anaemia may also occur, and haemoglobin precipitation in the renal tubules may cause acute renal failure. The principal lectin, ricin, is the most potent toxin known to man. Management is largely symptomatic and supportive. The beans of Ricinus communis are also highly allergenic and may cause anaphylaxis. Severe liver damage can also be caused by the phallotoxins and amatoxins found in Amanita phalloides and some of the other Amanita fungal species. Cooking or drying does not destroy these toxins. Vomiting, abdominal pain and diarrhoea often occur 6-12 hours after ingestion, and albuminuria, haematuria, renal failure and liver failure may occur around 1-3 days later. Treatment consists of emptying the stomach and replacing fluid loss. Specific antidotes are of unproven value, but thioctic acid and high doses of penicillin may be of value in preventing the liver and renal damage.
Blue-green algae are actually cyanobacteria, which grow as blue-green or brown rafts or sediments, usually in stagnant water, and which produce endotoxins. Their disagreeable odour usually prevents human consumption, but deaths have occurred in cattle. In humans local irritation and allergic skin reactions may occur. Consumption of contaminated water by humans may result in acute gastroenteritis, which usually resolves in 1-2 days. Occasionally a hepatitic picture or atypical pneumonia has been reported. Treatment is normally symptomatic and supportive. O
TABU 1.13 Plants and toxicity Plant or fungus
Latin name
Toxic features
Black (garden) nightshade Blue-green algae
Solarium nigrum Microcystis/Anabaena/ Aphanizomenon/ Oscillatoria Bryonia dioica Ricinus communis Clitocybe sp. Cicuta vimsa Daphne mezereum
Gastrointestinal Hepatotoxic Dermatological
Atmpa belladona Amanita phal/oides Dieffenbachia Amanita muscaria Digitalis purpurea Heracleum mantegazzianum Conium maulatum Oenanthe cmcata Hyoscamus niger Inocybe sp. Laburnum anagroides Conva/laria Psilocybes sp. Aconitum nape/lus
Anticholinergic Hepatotoxic Gastrointestinal Hallucinogenic Cardiotoxic Dermatological
Nerium oleander Thevetia peruviana Solanum tuberosum Primula obconica Philodendron Monstera deliciosa Datura stramomium Arum maculatum Solanum dulcamara
Cardiotoxic Cardiotoxic Gastrointestinal Dermatological Gastrointestinal Gastrointestinal Anticholinergic Gastrointestinal Gastrointestinal
Taxus baccata
Gastrointestinal
Bryony (white/red) Castor oil plant Clitocybe fungi Cowbane/water hemlock Daphne/mezereon/spurge olive Deadly nightshade Death cap fungus Dumbeane/Leopard lily Fly agaric Foxglove Giant hogweed Hemlock Hemlock water dropwort Henbane Inocybe fungi Laburnum/Golden rain tree Lily of the valley Magic mushrooms Monkshood/aconite/ wolfsbane Oleander (pink) Oleander (yellow) Potatoes (sprouting) Primula obconica Sweetheart vine Swiss cheese plant Thorn apple Wild arum/cuckoo pint Woody nightshade/ bittersweet Yew
Gastrointestinal Gastrointestinal Cholinergic (muscarinic) Convulsant Gastrointestinal
POISONOUS ANIMALS
1
ADDER ENVENOMATION The adder, Vipera hems, is the only indigenous poisonous snake in western Europe. Only 50% of those bitten develop signs of envenomation, which may occur either immediately, with shock, vomiting and explosive diarrhoea, or several hours later. The initial collapse may be due to activation of the kinin system; the later shock is more often due to hypovolaemia, caused by increased capillary permeability and fluid loss into the swollen limb, and direct cardiotoxicity of the venom (Fig. 1.13). Management Treatment includes reassurance, as shock may be exacerbated by the fear of impending toxicity. The limb should be kept still, but a ligature should not be used unless there is likely to be a delay of more than half an hour between the patient having been bitten and transfer to hospital. If a ligature is used, it should be tight enough to prevent
Cholinergic (nicotinic) Convulsant Anticholinergic Cholinergic (muscarinic) Cholinergic (nicotinic) Cardiotoxic Hallucinogenic Cardiotoxic
FIG. 1.13 Adder bite on the finger of a child A Note the twin puncture wounds and B subsequent oedema involving the hand and arm.
41
venous return but not to obstruct arterial inflow. If there are signs of toxicity the patient should be admitted and observed for at least a day after the bite. Pulse and blood pressure should be recorded, together with urinary output and fluid losses from diarrhoea and vomiting. Local swelling should also be noted, and the white cell count, urea and electrolytes should be measured each day. The use of antivenom should be considered if hypotension persists, ECG signs occur, the white count rises markedly to above 20000/mm3 or, in an adult, severe swelling has extended up the limb within 2 hours after the bite. Anaphylactic reactions to the antivenom occur in 1 % of patients and so antivenom should only be used when the indications described above are present. A history of asthma or allergy is a relative contraindication to its use. Antivenom is given by slow intravenous infusion and is stopped at the first signs of allergic reaction. Adrenaline (epinephrine) solution must be drawn up prior to administration of the antivenom and given intramuscularly if a reaction occurs (intravenously in the case of a severe reaction). Deaths from adder bite are extremely rare but local tissue necrosis may be severe, particularly in adults.
FISH ENVENOMATION
In the UK the only venomous fish regularly found are the Weaver fish (Trachinus vipera), which is found around the coast in the summer months, and the Lion fish (an aquarium species). Both contain heat-labile venom in their spiny dorsal fins, which causes severe local pain. Hypotension, and myocardial and respiratory depression may develop. Management Treatment is to remove any barbs and clean the wound, immersing the limb in water as hot as can be tolerated without discomfort to destroy the toxin. The wound should be examined at a later stage for signs of secondary infection.
VENOMOUS INVERTEBRATES
The Portuguese man of war (Physalia physalis) is the most poisonous jellyfish found around the coasts of the UK. Its sting contains substances capable of releasing histamine and other kinins. Local pain is common, but more serious symptoms include abdominal pain, dyspnoea, hypotension, muscular paralysis and convulsions. Most other jellyfish found around the UK are harmless, but the compass jellyfish (Chrysaora hyoscella), the lion's mane (Cyanea O MCQ1.30
42
capillata) and the sea nettle (Cyanea lamarckii) can cause a sting. Management The wound should be bathed in vinegar solution (4-6% acetic acid), and any tentacles still adherent removed with forceps, a gloved hand or adhesive tape. Treatment is otherwise symptomatic.
ARTHROPOD ENVENOMATION Wasp and bee stings contain amines, kinins, peptides and enzymes that cause local pain, erythema and swelling. Systemic effects are rare unless the stings are numerous or the subject is hypersensitive, in which case even a single sting may kill. Initial symptoms are generalized urticaria, flushing, dizziness, bronchospasm, collapse and coma. Serum sickness may occur after a week or more. Management The sting of the bee should be removed by flicking or scraping, taking care not to squeeze it and inject more venom. Severe pain may respond to local anaesthetic or aspirin. Swelling may respond to antihistamines and corticosteroids. Anaphylaxis should be treated immediately with adrenaline (epinephrine) (0.5-lmL of a 0.1% solution intramuscularly for an adult and 10|ig/kg for a child). The dose may be repeated every 10 minutes if necessary. Stings in the mouth, even in patients who are not hypersensitive, may cause severe respiratory tract obstruction. In allergic individuals, specific venoms have been used in increasing doses to produce desensitization.
POISONOUS SEAFOODS
Seafood may contain bacteria (e.g. Vibrio, Salmonella) or viruses (e.g. hepatitis A); toxicity may also occur as a result of contamination by dinoflagellates or decomposition by bacteria. Antemortem infestation by dinoflagellates of certain subtropical fish (such as groupers and snappers) may occur, but contamination usually involves shellfish, such as mussels, oysters, scallops and clams. The dinoflagellates contain neurotoxins (e.g. saxitoxin) which can cause nausea, vomiting and diarrhoea, followed by circumoral paraesthesiae, ataxia, muscular weakness and, in severe cases, respiratory paralysis. Treatment is symptomatic, with respiratory and cardiovascular support. Postmortem contamination of some oily (dark-meat) fish, such as mackerel, skipjack and tuna, sardines and pilchards, by Proteus bacteria may result in the production of histamine and other unidentified toxins that produce urticaria, flushing, abdominal pain, nausea, vomiting and diarrhoea and, in some cases, bronchospasm. This 'scombroid fish' poisoning occurs around 4 hours after ingestion,
generally lasts only a few hours and is seldom severe. Treatment is symptomatic. Prevention involves keeping the raw fish frozen or on ice to prevent decomposition by bacteria.
POISONING BY METALS IRON Although mortality from iron poisoning has fallen in recent years, it remains one of the most dangerous metals in overdose. Children are particularly sensitive to its effects. Abdominal pain, nausea and vomiting are often followed by gastrointestinal bleeding, encephalopathy, metabolic acidosis, pulmonary oedema, coma, shock, acute renal and liver failure. Doses of elemental iron of more than 150mg/kg body weight produce severe and possibly fatal toxicity. A serum iron level greater than 5mg/L (90 pmol/L) within 4 hours of the overdose is associated with an increased likelihood of severe poisoning. Coma and shock are manifestations of severe toxicity.
Management The stomach should be emptied if more than 60mg/kg has been ingested within the previous hour. Radiography of the abdomen in the first 2 hours may reveal whether or not iron tablets have been taken. Blood should be taken for urgent measurement of serum iron concentration. If coma or shock develop, desferrioxamine should be considered immediately without waiting for the serum iron result. The dose is 15mg/kg body weight/hour for 5 hours. It often causes hypotension if infused more rapidly than this, and can occasionally cause rash and anaphylactic-like reactions. Pulmonary oedema and ARDS have been reported in patients treated with more than 80 mg/kg/day for longer than 24 hours. With prompt treatment the mortality should be less than 5% in severe cases. 1
HEAVY METAL POISONING Heavy metals can cause acute or chronic symptoms,
SUMMARY 15 Iron poisoning • Children are particularly sensitive to the toxicity of iron • Abdominal pain, nausea and vomiting may be followed by gastrointestinal haemorrhage, encephalopathy and renal and hepatic failure • Severe poisoning is normally associated with plasma concentrations around 4 hours after ingestion of more than 5mg/L, with CNS signs and shock • Intravenous desferrioxamine should be given as soon as possible in severe iron poisoning
depending on the dose and duration of exposure. Acute ingestion of most heavy metals will cause gastroenteritis. Generalized convulsions may also be seen, particularly with lead poisoning, and renal failure and cardiac arrhythmias have also been recorded. Inhalation of heavy metal fumes may cause chemical pneumonitis and, in severe cases, pulmonary oedema, and a syndrome known as 'metal fume fever' may occur several hours after the inhalation of some metallic oxides. Chronic effects of heavy metal exposure are similar but milder. Chronic gastrointestinal symptoms and CNS effects occur, particularly after exposure to lead, manganese and mercury. Lead, thallium, bismuth and arsenic can also produce peripheral neuropathy, and gold, lead, cadmium and mercury may cause renal damage. Inhalation of heavy metal fumes can cause pulmonary fibrosis, particularly with beryllium, cadmium, tungsten, titanium and cobalt. An emphysematous picture has been seen with cadmium, and an asthma-like syndrome may occur as a result of sensitivity to chromium, vanadium and platinum. Nickel, chromium, cobalt, platinum and beryllium may also cause skin sensitization and subsequent dermatitis. Taking a full occupational history helps diagnosis. Clinical examination may reveal specific signs of poisoning, such as the blue line on the gums in chronic mercury poisoning or the raindrop pigmentation of the skin in arsenic poisoning. Toxicological examination of the urine, blood, or hair and nail clippings may also help, but this often has to be performed in specialized centres.
1
Management Treatment consists of preventing further exposure to the heavy metal, treatment of the complications of poisoning, and chelation therapy to enhance the elimination of the metal already absorbed. It must be remembered, however, that most chelating agents are toxic and should only be used when their benefits are likely to outweigh the risks of their use. Sodium calcium edetate is the treatment of choice for lead poisoning. It must be given by slow intravenous infusion. Dimercaprol, DMSA and DMPS are effective in severe mercury and arsenic poisoning. Finally, Prussian blue has been used successfully in the treatment of thallium poisoning.
FURTHER READING British National Formulary. British Medical Association and Royal Pharmaceutical Society of Great Britain, published biannually. An excellent reference text and practical guide to prescribing, with useful tables to prescribing in special circumstances and drug interactions. Laurence D R, Bennett P N 1997 Clinical pharmacology, 8th edn. Churchill Livingstone, Edinburgh. Highly readable, with a practical therapeutic flavour. Ritter J M, Lewis L D, Mant T G K 1998 A textbook of clinical pharmacology, 3rd edn. Edward Arnold, London. A practical guide to clinical pharmacology and drug therapy.
43
This page intentionally left blank
2
Heat cramps
Physicaland
Environmental Disorders
Spasms of painful muscular contraction may occur with sudden rises in temperature during strenuous activities such as long-distance running, or during work in very hot environments. Muscles of the legs and arms are usually affected, typically after the exertion or heavy work is over. There is usually hyponatraemia, and severe cramps may be accompanied by a rise in creatine phosphokinase and evidence of rhabdomyolysis. Part of the pathogenesis appears to be due to replacement of fluid and salt loss by water with too low a salt content; the condition is preventable by drinking fluids containing 0.25% saline.
2
Heat exhaustion John Moxham and Robert L Souhami
Disorders due to heat and cold 45 Whole body radiation exposure 47 Disorders due to extremes of barometric pressure 49
Submersion and drowning 51 Electric shock 53 Smoke inhalation 54 Chemical warfare 54
DISORDERS DUE TO HEAT AND COLD Heat produced by metabolism is lost mainly through the skin and, to a lesser extent, through the gut, urine and breath. Inadequate heat loss leads to sweating and vasodilatation. Cold produces cutaneous vasoconstriction and shivering, which results in increased muscle metabolism and heat production. In moving from a cold to a hot climate, acclimatization occurs over a period of 1-2 weeks; this process is not well understood. There is increased sweating and the salt content of sweat diminishes. Aldosterone secretion increases, at least at first, causing a low urinary sodium with loss of potassium. A progressive rise in temperature above 38-39°C causes irritability and mental confusion. At temperatures above 40-41°C vascular, renal and hepatic damage occur.
HEAT EXCESS Three syndromes due to excess heat occur: heat cramps, heat exhaustion and heatstroke.
Heat exhaustion or heat collapse is the commonest syndrome and is especially likely to occur in individuals exposed to a hot environment for a few days. The very young and the elderly (especially those on diuretics) are particularly at risk. The syndrome is due in part to salt and water loss, and in part to a failure of circulatory adaptation to heat. When water loss predominates, there is intense thirst and weakness, agitation and confusion. Water depletion is more likely to occur in acclimatized people (whose sweat contains less salt). The plasma Na+ and Cl~ rise. With salt depletion, there are muscle cramps, headaches, vomiting and myalgia. Haemoconcentration occurs with a rise in haematocrit and blood urea. Usually, salt and water depletion occur together, and the patient has a normal temperature and appears pale and clammy. The disorder is treated by rest and oral fluids. In water depletion (where plasma sodium is elevated) this should be with water. Typically 5-8 L may be given in 24 hours by mouth or as i.v. glucose. When salt depletion is present the oral fluids should contain salt (e.g. 5L of fluid with 20 g salt).
Heatstroke Heatstroke is a serious and sudden disease which may be fatal unless treated urgently. It is caused by a failure of thermoregulation, resulting in a rapid rise in body temperature. In normal individuals it is usually due to exercise or work in a hot, humid environment. When it occurs in sedentary individuals the patient is usually elderly, often with underlying disease such as cardiac failure, diabetes (with autonomic dysfunction), obesity or alcoholism. Atropine-like drugs, p-blockers, phenothiazines and diuretics predispose to the syndrome. Heatstroke can also occur in fit men working in hot environments, and there are some clinical differences in these cases. Typically the patient develops headache, dizziness and faintness, and abdominal pain and delirium may occur. Sweating stops and the body temperature rises rapidly (and may reach 43°C). Hypotension, renal failure and
45
rhabdomyolysis may occur; the latter is especially common in heatstroke following severe exertion. In this form of heatstroke sweating may continue. On examination the skin is hot and usually dry, and the patient exhibits tachypnoea and flaccidity. Coma and shock are grave signs. The blood shows leukocytosis and respiratory alkalosis (but may be acidotic in the exertional form), the urea is raised, and hypokalaemia and hyperphosphataemia occur. Myocardial necrosis may give ST changes and even an infarction pattern on the ECG. Liver function tests are abnormal, and acute renal failure may occur. Disseminated intravascular coagulation is present in mild degree in the elderly, but may be severe in exertional heatstroke. Management Treatment is urgent. The patient must be cooled as quickly as possible. The most effective way is immersion in cold water, the skin being rubbed to increase the efficiency of cooling. An alternative is to blow cold air over dampened skin. Core temperature must be monitored using a rectal thermometer. Hypotension can be treated with small quantities of saline, taking care to avoid circulatory overload. Hypoglycaemia, if present, can be treated with glucose, and severe acidosis by sodium bicarbonate. More serious complications, such as acute renal failure and disseminated intravascular coagulation, are treated in the usual way (Chs 20 and 23). Cerebellar degeneration may occur, and coma with cortical damage is a terminal event. 1
SUMMARY 1 Clinical features of heatstroke Symptoms • Headache • Dizziness/faintness • Abdominal pain Signs • Increased body temperature • Hot, dry skin (sweating may be absent) • Tachypnoea • Flaccidity • Hypotension • Delirium -> shock/coma Results/complications • Hepatic and renal failure • Leukocytosis, alkalosis/acidosis, hypokalaemia • Rhabdomyolysis • Myocardial necrosis • Disseminated intravascular coagulation • Cerebellar degeneration • Coma, cerebral damage
as 'ecstasy'. Muscle contraction begins after the start of anaesthesia, and body temperature rises rapidly. The anaesthetic must be stopped, the patient cooled and ventilated, and i.v. dantrolene sodium given (2-10mg/kg). Acidosis should be treated. 0
HYPOTHERMIA
Neuroleptic malignant syndrome This syndrome is characterized by muscle rigidity giving rise to hyperpyrexia, tachycardia and impaired consciousness. It is an idiosyncratic reaction to drugs that block dopaminergic transmission, such as phenothiazines and butyrophenones. The increase in muscle tone develops over 12-72 hours. Death from respiratory failure may occur. Treatment is by muscle relaxants, including neuromuscular blocking agents, and ventilation if necessary. Recovery may take several days.
Significant hypothermia is an uncommon problem mainly affecting the elderly, in whom the response to cold may be defective (p. 178). Hypothermia contributes to the excess mortality in this population during winter months. It is defined as being present when the deep body temperature falls below 35°C. As the mouth temperature may fluctuate depending on the ambient air temperature, it is best to use a rectal thermometer when monitoring hypothermic patients. A low-reading thermometer is necessary. The rectal temperature is about 0.5°C higher than oral.
Malignant hyperpyrexia
Aetiology
This is an autosomal dominant disorder in which hyperpyrexia is produced by skeletal muscle contraction following anaesthetic agents such as halothane and suxemethonium and local anaesthetics. It can also occur with drugs such as amphetamines and derivatives such
Hypothermia may be due simply to an age-related impaired thermoregulatory response to a cold environment (Ch. 7, p. 178). In the majority of patients, however, there is an associated underlying pathological cause, including any cause of autonomic dysfunction (p. 178). Hypothyroidism and hypopituitarism are both associated with hypothermia, and the risk is also higher in immobile or demented patients, or in the presence of an acute illness such as bronchopneumonia. There is a clear association between phenothiazines and impairment of temperature regulation, and hypothermia may also be precipitated by sedative drugs, such as hypnotics and alcohol. Although
1
46
Case 2.1
2
MCQ2.1
3
MCQ2.2
a mild drop in body temperature is common, clinically important hypothermia is unusual. However even modest falls in body temperature may produce changes in coagulability, which may predispose to myocardial infarction. Immersion hypothermia is produced by shipwreck. Exposure to cold weather occurs in hillwalkers and climbers, especially if they have not eaten or if they drink alcohol.
Clinical features Hypothermic patients typically live alone in poor housing and have impaired mobility. A typical case would be that of an old person who gets out of bed in the middle of the night to go to the lavatory, falls, and then lies all night on the cold floor in thin nightclothes until discovered the next morning by a neighbour. The skin has a greyish look owing to a combination of vasoconstriction and cyanosis; the face may appear puffy, resembling myxoedema. The diagnosis is often first suspected during examination, when it is found that the patient's skin feels cold in normally warm areas, such as the axilla or the abdomen. There may be ataxia and slow mental response. The patient is often confused when the temperature falls below 35°C, and drowsiness and loss of consciousness occur when the temperature falls below 29-33°C. Shivering is absent below this temperature; instead, there is increased skeletal muscle tone with neck stiffness and abdominal rigidity. The heart rate is slowed and the ECG may show a prolonged PR interval and J waves (Fig. 2.1). Respirations are slow and shallow, and there may be hypoxia and hypercapnia. Hypoxia is exacerbated by a shift of the oxygen dissociation curve to the right, leading to impaired release of O2 from haemoglobin. Acute pancreatitis is often found at necropsy, but this is only rarely diagnosed in life. Impaired renal and respiratory function may lead to a raised blood urea or bicarbonate. Blood sugar levels may be raised, but do not indicate diabetes mellitus, and will fall as the temperature returns to normal. Serum asparate aminotransferase and creatine kinase may be raised due to muscle damage.
Management The lower the deep body temperature, the higher the mor-
SUMMARY 2 Clinical features of hypothermia • • • • • • • •
Contusion/impaired consciousness Cold, greyish skin Shivering absent Increased skeletal muscle tone Slow heart rate, prolonged PR interval and J waves Slow, shallow respiration, hypoxia and hypercapnia Raised blood urea or sugar levels Raised serum asparate aminotransferase and creatine kinase
2
tality (about 50% overall). This is because many hypothermic patients have a serious underlying illness. Patients with mild hypothermia (core temperature 32-35°C) should be wrapped in a space blanket and nursed in a side ward where the ambient temperature is 28-30°C. Their temperature should be allowed to rise gradually, at a rate of about 0.5°C per hour, as fast surface rewarming carries the risk of hypotension. For this reason, the patient's pulse and blood pressure must be monitored. If the blood pressure drops, the space blanket should be removed or the room temperature lowered so that the patient is temporarily cooled. Intravenous fluids are hazardous and may produce acute pulmonary oedema. A broad-spectrum antibiotic is usually given parenterally because bronchopneumonia is nearly always present, even if not clinically apparent. The ECG should be monitored, as both bradyarrhythmias and ventricular fibrillation may occur. The patient is at serious risk of developing a pressure sore and must be nursed on a suitable mattress and turned regularly. When the deep body temperature is below 32°C a more aggressive approach to resuscitation is sometimes advocated, although there is little evidence that this reduces mortality. These measures include positivepressure ventilation to correct hypoxia, measurement of central venous pressure, and active rewarming using a radiant heat cradle over the torso or warmed intravenous fluids.
Thyroid hormones should not normally be given to hypothermic patients. If there is good clinical or laboratory evidence of hypothyroidism, then triiodothyronine (5ug) may be given by slow intravenous injection every 12 hours. A particular problem is presented by patients who have become hypothermic as a result of immersion at sea. They may develop ventricular fibrillation on rescue if they exert themselves. They should therefore be kept still and rewarmed slowly. 3
WHOLE BODY RADIATION EXPOSURE
FIG. 2.1 Electrocardiogram showing J wave (arrowed) in a hypothermic patient
There are two broad types of ionizing irradiation: photons (y and X-rays) and particulate (a and |3 particles). Radiation dose is defined in a variety of ways. The energy
47
deposited in a tissue is measured in grays (Gy; IGy = 1 J/kg). Because different types of radiation have different tissue effects, a unit called the Sievert (Sv) is sometimes used, which weights the radiation dose according to the type of radiation. Particulate radiations are absorbed according to their mass and energy, but do not penetrate deeply into tissues (see also Ch. 6, p. 159). Particulate irradiation transfers more energy and is much more ionizing than Y or X-rays.
EXPOSURE Exposure to ionizing irradiation comes about in three ways: • Background irradiation. We are exposed to approximately 2-3 mSv per year from solar and geological irradiation. Cosmic rays are mostly very high-energy protons. Secondary radiations, from the upper atmosphere, are largely y-rays. Geological irradiation is largely due to radon. • Medical exposure. The therapeutic uses of ionizing irradiation are described in Chapter 6. Accidental exposure of patients or staff has been rare since the advent of stringent precautions following the radiation-induced damage to skin and eyes in the early days of therapeutic and diagnostic radiation. Exposure to whole-body radiation forms part of the treatment of leukaemia and lymphoma. The resulting bone marrow suppression is treated by allogeneic (or autologous) haemopoietic stem cell transplantation. • Military and industrial irradiation. The atomic bombs dropped on Hiroshima and Nagasaki led to numerous cases of acute leukaemia and other cancers. Fallout from nuclear tests has increased annual background radiation by 1%. Industrial exposures also occur, the most dramatic example of which has been the ingestion of radium by radium dial painters from 1916 to 1926, resulting in a great increase in risk of bone sarcoma and cancer of the air sinuses of the skull. The accident in the Chernobyl nuclear power station in 1986 resulted in many deaths due to acute radiation exposure, and an increase in background radiation over a wide geographical area.
TISSUE DAMAGE The tissue-damaging effect of ionizing irradiation is probably related mainly to damage to DNA, leading to strand
1 48
MCQ2.3
breakage and impaired reproductive integrity of the cell. At 0.1 Sv total body exposure there is a slight fall in blood lymphocyte count. At ISv there may be mild radiation sickness with slight nausea and a more profound lymphopenia, and a fall in neutrophils and platelets 2-3 weeks after exposure. Following greater degrees of whole-body exposure certain tissues are damaged acutely by relatively low doses: • Bone marrow. This can regenerate after exposure to 10 Gy, but above this dose permanent aplasia may occur. The white count and platelet count begin to fall within 10 days of exposure. • Intestine. Doses of 10 Gy or over cause severe loss of crypt cells, leading to loss of villi and extensive ulceration. The onset of nausea and vomiting is 1-2 hours after exposure, often recovering a few hours later, but above 10 Gy permanent and fatal damage to the gut occurs, with death in 4-14 days. Death is due to severe diarrhoea, consequent salt and water depletion, and severe Gram-negative sepsis. • Skin. Erythema occurs at doses below 10 Gy. At 20 Gy the skin starts to desquamate and ulcerate. • Lung. Above l0 Gy in a single fraction pneumonitis occurs, and is increasingly severe with increase in dose. Long-term changes include glomerular loss and interstitial nephritis, infertility, pulmonary fibrosis, neuronal loss and gliosis, intestinal stricture and hepatic fibrosis. After acute radiation exposure (such as at Chernobyl and Hiroshima) there is an increased risk of leukaemia at 5-10 years. The safe lower limit is not easily quantifiable but is probably below l0c Gy. Solid tumours may also occur, including bone cancer in radium dial painters, skin cancer, and lung and breast cancer. The risk of solid tumours appears to be 1 in 2000 following total body exposure of 1-2 cGy.
Clinical features After acute whole-body exposure, the clinical features depend on the received dose. Following an initial period of nausea and vomiting (sometimes with parotid swelling), the patient may be relatively well for 7-10 days and then develop a syndrome of haematological failure. There is depression of the white count and platelets, with infection, bruising and bleeding. At the same time skin reactions occur, with desquamation, alopecia and ulceration. If the whole-body dose is above 15 Gy the gastrointestinal syndrome may predominate and be the first sign of toxicity. In a patient with severe leukopenia severe diarrhoea and fluid loss are followed by septicaemia from gut bacteria. This is almost always fatal. Higher doses of whole-body radiation (25-60 Gy) cause cardiovascular collapse and shock.
Management Management is supportive. Antiemetics are given in the acute phase, and fluid losses from diarrhoea are replaced. Transfusion of blood and platelets and intensive antibiotic treatment for gut derived organisms are used during the phase of myelosuppression and infection. Haemopoietic growth factors such as GCSF may be of value. Allogeneic bone-marrow transplantation may help the minority of patients for whom there is a donor, and in whom the haematological toxicity is the major life-threatening complication. It is of no value if the major toxicity is in organs such as the lungs or gastrointestinal tract. Accidental exposure to radionuclides is treated according to the isotope. Potassium iodide is given for I31 I ingestion, and soluble phosphate for 32P overdose. Overdose with bone-localizing isotopes (caesium, radium, strontium) is treated with EDTA and large doses of oral calcium. There has been some interest in drugs that limit damage from radiation: unfortunately, these have to be given before or immediately after exposure. The best known is ethyol, which may also protect normal tissues from cytotoxic drug damage. Late effects occur 3-10 years after exposure. There is an increased risk of acute myeloid leukaemia. The risk of solid tumours is about 1 in 2000. Tumours include cancer of skin, breast and lung. This is a small increase compared to the background incidence in the population.
height. Commercial aircraft are maintained at a pressure equivalent to 2500 metres, so that no additional oxygen is needed unless a patient has severe cardiac or respiratory disease. If there is a loss of pressurization, extra oxygen is made available through masks. Acclimatization to altitude is a complex process. On rapid ascent the relative hypoxia stimulates ventilation, but this stimulus diminishes over a few weeks. This hyperventilation diminishes Paco2, with the consequent development of a respiratory alkalosis. The respiratory centre appears to adapt to a lower Paco2. The acute circulatory adaptation consists of a rise in cardiac output, a fall in renal, cardiac and cutaneous blood flow, and a rise in cerebral blood flow. These changes slowly reverse, and after several weeks cardiac output on exercise is lower than at sea level. The red cell mass increases greatly and with it the total oxygen-carrying capacity of the blood. The oxygen dissociation curve does not shift substantially (as the alkalosis shifts it to the right and the hypoxia to the left). There is an increased formation of tissue capillaries, greatly increasing tissue oxygenation. There are four recognized syndromes of altitude sickness: • • • •
2
Acute altitude sickness Acute pulmonary oedema Acute cerebral oedema Chronic altitude sickness.
Prognosis With adequate treatment, most patients will survive acute exposures up to 10 Gy. Above this dose, bone-marrow failure and the intestinal syndrome are usually fatal. 1
DISORDERS DUE TO EXTREMES OF BAROMETRIC PRESSURE
ALTITUDE SICKNESS The effects of reduced barometric pressure result from the low partial pressure of oxygen and reduced oxygencarrying capacity of the blood. Figure 2.2 shows this relationship. The barometric pressure at sea level is 100 kPa, and the partial pressure of oxygen is 21% of this, i.e. 21 kPa. At 5500 metres the barometric pressure is reduced to 50% (50kPa). The partial pressure of oxygen is, however, less than 20% of this (l0kPa) because the proportion of water vapour rises. Because of the sigmoid shape of the oxygen dissociation curve, oxygen saturation is reasonably well maintained until an altitude of 5000 metres. A precipitous fall in saturation then occurs with increasing
FIG. 2.2 Effect of altitude on alveolar Pao2 and oxygen saturation Because of the steep slope of the oxygen dissociation curve, increasing altitude above 5000 metres causes a precipitous fall in saturation. In an unacclimatized person, acute changes occur at: IT1 3000 metres (10000 feet) - slightly impaired memory and judgement, increased heart rate, abdominal cramps and nausea; [B] 3500 metres (12000 feet) - headache, nausea, diminished visual acuity, and possible pulmonary oedema; [C] 5500 metres (18000 feet) - impaired consciousness after several hours in many people; and [D] 6750 metres (22000 feet) - loss of consciousness.
49
Acute altitude (mountain) sickness This syndrome occurs in unacclimatized individuals who ascend rapidly to heights in excess of 2500 metres. People who are unfit, or very young, or those who have respiratory or cardiac disease, are especially prone. The symptoms usually begin at 12-24 hours after ascent. Lightheadedness is followed by lethargy irritability and severe headache, usually occipital in position. Other symptoms include nausea and vomiting, dyspnoea with periodic respiration, and abdominal pain. Physical examination reveals little, although ataxia (shown by walking heel to toe) may be present. The cause of acute altitude sickness is unknown. It is possible that the hypoxia causes mild cerebral and brainstem oedema. This is suggested on MRI scans and by multiple petechiae in the brain in fatal cases. The syndrome is preventable by slow ascent. Individual susceptibility varies greatly and mountainous hikes and climbs should never put pressure on participants to ascend rapidly, especially if they start to feel unwell. When starting an ascent above 3000 metres a reasonable pace is 300m/day, resting for a day every 3 days. Even this may be too fast for some people. Dehydration should be avoided, and a good diet maintained. Treatment is to avoid sedatives, to take mild analgesics for headache, and if the symptoms do not abate, to descend to 1000m to await recovery. Acetazolamide can alleviate the symptoms of acute altitude sickness by acting as a respiratory stimulant, lowering the Paco2 and raising the Pao2. If ascent cannot be made slowly it may be advisable to start acetazolamide (250 mg b.d.) before ascent, and climbers should be warned of the side-effects, particularly paraesthesiae. Acute pulmonary oedema Rapid ascent to heights greater than 3000 metres may provoke the sudden onset of acute pulmonary oedema. Hypoxia is the cause, but the pathogenesis is unclear. The symptoms usually begin 5-36 hours after ascent; acute dyspnoea, haemoptysis and widespread crackles in the lungs occur. Pathologically there is acute oedema and a 'hyaline' membrane in bronchioles. Treatment is with urgent evaluation to a lower altitude, oxygen and diuretics. Nifedipine has been shown to be useful prophylactically in those who have had a previous episode of pulmonary oedema. Acute cerebral and retinal oedema Acute hypoxia increases cerebral blood flow and intracranial pressure, and can cause cerebral oedema. This is asso-
50
1
Fig. 2.1
4
Fig. 2.2
2 Case 2.2 3 MCQ 2.4
ciated with headache and brain dysfunction. The patient may be incoherent, drowsy, ataxic, and progress to coma. There may be papilloedema. Deepening coma leads to death. The treatment is urgent descent to a lower altitude and oxygen. Dexamethasone (i.v.) should be given. Cerebral and pulmonary oedema often accompany each other. Many people ascending to high altitude develop asymptomatic retinal haemorrhage.1 Occasionally this may leave a permanent blind spot. Oedema of the retina is assumed to be the cause. Retinal oedema occurs in the absence of cerebral oedema. Pink optic discs and retinal haemorrhage are not in themselves a reason for urgent descent.
Chronic altitude (mountain) sickness Individuals (usually middle-aged men), who have lived for many years at altitudes above 4000 metres may develop polycythaemia and a chronic insensitivity of the respiratory centre to hypoxia. Such individuals hypoventilate and develop a raised Paco2. There is central cyanosis, with cough, headache and giddiness. Patients are cyanosed, with vascular conjunctivae and finger clubbing. There may be RV strain on ECG as a result of pulmonary hypertension. The CNS symptoms are similar to those of polycythaemia rubra vera and are due to decreased cerebral blood flow (a consequence of the raised haematocrit) and hypoxia. Not all people living at high altitude develop this syndrome, which appears in part to be an excessive response to decreased inspired Pao2. The syndrome can only be treated by permanent descent to a lower altitude.
INCREASE IN BAROMETRIC PRESSURE
An increase in barometric pressure is encountered in diving or in mining.
Breath hold diving During a breathhold dive the body directly encounters the increased pressure (1 atm for every 10 metres descent). The breathhold causes a rise in Paco2 and a fall in Pao2. The main respiratory stimulus is the raised Paco2, so that hyperventilation before diving leads to a lack of stimulus to breathe (owing to CO2 depletion). This may cause fatal loss of consciousness from hypoxia (which does not cause an irresistible urge to breathe and thus terminate the dive). As the diver surfaces, decompression lowers Pao2 and again may cause loss of consciousness.
Lung rupture, air embolism, pneumomediastinum During a breathhold dive the air in the lung is compressed and re-expands to its previous volume on ascent, with no risk of lung rupture. If a diver breathes air below the surface he must allow time for the excess air under pressure to be exhaled or the lung may rupture. Divers are taught not to ascend more rapidly than the gas they exhale. A diver breathing air may hold his/her breath while ascending rapidly, without breathing out. This often happens if the diver has accidentally lost the air supply. During the rapid ascent the lung may rupture. Lung rupture may be into the mediastinum or into the pleural space, causing pneumomediastinum and pneumothorax, respectively. The symptoms are breathlessness, cough and haemoptysis during the ascent. Air embolism may occur and cause dysphasia, paralysis, visual disturbance or convulsions. Mediastinal air may cause dysphagia and surgical emphysema in the neck. Treatment is with 100% oxygen to eliminate inert gas, and recompression.
Deep diving, decompression sickness In deep diving the gas must be delivered at the same pressure as the surrounding water. If the gas is air, the high pressure of N2 causes mental confusion below 50 metres. Helium/oxygen mixtures are better tolerated and descents as low as 700 metres can be undertaken. These mixtures must be used below 50 metres. At greater depths than 700 metres neurological disturbances occur owing to the high gas tensions. Very high oxygen concentrations in the inspired gas (even though they reduce inert gas narcosis and the risk of decompression sickness) are toxic to the lung and CNS. This toxicity is related to the level of inspired Pao2 and the duration of the dive, and must be carefully regulated. When breathing air, the nitrogen dissolved in blood (PaN2) increases and, on rapid decompression, forms bubbles, which come out of solution in small blood vessels. Ischaemia results, causing pain in joints, spinal cord injury, chest pain, cyanosis, confusion, visual defects, paralysis and fits. Minor confusion occurs with lesser degrees of compression injury. Treatment is by recompression, followed by very gradual decompression over days. Some instances of air embolization during diving occur in individuals who shunt blood from the right atrium to the left via a patent foramen ovale. About 25 % of the population have minor degrees of patency of the foramen ovale. Figure 2.3 shows the relationship between depth, duration of dive and the need for controlled ascent to the surface. QQ
REFERENCE Bennett PB. Elliott DH (eds) 1993 The physiology and medicine of diving. WB Saunders, London.
2
FIG. 2.3 Relationship between depth, duration of dive and need for controlled ascent to the surface
SUBMERSION AND DROWNING Drowning is a relatively common cause of accidental death, particularly in children, in whom only motor accidents and cancer are more common causes of death. In adolescents and adults, alcohol and drugs are frequently a contributory factor. Spinal injury is a relatively common problem, particularly after submersion following diving. There are considerable differences in the osmotic pressure of salt water (5% NaCl), fresh water (0% NaCl) and plasma (0.9% NaCl). It has been suggested that when large amounts of salt water are aspirated into the lung, water may be sucked into the alveoli from pulmonary capillary plasma, causing death from pulmonary oedema.4 When fresh water is aspirated, however, large volumes may pass into the pulmonary circulation, causing haemolysis and consequent potassium release, which may lead to cardiac arrest. In fact, in both cases death can result from acute reflex laryngospasm, causing asphyxia. The differences between submersion in fresh and salt water are probably trivial; the major factors determining survival are the duration of submersion and the severity of the consequent hypoxia.
RESUSCITATION FROM NEAR-DROWNING A patient who is nearly drowned needs urgent resuscitation. The basic techniques are the same as for any 'sudden death', but the physiology of drowning raises special issues. In both fresh- and sea-water drowning gastric aspiration must be performed once a cuffed endotracheal tube is in place. Large volumes of water tend to be swallowed during submersion, and vomiting during resuscitation is common.
51
Similarly, once in hospital, ventilation with positive endexpiratory pressure is required in an attempt to reinflate atelectatic and waterlogged lungs. Acute respiratory distress syndrome (ARDS) is a complication. Hypothermia is frequently an associated problem and septicaemia is a common complication. Defibrillation for VF or VT is less effective in severe hypothermia. Patients who are breathing and coughing have a good prognosis (Table 2.1). Sea-water drowning can be associated with cardiac arrest produced by the rapid absorption of Ca2+ and Mg+ into the blood. Treatment by basic life support is frequently effective in sea-water drowning, if begun within 5 minutes. Fresh-water drowning may produce massive intravascular haemolysis, associated with ventricular fibrillation and
TULEJh Mortality following submersion Mortality (%)
Grade
Definition
1
Normal lung auscultation with coughing Abnormal auscultation, with crackles in some regions Auscultation: acute pulmonary oedema, no hypotension Acute pulmonary oedema, plus hypotension Isolated respiratory arrest Cardiopulmonary arrest
2 3 4 5 6
0 0.6 5.2 19.4 44
93
Modified from Szpilrnan
CASE STUDY 2.1 SUBMERSION AND DROWNING A 26-year-old woman went for a swim with her friend at the local pool. After she had been in the water for some time swimmers at the side of the pool noticed her thrashing around beneath the surface. The onlookers and pool staff pulled her out of the water at the shallow end. She was unconscious, not breathing, and had no detectable pulse. One of the onlookers was medically qualified. Mouth-to-mouth resuscitation and chest compression was initiated and the emergency services were called. On arrival at the scene the ambulance crew documented ventricular fibrillation on the ECG, shocked the patient and restored sinus rhythm. The patient was transferred to the local accident and emergency department. On arrival in A&E the patient was breathing and had a satisfactory blood pressure. There were no signs of external trauma. The axillary temperature was 36.0°C. There was vomitus in the mouth and the patient had obstructed breathing. The Glasgow Coma Scale was 3. The patient became greatly
O MCQ 2.5
52
agitated. Arterial blood gases, breathing supplementary high-flow oxygen, showed ^302 27.3 kPa, Faco2 9.2kPa, bicarbonate 16, pH 7.07. The patient was sedated, intubated and ventilated. She was given intravenous antibiotics and steroids. Additional history obtained from her friend revealed that the patient had been depressed for some time but was not, as far as the friend knew, taking any medication. There was no past history of attempted suicide or epilepsy. Questions 1. Wharf is the prognosA for this patient? 2. On afrival it A&E, fifhat ire the most important management issues? 3. A chest X~fay was performed; what might it show? 4. What is ydur interptetatidn of the arterial blodd gas results? For the next few days the patient was managed in the intensive care unit.
The acid-base status returned to normal. A CT brain scan showed no abnormalities. The chest X-ray initially showed bilaterial patchy air space ©pacification, but subsequently cleared (CASE FIG. 2.1.1). Gas exchange gradually improved and the patient was extubated. Moderate hypoxia persisted; the patient was treated with CPAP and transferred to the high-dependency unit. The patient became febrile, was diagnosed as having a secondary chest infection and treated with antibiotics. One week after admission the patient's jPao2 was within normal limits. The patient was alert, mobilized, and discharged 9 days after admission. She had no recollection of the events that led up to her submersion in the swimming pool. Question 5. What would you regard as being the main factor or ,„, factors that ultimately y resulted in a good outcorne for this patient?
CASE STUDY 2.1
2
CONTINUED
CASE FIG. 2.1.1 Chest X-ray. There is bilateral air space shadowing throughout the lungs, affecting the left lung more that the right Discussion Submersion and drowning is a common cause of death in young people. The most important factor determining outcome is the severity and duration of hypoxia. Clearly, cerebral and spinal trauma may also be critical in patients who, for example, dive into shallow water. Severe hypoxia causes cardiac arrhythmias, cardiopulmonary arrest, brain damage and acute lung injury. Ventricular fibrillation and
cardiopulmonary arrest indicate a poor prognosis (Table 2.1). The most important management issues are to sustain and improve tissue oxygen delivery. This patient's ventilation was inadequate and the upper airway was compromised, hence the importance of intubation and mechanical ventilation. Hypothermia is often a severe problem, but not in this particular case. The patient was treated with steroids, ostensibly to reduce lung
hyperkalaemia, which can be difficult to treat. Survival after prolonged submersion during warm weather is unusual, but survival (with normal cerebral function) has been recorded in children, even after 30 minutes' immersion, particularly in low-temperature water. Sudden death due to a combination of vagal slowing of the heart and intense peripheral vasoconstriction may occur in previously fit individuals who dive into cold water. O
FURTHER READING Szpilman D. Near drowning and drowing classification: a proposal to stratify mortality based on the analysis of 1821 cases. Chest 1997:112:660-665.
injury, but there is little evidence to support such therapy. The chest X-ray showed bilateral airspace shadowing consistent with pulmonary oedema (figure). Hypoxia causes increased pulmonary capillary permeability, alveolar flooding, and can lead to established ARDS. Many patients rescued from submersion vomit and some aspirate, and atelectasis may occur. Acute laryngospasm stops large volumes of water filling the lungs and the hypoxic lung injury is the more important lung insult. The arterial blood gas results show a severe combined respiratory and metabolic acidosis (i.e. the Paco2 is raised and the bicarbonate is reduced). This reflects reduced ventilation and inadequate oxygen delivery to all tissues. Hence the crucial importance of restoring the circulation and ventilation. With appropriate therapy the acid-base abnormalities were rapidly corrected. This patient survived and avoided hypoxic brain damage because of the prompt and effective poolside resuscitation (mouth-to-mouth resuscitation, chest compression and cardioversion). Without such rapid intervention the prognosis would have been very poor.
ELECTRIC SHOCK Injury following electric shock depends on the voltage and current. Below 100 V sudden death is less likely. Alternating current appears to be much more dangerous than direct, as it produces muscle spasm and is more likely to stop the heart. The direction of flow is also important, as flow from hand to hand or hand to foot traverses the heart. At high voltage, the body heats up as the current flows. This heating is much more severe in a small cross-sectional area (fingers) than in a large one (trunk), and burns and charring are thus found mostly in the hands. The upper limbs and trunk are less affected, and deep tissues more damaged than the superficial. The skin burns do not correlate with the level of internal injury. Burns occur at the skin, and arcing of the current may ignite clothing, causing further burns.
53
Clinical features With high voltage, cardiac arrest occurs. Cardiac resuscitation is essential, as is a careful assessment for burns which may manifest themselves later. Arrhythmias may recur for up to 2 days after resuscitation. Intestinal perforation and liver and gallbladder injury may occur. There may be cerebral and spinal cord damage, and peripheral nerves may be permanently damaged. Spinal cord injury may have a delayed onset, with paraplegia or a tabes dorsalis-like syndrome. Acute muscle necrosis may result in renal failure.
Treatment After resuscitation the cardiac rhythm must be monitored for 2 days after the last rhythm disturbance. Hyperkalaemia may occur as a result of acute tissue necrosis, and may need immediate treatment with glucose and insulin or haemodialysis. Renal failure due to rhabdomyolysis must be treated. Intravenous fluids should be used to maintain urine flow, which will minimize the danger of renal failure due to massive myoglobinuria. Mannitol or a diuretic may be needed to maintain urine output. A surgical assessment must be made of burns and charring, and peripheral circulation. Debridement, fasciotomy and even amputation may be necessary. An extreme example of high-voltage injury is a lightning strike. Cardiopulmonary resuscitation is essential, as described above. Rhabdomyolysis and burns are treated in the same way as in other electric-shock injury. With effective resuscitation, over half the victims will survive.
SMOKE INHALATION
54
Smoke inhalation causes anoxia, frequently exacerbated by carbon monoxide poisoning and, if plastics are burned, hydrogen cyanide poisoning. Lung and airway injury is mainly chemical rather than thermal. Initial effects are mainly on the airways, including laryngeal oedema and bronchoconstriction; severe pulmonary oedema can develop. Factors predictive of severe injury include fire in an enclosed space, black sputum, burns around the mouth, reduced consciousness, altered voice, and symptoms and signs of respiratory distress. In fires involving plastics, carboxyhaemoglobin levels generally reflect hydrogen cyanide levels. Carboxyhaemoglobin levels should be measured in all cases and levels greater than 10% indicate significant exposure; above 25% indicates severe exposure. High CO levels cause hypoxia; the true arterial oxygen saturation is not demonstrated by pulse oxymetry, and the %CO must be subtracted from the oxymeter reading to give the correct value. Treatment is supportive, including humidified oxygen, bronchodilators and mechanical ventilation in severe cases. Steroids are useful when airways obstruction is severe and persistent. Severe hydrogen
cyanide poisoning requires treatment with sodium nitrite and thiosulphate. In patients surviving smoke inhalation injury the long-term prognosis for pulmonary function is good.
PASSIVE SMOKING Breathing other people's cigarette smoke is a much less serious cause of morbidity and premature death than active smoking, but it does represent one of the most serious causes of indoor air pollution that can affect health. Respiratory symptoms such as wheezing, coughing and the development of respiratory infections are increased in the children of smoking parents. The effect is particularly noticeable in children aged under 1 year. Various international expert committees have concluded that exposure to environmental tobacco smoke increases the incidence of lung cancer in non-smokers, the observed risk being some 30% higher than expected and contributing approximately 300 cases of lung cancer annually in the UK. There is also evidence that environmental tobacco smoke can exacerbate asthma in adults.
CHEMICAL WARFARE Chemical weapons were first used on a large scale during the 1914-18 war, and although a wide range of chemicals were subsequently developed they were not used extensively until the Iran-Iraq war. Their use, but not their possession, is banned by an international treaty. The agents most readily available are nerve gases and mustard gas (see below). Other chemical agents include lewisite, hydrogen cyanide, and riot control agents such as CS gas, phosgene and chlorine. Biological weapons such as anthrax and Botulinus toxin are also potential weapons. When the use of these weapons is threatened, protection of those involved in, or close to, the conflict with respirators and protective clothing is important. Obviously, civilian populations are very vulnerable. Rescue of casualties by medical teams may expose these personnel to risk, so they should also take preventative measures. For all casualties of poisoning by chemical and similar weapons, decontamination is essential, particularly before they are transferred to areas where unprotected staff may be working. Mustard gas (sulphur mustard) is an alkylating agent (as is nitrogen mustard). It is a 'vesicant', causing skin blistering, sloughing of respiratory epithelium, ocular damage and, in a small number of cases, subsequent bone marrow depression. There is no antidote and the treatment is supportive, including careful management of the skin damage, which often takes many months to treat. Overall mortality of mustard gas exposure is only about 2%.
Nerve agents are organophosphorus compounds, closely related to insecticides. They inhibit the action of acetylcholinesterase, leading to parasympathetic overactivity and ultimately neuromuscular blockade. Clinical manifestations are meiosis, bronchoconstriction, hypersecretion and hypersalivation, rapidly progressing to general paralysis (including the respiratory muscles), convulsions and death. These events may occur in minutes, so rapid treatment is essential; this includes the use of atropine and oximes (which reactivate acetylcholinesterase). If there is a risk of nerve gases being used, pretreatment with pyridostigmine, which binds reversibly to acetylcholinesterase and thus 'protects' it from the effects of the nerve gas, is useful. Many armies now equip personnel with individual antidote packs for use in the field.
FURTHER READING
2
Howard J, Tyrer F H 1987 Textbook of occupational medicine. Churchill Livingstone, Edinburgh. A comprehensive and very readable textbook describing environmental and work hazards. Raffle P A B, Lee W R, McCallum R I, Murray R 1987 Hunter's diseases of occupations. Hodder and Stoughton, London. A traditional and comprehensive text covering the entire field of occupational medicine. Skinner D, Driscoll P Earlam R (ed) 1991 ABC of major trauma. BMV Books, London. A concise, practical account of important topics in major trauma. Ward M, Milledge J S, West J B 1994 High altitude medicine and physiology, 2nd edn. Chapman and Hall, London. An excellent book covering all medical aspects of high altitude medicine.
55
This page intentionally left blank
3
link to form the backbone of each strand, and the bases on each strand face each other and pair by hydrogen bonding. The base pairing is specific: adenine always pairs with thymine and guanine with cytosine. The specific base pairing allows DNA molecules to be copied precisely when cells divide. A sequence of bases coding for a gene is usually divided into coding regions (exons) and non-coding regions (introns). DNA is transcribed by synthesizing a singlestrand ribonucleic acid (RNA) molecule, using one of the DNA strands as a template. The resultant messenger RNA (m-RNA) molecule is processed to splice out the noncoding regions and to modify each end, and then migrates into the cytoplasm, where it directs the synthesis of a specific protein by a process known as translation. This process involves the interaction of the m-RNA with both ribosomes in the cytoplasm and a series of molecules known as transfer RNA (t-RNA) (Fig. 3.2). t-RNA is a specialized molecule to which can be attached a specific amino acid. Each t-RNA carries a three-base coding region which pairs specifically with a corresponding sequence of three bases on the m-RNA. The sequence of three bases is known as a codon and is specific for each amino acid. The sequence of codons makes up the genetic code. There are also three codons which determine the end of a protein; these are known as stop codons. A gene may occupy a sequence of one to tens of kilobases (one kilobase = 1000 base pairs), depending on the length of the resultant protein and the number of introns in the gene. A chromosome consists of a continuous molecule of DNA coding for many thousands of genes. In a chromosome, DNA is intricately coiled and combined with proteins, including histones, which results in a compact structure that can be seen with a light microscope. Often, special stains are used which create a pattern of light and dark bands. These band patterns are specific for each chromosome, and reflect their macrostructure. Figure 3.3 demonstrates the relative size of a gene, in relation to a chromosome band and the chromosome itself.
TheGeneticBasis of Disease Robin M Winter
DMA, genes and chromosomes 57 Ways of looking at genes 58
Loci, alleles and segregation 63 Chromosomal disorders 65 Single gene disorders 69
Types of single gene mutation 60
Multifactorial disorders 72
Chromosome studies 61
Management of genetic disorders 74
Cell division 63
In the western world, chronic diseases with a substantial genetic component occur in 5-10% of the adult population. Furthermore, more than one in 50 babies has a recognizable congenital anomaly at birth, many of which will have a genetic cause. Genetic disorders and malformations account for around 30% of paediatric hospital admissions and up to 50% of deaths under the age of 15 years. The relative frequency of the different types of genetic disorders in the UK is shown in Figure 3.1. In certain populations, specific genetic disorders are of such high incidence as to represent significant public health problems, e.g. the thalassaemias in Mediterranean and oriental populations, and sickle cell anaemia and other haemoglobinopathies in Afro-Caribbean populations. The incidence of affected homozygotes with these disorders can be as high as one in 50 births in some areas.
DNA, GENES AND CHROMOSOMES The basic unit of inheritance is the gene. A gene is a length of deoxyribonucleic acid (DNA) that codes for a specific protein. The DNA molecule is a double helix, i.e. it is formed from two interwoven strands. Each strand consists of a chain of nucleotides, and each nucleotide is made up of a deoxyribose sugar and a nitrogenous base. There are four possible nitrogenous bases: adenine (A), thymine (T), guanine (G) and cytosine (C). The deoxyribose sugars
FIG. 3.1 The relative frequencies of different types of genetic disorder in the United Kingdom
57
FIG. 3.2 DNA transcription and translation (After Emery A E H 1984 An introduction to recombinant DNA. John Wiley, London.) See text of details.
FIG. 3.3 The size of a gene relative to a chromosome and chromosome band, illustrated by the b-globin gene This is situated on chromosome 11 in band 11p15.5, which may contain around 4000kb. The gene itself is around 1600 base pairs long and is part of a cluster of similar genes, the (3-like globin gene cluster.
WAYS OF LOOKING AT GENES SOUTHERN BLOTTING There are three basic steps in the process of Southern blotting for the analysis of the sequences of DNA that make up genes (Fig. 3.4):
58
1. Use of restriction enzymes. Restriction enzymes, which originate from bacteria, cut double-stranded DNA at
FIG. 3.4 DNA analysis S DNA is cut at specific points by restriction enzymes into different sized fragments. H These fragments are separated by electrophoresis on an agarose gel and blotted onto nitrocellulose paper (Southern blotting). Specific genes cannot be visualized at this stage, [c] A radioactive DNA probe is used to locate a specific gene. The position of the gene on the gel depends on the size of the DNA fragment in which it is contained.
specific base sequences. The distance between such restriction enzyme recognition sites may range from one to tens of kilobases, so that the genome is cut into fragments of differing sizes. 2. Electrophoresis and Southern blotting. Fragments generated using restriction enzymes can be separated by electrophoresis on an agarose gel. The fragments are then denatured (i.e. double-stranded DNA separates into single-stranded DNA) and a mirror image of the pattern of fragments is made on to nitrocellulose paper by a process known as Southern blotting. 3. Use of DNA probes. At this stage, single-stranded fragments of DNA have been separated according to size, and fixed on to the nitrocellulose filter paper. A gene probe must now be used to identify the individual gene sequences present in specific bands. A gene probe is a radioactively labelled single-stranded length of DNA whose sequence is specific for a particular gene, or length of chromosome. It is sometimes made using mRNA coding for a specific protein, by a process known as reverse transcription. The single stranded probe recognizes complementary sequences of DNA on the Southern blot, and anneals to them. Autoradiography can be used to locate the position of the gene probe, which will mark the position of all similar sequences on the Southern blot. If a gene-specific probe has been used, only a few bands will be seen on the autoradiograph, according to how many restriction enzyme recognition sites there are within the gene itself. Different
3
restriction enzymes will generate different patterns, using the same probe. The position of the various restriction enzyme cutting sites within the gene can be inferred, and a restriction map produced.
POLYMERASE CHAIN REACTION (PCR) The polymerase chain reaction (PCR) is a way of amplifying specific stretches of DNA so that further genetic analysis can be carried out on them. The revolutionary nature of the technique derives from the fact that large amounts of specific DNA sequence can be copied from only a few (or even a single) DNA molecules. At the start of the process the DNA double helix is denatured by heat to give two single strands. Two specific primers are then needed to amplify the specific sequence of interest. The primers are made up of single-stranded DNA with a specific complementary sequence to the sequences flanking the target DNA sequence (Fig. 3.5). DNA polymerase is then used to copy the target DNA, starting from the primer sequence on both of the original DNA strands. At the end of this process of DNA extension two double helices containing the target sequence will have been made. These double helices are then denatured and the process is repeated several times. At each step the number of copies of the target sequence doubles.
POLYMORPHIC MARKERS Restriction fragment length polymorphisms (RFLP) The restriction enzyme cutting sites in and around genes are variable, as a common, harmless base change may create or destroy a cutting site. Thus, in some individuals, different patterns may be seen on Southern blotting using the same restriction enzyme and the same gene probe. This is because the gene in question will be contained in fragments of different lengths according to the presence or absence of specific cutting sites. Such restriction fragment length polymorphisms (RFLPs) are extremely important because they act as genetic markers, allowing abnormal genes to be tracked through families (Fig. 3.6).
Short tandem repeat polymorphisms (STRPs) The first generation of DNA markers involved RFLPs in known genes or DNA sequences. Use of these markers required Southern blotting. More modern maps use short tandem repeat polymorphisms (STRPs), which are detectable by PCR. The genome contains many stretches of repeated di-, tri- or tetranucleotides of variable length. One of the commonest is the CA repeat. At a specific chromosomal location in an individual there may be (for
FIG. 3.5 Polymerase chain reaction
example) a (CA)10 repeat on one chromosome and a (CA)20 repeat on the other. This length difference can be detected and is the basis of a polymorphism that can be used for linkage studies. Tetranucleotide repeat sequences are easier to analyse and are the basis of the latest generation of genetic maps.
59
TABLE 3.1 Molecular mechanisms of single gene mutation, illustrated by the haemoglobinopathies Abnormality of DNA
Effect
Example
Deletion of gene
Diminished or absent protein, depending on the number of genes involved
Most forms of a-thalassaemia
Point mutation (i.e. single base change)
Substitution of a single amino acid in the protein
Sickle cell anaemia, Hb E, C and many other examples Hb McKees Rocks, some forms of (3-thalassaemia Hb Constant Spring (a-chain)
Creation of a stop codon leading to a short protein chain Removal of a stop codon, leading to an elongated protein chain Alteration of splicing signal
FIG. 3.6 Restriction fragment length polymorphism (1) Shows the two alleles E and H of a gene at a specific locus. The alleles are represented by the coloured blocks on each of the two chromosomes. The arrows indicate restriction enzyme recognition sites. In allele A there is an extra site in the middle of the gene, so that when a DNA sample from this individual is cut with the restriction enzyme and a Southern blot made, three bands will be seen (2). The largest band represents allele B and the two smaller bands allele A. (3) Shows a pedigree where alleles A and B are being passed from generation to generation. Allele B causes an autosomal dominant disorder (e.g. neurofibromatosis) in this family so that the RFLP can be used to track the abnormal gene.
Some forms of a- and p-thalassaemia
Insertion or deletion of a number of nucleotides that are not a multiple of three
Frameshift mutation
Hb Cranston, Tak and Wayne Some forms of p-thalassaemia
Fusion of genes
Absence of normal product and presence of a new protein resulting from the fused genes
Lepore haemoglobins involving (3- and 8-globin chains ((3-thalassaemias)
TRINUCLEOTIDE REPEATS Single-nucleotide polymorphisms (SNPs) The most common type of polymorphism in the human genome is a single base pair change known as a singlenucleotide polymorphism (SNP). These SNPs can now be detected by oligonucleotide microarrays (so called 'gene chips'). This will allow for rapid typing of thousands of polymorphic changes in marker loci and known genes that might predispose to disease. A major project is under way to map thousands of SNPs throughout the human genome.
TYPES OF SINGLE GENE MUTATION
60
At the molecular level there are many mechanisms that can give rise to a malfunctioning gene (Table 3.1). The haemoglobinopathies best illustrate the full range of molecular defects that can occur. A mechanism of mutation, only recognized in recent years, involves the expansion of trinucleotide repeats.
An unusual form of mutation consists of expansion of a CAG sequence within a gene, sometimes leading to a sequence of polyglutamine within the coded protein. This disrupts its function. Table 3.2 gives details of eight disorders caused by trinucleotide repeat mutations. For reasons unknown, they all involve abnormal neurological function. Trinucleotide repeat mutations often show the phenomenon of anticipation. This means that the severity of disease appears to increase as the gene is passed down the generations of a pedigree. The clearest example is in myotonic dystrophy, where a grandparent may just have cataracts without overt myotonia, a daughter may have the classic 'adult' form of the disease with myotonia, and her child may have the severe congenital form of the disorder with severe early hypotonia and mental retardation. The explanation for this is that the trinucleotide repeat expands (i.e. the number of repeat sequences increases) each time the gene is copied and passed on to the next generation. In fragile X syndrome premutation carriers can occur. These are males or females who have no clinical or cytogenetic abnormalities but who carry an increased number of trinucleotide repeats in the fragile X gene. When passed on by a female such a premutation can mutate to the full
3
TABLE 3.2 Triplet repeat mutations and human disease Disease
Clinical features
Chromosome location
Huntington's chorea
Choreoathetosis, dementia
4p16
Spinocerebellar ataxia typel
Cerebellar ataxia
6p21
Friedreich's ataxia
Cerebellar ataxia
9q13-21
Machado-Joseph disease
Cerebellar ataxia, extra-pyramidal signs, ophthalmoplegia
14q32
Myotonic dystrophy
Myotonia, frontal balding, cataracts, diabetes, male infertility
19q13
Dentato-rubropallido luysian atrophy
• Chorea, seizures, dementia
12p12
Chromosome 1
Spinobulbar muscular atrophy (Kennedy's syndrome)
Muscular atrophy/fasciculation, gynaecomastia
Xq21
Fragile X mental retardation
Non-specific mental retardation, fragile X chromosome on cytogenetic examination
Xq28
References Mandel J-L 1993 Questions of expansion. Nature Genetics 4: 8-9 Richards R I, Sutherland G R 1992 Dynamic mutations: a new class of mutations causing human disease. Cell 70: 709-712
mutation (where the repeat is expanded) and a fully affected child can be born.
CHROMOSOME STUDIES Chromosomes are usually visualized during mitosis, at metaphase (p. 63). At this stage the DNA is coiled and condensed, and the chromosomes consist of two identical chromatids, joined together at the centromere (Fig. 3.7). The position of the centromere is specific for each chromosome. In some chromosomes (1-3) the centromere is close to the centre (metacentric); in others (13-15, 21-22) it is near one end (acrocentric), and in the remainder the centromere is somewhere in between these two extremes (submetacentric). By convention, all chromosomes are divided by the centromere into a short arm (p) and a long arm (q).
CHROMOSOME BANDING Like other cell structures, chromosomes must be stained in order to visualize them with the light microscope. Using various methods, a pattern of bands can be produced which
FIG. 3.7 Chromosome nomenclature, using chromosome 1 as an example
is specific for each chromosome. A number of staining techniques are commonly used: • G (Giemsa) banding is the most widely used technique. Light and dark bands are produced. • Q (quinacrine) banding requires a fluorescent microscope. The band patterns are similar to G-banding. Certain chromosome structures, e.g. the long arm of the Y, are particularly well stained. • R (reverse) banding produces a negative image of G-banding. • T (telomere) banding preferentially stains the telomeres (ends of the chromosomes). • C (centromere) banding stains centromeric regions.
Band nomenclature The banding pattern is specific for each chromosome, and a convention exists for labelling each band. The long and short arms are divided into regions by particularly prominent bands (landmark bands) (Fig. 3.7). Within each region, individual bands are numbered from the centromere distally, and landmark bands are included in the distal region they demarcate. Thus, in Figure 3.7 band Iq32 means band 2 in region 3 of the long arm (q) of chromosome 1.
FLUORESCENT IN SITU HYBRIDIZATION (FISH) Fluorescent in situ hybridization (FISH) is an important technique for recognizing very small deletions of chromo-
61
Abnormalities in chromosome number The normal diploid number of chromosomes in humans is 46. Individuals with chromosome counts that are not multiples of the normal haploid number (23) are said to be aneuploid. A fetus can receive higher multiples of the haploid number of chromosomes to give 69 (x3) or 92 (x4) chromosomes. Such triploid or tetraploid fetuses usually miscarry early. If individuals carry one extra chromosome, they are said to be trisomic for the chromosome concerned. Very occasionally, an individual can have two extra chromosomes (double trisomy). Monosomy is the situation where one chromosome is missing. In liveborn children it is virtually only seen for the sex chromosomes, giving monosomy X (Turner's syndrome, p. 69).
Translocation, deletion and insertion
FIG. 3.8 Chromosome FISH in a patient with Williams' syndrome One probe (white arrows) identifies the two No 7 chromosomes. The other probe (elastin, black arrow) is missing from one chromosome 7 indicating a microdeletion.
some material. The technique involves preparing a DNA probe, specific for a particular gene or region of the chromosome. This probe is then labelled with a fluorescent tag. A chromosome slide is prepared and the probe is used to label the specific chromosomal region containing the gene under investigation. For a gene on the autosomes, two labelled tags should show up. If there is a deletion on one chromosome, then only one tag will be visible. FISH can detect chromosome deletions that are much smaller than those visible by conventional light microscopic techniques. Another technique involves chromosome painting. In this technique, probes derived from the whole length of a specific chromosome are labelled with a fluorescent dye (Fig. 3.8). If these probes are then used in the same way as the FISH technique, the whole chromosome is labelled with the fluorescent dye. By using different fluorescent dyes and computer image manipulation, each of the 24 chromosomes can be labelled in a different colour. Chromosome painting is useful for detecting subtle or complicated translocations of the chromosomes (see below).
TYPES OF CHROMOSOME ABNORMALITY
62
Chromosome abnormalities can be divided into those involving the number of chromosomes, and those involving breakage or rearrangement.
Breakage of chromosomes can result in loss of material (deletion), exchange of material between two nonidentical chromosomes (reciprocal translocation), inversion of a segment of chromosome (pericentric inversions involve the centromere, paracentric inversions do not), and joining of the two ends of the same chromosome (to give a ring chromosome). Horizontal splitting of the centromere can result in a chromosome with identical long and short arms, an isochromosome. A translocation between the long arms of two acrocentric chromosomes, joined at the centromere, is known as a Robertsonian translocation. These possibilities are illustrated in Figure 3.9.
KARYOTYPE NOMENCLATURE The convention in karyotype nomenclature is to give the number of chromosomes first, followed by the types of sex chromosomes, followed by the types of any additional, missing or abnormal chromosomes. Thus, for example: • • • • •
46,XX - normal female 45,X - Turner's syndrome 47,XY + 21- male with trisomy 21 69,XXY - triploidy, XXY sex chromosome complement 45,X/46,XX - mosaic Turner's syndrome.
For inversions or translocations, the numbers of the chromosomes involved are given in brackets (the chromosome with the lowest number being given first). This is followed by the bands or regions involved in further brackets. Symbols are used to indicate the type of rearrangement involved. Thus, 46,XX,t(9:21) (qll :pll) karyotype means that chromosome 9 has broken at band qll and chromosome 21 has broken at band pll. The small letter t (for translocation) indicates that material has been exchanged between the two chromosomes.
3
FIG. 3.9 Types of chromosome aberration ffl Two normal non-homologous chromosomes. DEI A reciprocal translocation between the two chromosomes. Note that material has been exchanged between the short arms. Q-] A pericentric inversion of the large chromosome. Breaks have occurred in the long and short arms and the middle segment of the chromosome has become inverted. [B] A deletion. The top part of the large chromosome has been lost. DEI An isochromosome. The small chromosome consists of two identical short arms due to misdivision after replication. DEI A ring chromosome. Both ends of the small chromosome have joined to form a ring.
CELL DIVISION MITOSIS Division of somatic cells is known as mitosis. This is divided into four stages (Fig. 3.10). Between cell divisions, in interphase, the chromosomes are extremely elongated and cannot be seen with the light microscope. 1. Prophase. As a preparation for cell division, the chromosomes replicate to give the classic structure with two chromatids, and they begin to condense. 2. Metaphase. The chromosomes line up at the centre of the cell. 3. Anaphase. Each chromosome separates longitudinally at the centromere, and the two chromatids pass to opposite poles of the cell. 4. Telophase. Two new daughter cells are created by the formation of a nuclear envelope around each new set of chromosomes.
FIG. 3.10 Mitosis and meiosis See text for details.
different gametes of an individual. This is brought about by two separate means: 1. Different gametes receive different combinations of maternally and paternally derived chromosomes. 2. There is an exchange of genetic material between the two members of an homologous pair of chromosomes, known as crossing over. This process results in the creation of a chromosome containing part of the maternal and part of the paternal member of an homologous pair, known as a recombinant chromosome. Without crossing over, alleles on the same chromosome would always be inherited en bloc. Crossing over takes place during the first step of meiosis (meiosis I), which is divided into prophase, metaphase, anaphase and telophase, as in mitosis. However, meiosis I differs in that homologous members of a pair of chromosomes line up and exchange genetic material during prophase, whereas at anaphase each member chromosome passes to an opposite pole without division at the centromere. Meiosis I is known as reduction division, because it results in the formation of two daughter cells containing 23 chromosomes, each of which has two chromatids that may not be identical because of crossing over. The second step, meiosis II, is similar to mitosis except that each 'parent' cell now has only 23 chromosomes (each with two chromatids), and each 'daughter' cell contains 23 chromatids at telophase. Fusion of parental gametes at fertilization restores the diploid number of chromosomes.
MEIOSIS During the production of gametes, the normal diploid complement of 46 chromosomes must be reduced to the haploid number of 23 in the gametes by the process known as meiosis. During meiosis there is the independent assortment of maternally and paternally derived genes in the
LOCI, ALLELES AND SEGREGATION The genes determining a particular trait are situated at identical points or loci on each member of a homologous pair of chromosomes. The two genes on each chromosome
63
FIG. 3.11A Inheritance of alleles at autosomal loci
FIG. 3.12A Autosomal recessive inheritance with first cousin parents The boy at the bottom of the pedigree is homozygous for an abnormal gene inherited from the great-grandmother through both parents. The double line indicates consanguineous marriage.
FIG. 3.11B Inheritance of alleles at X-linked loci
at a particular locus may not be identical, and are known as alleles. If two alleles at a locus are identical, the individual is said to be homozygous at that locus; if the alleles are not identical, the individual is said to be heterozygous. The chance of a child inheriting one particular allele from a heterozygous parent is 1 in 2 (50%). For autosomal loci, if both parents are heterozygous, the chance of a child being homozygous for one particular allele is 1 in 4 (25%) (Fig. 3.11A). If a locus is on the X chromosomes, males can only carry one allele (because they only have one X chromosome). They are said to be hemizygous for a particular allele. All daughters of a male hemizygous for an abnormal gene will receive that gene; on the other hand, none of the sons will receive the abnormal gene (because a male must pass on a Y chromosome to his sons, and not an X). Each time a heterozygous female has a child, there is a 50% chance it will be a boy, and if it is a boy, a 50% chance that he will be affected. Likewise there is a 50% chance of a girl and a 50% chance she will be heterozygous (Fig. 3.11B).Q
O MCQ 3.1
64
O MCQ 3.2
FIG. 3.126 Autosomal dominant inheritance Note that the disease is passed on from parent to child and that both males and females are affected. There is also transmission of the disease from father to son.
DOMINANT AND RECESSIVE INHERITANCE Disorders where it is only necessary to carry one abnormal allele in order for an individual to be affected are said to be dominant. In autosomal dominant disorders, the abnormal gene is carried on a non-sex chromosome; in X-linked disorders, the gene is carried on the X chromosome. In recessive inheritance an individual is only affected if he or she does not carry a normal allele at all. For autosomal recessive inheritance, affected individuals will be homozygous for the abnormal allele and both of the parents will be heterozygote carriers. In X-linked recessive disorders males hemizygous for the abnormal allele will be affected, whereas heterozygous females will be unaffected. Typical pedigree patterns are shown in Figures 3.12 and 3.13.2
RECENT ADVANCES THE HUMAN GENOME PROJECT
FIG. 3.13. X-linked recessive inheritance Note that half of the sons of a carrier female are affected and half of the daughters are carriers. All the daughters of an affected male are carriers and all the sons are normal, because a male passes on his one X chromosome to his daughters and his Y chromosome to his sons.
NEW MUTATION, PENETRANCE AND GENE EXPRESSION Abnormal alleles have to arise somewhere in a pedigree by the process of new mutation. Sometimes this can be inferred in a case where an affected individual for an autosomal dominant disorder has normal parents. However, many autosomal dominant disorders also display incomplete penetrance or reduced expression. This means the gene carriers sometimes show no signs, or only a few minor signs, of the condition. The two phenomena are therefore important in the context of genetic counselling. If a person has an autosomal dominant disorder but there is no family history, both parents must be examined very carefully in order to determine whether either of them carries the abnormal gene. If they do not, the chance of their having a further affected child will be small (as this would require a second, unconnected, new mutation). On the other hand, if one parent shows very minor signs of the condition the recurrence risk would be 50% for a further affected child.
GENE MAPS AND LINKAGE The presence of loci close to one another on chromosomes leads to the phenomenon of linkage. The closer together loci are on a chromosome, the lower the probability that a crossover will take place between them during meiosis. I, and the higher the probability that two alleles inherited from the parent will be passed on together to an offspring. Linkage between loci can be studied in suitable families by looking at the joint inheritance of specific traits, and an estimate can be made of the distance separating the loci. These family studies are informative for linkage but do not give information about the chromosomes on which the loci are situated. This problem is known as gene assignment and can be tackled by a number of different methods, such as somatic cell hybrids. Using these methods, a human gene map is being constructed giving information about the
3
There are thought to be around 100000 genes in humans, and the total number of DNA bases in the haploid genome is around 3000000000 (3000 megabases). The ultimate goal of the human genome project is to locate every gene and to understand its function. It may not be absolutely necessary to sequence all of the 3000 megabases, as genes are known to be separated by large tracts of non-coding DNA sequences that may have no function. The first phase of the project was to create dense genetic maps of polymorphic genetic markers so that genetic diseases and traits can be located by linkage analysis. Markers are evenly spaced every megabase or so. At the same time the genome was broken up into overlapping DNA fragments (contigs) to provide a physical map. Gradually the genetic markers, known genes, and also parts of the coding sequences from expressed genes of unknown function (Expressed Sequence Tags - ESTs), are being located on contigs. This means that if researchers map a disease to a marker by linkage studies they are able to locate the marker on a physical fragment of DNA (the contig) and ask if any candidate genes are present on the same piece of DNA. If a suitable candidate is not found, the overlapping DNA fragments on either side can be examined and so on. The first draft of the entire sequence of the human genome was completed in the year 2000 and contains 90% of the entire sequence. The final sequence, with 99.99% accuracy, is expected to be completed by 2003, or perhaps earlier. The entire gene sequence of model organisms is also being examined. The fruitfly (Drosophila), an important organism in studying the mechanisms of embryonic development, has already been sequenced. Progress is being made in sequencing the genome of the mouse, which provides important models for many medical disorders. assignment of various loci and their distance from others on the same chromosome.
ICHROMOSOMALDISORDERS FREQUENCY OF CHROMOSOMAL DISORDERS About seven per 1000 babies are born with detectable chromosomal anomalies. Of these, three will have sex chromosome anomalies, 1.5 autosomal trisomies (mainly Down's syndrome) and the remaining 2.5 will have chromosomal rearrangements. Most of the latter are balanced, i.e. no genetic material is lost or gained. Of the autosomal trisomies, only trisomy 21 (Down's
65
syndrome) cases are likely to survive into adulthood. The sex chromosome anomalies will frequently present with infertility or amenorrhoea. Unbalanced chromosomal rearrangements usually cause severe physical and mental handicap. However, balanced rearrangements have no effect on the carrier, although they predispose to recurrent miscarriage and children with unbalanced chromosome complements. An unbalanced karyotype means that there is duplication or deletion of some genetic material.O
TABLE 3.3 Chromosomal types of Down's syndrome Type of Down's syndrome
Chromosome complement
Comment
Standard trisomy 21
47,XX,+21 or 47,XY,+21
Approximately 95% of Down's syndrome children
Translocation Down's syndrome
e.g. 46,XY,-14,+t(14;21) 46,XX,-21,+t(21q;21q)
In about 2-3% of cases, an extra chromosome 21 is attached to another chromosome. It is essential to examine the chromosomes of the parents, as one may carry a balanced translocation
Mosaic Down's syndrome
e.g. 46,XX/47,XX,+21
Can be demonstrated in about 2-3% of cases
DOWN'S SYNDROME Between one in 700 and one in 1000 liveborn infants have Down's syndrome. The characteristic physical features are well described in paediatric texts and are present at birth, allowing immediate clinical diagnosis in most cases (Fig. 3.14). The head is foreshortened (brachycephaly) and there are usually three fontanelles. The eyes have an upward slant and crescents of skin are present covering the inner canthi (epicanthic folds). Brushfield spots are commonly seen. These are small white spots, situated around the outer third of the iris. The nasal bridge is flat and the tongue protuberant and deeply furrowed. A single transverse palmar crease is present on the hand, together with a short, incurved fifth finger (clinodactyly). A wide gap is present
between the first and second toes, often with a longitudinal plantar crease. Hypotonia and delayed development are universal. Congenital heart defects (particularly A-V canal defects) and duodenal atresia can occur. It is essential that the chromosomal type of a Down's syndrome child is obtained. There are three possibilities (Table 3.3): • In about 95% of cases there is an extra, free-lying chromosome 21. This form of Down's syndrome is associated with increased maternal age. The risk at a maternal age of 37 years is 1 in 250, at 40 years 1 in 100, and at 45 years 1 in 40. • In 2-3% of cases there is a chromosome translocation, usually involving Robertsonian translocation (p. 62). The parents of such individuals must be checked to see whether they carry a balanced translocation. • The remaining cases are mosaic. In these infants the degree of mental retardation can vary according to the proportion of abnormal cells. The recurrence risks for Down's syndrome are set out in Table 3.4.
TRISOMY 18 (EDWARDS' SYNDROME)
FIG. 3.14 Down's syndrome
1
66
Case 3.1
This autosomal trisomy occurs in approximately one in 5000 live births. There is usually low birthweight, hypotonia, a prominent occiput, a small chin, a short sternum and characteristic hand and foot abnormalities. The index and little fingers of the hand overlap the middle two and the nails are small; in the feet the hallux is dorsiflexed and the lateral profile of the foot is convex, with a prominent heel (a so-called 'rocker-bottom foot', caused by a vertical talus). Analysis of the dermatoglyphic patterns of the digits reveals an increased number of arch patterns. Internal malformations are common, especially congenital heart defects (ventricular septal defects, patent ductus arteriosus) and renal abnormalities (horseshoe kidney,
3
CASE STUDY 3.1 GENETIC COUNSELLING DOWN'S SYNDROME A couple is referred for genetic counselling because they have had a child with Down's syndrome. Question 1. What facts do you need to know before being able to provide accurate genetic counselling? It is crucial to know the age of the parents, particularly the mother. It would also be important to know whether there was any other family history of Down's syndrome. It is essential to know the precise karyotype of the baby. In this case, the karyotype was 46,XY,+t(14;21). This is a karyotype of a male with Down's syndrome, caused by a chromosome translocation of a chromosome 21 to a chromosome 14. Question 2. What further tests would you need to carry out before being able to counsel the parents?
Discussion Most cases of Down's syndrome have standard trisomy 21. In other words, there are 47 chromosomes, and the extra chromosome is a free-lying chromosome 21. The chances of having a baby with this form of Down's syndrome increases with the age of the mother. Recurrence risks after a baby with standard trisomy 21 are mainly related to the age of the mother, although they are slightly increased over the general population risk at any maternal age. Two to 3% of babies with Down's syndrome have a chromosome translocation. In this case it is essential to test the karyotype of the parents. In many cases both parents might have a normal karyotype, in which case the recurrence risk would be small. Nevertheless, one parent can carry a balanced chromosome translocation, as in the current case. Where the mother carries a balanced
14;21 chromosome translocation, the risks of a further baby with Down's syndrome are about 10%. In a future pregnancy an amniocentesis or chorionic villus sample (CVS) can be offered to check the chromosomes of the baby. Serum screening tests for Down's syndrome are not appropriate in this situation, as they do not provide a definitive answer as to whether the baby has Down's syndrome. The balanced translocation may also be carried by other family members. In this family, the wife's parents should be tested if possible, to see whether they carry the translocation. If one of them does, then testing should be offered to other family members, such as the wife's siblings. The other normal children of the present couple should be offered testing when they are of an age to give informed consent.
It is essential to examine the chromosome types of the parents, as one of them may be a translocation carrier. In this case, the mother had a 45,XX, +t(14;21) karyotype. This means that she was a balanced carrier for a 14;21 translocation (Case Fig. 3.1.1). Question 3. What risks would you give for a baby with Down's syndrome in a further pregnancy, and what tests could be carried out in a future pregnancy? 4. What further tests must be carried out?
CASE FIG. 3.1.1 A balanced 14;21 chromosome translocation (arrow) Note that there is only one chromosome number 21 and 45 chromosomes in all. Clinically this is a normal female.
hydronephrosis). Aplasia of the radius, facial clefts and exomphalos each occur in about 20% of cases. Prognosis is very poor, with 50% of cases dying before 2 months, 90% before 1 year and 99% before 10 years; long-term survivors are very severely retarded. Most cases are caused by an extra chromosome 18 (rather than a chromosome translo-
cation) and there is an association with increased maternal age. The risk of recurrence after a trisomic case is about 1 in 100 for a baby with a chromosomal trisomy (not necessarily trisomy 18); however, these risks might have to be modified for older mothers (see section on Down's syndrome).
67
TABLE 3.4 Recurrence risks for Down's syndrome Risk to other relatives (excluding offspring of an affected patient)
Type of Down's syndrome
Risk to siblings of affected patient
Standard trisomy 21 Mother <40 years old
1%
Mother >40 years old
Maternal age risk
Translocation (Parents have normal chromosomes)
Maternal age risk
Maternal age risk
10%
Depends on chromosomes of relative Depends on chromosomes of relative Depends on chromosomes of relative
Translocation (One parent carries the translocated chromosome) Mother carries 14:21 translocation Father carries 14:21 translocation Either parent 21:21 translocation
2% 100%
1%
Mosaic
Probably similar to maternal age risk
Maternal age risk
TRISOMY 13 (PATAU'S SYNDROME) This occurs in about one in 8000 live births. There are significant craniofacial abnormalities, with punched-out scalp lesions (aplasia cutis), microphthalmia, and low-set, malformed ears. Many cases have severe bilateral cleft lip and palate and some cases have hypotelorism or cyclopia (a single central eye with a proboscis-like nose), indicating underlying holoprosencephaly of the brain (failure of midline separation of the cerebral hemispheres). In the hands and feet an extra, hypoplastic digit on the ulnar or fibular side is common (postaxial polydactyly). Brain, heart and kidney malformations are very common. Survival past the first year of life is very unusual and retardation is severe. Most cases arise by standard trisomy, but some are the result of a Robertsonian translocation involving chromosome 13. The risk of recurrence after a trisomic case is about 1 in 100 for a baby with a chromosomal trisomy (not necessarily trisomy 13); however, these risks might have to be modified for older mothers (see section on Down's syndrome).
1
68
MCQ 3.3
FIG. 3.15 Turner's syndrome (45,X) Characteristic fades, webbing of the neck, absent breast development and widely spaced nipples.
SEX CHROMOSOME ABNORMALITIES Klinefelter's syndrome Klinefelter's syndrome (47,XXY) occurs in about one in 1000 males. Adult individuals tend to have eunuchoid proportions with female fat distribution and gynaecomastia. The testes are small. Pituitary gonadotrophins are raised and androgen production is low. Affected individuals are sterile, as they produce no sperm. Androgen therapy may help to improve libido and encourage the development of male secondary sexual characteristics. Intelligence is usually normal, although mild to moderate retardation may be seen.
XYY males About one in 1500 males is XYY. Such individuals are physically normal, although they tend to be tall. Although an increased tendency to psychopathic behaviour has been reported, prospective studies have shown that the majority of affected individuals lead normal lives.
Turner's syndrome The incidence of Turner's syndrome (45,X) is one in 5000
births. Affected individuals are short, tend to have a web of skin on the lateral borders of the neck (Fig. 3.15), and may have other physical abnormalities, such as a broad chest with widely spaced nipples and an increased carrying angle at the elbows. Coarctation of the aorta can occur. The vagina and internal genitalia are normally formed, but the ovaries consist of simple streaks of fibrous tissue without ovarian follicles, so that primary amenorrhoea is the rule. Treatment consists of oestrogen replacement around puberty to promote the development of secondary sexual characteristics.
cific oncogenes (see p. 149). In other cases the precise nature of the genetic change is not known. Occasionally, an individual with a specific chromosome abnormality will be predisposed to develop particular types of cancer (see Table 6.3, p. 150). A group of single gene disorders exists that result in an increased tendency to chromosome breakage, owing to abnormalities of DNA repair after damage by agents such as ultraviolet light and radiation. These disorders, most of which are autosomal recessive, also predispose to malignancies (see Table 6.3, p. 150).
3
47,XXX females Females with a chromosome constitution 47,XXX have no physical abnormalities. However, primary and secondary amenorrhoea may occur, and average IQ is 20-30 points lower than in XX females, so that learning difficulties are more common than in the general population. Nevertheless, the majority of affected females (about 70-80%) have normal intelligence. 1
CHROMOSOME DELETIONS AND DUPLICATIONS A large proportion of individuals with chromosome abnormalities have the normal number of chromosomes but a small piece of a specific chromosome is missing or duplicated. Sometimes there may be a combination of a chromosome deletion and duplication. Any part of any chromosome can be involved. Significant chromosome deletion or duplication usually causes a combination of congenital malformations, with developmental delay. It is often difficult to predict the precise clinical picture from knowing the specific chromosome deletion or duplication, but there are a number of specific syndromes caused by particular chromosomal regions being affected. Microdeletion syndromes are also being recognized, where the deleted chromosome material must be detected by FISH (see above, page 61). Any child with a combination of malformations, or an unusual facial appearance, together with developmental delay, should have his or her chromosomes examined.
CHROMOSOME ABERRATIONS AND CANCER Cytogenetic analysis of any malignant cell will frequently reveal a non-specific chromosome abnormality. However, there are certain malignancies where a characteristic abnormality is found; in others, the development of a specific chromosome change can be of prognostic significance. In the case of Burkitt's lymphoma and chronic myeloid leukaemia, the chromosome translocations are known to bring together the loci for immunoglobulin genes and spe-
SINGLE GENE DISORDERS Sir Archibald Garrod first put forward the concept of an 'inborn error of metabolism' in 1908 after studying alkaptonuria, a familial disorder in which patients excrete large amounts of homogentisic acid. This led to the concept that an enzyme controlling a metabolic step can be missing or reduced, leading to failure of production of essential metabolites further down the metabolic chain (e.g. in albinism), or the accumulation of toxic substrates of the enzyme (e.g. in alkaptonuria and phenylketonuria) (Fig. 3.16). Today, McKusick's catalogue of genetic disorders lists over 4000 defects involving every organ system. Only a few important groups of disorders are described here.
AMINOACIDOPATHIES Defects in the metabolism of amino acids include a form of congenital hypothyroidism, albinism, disorders of the urea cycle and organic acid metabolism, as well as the disorders described below.
Phenylketonuria Phenylketonuria is an autosomal recessive disorder affecting about one in 10000 infants at birth. It is usually caused by a defect of the enzyme phenylalanine hydroxylase, which converts phenylalanine to tyrosine. The most common clinical presentation, now rarely seen in developed countries because of screening, is vomiting in early infancy, with eczema, depigmentation of skin and hair, hypertonia, seizures, and mental retardation developing during the first years of life. Fortunately, screening at birth is now widely available, in which a drop of blood, obtained within the first few days of life, is placed on a filter paper and a bacterial inhibition assay used to measure phenylalanine levels (the Guthrie test}. Affected infants can be treated by giving an artificial diet low in phenylalanine until at least 8 years of age. If dietary control is strict the prognosis for mental development is good. Females with phenylketonuria run a very high risk of having abnormal children, unless a strict diet is reintro-
69
FIG. 3.16 Partial metabolic pathway of phenylalanine, tyrosine and related compounds showing position of 'metabolic blocks' caused by enzyme deficiencies DO Deficiency of phenylalanine hydroxylase results in an inability to metabolize phenylalanine, leading to phenylketonuria. E Tyrosinase deficiency leads to an inability to produce melanin, thus causing albinism. [3 Deficiency of homogentisic acid oxidase leads to the accumulation of homogentisic acid, and hence to alkaptonuria. OS Deficiency of any one of several enzymes at this point means that thyroxine cannot be synthesized. The result is familial hypothyroidism.
TABLE 3.5 transport disorders Disorder
Site
Metabolites affected
Clinical features
Inheritance
Intestinal disaccharidase deficiency Hypophosphataemic rickets
Small intestine
Maltose, sucrose, lactose
Autosomal recessive
Renal tubules
Phosphates
Abdominal pain and distension, diarrhoea Rickets (vitamin D-resistant)
Hartnup disease
Renal tubules
Amino acids (mono-aminomonocarboxylic group)
Red, scaly facial rash, ataxia
Autosomal recessive
Cystinuria
Renal tubules, small intestine
Cystine, ornithine, arginine, lysine
Renal stones
Autosomal recessive
Nephrogenic diabetes insipidus
Renal tubules
Insensitivity to ADH
Polyuria, polydipsia
X-linked dominant
duced throughout pregnancy. Their children do not have phenylketonuria themselves, but the abnormal metabolites cross the placenta during pregnancy and affect the developing fetus. Microcephaly, cardiac defects and mental retardation are common. Phenylketonuria is a heterogeneous disorder: the most common form results from a mutation at the phenylalanine hydroxylase locus itself. However, a rarer form caused by a defect in dihydropteridine reductase has been described. This enzyme is essential for the recycling of the cofactor tetrahydrobiopterine.
Homocystinuria Homocystinuria is an autosomal recessive disorder and affects one in 200000 infants. It is due to a defect of cystathionine (3-synthase and leads to the accumulation of homocysteine, methionine and other metabolites. Clinical 1 70
MCQ 3.4
X-linked dominant
manifestations include lens dislocation, mental retardation, osteoporosis, and thrombosis of arteries and veins. Affected individuals tend to be long and thin, making Marfan's syndrome part of the differential diagnosis. Treatment involves a low-methionine diet, and pyridoxine treatment in that proportion of patients who are vitamin B6 responsive.
Cystinosis Cystinosis, an autosomal recessive disorder, should be distinguished from cystinuria (see Table 3.5). There are abnormally high intracellular levels of free cystine, which lead to crystal deposition in the kidneys, conjunctiva, bones and leukocytes. Presentation is in childhood, with photophobia and crystalline deposits in the conjunctiva, and the effects of renal tubular malabsorption (Fanconi's syndrome). Renal failure can occur before the age of 10 years. Alkaptonuria Alkaptonuria is a rare autosomal recessive disorder caused by a defect in the enzyme homogentisic acid oxidase
(Fig. 3.16). Homogentisic acid, a byproduct of the metabolism of tyrosine and phenylalanine, cannot be metabolized and so accumulates in the body tissues and is excreted in increased quantities in the urine. Classically, the urine turns dark on standing and the sweat may be black, but these findings are not invariable. The homogentisic acid and resultant polymers also stain cartilage and other connective tissue; ochronosis is the name given to the generalized blue/grey pigmentation that results and is best seen in the cartilage of the ear and the sclerae. It can also be seen in the tendons of the hands, through the overlying skin, in older patients. The main clinical problem is arthritis, which affects the hips, knees, shoulders and spine. Onset is unusual before middle age. Radiological changes include narrowing and calcification of the intervertebral discs, together with some fusion of the vertebral bodies. Rarer complications include an increased incidence of ischaemic heart disease, calcification of the cardiac valves, and occasionally arterial aneurysms. Treatment is symptomatic.1
TABLE 3.6 Storage disorders Example
Symptoms
Glycogen storage disorders
12 types including: Von Gierke's disease (glucose-6-phosphate deficiency) Pompe disease (acid maltase deficiency)
Hepatomegaly, hypoglycaemia, muscle weakness, cardiac failure (Symptoms vary according to type)
Niemann-Pick disease Gaucher's disease Krabbe's disease Metachromatic leucodystrophy
Hepatosplenomegaly (in some), progressive neurological deterioration
Tay-Sachs disease
Progressive blindness and neurological deterioration
At least 8 types including: Hurler syndrome, Hunter syndrome, MaroteauxLamy syndrome, Morquio's syndrome, Sanfilippo's syndrome
Hepatosplenomegaly, abnormal bones (dysostosis multiplex), corneal clouding, mental deterioration
Sphingolipidoses (p. 1413)
Gangliosidoses (p. 1413)
Mucopolysaccharidoses (p. 1029)
3
The transport of metabolites across cell membranes often involves specific binding sites and transport proteins. Mutations can disrupt these mechanisms and result in a group of disorders characterized by the failure of essential metabolites to enter the appropriate body compartments. Some important disorders are outlined in Table 3.5.
STORAGE DISORDERS Macromolecules in the body are often in a perpetual state of accumulation and breakdown. Thus, if an enzyme needed to break down a macromolecule is deficient, increased accumulation occurs, leading to a variety of symptoms according to the type of molecule and the site involved. Storage material usually accumulates in the lysosomes. Several examples are given in Table 3.6.
CONNECTIVE TISSUE DISORDERS
Type
(p. 1028)
TRANSPORT DISORDERS
TABLE 3.7 Types of collagen and their functions
The main protein of connective tissue is collagen, of which there are at least four different types, each with its own functions (Table 3.7). Defects of collagen synthesis can cause a wide variety of disorders (Table 3.8). Some of these have been characterized at the molecular level, and various collagen probes are available for precise diagnosis. The specific collagen chain abnormality can sometimes be deduced from the clinical features (Table 3.8). Thus, some forms of osteogenesis imperfecta are caused by abnormalities of type I collagen, whereas type III collagen deficiency can result in a form of Ehlers-Danlos syndrome, with thin, atrophic skin and a tendency to spontaneous rupture of
TABLE 3.8 Connective tissue disorders Disorder
Clinical features
Ehlers-Danlos syndrome (At least 8 distinct forms)
Hyperextensible skin, loose joints, 'cigarette paper' scars, easy bruising, rupture of blood vessels, viscera etc.
Osteogenesis imperfecta (At least 4 distinct forms)
Multiple fractures of bones, blue sclerae, hyperextensible skin, easy bruising
Cutis laxa
Loose skin, premature aged appearance, hernias, diverticula and emphysema
(Several different forms)
Type
Function
Marfan's syndrome
I II III IV
Major collagen in skin, tendon, bones, heart valves and scar tissue Major collagen in cartilage Found mainly in blood vessels and intestine; also in skin Found mainly in basement membranes
Tall stature, span greater than height, loose joints, dislocated lens of eyes, aortic and mitral incompetence, dissection and aneurysms of the aorta
Pseudoxanthoma elasticum
Angioid streaks of retina, linear yellow raised skin lesions, vascular disease
71
CASE STUDY 3.2 LENS DISLOCATION IN A TALL BOY A 14-year-old boy was referred to the genetic clinic because dislocation of the lenses of both eyes had been diagnosed after an episode of blurred vision. He was also noted to be tall.
Marfan's syndrome. Other physical features of Marfan's syndrome are a high-arched palate, pectus excavatum 1 or carinatum, arachnodactyly (long thin fingers) 2, 3 skin striae (stretch marks), particularly over the shoulders, loins and buttocks, and loose joints. In Marfan's syndrome the lens of the eye classically dislocates upwards, whereas in homocystinuria it dislocates downwards. An echocardiogram should be carried out to look for mitral or aortic valve incompetence and dilation of the aortic root, which precedes a possible dissecting aneurysm of the aorta. Urine should be sent to look for homocystine, although a methionine loading test might be necessary where the diagnosis of homocystinuria seems likely. In the present case, span was 2 cm longer than height, which was on the 98th centile. There was a high-arched palate and significant arachnodactyly. The heart was normal. The patient's father was said to have been tall and had died suddenly at the age of 42 from a ruptured aortic aneurysm. There was no evidence of homocystine in the urine. The diagnosis of Marfan's syndrome
Questions ' What is the differential diagnosis?
What would you ask about inthe family history? What investigation would you carryout? Dislocation of the lenses associated with tall stature suggests a connective tissue disorder. The differential diagnosis lies between Marfan's syndrome and homocystinuria. In the family history, one would ask about tall stature in other family members, and heart defects or sudden death caused by ruptured aneurysms or other vascular problems. The latter would suggest Marfan's syndrome. One would also ask about parental consanguinity, which might suggest the recessive disorder of homocystinuria. In the clinical examination one would measure both height and span. A stature above the 90th centile with span greater than height suggests
blood vessels and other internal organs. Defects of the connective tissue protein elastin are thought to cause the different forms of cutis laxa. Both collagen and elastin are abnormal in pseudoxanthoma elasticum (Ch. 12, Table 12.39). Marfan's syndrome has been shown to be caused by a defect in fibrillin protein.
MULTIFACTORIAL DISORDERS Many common malformations, some diseases and many normal traits are said to have a multifactorial origin, in that both genetic and environmental factors contribute to their O Fig. 3.1 0 Fig. 3.2 3
72
Q Case 3.2 0 Fig. 3.4 6
Fig. 3.3 Fig. 3.5
therefore seemed very likely (De Paepe et al, 1996). Discussion Marfan's syndrome is an autosomal dominant condition caused by mutations in the fibrillin gene on chromosome 15. The gene can be examined to look for mutations in suspected cases, but this is technically difficult because of the size of the gene, and in many cases diagnosis relies on clinical findings. Apart from dislocation of the lens, other clinical complications include joint laxity and associated scoliosis, in addition to mitral and aortic valve incompetence and aortic root dilation leading to aneurysms. Prophylactic p-blocker therapy can be given to alleviate the risk of aneurysms. Regular follow-up is needed for cardiac, orthopaedic and ophthalmological problems. Affected individuals have a 50% chance of having similarly affected children.
Reference De Paepe A, Devereux RB, Dietz HC, Hennekam RCM, Reed E (1996) Revised diagnostic criteria for Marfan syndrome. Am J Med Genet 62: 417-426.
aetiology. Furthermore, the genetic component is thought to be due to several genes acting together - so-called polygenie inheritance. A good example is the inheritance of height. The genetic component is determined by several genes, and final height correlates between parents and children. Nevertheless, environmental factors (such as nutrition) can play an important role. The contribution of the many factors involved results in a gaussian (normal) distribution of height in the general population.
COMMON MALFORMATIONS There are many clues which suggest that a common malformation has a multifactorial origin: • After one affected family member, the risk to other firstdegree relatives is usually in the range 1-5%, depending on the condition.
TABLE 3.10 Some common disorders of multifactorial origin, with possible geneti c markers
TABLE 3.9 Recurrence risk (%) in some common multifactorial malformations Normal parent
Condition
Affected parent Risk of second Risk of third Risk of affected child affected child affected child
Cleft palate alone 2 Cleft lip ± cleft palate 4 Neural tube defect 4 Club foot 3 Dislocation of hip 6 Congenital heart disease 1-4 (varies with type) Hirschsprung's disease (long segment): Male index case 8 14 Female index case Pyloric stenosis: Male index case 3 7 Female index case
8
7
10 10 10 10
4 4 3 12
5-10
1-10
-
-
_
4 13
• The presence of additional affected family members increases the risk to subsequent offspring. • Where a condition can have varying degrees of severity (e.g. cleft lip, with or without cleft palate), risks are higher for relatives of an individual with a more severe malformation. • If there is a sex difference in incidence, risks are greater for relatives of an affected individual of the less commonly affected sex. • The risk declines rapidly as one passes from first- to second-degree relatives. It is thought that everyone inherits a liability to a particular malformation. The degree of liability can vary in different individuals and families, according to the number of adverse genes and environmental factors present. If the liability exceeds a given threshold, the malformation is manifested. Individuals from families where there is more than one affected member will, on average, have a higher liability, as will relatives of more severely affected individuals. Similarly, where a condition is less common in a particular sex, affected persons of that sex must carry a greater liability, as will their relatives. Some common multifactorial malformations with their recurrence risks are given in Table 3.9.O0O
COMMON DISEASES, GENETIC MARKERS AND DISEASE ASSOCIATION Many common diseases, e.g. the common allergies and some forms of epilepsy, have been proposed as candidates for multifactorial inheritance. As more research is carried out into these conditions, heterogeneity is recognized and subtypes are defined. Subdivision is aided by the identifi-
Disorder
Marker
Insulin-dependent diabetes mellitus
HLA haplotypes, e.g, B8, B15, DW3, DW4
Coeliac disease Ankylosing spondylitis Belter's disease Anterior uveitis Peptic ulceration Alzheimer disease
HLA-A1-B8-DW3
3
HLA-B27
Blood group 0 APoE
cation of genetic markers, which may indicate that a major contribution to the disorder is being made by a gene on a specific chromosome. These genetic markers are particular blood groups, tissue types or restriction fragment length polymorphisms (RFLPs) at specific gene loci which are found to occur more commonly in individuals with the disorder (Table 3.10). A good example of the complex interaction between environmental factors and genetic loci is provided by the various possible causes of atheroma. A proportion of patients with early-onset atherosclerosis show abnormalities of lipoproteins or lipoprotein receptors which are determined by various gene loci. In some patients a single gene defect (e.g. of the cell membrane low-density lipoprotein receptors) can strongly predispose to atheroma. In the majority of cases, however, factors such as diet, smoking and high blood pressure may play the predominant role, with minor abnormalities of the lipoproteins merely providing an extra predisposition. The genes that predispose to common disorders are now being sought using genetic linkage techniques.
Linkage disequilibrium and pleiotropy There are two possible explanations for the association of a genetic marker and a specific disease: linkage disequilibrium and pleiotropy. Linkage disequilibrium If a genetic marker (e.g. an SNP, p. 60) is extremely closely linked to a disease locus, specific marker alleles may not be separated from the disease allele by recombination over the generations and an association will be observed in random individuals. This is known as linkage disequilibrium. It should be noted that linkage disequilibrium is a special case, observed only with very close linkage. In most cases of linkage, recombination over many generations will mean that a particular marker allele will not necessarily be associated with the disease in individuals picked at random. Pleiotropy The allele at the marker locus itself may predispose an individual to develop the disease, owing to some function
73
RECENT ADVANCES IN GENE THERAPY Gene therapy, defined as the replacement of a defective gene product, has been carried out for many years, for example in the treatment of haemophilia A and insulindependent diabetes (see Table 3.12). However, recent attempts at gene therapy have involved replacing a defective gene itself, so that it functions in situ to produce the appropriate protein. This approach involves targeting normal genes to a specific tissue so that they are integrated into the genome and function under appropriate regulatory control. At present the accessibility of the affected organ or organs limits the feasibility of this form of therapy to a few diseases only. Genetic disorders affecting the bone marrow are obvious candidates because marrow can be removed and cultured and manipulated in the laboratory before being retransplanted; immunodeficiency diseases and haemoglobinopathies are therefore among the first disorders where attempts at gene therapy have been made. Other organ systems where gene therapy is being tried include the liver and the lungs. Gene therapy for neurological disorders and muscular dystrophies will be more difficult, but is being explored.
of the gene. Some of the disorders associated with specific HLA types may be examples of a pleiotropic effect. For example, a specific HLA type may predispose to infection with specific viruses, leading to some forms of insulindependent diabetes mellitus.
EEIS2 =E :ZZL IE :Z :y 32 SS22 =23 SCREENING
The treatment of many genetic disorders is often most successful if the disorder is diagnosed at an early, presymptomatic stage. In addition, the prevention of genetic disease by genetic counselling and prenatal diagnosis requires the identification of asymptomatic gene carriers. For these reasons, genetic screening programmes have been developed. Depending on the nature and frequency of the condition, screening can involve the entire population, subgroups of the population (for example particular ethnic groups), or specific families in which a genetic disorder is known to be segregating (Table 3.11).
O MCQ 3.5
74
2
Case 3.3
In order to introduce normal genes into the appropriate cells a vector must be used. Vector systems that are being tried include inactivated retroviruses, adenoviruses and liposomes (lipid vesicles containing the appropriate DNA that fuse with the host cell membrane). The Table below summarizes some of the disorders where gene therapy is being attempted. Diseases where gene therapy has been attempted or considered Genetic disorder
Target organ
Adenosine deaminase deficiency (immunodeficiency) Thalassaemia/sickle cell disease Hypercholesterolaemia Phenylketonuria Haemophilia A Cystic fibrosis Duchenne muscular dystrophy
Bone marrow Bone marrow Liver Liver Liver Lung Muscle
TREATMENT OF GENETIC DISORDERS It is still technically difficult to replace missing or defective genes; although it may be possible to isolate and replicate a gene in the laboratory, it is much more difficult to ensure that a replacement gene reaches the correct tissue, and is properly regulated. Efforts are now being made to introduce normal genes into cells to correct genetic defects (see Recent Advances box). There are also a number of treatment strategies for genetic disorders which aim to ameliorate the phenotypic effects. Many common malformations of multifactorial or chromosomal origin can be corrected surgically, and a variety of treatments have been devised for single gene disorders (Table 3.12).
GENETIC COUNSELLING Most doctors will be faced at some stage with questions about the risk of a genetic disorder in patients or their families. Straightforward situations, such as Down syndrome or neural tube defect, can be dealt with by the nonspecialist but complex problems, involving the diagnosis of rare disorders or the use of carrier detection tests and linkage studies, require a specialist opinion.O Whatever the problem, there are a number of essential steps in genetic counselling: 1. Detailed family history. A pedigree of at least three gen-
TABLE 3,11 Screening for genetic disorders Disease
Group screened
Method
Purpose
Phenylketonuria
Total population of neonates
Guthrie test
Early dietary treatment of affected homozygotes
Hypothyroidism
Total population of neonates
TSH levels from dried blood spot
Early thyroxine therapy
Cystic fibrosis
Individuals of reproductive age
Direct DMA analysis of gene mutations
Prenatal diagnosis where both parents are carriers
Sickle cell anaemia and other haemoglobinopathies
Offspring of heterozygote mothers (total population of neonates in some regions)
Haemoglobin electrophoresis
Prophylaxis and early treatment of complications Prevention by counselling and prenatal diagnosis
Tay-Sachs disease
Individuals of Ashkenazi Jewish extraction
Carrier detection by serum enzyme analysis
Prenatal diagnosis where both parents are heterozygous
Adult-onset polycystic renal disease
Relatives of affected individuals
Renal ultrasound, blood pressure, gene tracking in families using DNA probes
Early treatment of hypertension and renal failure
Multiple endocrine adenomatosis
Relatives of affected individuals
Calcitonin, urinary VMA, gene tracking in families using DNA probes
Early treatment of endocrine tumours
Familial polyposis coli
Relatives of affected individuals
Sigmoidoscopy, gene tracking in families using DNA probes, ophthalmoscopy for associated retinal lesions
Identification of gene carriers, early treatment of malignancy
Familial breast cancer
Females in families with multiple affected members
Mutation analysis of BRCA1 and BRCA2 genes
Identification of gene carriers. Prophylactic mastectomy or medical treatment
erations should be taken and details of racial background and consanguinity (i.e. whether parents have common ancestors) obtained. 2. Accurate diagnosis in affected family members. An accurate diagnosis in affected family members must be made. This should include both a pathological diagnosis (established where possible from original notes and investigations) and an assessment of any genetic subgroup of the disorder. 3. Ancillary tests. Chromosome analysis, DNA marker studies or other carrier detection tests may need to be carried out, according to the nature of the problem. 4. Risk assessment. For single gene disorders risk assessment is sometimes straightforward, providing a correct diagnosis is available. For instance, the recurrence of risk for a couple who have had one child with phenylketonuria is 1 in 4, because phenylketonuria is autosomal recessive. Difficulties arise where a disorder has different inheritance types (e.g. retinitis pigmentosa) and with X-linked disorders, where carrier detection tests may need to be applied, new mutations have to be considered and risks must be modified to allow for normal sons in the pedigree. In addition, disorders with a late age of onset (such as Huntington's chorea) or of variable expression (such as tuberous sclerosis) can present problems that may require a specialist opinion. Where linked DNA probes are used, risk assessment can become complex. If a condition is caused by a chromosomal abnormality or is multi-
factorial, empirical risks derived from follow-up studies must be used. 5. Prenatal diagnosis. The availability of prenatal diagnostic tests (Table 3.13) has to be assessed and any possible risks to the mother or fetus weighed against the risk of fetal abnormality.© 6. Communicating risks. Having marshalled all the facts, sufficient time must be set aside to discuss the risks in detail with the patient. A non-directive approach should be taken, whereby objective risks are given and discussed in detail, in the light of the severity of the condition and the availability and reliability of prenatal diagnosis. These factors may be crucial in the final decision of the parents. It is best to give the risks as a proportion (i.e. 1 in 2, 1 in 100 etc.) and to emphasize that a 1 in 20 risk of a child being affected means that 19 times out of 20 the child will not be affected. In order to put the risks into perspective, it is also worth pointing out that over 1 in 50 children are born with significant abnormalities at birth. In comparison to these background risks, a genetic risk of 1 in 20 is generally regarded as low, and those of greater than 1 in 10 as relatively high. However, the perception of an 'unacceptable' risk will depend on a large number of factors. The severity of the condition and the availability of treatment will obviously affect the willingness of a couple to have further children. For example, a 1 in 20 risk of a child with isolated cleft lip and palate will often be seen as acceptable, whereas the
3
75
TABLE 3.12 Therapy for single gene disorders*
TABLE 3.13 Techniques of prenatal diagnosis
Treatment
Procedure
Timing
Types of disorder detected
Villus biopsy
Transcervical 9-11 weeks Transabdominal 12-1 6 weeks
Cytogenetic abnormalities Enzyme defects Single gene defects (DNA probes)
Maternal ct-fetoprotein
16-1 9 weeks
a-fetoprotein Raised: neural tube defects Lowered: Down's syndrome Lowered: Edwards' syndrome (N.B. These are screening tests; diagnosis must be confirmed by further investigation)
Amniocentesis
16-20 weeks
Cytogenetic abnormalities Enzyme defects Neural tube defects Single gene defects (DNA probes)
Ultrasound
From 16 weeks
Anatomical defects Neural tube/hydrocephalus Body wall defects Limb reduction defects Hydrops Major urinary anomaly Bone dysplasias Cardiac defects Craniofacial anomalies
Fetoscopy/ cordocentesis
16-20 weeks
Fetal blood sample Clotting disorders Haemoglobinopathies Cytogenetic abnormalities Fetal skin biopsy Epidermolysis bullosa Ichthyosis Albinism Fetal liver biopsy Urea cycle enzyme defects Fetal visualization Craniofacial defects Digital defects Genital defects
Replacement therapy Replacement of deficient protein Replacement of deficient vitamin or coenzyme: Vitamin B12 Vitamin D Biotin Replacement of deficient metabolite: Cortisone Thyroxine Organ or cell replacement Kidney Bone marrow Blood transfusion Amelioration therapy Restriction of substrates in diet: Phenylalanine Methionine Galactose Drug therapy to remove harmful metabolites: Penicillamine Cholestyramine Iron chelating agents Avoidance of harmful drugs or dietary factors Preventive therapy Removal of potentially malignant tissues Removal of site of destruction of diseased cells (e.g. spleen)
Disorder
Haemophilias Diabetes
Methylmalonicacidaemia (some types) Vitamin D-resistant rickets Biotinidase deficiency Adrenogenital syndrome Congenital hypothyroidism Polycystic renal disease Immunodeficiencies Osteoporosis Thalassaemias
Phenylketonuria Homocystinuria Galactosaemia Wilson's disease Hypercholesterolaemia Thalassaemias G6PD deficiency Porphyria
Polyposis coli Spherocytosis
* After Emery & Malcolm (1995)
same risk for a child with severe, untreatable mental retardation may seem too high. 7. Sympathy and understanding. If a couple have given birth to an abnormal child, the genetic counselling clinic is often the place where considerable feelings of guilt are expressed. Alternatively, there may be an understandable tendency to blame poor medical care or environmental factors for the abnormalities. Time should be set aside to discuss all these feelings in a sympathetic and understanding manner, as they are part of the normal reaction to the birth of an abnormal child. Guilt and blame are usually the result of lack of information. Once a couple have been fully informed of the nature and causes of a child's problems, they can be helped to accept the fact that many genetic abnormalities are unavoidable.
76
Successful genetic counselling requires a combination of
communication skills, detailed genetic knowledge, and a sound clinical background in both adult and paediatric medicine, if couples are to be helped to make the most appropriate decisions about childbearing. It is this combination that makes the practice of clinical genetics so rewarding.
FURTHER READING Emery A E H, Malcolm S 1995. An introduction to recombinant DNA in medicine, 2nd edn. John Wiley, Chichester. A good introduction to the techniques and uses of DNA analysis in medicine. Rimoin D L, Connor J M, Pyeritz R E 1996. Emery and Rimoin's principles and practice of medical genetics, 3rd edn. Churchill Livingstone, Edinburgh. A comprehensive multiauthor text covering most of clinical genetics.
Harper P S 1998. Practical genetic counselling, 5th edn. Butterworth-Heinemann, Oxford. A comprehensive introduction to the problems of clinical genetics.
The UK Medical Research Council Human Gene Mapping Project Resource Centre (MRC HGMP-RC).
Lander E S, Schork N J 1994. Genetic dissection of complex traits.
This Centre exists to provide specialist resources and
Science 265: 2037-2047. An excellent review of the techniques for finding the genes involved in multifactorial inheritance. McKusick V A 1998. Mendelian inheritance in man, 12th edn. The Johns Hopkins Press, London. A catalogue of all known single gene disorders in man. . Mueller R F, Young I D 1998. Emery's elements of medical genetics, 10th edn. Churchill Livingstone, Edinburgh. An excellent
services
introduction to medical genetics.
Worldwide Web computer addresses A vast amount of free information is available through the Worldwide Web (WWW). A few useful addresses are given below:
a
URL: .. http://www.hgmp.mrc.ac.uk/
OMIM (Online Mendelian Inheritance in Man) This database is a catalogue of human genes and genetic disorders authored and edited by Dr Victor A McKusick and colleagues at Johns Hopkins and elsewhere. This is an excellent place to look for up-to-date clinical and molecular information about genetic disorders. URL: http://www3.ncbi.nlm.nih.gov/omim/
77
This page intentionally left blank
THEIMMUNESYSTEM
4
4
INNATE IMMUNITY
Immunological Disorders
The components of the innate immune system provide a constant, unchanging system of protection for the healthy individual (Table 4.1). These physical and chemical barriers are an essential contribution to good health.
David Edgar and Herb Sewell Physical barriers and phagocytes
The immune system 79
Hypersensitivity 96
Immunodeficiency
Immune-suppression 102
85
INTRODUCTION This chapter describes the components of the immune system and their interactions in the defence against infection. It is only intended to provide the reader with sufficient basic scientific detail to understand the clinical disorders described. Abnormal or inappropriate immune responses cause the clinical conditions of immunodeficiency and allergy, and these are discussed with an emphasis on clinical presentation, investigation and management. The principles of autoimmunity, along with conventional and novel immunosuppressive therapies, are also discussed. Throughout, the chapter highlights how recent advances in understanding the immune response at a molecular level have had an impact on clinical practice. The human immune system has developed to combat infection by a diverse range of potential pathogenic microorganisms: bacteria, viruses, fungi, protozoa and helminths. It is a complex but effective system comprised of multiple components which have both specific and overlapping functions. The immune system is conventionally subclassified into the innate and adaptive components, the essential functions of which are: • The differentiation of self from non-self; • The recognition of foreign proteins by specific molecules (antibodies, T-cell receptors); • The recall of previous exposure to specific organisms and the production of a rapid, more effective response upon re-exposure. The last two are characteristic of adaptive immunity.
The intact skin and mucous membranes constitute a barrier to the entry of microorganisms. These agents must therefore rely on physical damage, such as injuries or insect bites, to gain access to the body. Numerous natural antimicrobial substances also exist that fatally damage microorganisms. These include unsaturated fatty acids that are secreted on to the skin, lysozyme that is secreted in tears, and others, including gastric acid. Interferons are a further family of molecules (oc,P,y) that block viral replication and promote antiviral immune responses. However, some microorganisms have developed specific attachment and penetration mechanisms to bypass these initial defences. An example is rhinoviruses, which penetrate the respiratory mucosa by first attaching to a cell surface adhesion molecule ICAM-1 (intercellular adhesion molecule-1). If microorganisms are successful in breaching the physical defences, they are usually phagocytosed and killed by polymorphonuclear leukocytes (PMN) or macrophages. Some bacteria (e.g. pneumococci) can resist phagocytosis by virtue of their capsules, whereas others (e.g. staphylococci) release toxins that destroy phagocytes. Whereas some microorganisms can survive within phagocytic cells (e.g. mycobacteria), giving rise to chronic infection, most are killed in the phagolysosomes by a combination of acid pH, oxygen metabolites (e.g. hydrogen peroxide) and various cytotoxic proteins. However, not all killing is intracellular, and macrophages or PMN can secrete toxic molecules in order to kill large targets, e.g. worms (helminths). In the case of viruses and tumours, natural killer (NK) cells also play an essential role.
TABLE 4.1 Innate and adaptive immune systems Innate Physical protection (skin, mucous membranes) Chemical protection (lysozyme, gastric acid) Interferons Phagocytes Complement
Adaptive Antibody Lymphocytes
79
complement and phagocytes are recognized as primary immunodeficiency diseases (PID). In addition, individual elements of the innate system are essential in stimulating the adaptive response during antigen presentation. Although classification into innate and adaptive helps our understanding of the immune response, it is important to remember that these elements are interdependent and function as an integrated system.
ADAPTIVE IMMUNITY
FIG. 4.1 Complement activation pathways The central event in complement activation is cleavage of C3 with the subsequent formation of C5 convertase. The generation of cleavage products (indicated by blue lines) augments the inflammatory response by attracting and activating phagocytes and causing activation and degranulation of mast cells. The deposition of C3b on cellular surfaces to promote phagocytosis is known as opsonization. The terminal pathway components (C5-C9) create the membrane attack complex (MAC) which causes osmotic cell lysis.
Complement system A further line of innate defence is the complement system (Fig. 4.1), a cascade of serum proteins which, when activated in succession, mediate three important effects: • Release of small peptides that stimulate inflammation and attract phagocytes; • Deposition of the cleavage component (C3b) on microbial membranes, which promotes phagocytosis via C3b receptors on phagocytic cells; • Assembly of complement components (C5-C9) into lytic complexes which puncture cell membranes, causing osmotic death. This activation 'cascade' is triggered by numerous microbial surfaces, notably the endotoxins of Gram-negative bacteria, by C-reactive protein (CRP) and mannan-binding lectin (MBL). Through interactions with antibody, phagocytes and mast cells, the complement cascade has an important role in integrating the response to infection.
Summary
80
The innate immune system is essential in the defence against infection, and deficiency can result in serious clinical consequences. The vulnerability to infection of patients with severe burns emphasizes the protective value of normal skin. As will be described later, specific defects of
The adaptive immune system differs in two important respects from the innate, with its characteristics of specificity and memory. The adaptive system responds to the environment and 'remembers' specific encounters with foreign antigens. The most important cells involved in the adaptive response are lymphocytes (B and T cells). The antigen recognition molecules on the surfaces of B and T cells (antibody and T-cell receptors) confer the specificity of the adaptive system. These molecules recognize and bind to specific antigens through amino acid sequences that are complementary in structure to the target antigen. Immunological memory is generated after the first antigen exposure (primary response) because antigen-specific lymphocytes proliferate and generate an increased pool of cells. These memory cells, responsive to the specific antigen, remain relatively inactive until the same antigen is encountered again (secondary response). Subsequent stimulation of memory cells results in a secondary immune response that is more rapid and quantitatively greater than the primary response (Fig. 4.2).
Lymphocytes Lymphocytes originate from stem cells in the bone marrow. B lymphocytes complete their maturation in the bone marrow, but T lymphocytes require passage through the thymus, where they complete their maturation and education process. Crucially, it is in the thymus that T cells learn to identify 'self proteins', and any autoaggressive T cells are either allowed to die (by apoptosis) or are rendered non-reactive (tolerant). The bone marrow and thymus are referred to as primary lymphoid organs. The secondary lymphoid organs include lymph nodes, the spleen, Peyer's patches, tonsils and adenoids. These are strategically located to encounter microorganisms entering the body through external tissues, blood, gut, and upper airway, respectively. The structure of secondary lymphoid tissue is exemplified by the lymph node, where the cortex contains mainly B lymphocytes and the paracortex T lymphocytes, whereas antibody-secreting plasma cells are found in the medulla. Peripheral blood normally contains 70-90% T cells, 5-10% B cells and approximately 1-10% natural killer (NK) cells. A characteristic of lymphocytes is their ability to 'traffic' from peripheral blood into the tissues and secondary lymphoid organs. This property allows lym-
4
FIG. 4.2 Primary and secondary antibody responses Primary and secondary antibody responses to antigen. This demonstrates the characteristics of the adaptive immune response, i.e. specificity and memory. Upon re-exposure to antigen the immune system recognizes the antigen due to immunological memory. The resulting response has a shorter lag time (lag 2) and a quantitively greater antibody response.
phocytes to encounter antigen in almost all physical locations. The lymphoid tissues of the gut, genitourinary tract, breast and lungs behave, to a certain extent, autonomously, in that particular B cells (largely IgAsecreting) and T cells recirculate selectively through them. This recirculation is mediated by the expression of specific homing receptors and is referred to as the mucosal immune system. The result is that primary antigen exposure at one mucosal site will facilitate protective immunity at other mucosal sites. B cells
The main function of B cells is antibody production. Some B cells are stimulated directly by polymeric antigens and these responses are termed T-independent (e.g. bacterial capsular polysaccharides). Most B-cell responses are however T-cell dependent. For T-dependent responses, B cells are triggered to proliferate by interaction between their surface Ig and the antigen, but they require additional signals from T-helper cells in order to differentiate into plasma cells and secrete antibody. These signals consist of non-antigen specific cytokines (particularly IL-4 and -6) and cell-cell-mediated signalling. The interaction of these cell surface molecules, e.g. gp39 (CD40 ligand, CD40L) on T cells with CD40 on B cells, is essential in facilitating effective B-cell antibody production. During T-dependent responses some proliferating B lymphocytes are retained in germinal centres instead of differentiating 'terminally' into plasma cells. These are the memory B cells. Antibodies Antibodies are a family of five major classes of molecule which have a primary role in combating microorganisms free in the blood or tissue spaces, primarily viruses in their
FIG. 4.3 Immunological molecules V = variable, D = diversity, J = joining, C = constant, HC = heavy chain, LC = light chain, VH/L = variable region of heavy/light chain, CH1(2,3) = constant region 1 (2,3) of heavy chain, CL = constant region of light chain.
extracellular stage, and many bacteria. The antibody or immunoglobulin (Ig) molecule is ideally suited to its function of promoting the removal of foreign antigens. Its basic structure is seen in antibodies of the IgG class (Fig. 4.3). The N-terminal half is composed of heavy (H) and light (L) chains and is responsible for binding to antigen (Fab portions). The C-terminal half (Fc), which consists of portions of heavy chains, determines the class of antibody and is responsible for the other biological functions of the molecule. The major role of antibody molecules is to bind to microorganisms via the Fab portion, enhancing phagocytosis, as phagocytes possess Fc receptors. This process of coating microorganisms with antibody is known as opsonization. The basic four-chain structure is preserved in all five classes of immunoglobulin, but each class has certain characteristics that subserve its specific functions. • IgG molecules are involved in the activation of complement, attachment to phagocytic cells, passage into the tissues and transport across the placenta. The four IgG subclasses (IgG1, IgG2, IgG3 and IgG4) vary somewhat in these functions. • IgM is a large molecule with a pentameric structure. It is mainly confined to the bloodstream and is very efficient at activating complement and agglutinating foreign material because of its 10 antigen-combining sites per pentameric complex. • IgA is the predominant immunoglobulin class secreted at mucosal sites. It has a dimeric structure and is protected from proteolytic damage by a special polypeptide, the secretory chain (Sc). Sc is produced by the mucosal epithelial cells and acts as a receptor-transporter, binding to and taking the antibody into external sites. IgA can
81
TABLE 4.2 Immunoglobulin structure and function Class & subclass
Structure
Major functions*
Monomer Monomer Monomer Monomer
C&O
Pentamer
c
Dimer
Mucosal protection Mast cell activation Antigen binding
IgG
IgG, IgG2 IgG3 IgG4 IgM IgA
IgE IgD
Monomer Cell surface bound
c C&O 0
*C, complement activation; 0, opsonization.
therefore survive proteolytic attack in secretions of the eyes, lungs, nose, gut and urinary tract. • IgE attaches via its Fc region to receptors on mast cells. When two bound IgE molecules are cross-linked by antigen, intracellular signalling results in the release of mediators from mast cell granules which cause the clinical features of acute allergy. • IgD is found mainly on B-cell membranes and acts as an antigen receptor. Its soluble form is not thought to have a significant physiological role. The properties of the various Ig classes and subclasses are summarized in Table 4.2. Antibody genes Genes on three different chromosomes code for antibody molecules. The genes of heavy and light chains are not continuous in the germline, but consist of separate clusters of gene segments separated by non-informative regions called introns. The clusters are named according to the part of the immunoglobulin molecule that they encode (Fig. 4.3), i.e. V, variable; D, diversity (heavy chains only); J, joining; and C, constant. During the development of a B cell, the germline DNA encoding the heavy-chain genes undergoes somatic rearrangement and recombination such that a complete heavychain variable region gene, V-D-J, is assembled. After transcription, RNA is spliced to link the V-D-J segment with a C segment to encode a complete heavy chain (V-D-J-C). Once this is accomplished, the light-chain genes rearrange to encode a complete light chain (V-J-C). Heavy and light chains then link together to form a complete antibody molecule. If rearrangement is not successful, the developing B cell is aborted. Enzymes (recombinases) encoded by two genes termed RAG1 and
1 82
MCQ4.1
RAG2 largely control the recombination events in lymphocyte progenitors. Defects or mutations associated with these genes can profoundly and adversely affect the development of the immune system. After gene rearrangement, the B cell does not restore the germline configuration and daughter cells will retain this unique rearrangement, ensuring continued antigenic specificity of that clone and its entire subsequent offspring (progeny). This is the molecular basis of immunological memory, thus maintaining immunological specificity in the clonal progeny. The heavy-chain C gene can, however, change to allow class switching (e.g. IgM-IgG) during the immune response, as occurs in moving from a primary to a secondary response. During the life of a B cell, point mutations may occur within the variable regions (somatic mutation), resulting in a change of affinity of the antibody molecule. Increased affinity for antigen confers a selective advantage to any B cell. This phenomenon results in affinity maturation whereby, as an immune response progresses, antibodybinding affinity increases. The huge potential diversity (i.e. the ability of humans to respond to a multitude of different foreign antigens) of antibody binding specificity (up to 108 specificities) is thus achieved by a number of mechanisms: • Association of different heavy chains with either K or X light chains; • Association of V genes with different (D) and J genes; • Genetic joining errors; • Somatic mutation. Genetic differences between antibody molecules are known as isotypic if they occur in the constant region and as idiotypic if they reside in the hypervariable regions (the sites associated with direct binding to antigen; Fig. 4.3). The idiotype of an antibody is the portion defining the uniqueness of that variable region, and may include both the antigen-combining site and the adjacent regions. There are also allelic differences known as allotypes, mainly within the C regions, which enable the antibody molecules of different individuals to be distinguished.1
T ce//s The major effector role of T cells is the elimination of viruses, fungi and protozoa, but they also act as coordinators of the overall adaptive immune response. B and T lymphocytes are impossible to distinguish by light microscopy and therefore more sophisticated techniques are needed (e.g. flow cytometry) which can identify specific cell typespecific surface antigens (CD antigens). All T cells bear the CD3 antigen, which is associated on the cell surface with the T-cell receptor (TCR). Cytotoxic T cells (Tctx) are responsible for killing abnormal host cells (e.g. virally infected, malignantly transformed or transplanted cells) and, in addition to possessing CD3, are also positive for the surface molecule CDS. They destroy target cells by several mechanisms, including cell membrane interactions (such as that of the Fas antigen
4
FIG. 4.4 Interaction of T cell receptor and HLA molecules The T cell is 'restricted' in that CD8+ T cells only recognize antigen when it is presented in association with HLA class I molecules. CD4+ cells only recognize antigen in association with HLA class II molecules.
(CD95) with its ligand) and the release of cytotoxic substances: perforins, granzymes and other cytokines. Helper T cells (Th), in addition to expressing CDS, also express CD4. It is helpful to remember some of these more common CD numbers, as these are important in describing primary immune deficiency states and lymphoproliferative diseases.
FIG. 4.5 Antigen processing and presentation 2 = 2 -microglobulin, TAP = transporter of antigenic peptides, class 1, WV = peptide, =C = HLA class II.
= HLA
TABLE 4.3 Major HLA associations The T-cell receptor (TcR, Fig. 4.4) The T-cell receptor is a two-chain (a and , or y and 6) molecule, rather like a shortened immunoglobulin. However, it has a more complicated combining site than antibody, and recognizes linear fragments of small foreign peptides in combination with molecules of the human leukocyte antigen system (HLA). The TcR-associated CD4 or CD8 molecules determine whether the individual T cell recognizes antigen in association with class I or class II molecules. CD8-expressing T cells only recognize antigen when it is presented with HLA class I molecules, whereas CD4-expressing T cells are only stimulated by antigen in association with HLA class II molecules. The human leukocyte antigen (HLA) systems The HLA system is the major determinant of transplant rejection responses. However, its normal physiological function is mainly to control cell-cell interactions, particularly within an individual's own immune response. The HLA genes lie on the short arm of chromosome 6 and are grouped into two major sets, referred to as class I and class II. Each set contains three genetic loci that have a large number of alleles coding for HLA antigens. The genes for some complement components and cytokines also lie within the same region (the class III region), but their products are quite unrelated to class I and class II molecules. Class I molecules consist of a large oc chain, and a small P chain known as pVmicroglobulin. 2-Microglobulin is encoded on a different chromosome and shows no sequence variability. Class I antigens (i.e. alleles at the A, B and C loci) are expressed on all nucleated cells (two from
Disease
HLA-B
Ankylosing spondylitis Rheumatoid arthritis SLE Celiac disease IDDM* Hashimoto's disease
27
HLA-DR
4 3 8 8
3 3,4 5
*IDDM, insulin-dependent diabetes mellitus.
each locus on diploid cells). Class II HLA molecules are two-chain ( and ) structures both chains are encoded in the HLA locus and are polymorphic. Class II antigens (alleles at the DP, DQ and DR loci) are expressed on a more limited range of cells: classic antigen-presenting cells, B lymphocytes and activated T lymphocytes. Class I and II antigens are central to antigen presentation and the generation of an effective immune response. Knowledge of the HLA alleles expressed by an individual is clearly essential for most organ transplantation. In addition, particular HLA types are also known to be associated with certain diseases (Table 4.3). In some circumstances the HLA association is so strong as to be helpful in diagnosis, e.g. HLA B27 and ankylosing spondylitis. Antigen presentation (Fig. 4.5) Antigen-presenting cells (APC) include macrophages, dendritic cells of the spleen and lymph nodes, Langerhans' cells of the skin, and B cells. Antigenic fragments are pre-
83
FIG. 4.6 CD4 + cell activation after antigen presentation The binding of cell surface receptors to their cell-bound or soluble ligands results in a series of positive (+) or negative (-) signals transmitted to the CD4 T cell nucleus. Secretion of IL-2 activates both the secreting T cell and its near neighbours. sented to T cells in specialized 'antigen-binding grooves' in HLA class I and class II molecules. Class I molecules present peptides which are endogenously synthesized, e.g. viral proteins in an infected cell, whereas class II molecules present peptides from external proteins (e.g. extracellular microorganisms) which have been engulfed and degraded to peptides by the APC. There are distinct intracellular pathways involved for class I and class II presentation. Class II molecules are synthesized within the rough endoplasmic reticulum (RER) and, bound to a second molecule called the invariant chain, are transported to the endosomal compartment. There the invariant chain is replaced by antigenic fragment and the complex is transported to the cell surface. Class I molecules are also synthesized in the RER and are initially anchored on the inner surface of this organelle. Peptide fragments generated in cytoplasmic proteasomes are transported into the RER by specialized transporter proteins TAP-1 and TAP-2 (TAP = transporter of antigenic peptides). The peptide fragments then bind to the class I molecule and this complex associates with pVmicroglobulin before being transported to the cell surface (Fig. 4.5). * In addition to TcR recognition of the HLA/antigenic fragment, the CD4 molecule binds to a non-polymorphic region of the HLA class II molecule. Several other adhesion molecule pairs (LFA1/ICAM-l, CD2/LFA-3) link together, strengthening the cellular adhesion. The interaction of a T-cell surface molecule CD28 with B7 molecules on APCs is believed to be crucial to T-cell activation, as is the secretion by the APC of IL-1.
1 MCQ 4.2
84
Th-cell activation (Fig. 4.6) CD4+ T-cell activation is dependent on a series of 'costimulatory' signals consisting of cell-cell surface binding and soluble cytokines.* The result of these 'positive signals' is the generation of gene transcription factors (such as NFAT - nuclear factor of activated T cells) which 'switch on' genes (e.g. IL-2 gene) within the T-cell nucleus. Once IL-2 is secreted, it acts on both the responding and neighbouring cells. In contrast to CD28, a molecule termed CTLA4 appears to be crucial in donwegulating the T-cell immune response. CTLA4 appears on T cells late in their activation and also binds to B7 molecules (see above), but this binding delivers a negative signal to 'switch off responding T cells. Constructs of CTLA4 have recently been used in clinical trials (phase I and II) to downregulate unwanted T-cell responses in transplantation rejection and in autoimmune disorders. The increase in understanding of the key signalling molecules involved in antigen presentation will undoubtedly result in further attempts at therapeutic manipulation. Regulation of immune responses Both T and B cells are activated by recognition of specific antigens. Effective removal of antigen is therefore an important physiological endpoint for an immune response. However, the immune system has several additional mechanisms that regulate the nature and intensity of the immune response: • Apoptosis (programmed cell death) is now recognized as an important regulatory mechanism for the disposal of immune cells which have completed their function. • Anti-idiotype antibodies are directed against the V region of the Fab portion (idiotype) of other antibody
4
TABLE 4.4 The major cytokines aiid their functions Cytokine
Natural source
Functions
Potential clinical uses
TNF-a and p
Macrophages
Antitumour, antiviral, vascular damage, PMN activation, bone resorption, induces IL-1 etc.
Anti-TNF moAb used for rheumatoid arthritis, inflammatory bowel disease
Interferon-
Macrophages
Antiviral
lnterferonInterferon-y
Fibroblasts T eel Is
Antiviral Antiviral, activates macrophages, increases mycobactericidal activity
IL-2 IL-5 IL-6
T cells T cells, mast cells T cells, fibroblasts, ARC, hepatocytes T cells, monocytes Macrophages
Activates T, B and NK cells Eosinophil growth and activation B-cell growth and differentiation; induces acute-phase response Neutrophil activation and chemotaxis Granulocyte growth and maturation
Hepatitis B&C, papillomatosis, Kaposi's sarcoma, hairy cell leukemia, chronic myeloid leukaemia Multiple sclerosis Multidrug-resistant TB, lepromatous leprosy, visceral leishmaniasis, IFNyR deficiency, chronic granulomatous disease, hyper-lgE syndrome, chronic mucocutaneous candidiasis Melanoma, renal cell carcinoma Anti IL-5 moAb in phase II clinical trials for asthma
IL-8 G-CSF
IL-8 receptor antagonist in preclinical trials for airway disease Cyclical neutropenia, chemotherapy 'rescue'
After activation, however, there is a preferential commitment towards either a Thl or a Th2 pattern (Fig. 4.7). Thl cytokines are IL-2, IL-12 and IFN-y, favouring a cellular immune response, whereas Th2 cytokines, favouring an antibody response, are IL-4, IL-5, IL-6 and IL-10. There is mutual suppression between these two dominant patterns of cytokine secretion such that, once a response has become committed in either direction, this pattern will tend to be maintained. It is therefore currently believed that the 'suppression' of immune response seen in certain situations is the net result of a balance in the type of cytokines secreted in the microenvironment, rather than the function of a single cell type. This is important in understanding the influence of the immune response on the pattern of clinical diseases such as leprosy (see hypersensitivity section).1
FIG. 4.7 T cell differentiation The blue lines indicate secretion of soluble mediators, the black lines indicate suppressive activity. For explanation see text.
molecules and may block or modulate antibody function. • A specific T-suppressor cell subset has not been identified in humans. There is, however, increasing evidence, in both animals and humans, that the pattern of cytokines secreted by CD4+ T cells will preferentially induce either a predominantly cellular or an antibody response. The major cytokines, their actions and potential clinical importance are summarized in Table 4.4. Prior to activation, most CD4+ T cells are 'ThO' (i.e. they have the potential to secrete a wide range of cytokines).
IMMUNO DEFICIENCY
Immunodeficiency is classified asprnnory (where the cause is/was previously unknown) or secondary, where there is a recognized cause for the immune defect, such as cancer, infection, drug treatment, radiotherapy or malnutrition.
PRIMARY IMMUNODEFICIENCY Understanding of primary immunodeficiency has increased rapidly over recent years with the identification of specific molecular lesions in a number of these previously poorly understood conditions. Research into these conditions has increased our understanding of the cell biology of the immune response and led to new diagnostic strategies and experimental forms of gene therapy in humans.
85
Primary immunodeficiency diseases (PID) are subclassified according to the individual immunological components involved, hence there are antibody, T-cell or combined deficiencies, as well as phagocytic and complement component deficiencies. The defect in each condition leads to preferential susceptibility to certain types of organisms. Typically, antibody deficiency causes susceptibility to bacterial infection: T-cell deficiency to viral and fungal infections; and some complement deficiencies to meningococcal infections. These associations are important in consideration of the initial immunological differential diagnosis.
What are the characteristics of infection in PID? If the clinical history of infection can be described as serious, persistent, unusual or recurrent (SPUR), then immunodeficiency should be part of the differential diagnosis. 'Serious' suggests a potentially life-threatening infection (meningitis or septicaemia). 'Persistent' suggests that an infection is particularly resistant to conventional therapy. Infections may be 'unusual' in terms of site (liver/ brain abscess, or osteomyelitis) or organism (Pneumocystis, Aspergillus, Mycobacteria), and these should always raise the possibility of immune deficiency. Finally, 'recurrent' infection is particularly important. The child or adult who repeatedly presents with infection deserves further investigation of his or her immune status. It is difficult to be specific about how many infections constitute a 'recurrent' problem, and this inevitably involves an assessment of both frequency and severity of infection, evidence of organ damage, impact on systemic wellbeing and normal daily activity. The '10 warning signs of immune deficiency' are by no means exhaustive, but do give practical guidance on the clinical features that should prompt investigation for PID (Table 4.5)
When to suspect the diagnosis? Patients with PID may present with a history of infection or with a family history of an affected relative. More com-
TABLE 4.5 Ten warning signs of immune deficiency
86
1. 2. 3. 4. 5. 6. 7. 8. 9. 10.
8 or more new ear infections/year 2 or more serious sinus infections/year 2 months antibiotics without effect 2 or more episodes of pneumonia within a year Failure to thrive Recurrent, deep abscesses Persistent thrush after 1 year of age Need for intravenous antibiotics 2 or more deep-seated infections (sepsis, meningitis, cellulitis) Family history of PID
monly, they may present with the long-term complications of their condition (e.g. bronchiectasis). They may also present with a combination of clinical features and laboratory abnormalities that may not initially alert the non-specialist to the underlying diagnosis (e.g. chronic ill health, autoimmune phenomena). It is very typical for patients with PID to suffer a prolonged delay before the correct diagnosis is made, despite attending many doctors. During this period of delay they suffer significant morbidity and even mortality, and it is therefore essential that there is increased awareness of these conditions to allow earlier diagnosis and treatment. The simple guidelines from the history (Table 4.5) are useful in determining the most appropriate first line of immunological investigation. It is important that investigations are used appropriately and that expert advice is available, both in the selection of tests and in the interpretation of results. The general principles guiding investigation for immune deficiency include determining both that the relevant components of the systems are present, and that they are functionally intact. It is particularly important in the investigation of children that all immunological results are compared to appropriate, age-related normal ranges. Increasingly, specific molecular tests are used to confirm diagnoses, and therefore subtler variant forms of immune deficiency are being recognized.
Primary antibody deficiency diseases X-linked agammaglobulinaemia (XLA/Bruton's type) Clinical features Affected boys usually present between 6 months and 2 years of age. There may be a family history of affected male relatives. The most common complaint is of recurrent bacterial infections (typically Streptococcus pneumoniae or Haemophilus influenzae), usually affecting the respiratory tract, which if untreated lead to bronchiectasis. Boys may present with ear or joint infection and some have a nonspecific arthropathy that responds to the introduction of immunoglobulin replacement therapy. Chronic diarrhoea and a malabsorption syndrome may occur as a result of Giardia lamblia infection. A helpful physical sign is the absence of tonsillar lymphoid tissue or lymphadenopathy. A particular long-term complication in XLA is mycoplasma or ureaplasma arthritis. This is distinct from the more frequent non-specific arthropathy and is difficult both to diagnose and to treat. XLA patients are also susceptible to enterovirus infection (polio, coxsackie or echoviruses). Oral polio vaccine is therefore contraindicated, as it may cause paralysis, and a chronic meningoencephalitis may result from coxsackie or echovirus infection. This latter complication has become rarer since the advent of intravenous immunoglobulin therapy, but it still occurs either as a generalized condition or in a more limited form, causing sensorineural deafness. The prevalence of XLA is thought to be approximately 1 in 100000 in the UK, but
with the advent of molecular testing a milder, previously undiagnosed, form is being identified. Investigation Serum IgG level is usually less than 2g/L, with serum IgA, IgM and IgE being undetectable. Measurement of IgG subclasses is not usually helpful. Isohaemagglutinins are typically absent, as are specific antibodies to previously administered vaccines. Mature B cells are not usually detectable in peripheral blood, but T-cell numbers and function are normal. Neutropenia may be a feature. In the atypical, less severe, cases immunoglobulin levels are more variable and low numbers of circulating B cells are detected (typically in young teenage or adult males). In such cases the diagnosis can be difficult and test immunization responses to protein and polysaccharide antigens (usually tetanus toxoid and pneumovax II) are very helpful. Antigen-specific antibody levels are measured before and 4 weeks after immunization. Results require expert interpretation. The underlying molecular lesion has been characterized as a defect of the intracellular tyrosine kinase 'Bruton's tyrosine kinase' (Btk), coded for at X21.3-22. This kinase is essential for normal B-cell maturation, and B-cell development is therefore arrested at the pre-B stage. Family assessment to identify carriers is possible and should be undertaken, with appropriate genetic counselling. Rare autosomal recessive cases occur. Management of antibody deficiency Replacement therapy with regular intravenous immunoglobulin (ivlg) is now the standard treatment for primary antibody deficiency. This lifelong treatment is extremely effective in controlling infection, improving quality of life and preventing end-organ damage. The usual dose is 400mg/kg, given every 3 weeks. Regular preinfusion serum IgG levels are measured and should be maintained within the physiological range (usually >8g/L). Patients contribute to their own monitoring by completing diary sheets which record their general wellbeing, frequency of infections and antibiotic requirement. Patients must be weighed regularly and appropriate increments in ivlg dose made, because growth (in children) and weight (in adults) often increases significantly after the initial diagnosis and treatment. Various ivlg preparations differ in their con-tent. Once a patient is established on a particular product, it must not be changed without clear clinical indications. The main potential side-effect of treatment is reaction to the infusions. This may be related to infusion rate, intercurrent infection, or anti-IgA antibodies in IgA-deficient patients. Transmission of viral infection is now a very small risk because of careful viral screening and new antiviral steps in the production of ivlg from pooled donor sera. Recent advances include self-administration of ivlg at home and the development of subcutaneous administration (sclg), which is of particular value in the very young. Although immunoglobulin replacement is the mainstay of
treatment for antibody deficiency, there are other aspects of therapy. When respiratory infection occurs, patients should be treated over an extended period (usually 10 days) with high-dose antibiotics, guided by antibiotic sensitivity. Patients should be encouraged to undertake regular breathing exercises to assist with expectoration of sputum, and in those with established lung damage postural drainage should be undertaken daily. Regular assessment of pulmonary function is advised; however, 'routine' use of X-ray and CT examination (e.g. at annual review) is not advised in patients with PID. Many of these conditions predispose to a range of malignant diseases, and 'non-essential' exposure to radiation should therefore be avoided.
4
Common variable immune deficiency (CVID)/ acquired hypogammaglobulinaemla Clinical features This condition usually presents in adults with established lung disease or recurrent pyogenic infections. It is very typical for there to be a diagnostic delay of many years, during which respiratory function has deteriorated. Patients with CVID are at increased risk of autoimmune phenomena, including thrombocytopenia, haemolytic anaemia, malabsorption syndromes and organ-specific autoimmune disease. They have a particular tendency to granuloma formation and may present with lymphadenopathy or hepatosplenomegaly. The finding of typical granulomata on imaging may be helpful in establishing the diagnosis. These are usually non-caseating and steroid responsive, but treatment is not necessary if lesions are asymptomatic. A further characteristic complication of CVID is nodular lymphoid hyperplasia (NLH), in which lymphoid tissue of the gut becomes hyperplastic and produces characteristic filling defects on small bowel radiology series. NLH is thought to be a prelymphomatous condition, but CVID patients without NLH also have an increased risk of malignancy, particularly of lymphoma. CVID prevalence is estimated as 2-4 :100000 in the UK, but is probably underdiagnosed. IgG subclass and specific antibody deficiencies are thought to be related conditions, and some will progress to more typical CVID. Investigation Total serum IgG level is usually less than 3g/L; the levels of IgA and IgM are more variable. The diagnosis can therefore be difficult, and test immunization as described in investigation of XLA is required. In CVID the responses are poor or absent. Measurement of IgG subclasses is not usually helpful. Peripheral blood lymphocyte subset analysis may indicate a reduction in the proportion of CD4+ T cells that also carry the CD45RA antigen. Lymphocyteproliferative responses may be reduced. Unlike XLA, a single genetic defect has not been described for CVID, but B cells from these patients do not develop normally into plasma cells. It is thought that there is an abnormality of T-cell regulation of B cells in CVID.
87
Management CVID patients require immunoglobulin replacement therapy as for XLA, with the possible addition of steroids for symptomatic granulomatous disease. CVID patients who are deficient in IgA should always be prescribed an ivlg preparation that is known to be low in IgA in order to reduce the risk of infusion reactions (see below). IgA deficiency Clinical features IgA deficiency is the most common primary immune deficiency in the UK, with a prevalence of approximately 1: 600. Most people with IgA challenge are identified by chance and are asymptomatic. The challenge is therefore to identify those in whom there is a significant immune deficiency. The history is crucial because IgA deficiency is known to be associated with an increased risk of pulmonary/sinus infections, allergy, celiac disease, other autoimmune diseases and malignancy. One must therefore look carefully for any suggestive clinical features in patients presenting with incidentally identified IgA deficiency. Furthermore, IgA deficiency can be a feature of some combined immune deficiencies (e.g. ataxia-telangectasia (page 93) and Wiskott-Aldrich syndrome (page 92)), and there may be clinical features suggestive of these diseases; IgA-deficient patients may form anti-IgA antibodies, which create a high risk of transfusion reactions to IgAcontaining blood products. If immunoglobulin replacement therapy is required, a product containing the lowest possible concentration of IgA must be used. Investigation IgA deficiency is defined by a laboratory measurement of serum IgA <0.05 g/L. The automated methods used in most routine laboratories are not sufficiently sensitive to detect these levels. Therefore, a routine report of 'low' level of serum IgA does not necessarily indicate a diagnosis of IgA deficiency. Once IgA deficiency is established, however, the patient must be fully evaluated to determine whether there is a clinically significant immune deficiency. A number of these patients will have associated IgG subclass deficiency and/or a failure of antibody responses to test immunization. If a combined immune deficiency syndrome is suspected, more extensive investigations are required (see ataxia-telangectasia (p. 93) and Wiskott-Aldrich syndrome (p. 93)).
88
Management It is only the minority of IgA-deficient patients who have a significant history of infection, and usually other laboratory evidence of immune deficiency (IgG subclass deficiency, failure of response to test immunization, combined immune deficiency syndromes), who require treatment. Options include prolonged high-dose antibiotics for infectious episodes, prophylactic antibiotics, and immunoglobulin replacement therapy. Very few patients without IgG subclass deficiency or failure of immunization responses require immunoglobulin replacement, which suggests that
isolated IgA deficiency, in the absence of such defects, is a relatively benign condition. IgG subclass deficiency Clinical features IgG subclass deficiency is regarded as a part of a spectrum of conditions, including CVID and IgA deficiency. In common with IgA deficiency, patients may be asymptomatic or give a typical history of recurrent bacterial infection. The simple identification of a slightly reduced level of an IgG subclass is not sufficient in itself to warrant a diagnosis of significant primary immune deficiency. IgG subclass deficiency is usually suspected when the clinical history is suggestive of antibody deficiency, but total IgG (and other immunoglobulin classes) are normal and other primary antibody deficiencies have been excluded. Full immunological assessment is essential before treatment decisions are made. Investigation IgG subclass development occurs slowly during early childhood, and it is therefore important to relate results to the correct age-related ranges. Total serum immunoglobulin levels are usually normal, or may be high if there is a compensatory rise in the level of the non-deficient subclass (usually IgG^. On investigation, T-cell numbers and function (measured by in vitro proliferation assays) are usually normal. A failure of specific antibody response to test immunization would support a diagnosis of clinically significant IgG subclass deficiency. Management Not all patients will require ivlg and a careful assessment of the clinical history and investigative results is required. As discussed under IgA deficiency, several therapeutic strategies may be introduced and monitored for evidence of clinical response. Specific antibody deficiency Clinical features These patients are particularly susceptible to pneumococcal infection, but their total serum IgG and IgG subclass levels are normal. The clinical features are otherwise typical of other antibody deficiency syndromes, except that the diagnostic delay is likely to be longer because of the subtlety of the defect. Investigation These patients fail to mount a specific antibody response to polysaccharide antigens (e.g. Pneumovax II) but respond normally to protein antigen (e.g. tetanus toxoid). By definition, they will have normal total serum immunoglobulin and IgG subclasses. Management As for IgG subclass deficiency, the appropriate therapeutic option for each individual patient is based on a combined assessment of the clinical severity of the defect and the investigative results. The typical clinical features
described will usually indicate a requirement for ivlg; however, equivocal responses to immunization do occur in some individuals who do not require specific therapy. Transient hypogammaglobulinaemia of infancy Clinical features As passively acquired maternal immunoglobulin disappears and the infant begins to produce its own immunoglobulin, there is normally a physiological low level of serum antibody levels between 3 and 6 months of life. In some infants this 'physiological nadir' is profound, prolonged, and associated with bacterial infections. There are no other specific features: this is a diagnosis of exclusion and the clinical priority is to ensure that the child does not have a primary immune deficiency, such as severe combined immune deficiency (SCID, p. 93), X-linked agammaglobulinaemia (XLA, p. 86) or very early-onset common variable immune deficiency (CVID, p. 87). Investigation Serum IgG and IgA levels will usually be below the agerelated normal ranges, but IgM levels may be normal and isohaemagglutinins should be detectable. Differentiation from primary antibody deficiency may be difficult at this stage, but it is essential that a primary immune deficiency be excluded. Close clinical and laboratory monitoring of such infants is required for evidence of emerging antibody production. A diagnosis of transient hypogammaglobulinaemia can only be made retrospectively when antibody levels have returned to normal and the baby is clinically well. Management Decisions regarding treatment depend on the severity of the clinical history. If there are only occasional minor infections, no treatment is indicated. If frequent infection is causing significant morbidity the range of therapeutic options for antibody deficiency should be considered. If immunoglobulin replacement is deemed necessary, despite diagnostic uncertainty, it is essential to observe the patient closely for signs of recovering endogenous antibody production. This may be detected by a rise in IgM or IgA levels in preinfusion testing (intravenous immunoglobulin (ivlg) products do not contain IgM or IgA). Planned withdrawal of ivlg is also possible to allow repeat immunological assessment, including test immunization. Withdrawal of ivlg must, however, be for a prolonged period before immunization, as the half-life of IgG in the circulation is approximately 3 weeks. Immune deficiency with associated hyper-IgM Aetiology This is a disorder of T-cell function which prevents IgMproducing B cells from differentiating into IgG-producing plasma cells. The molecular lesion is of the T-cell surface protein gp39 (CD40 ligand/CD40L) and the gene is located at Xq26-27. The interaction between B cells (expressing CD40) and T cells (expressing CD40L) is crucial in trig-
gering IgM-producing immunoblasts to differentiate into IgG-secreting plasma cells.
4
Clinical features As this is an X-linked condition (although autosomal recessive cases are reported), affected boys present with recurrent pyogenic infections related to their hypogammaglobulinaemia and a commonly associated neutropenia. A typical presentation is with Pneumocystis carinii pneumonia (PCP) in infancy, which is an unusual infection in antibody deficiency and the susceptibility is probably explained by an associated underlying T-cell defect. There is also increased susceptibility to cryptosporidial infection, with ascending cholangitis and chronic liver impairment. There is an increased incidence of malignancy, particularly lymphoma and a range of autoimmune diseases. Investigation Serum levels of IgG are usually less than 3g/L, but IgM levels may be up to lOg/L (normally <3g/L). Neutropenia is common, but T-cell numbers and response to mitogens are normal. The failure of CD40L expression on stimulated T-cells in vitro can help confirm the diagnosis, but mutated forms of the CD40L gene may not be identified without more sophisticated genetic analysis. Management Commencement of ivlg therapy usually results in normalization of both serum IgM and neutrophil counts. The particular susceptibility of these patients to PCP is an indication for primary/secondary prophylaxis with oral cotrimoxazole. Allogeneic bone marrow transplantation is the definitive treatment in childhood. For those (usually older) patients with established chronic liver disease (probably caused by chronic cryptosporidial infection), combined liver and bone marrow transplantation is now considered. Experience to date is too limited to give definitive statements regarding prognosis.
Complement deficiencies The complement system is represented in Figure 4.1. The clinical features of deficiency depend on which part of the activation cascade is interrupted. The major points will be described. Individual complement component deficiency Clinical features Individual complement component deficiencies are rare, and in most cases are inherited as autosomal recessive conditions. Classic pathway component deficiency (Cl, C2 and C4) may present with recurrent bacterial infection or with immune complex-mediated disorders ('lupus-like syndromes'). C2-deficient patients are especially prone to pneumococcal infection. C3 deficiency is very rare; it is associated with recurrent bacterial infection. Deficiencies of properdin (X-linked) or the terminal pathway components C5, C6, C7, C8 and C9 are associated with recurrent neisserial (meningococcal or gonococcal) infection. Any
89
CASE STUDY 4.1 RECURRENT INFECTION An 11-year-old girl was referred because of a history of recurrent infection. She had been fully immunized as an infant. At the age of 4 years she had recurrent otitis media and underwent surgical insertion of tympanic membrane vents (grommets). These had required reinsertion the following year. She was well until the age of 9 years, when she presented to hospital with chest pain and pyrexia. Left basal pneumonia was diagnosed and she was treated as an inpatient. Four months later she presented with recurrent symptoms. Chest X-ray again confirmed left basal consolidation. After antibiotic treatment she was discharged and returned to school. However, her parents noted that she suffered from frequent unexplained pyrexias and persisting chest pain. Her school performance deteriorated, she complained of fatigue and withdrew from sporting activities. She had no history of allergy or family history of recurrent infection. Investigations Hb 11.5g/dL, WCC 9.2 x 109/L, IgG 4.59 g/L, IgA < 0.07 g/L, IgM 0.28 g/L. Questions 1. Give two likely explanations for her recurrent symptoms, 2. Do her preliminary investigations establish a diagnosis? 3. What further general investigations are indicated? 4. What further immunological investigations are required?
She was referred to an immunology clinic, where the details of history were confirmed and further investigation undertaken. The history was suggestive of recurrent bacterial infection and, with the suggestion of IgA deficiency, an antibody deficiency syndrome should be considered as the most likely diagnosis.
90
Further investigation indicated IgA < 0.05 g/L IgG subclasses: IgGj 4.5 g/L (4.5-9.4); IgG2 0.4g/L (1.6-5.1); IgG3 0.5 g/L (0.3-1.1); IgG4 0.07g/L (0.01-1.2) Classic complement pathway (CH50): normal Nitroblue tetrazolium (NET): normal Lymphocyte phenotype: CD4+ T-cell numbers low. CD45RA expression very low on CD4 T cells Immunization responses: failure to increase specific antibody levels after immunization with tetanus toxoid and Pneumovax II CT scan of chest: no evidence of structural lung damage. A diagnosis of common variable immune deficiency was reached and treatment commenced with prophylactic ivlg (400mg/kg three times weekly) commenced. The girl made a rapid response, with a cessation of her febrile episodes, no further chest infections and a significant improvement in energy levels. Her school performance improved and she re-engaged in her competitive sporting activities. Her weight correspondingly increased, to the extent that her ivlg dose had to be carefully monitored and increased appropriately. After 9 months on hospital-based therapy she opted for a home treatment programme. She and her mother were trained in all aspects of home infusion therapy by an immunology nurse specialist, and home therapy, under the guidance and monitoring of the Regional Immunology Centre, has been successfully established. Discussion The history of recurrent infection in this case was probably not remarkable up to the age of 9 years. It is common for children to present with otitis media, but tympanic membrane vents are usually indicated for chronic secretory otitis media ('glue ear'). There may therefore be
some doubt as to the exact diagnosis at the age of 4 years. The episode of pneumonia at the age of 9 years was significant, particularly because of the recurrence 4 months after initial treatment, and the persisting pleuritic pain and recurrent fevers thereafter. It was therefore appropriate to consider a primary immune deficiency and the initial investigations by the paediatrician were abnormal. The total serum IgG was slightly below the age-related normal range, and although IgA was reported as being, 'low', the level quoted was not low enough to confirm IgA deficiency. The additional investigations undertaken at the immunology clinic confirmed that the total serum IgA was <0.05 g/L and IgG2 subclass was low. The measurement of specific antibody response to immunization confirmed a significant defect in antibody production. Tetanus toxoid is a protein antigen (T dependent), whereas Pneumovax II is polysaccharide (T independent). Thus, these two antigens test the functional integrity of both the Tdependent and the T-independent responses. A healthy response should result in a minimum fourfold (usually much greater) rise in specific antibody level. Because there were low levels of IgG and IgA, low IgG2 and a failure of normal immunization response, the diagnosis was common variable immune deficiency (CVID). The lymphocyte phenotype is not diagnostic, but the relative reduction in CD4 T cells (and the CD45RA subset in particular) is typical of CVID. The clinical presentation described is reasonably typical, with the exception that the diagnosis was made before structural lung damage had occurred. Presentation in the second and third decades of life is common, but can be at any age. Usually there is a delay of many years from the onset of infection to
4
CASE STUDY 4.1 CONTINUED diagnosis, and during this period structural lung damage occurs. Ivlg treatment is proven to prevent infection and its complications, and in this case a specialist immunology service established home therapy for
the child. Home therapy is increasingly seen as a desirable option for patients with primary immune deficiency, as it reduces the need for hospital visits that interfere with normal school or work activities.
patient presenting with a recurrence of meningococcal infection should therefore be investigated for complement deficiency. Investigation Investigation of the complement system is indicated in any patient with symptoms of recurrent bacterial (especially neisserial) infection, 'lupus-like' disorders or angioedema. Total C3 and C4 levels are readily measured, but the most useful screening tests for deficiency are the assays that test the functional integrity of the classic and alternative pathways (known as CH50 and AP50, respectively). If an abnormality is detected, further characterization is necessary to identify the individual component that is defective. Management This is dependent on the clinical presentation. For patients with recurrent bacterial infection, prophylactic antibiotics may be indicated. For those susceptible to pneumococcal and or neisserial infection, immunization with pneumococcal capsular polysaccharide and meningococcal vaccines is often advised. In some cases intramuscular penicillin is kept at home for early treatment of suspected meningococcal disease, and it is advisable for patients to wear a medical warning bracelet. For patients with prominent joint symptoms, further rheumatological assessment may be advised. C1-inhibitor deficiency Defects of the control protein C1-inhibitor (C1-INH) are inherited in an autosomal dominant manner and cause hereditary angioedema. There is a failure of the normal regulation of the classic pathway that results in uncontrolled activation of complement and kinin pathways in response to even minor trauma. Clinical features Patients present with recurrent deep tissue swelling following apparently minor trauma (typically dental treatment). This may affect any part of the body, but is of most concern when the airway is compromised. Symptoms usually begin in early adolescence, although late presentation is increasingly recognized. An interesting feature is that attacks may begin, or become more severe, after commencement of the oral contraceptive pill, hormone replacement therapy, or during pregnancy. Although inherited as an autosomal dominant trait, patients may not give a significant family history as approx-
Integrating treatment into family life also empowers the patient and emphasizes that these conditions, like many other medical conditions, can be prospectively managed, preventing illness and maintaining good health.
imately 20% of cases are caused by new mutations in the C1-inhibitor gene. As with other immune deficiencies, there is often a period of diagnostic delay during which patients will have suffered symptoms, often of a lifethreatening nature. It is typical for children with this condition to suffer recurrent abdominal pain (caused by intestinal wall swelling), rather than swelling at other sites. In one series, 30% of patients had an undiagnosed relative who had died of laryngeal oedema, 34% had had an unnecessary laparotomy and 10% had had endotracheal intubation or tracheotomy prior to diagnosis. Investigation During an acute attack there is a characteristic pattern of serum complement levels which is caused by inefficient and excessive activation of the classic complement pathway. Serum C4 and C2 are low but C3 levels are usually normal. This is a very valuable pointer to the diagnosis hereditary angioedema, and measurement of C3 and C4 in any patient with angioedema will help differentiate this from allergic angioedema. In 85% of cases there is a low level of C1-inhibitor level (usually less than 50% of the lower limit of normal) but in 15% of cases the enzyme level is normal. This latter group have 'functional Clinhibitor deficiency', the enzyme being present but nonfunctional. Management Prophylactic treatment with androgenic steroids (danazol 200-400 mg daily, stanozolol 2.5-10 mg/day - alternate-day dosage may be possible) or antifibrinolytics (tranexamic acid up to 4g/day) is usually effective. Antifibrinolytics are the preferred alternative for female patients because of the androgens' virilizing side-effects. If laryngeal oedema occurs (e.g. after dental extraction) it is life-threatening and requires emergency intravenous administration of Cl-INH concentrate (1000-1500 units i.v). Patients are advised to wear a medical warning bracelet. C1-inhibitor concentrate should also be given prior to surgical procedures, and routine dental work should only be undertaken in hospital, where laryngeal oedema can be dealt with effectively. Cellular immune deficiency Because of the central role of T cells in coordinating the immune response, isolated T-cell deficiency is rare. The following will first consider those conditions in which the T-cell defect is the major feature, and then those in which a combined defect is more prominent.
91
DiGeorge's syndrome This is a rare syndrome associated with a developmental abnormality of the third and fourth pharyngeal pouches. The full syndrome consists of: • Abnormal facies with low-set ears, 'fish-shaped' mouth, hypertelorism, notched ear pinnae, micrognathia and a downward slant of the eyes;1 • Hypoparathyroidism (often presenting with neonatal hypocalcaemic tetany); • Congenital heart disease (particularly aortic arch defects: truncus arteriosus, interrupted arch or Fallot's tetralogy); • Cellular immune deficiency. Not all of these clinical features are present in every case, and the immune function usually improves with time. DiGeorge's syndrome is now recognized as one of a group of related disorders that share a common genetic lesion. This is usually a deletion at 22qll, and the group of conditions is referred to as the CATCH 22 syndrome (cardiac anomalies, abnormal facies, thymic hypoplasia, cleft palate and hypocalcaemia). Other clinical syndromes in this group include velocardiofacial syndrome, Kallman's syndrome and Schprintzen's syndrome. Not all the CATCH 22-associated conditions include immune deficiency. Investigation Diagnosis is based on the typical morphological features, associated with recurrent viral or fungal infections such as oral and perineal candidiasis and viral pneumonia. Chest X-ray may show an absent thymic shadow with an abnormal cardiac outline (Fig. 4.8). It is usual to find a reduced number of circulating T cells, but the degree of immunological deficiency is variable and is probably only significant in approximately 20% of cases identified by other criteria. Lymphocyte proliferation in response to mitogens (PHA and PMA) may be reduced. Antibody deficiency is rare. It is now possible to detect the chromosome 22qll lesion by fluorescent in-situ hybridization (FISH). However, as the range of clinical associations with 22q11 lesions is wide and the degree of immunodeficiency variable, the simple demonstration of a 22qll deletion does not necessarily imply that there is clinically important immune deficiency. Management Awareness of the features and early recognition of DiGeorge's syndrome is important, particularly as these infants may be subjected to neonatal cardiac surgery. Calcium levels must be monitored and supplemented as necessary. All blood transfusions must use X-irradiated (25 Gy/unit) blood only, and live immunizations are con-
FIG. 4.8 Di George's syndrome
Chest X-ray of a one-week-old female infant with hypocalcaemia and Fallot's tetralogy. Note the abnormal enlarged cardiac outline and absent thymic shadow consistent with her diagnosis of Di George's syndrome.
traindicated (MMR, oral polio vaccine). Antibiotic prophylaxis to prevent PCP should be considered. In our unit this is instituted if the absolute CD4 count is below 0.4 x 109/L or if there is reduced T-cell proliferation to phytohaemagglutinin (a T-cell mitogen). In cases with severe cellular immune deficiency, bone marrow transplantation is suggested. The place of fetal thymus grafting is still experimental, although there have been some recent encouraging results showing reconstitution of T cells. Other cellular deficiencies Isolated T-cell deficiencies occur but are very rare. The diagnostic approach involves recognizing a suggestive history and undertaking both quantitative and functional assessments of lymphocytes. Chronic mucocutaneous candidiasis (CMC) affects both males and females and presents with chronic candidal infection of skin and mucous membranes.2There may be an associated endocrine deficiency which may precede the immune deficiency, most commonly hypoparathyroidism or Addison's disease. There are normal T-cell responses to non-specific mitogens but a specific failure of proliferative response to Candida. NK cell deficiency is also reported; patients have an increased susceptibility to herpesviruses. Functional studies of NK cells are only performed in specialist centres.
Combined immune deficiencies Wiskott-Aldrich syndrome
92
1
Fig. 4.1
2
4
Figs 4.6, 4.7
Figs 4.2, 4.3, 4.4
3
Fig. 4.5
5
6
MCQ 4.3
Figs 4.8,4.9
Clinical features This X-linked disorder presents in young boys with a typical triad of eczema, thrombocytopenia and recurrent
infection.3 Immune deficiency may be mild. There is a high frequency of malignant lymphoma in the second and third decades of life, and severe autoimmune vasculitis or glomerulonephritis may occur. If untreated, death from one of these causes is usual in the second or third decade. Investigation Platelets are small and have abnormal expression of surface glycoproteins (CD43 and gpIb). There are defects affecting the cytoskeletal proteins, including actin, and associated defects of T-cell proliferation. The molecular defect is mutation of the WASP gene at Xp11.22. Characteristically there is a failure of response to polysaccharide antigens and progressive lymphopenia. Management These patients require careful clinical and laboratory assessment to establish optimum management. Increasingly, affected males are offered bone marrow transplantation in early childhood in order to reduce the risk of long-term complications and increase life expectancy. Ataxia-telangectasia (AT) Clinical features This progressive neurological and immunological disorder presents in early childhood with neurological manifestations, including cerebellar ataxia, nystagmus and oculomotor dyspraxia. Telangiectases are typically seen on the elbows, conjunctivae and ear lobes. 4 There is a progressive, combined immune defect that is variable in its immunological features. Patients ultimately develop lymphoid leukaemia/lymphoma in the second and third decades and this, combined with progressive combined immune deficiency, is the usual cause of death. Investigation The fundamental lesion is defective DNA repair leading to increased radiosensitivity (such as is seen in other disorders, e.g. Bloom's syndrome, xeroderma pigmentosa, Nijmegen breakage syndrome). Chromosomal breaks, inversions and translocations are commonly seen at the T-cell receptor, and immunoglobulin gene complexes on chromosomes 7 and 14, respectively. The serum afetoprotein is often raised. Heterozygotes for the AT gene mutations have an increased risk of developing a number of malignancies (including breast cancer), and family members need to be aware of this. Patients with AT gradually develop immune deficiency and, after comprehensive immunological investigation at diagnosis, this is confirmed and monitored by regular review of the clinical and laboratory features. Management Careful, continuing immunological assessment is essential in these patients, and treatment is dependent on the degree of immune deficiency. Patients commonly require ivlg by late childhood. There is no corrective treatment available for the underlying chromosomal instability.
Severe combined immune deficiency (SCID) Clinical features This group of conditions has a number of causes but the clinical features are similar in most cases. By definition, both humoral and cellular responses are impaired or absent. SCID typically presents early (in the first weeks and months of life) with a history of failure to thrive (FTT), unexplained diarrhoea, and recurrent bacterial, viral or fungal infection. Unexplained lymphopenia (<2.8 x 109/L) is often present and should always prompt investigation. Total lymphocyte counts may, however, be apparently normal in B-cell-positive variants, T-cell activation deficiencies and graft-versus-host disease (GVHD). GVHD may be related to maternofetal transfusion, where normally functioning maternal lymphocytes attack the immunodeficient child. If present, GVHD occurs in the first month of life with jaundice, typical skin rash 5and diarrhoea. It may also occur as a complication of blood transfusion, and all transfusions to potentially immunodeficient individuals should be irradiated (25Gy/unit) to eradicate immunocompetent lymphocytes, the potential inducers of GVHD.
4
Investigation When SCID is suspected, immunological advice should be sought urgently, with regard to both investigation and immediate management. In general, serum immunoglobulins are low and there is a low lymphocyte count, with diminished proliferative response to mitogens. Lymphocyte subset analysis is essential and a range of other investigations is needed to exclude SCID. The molecular basis of many variants of SCID is now recognized: each has a particular pattern of abnormalities and some of the more common are summarized in Table 4.6. Molecular characterization allows greater precision in diagnosis and carrier detection. Management Early diagnosis, prevention of infection and rapid bone marrow transplantation (BMT) are all crucial to ensure ultimate survival. Delay in making the diagnosis allows complications to occur (such as disseminated CMV infection), which reduce the chance of survival. BMT can be curative and, in the UK, is currently performed at two supraregional centres. With increasing characterization of the molecular basis of immune deficiency, it is hoped that gene therapy will become a practical possibility in this group of disorders.6
Phagocytic disorders Phagocytes may be defective in numbers or function. Table 4.7 summarizes the main disorders, the commonest of which are described below. Chronic granulomatous disease (CGD) Clinical features CGD typically presents in childhood with recurrent, deep abscesses caused by catalase-positive organisms (Staphy-
93
TABLE 4.6 The major features of some combined immunodeficiency syndromes Syndrome
Major immunological features
Molecular defect
Inheritance/associated features
X-linked SCID
Immunoglobulin low; T cells low, B cells normal/increased Immunoglobulin, T and B cells all low Immunoglobulin, T and B cells all low Immunoglobulin low. Progressive fall in T and B cell numbers IgG low, IgM high, T cell numbers normal Immunoglobulin normal/low, B cells normal, reduced CD4+ cells Immunoglobulin normal/low, B cells normal, reduced CD8+ cells.
IL-2 receptor y chain
(XL)
Mutation in RAG1/2 genes Stem cell defect Accumulation of lymphotoxic metabolites Mutation in CD40L gene Mutations in MHC II regulator genes TAP-2 gene mutation
(AR)
T-B- SCID Reticular dysgenesis Adenosine deaminase deficiency X-linked hyper-IgM MHC class II deficiency TAP-2 deficiency
(AR): Anaemia, granulocytopenia, thrombocytopenia (AR): Progressive onset, diagnosis may be delayed into childhood: flared ribs (XL) Neutropenia, thrombocytopenia, haemolytic anaemia, (AR) (AR) MHC class I deficiency
(XL), X-linked; (AR), autosomal recessive.
TABLE 4.7 Examples of phagocytic disorders Phagocytic defect
Clinical disorder
Numbers Adhesion
Cyclical neutropaenia Leukocyte adhesion defect (LAD-1) Schwachmann's syndrome
Chemotaxis
Intracellular killing
Chronic granulomatous disease G6PD deficiency IL-12R & IFNyR deficiency
Inheritance/associated features (AR) See text (AR) See text (AR) Anaemia, thrombocytopenia, pancreatic insufficiency, chondrodysplasia (XL/AR) See text (XL) Anaemia (AR) Susceptibility to mycobacteria and salmonella. See text
lococcus aureus, Aspergillus, Serratia, Nocardia).1 Presentation may be with osteomyelitis, unexplained granulomatous lesions, malabsorption or recurrent pneumonia. New cases have been diagnosed in adulthood. Inheritance may be X-linked or autosomal recessive. Investigation The diagnosis rests on the demonstration of a failure of the neutrophil respiratory burst. The most common screening test of neutrophil function is the nitroblue tetrazolium test (NBT) test, in which normal neutrophils reduce the yellow dye formazan into blue intracellular crystals. 2 This test
1 94
Fig. 4.10
0 Fig. 4.11 3
Fig. 4.12
may not be abnormal in all cases, and more sensitive screening techniques have been developed. The molecular defect is a deficiency of the 91 kDa chain of cytochrome b (X-linked CGD) or the 22 kDa chain of cytochrome b, or of p47 or p67 cytoplasmic factors (autosomal recessive CGD). These proteins are all involved in the energydependent process of intracellular killing. The definitive test is to demonstrate a failure of neutrophil-mediated bacterial killing. Management Antimicrobial prophylaxis (usually with co-trimoxazole) is the mainstay of therapy. Prophylactic interferon-y (IFNy) is not useful prophylactically, but may be a useful adjunct to conventional antibiotic and surgical management of abscesses. Allogeneic bone marrow transplantation, before the development of complications of infection, is now the treatment of choice for CGD if a suitable donor can be found. Cyclical neutropenia Clinical features This condition, which may present in childhood or adult life, is characterized by recurrent abscesses, usually occurring at intervals of approximately 3 weeks, although the periodicity can vary greatly. The neutrophil count is typically <1 x 109/L at times of infection, and the diagnosis should be suspected if there is clear periodicity to the history. Alternatively, the neutrophil count may be incidentally noted as low on a blood count during acute infection. Investigation Neutrophil counts should be measured on alternate days for a 4-week period and carefully analysed for any evidence of a cyclical pattern. A cyclical pattern may also be detected for other elements, including platelets, and other leukocytes.
Management This is dictated by the clinical severity of the condition. Prophylactic antibiotics may be adequate during times of low neutrophil numbers. In more severe cases, treatment with granulocyte colony-stimulating factor is considered. Leukocyte adhesion deficiency (type 1)
heterozygous for the genetic lesion, but this is clinically expressed as a dominant susceptibility. This is in contrast to most autosomal genetic disorders, in which the normal allele dominates, so that heterozygotes only show a minor clinical abnormality. The prevalence of these conditions is not yet established.
Clinical features This is typically a disorder of infancy and childhood. Chronic/recurrent skin ulcers and periodontitis are common. There is characteristically little pus formation and an associated peripheral blood neutrophilia. There is likely to be a neonatal history of delayed separation of the cord (>10 days).
Investigation Cell surface expression of IFNyR and IL-12R is detected by flow cytometry. Specialist functional assays of lymphocyte signalling are necessary to confirm and characterize the defects. Histologically, complete IFNyR deficiency is characterized by a failure to form granulomata, whereas partial deficiency is associated with good granuloma formation.
Investigation There is defective expression of the CD18 (B chain) of the adhesion molecules LFA-1, Mac-1 and CR4. The absent expression is demonstrated on both lymphocytes and phagocytes by flow cytometry. A second variant, LAD-2, is associated with defective expression of CD15.
Management Once the diagnosis is established, appropriate antimycobacterial therapy must be commenced. Experience with adjunctive IFN-y treatment in the partial forms is increasing and discussion with specialist centres is advised.
Management Antibiotics are the mainstay of therapy. Drug choice should be guided by antibiotic sensitivities. Prophylactic therapy may be necessary, depending on the frequency of infection. Bone marrow transplantation is necessary for severely affected individuals. /nferferon-y receptor (IFNyR) deficiency Clinical features Defects in the IFNyR (and IL-12 receptor) systems have recently been identified as important susceptibility factors for mycobacterial infection. These conditions have been identified in both children and adults. They typically develop infection with poorly pathogenic mycobacteria, salmonella, or the live vaccine Bacille Calmette-Guerin (BCG). There are three types of IFNyR defect identified. Complete deficiency determines a phenotype that is characterized by severe and fatal susceptibility to either BCG or disseminated non-tuberculous mycobacterial (NTM) infection. Partial IFNyR-1 deficiency is associated with a less severe clinical defect that may allow disseminated BCG infection with tuberculoid granulomata or clinical tuberculosis. Both complete and partial IFN-y deficiencies are inherited as autosomal recessive traits. A functional defect of the IFNyR has also recently been described which is characterized clinically by susceptibility to nontuberculous mycobacteria (NTM) and variable granuloma formation.3 A notable feature of the cases described to date is that a significant number are initially misdiagnosed as suffering from Langerhans' cell histiocytosis (LCH), because of the association of fevers, lymphadenopathy, granulomatous ulcers and lytic bone lesions. The condition is caused by a premature stop codon in the intracellular signalling domain of IFNyR that reduces the mycobactericidal properties of macrophages. Inheritance of this last type is 'dominant negative'. The affected individuals are
a
SECONDARY IMMUNODEFICIENCY Secondary immunodeficiency is much more common than primary immune deficiency in clinical practice. It may occur as a result of systemic disease, including diabetes mellitus, chronic hepatic and renal failure and systemic malignancy. Autoimmune disorders may be associated with immune deficiency as a consequence of both disease and treatment. Specific infections are also associated with secondary immune deficiency. The best known of these is human immunodeficiency virus (HIV), which leads to the acquired immune deficiency syndrome (AIDS; Chapter 11). HIV causes a progressive loss of CD4+ T cells and thus disrupts both antibody and cellular responses. Several other infections are associated with immune suppression. Measles predisposes to bacterial infection partly through its disruption of phagocytic function. Epstein-Barr virus may occasionally cause hypogammaglobulinaemia. Immunosuppressive drugs are widely used in the treatment of cancer and autoimmune disease and are an important cause of secondary immunodeficiency. When using these agents it is essential to monitor treatment carefully and maintain the lowest level of immunosuppression compatible with effective treatment. Malnutrition, infection and other iatrogenic causes, including radiotherapy, are also important causes of secondary immune deficiency. The mechanisms of secondary immunosuppression are usually multifactorial: specific intervention is not usually indicated, but susceptibility to infection must be recognized in patients who are at risk. Secondary antibody deficiency may occur in lymphoproliferative disorders such as multiple myeloma and chronic lymphocytic leukaemia, or in protein-losing states such as nephrotic syndrome or intestinal lymphangectasia. In the
95
lymphoproliferative disorders, where there is a failure of antibody synthesis, there is often a history of recurrent bacterial infection, and in these cases ivIg has been demonstrated to be beneficial. Interestingly, in the protein-losing states, recurrent infection is not usually a significant clinical problem, and antibody replacement therapy is the exception rather than the rule. Splenectomy is an important cause of secondary immune deficiency. These patients have a lifelong risk of suddenonset overwhelming sepsis caused by encapsulated organisms. This is related to the important role of the spleen in the immune response to polysaccharide antigens. Patients in whom Splenectomy is planned should be immunized with pneumococcal, meningococcal and Haemophilus influenzae type b vaccines. Annual flu immunization is recommended, and travel to malarial endemic areas should be avoided if possible. Patient education regarding the risks of splenectomy is very important, and they should be provided with warning cards or bracelets and advised to take penicillin early if they develop cough and fever. Prophylactic penicillin V (250 mg b.d.) should be given for the rest of the patient's life. Penicillin-allergic individuals should take erythromycin (250mg b.d.). Long-term follow-up is recommended both to monitor the need for repeat immunization and to reinforce medical advice. There are also a number of inherited syndromes, many of which are rare, associated with secondary immune deficiency.
HYPERSENSITIVITY
IMMUNOLOGICAL MECHANISMS In contrast to immunodeficiency syndromes, where the immune system is underactive, clinical disease may result from inappropriate overactivity. Overactivity of the immune system is referred to as hypersensitivity. The immunological mechanisms that cause hypersentivity were described and classified by Gell and Coombs (Table 4.8). Four types of hypersensitivity are described, each involving different immunological components. In some cases the hypersensitive response is directed at a foreign antigen (e.g. reactions to allergens, blood transfusions, transplanted organs or infectious agents) and in others it is directed at known 'self-antigens' (e.g. in autoimmune diseases). Finally, some hypersensitivity reactions appear to be directed at unknown antigens (e.g. Wegener's granulomatosis). The term hypersensitivity applies to all four types of reaction in the Gell and Coombs classification, whereas
1
96
Fig 4.13
2
Case 4.1
TABLE 4.8 Classification of hypersensitivity reactions (Gell and Coombs classification) Type of reaction
Effector mechanism
Clinical disorders
I
IgE, mast cells
Allergic rhinitis, urticaria, angiodema
II
IgG directed at cell surface antigens
Transfusion reactions, acute graft rejection, Graves' disease, myasthenia gravis, Goodpasture's syndrome
III
Immune complexes
Cryoglobulinaemia, SLE, post streptococcal glomerulonephritis
IV
CD4+ lymphocytes,
Delayed type hypersensitivity, contact eczema, granulomatous reactions
the term allergy is used in a more restricted sense to describe type I hypersensitivity reactions. In this section, we will use the Gell and Coombs classification to illustrate and explain the important clinical conditions associated with hypersensitivity reactions. In addition to allergy and autoimmunity, the hypersensitivity mechanisms involved in the response to infectious agents can influence the clinical manifestations of disease. Furthermore, the manipulation of the immune response (e.g. in mycobacterial disease) offers new possibilities for therapeutic intervention.
Type I hypersentivity Type I hypersensitivity reactions (the major mechanism in allergy) are the result of the immune system reacting to otherwise apparently innocuous antigen (allergen). The mechanism involves: • Formation of IgE antibody specific to the inducing antigen or 'allergen'; • Binding of this antibody (via Fc receptors) to mast cells and basophils; • Cross-linking of at least two cell-bound IgE molecules; • Degranulation of mast cells, with release of preformed mediators and the generation of late-phase mediators.
Type II hypersentivity Type II hypersensitivity involves the reaction of antibody with cell surface-bound antigen. This reaction then causes downstream activation of the complement system, and attraction and activation of phagocytes and mast cells. The effect is to focus inflammatory damage at the site of antibody binding or, in the case of receptor-binding antibodies, to modulate the function of the target organ. This mechanism is especially important in organ-specific
autoimmune disease (Graves' disease, myasthenia gravis, autoimmune haemolytic anaemia, Goodpasture's syndrome), but also in blood transfusion reactions and hyper acute graft rejection.
Type III hypersensitivity Type III reactions involve the formation of soluble immune complexes that circulate in the blood and cause damage at many sites. Formation of immune complexes is part of the normal immune response, and these are normally disposed of via the complement and reticuloendothelial systems. Complexes remain in the circulation if they are produced persistently or are inadequately disposed of. Such pathological complexes become deposited, typically in the renal glomerulus, in joints and the skin, causing inflammatory reactions at these sites. The experimental model for immune complex disease is serum sickness, in which nephritis, arthritis and rash typically occur 7-10 days after the injection of foreign protein. The best examples in human disease include chronic infection (e.g. hepatitis, malaria, streptococci), systemic lupus erythematosus (SLE), inhalation of antigens (e.g. farmers lung) and cryoglobulinaemia. 1 2
Type IV hypersensitivity This is also known as delayed-type hypersensitivity (type IV hypersensitivity) because in experimental systems signs develop 12 or more hours after antigen exposure. Importantly, the major immunological effectors of type IV reactions are T cells, instead of antibody, which mediates the reaction in types I-III hypersensitivity.
CLINICAL DISEASE ASSOCIATED WITH HYPERSENSITIVITY REACTIONS Allergy Clinical allergy is becoming increasingly prevalent in western societies: it is estimated that up to 20% of the UK population is now affected by allergy. The symptoms depend mainly on the nature of the allergen and the site at which mast cell degranulation occurs. The common clinical syndromes are of seasonal or perennial rhinitis, allergic asthma, urticaria, oral allergy syndrome, angioedema and anaphylactic reactions. The term atopy is used to describe a genetic susceptibility, expressed in the clinical triad of eczema, allergic rhinitis and asthma, which are commonly associated in many patients. Diagnosis The diagnosis of allergy is often thought to be difficult, but in the majority of cases a thorough clinical history combined with relatively simple investigations will prove adequate. The history is the most important component, and
one looks for typically allergic symptoms occurring consistently after exposure to the same agent, and improvement of symptoms during periods of avoidance. Where doubt remains, further investigation by skin-prick testing and/or the detection of allergen-specific IgE (e.g. by radioallergosorbent test - RAST) is necessary. Skin-prick testing is preferred, as it is a rapid, cheap and painless form of in vivo challenge. There are, however, limitations to its use, as it should only be undertaken by trained individuals in an environment with full resuscitative facilities available. Specific IgE testing using the RAST test has the advantage of easy accessibility. Although results correlate well with skin testing for most allergens, they are not directly comparable for every allergen. RAST testing should not be used as a screening test for allergy. Its use should be guided by careful clinical assessment.
4
Allergic syndromes Rhinitis Clinical features Seasonal or perennial rhinitis usually presents little diagnostic difficulty or need for specific investigation. The symptoms of a red, itchy, runny nose with associated swelling and itchy watery eyes are easily recognized. A history of seasonality and/or key triggering factors will usually indicate the offending allergen. Investigation This is required when the provoking allergen is not clear from the history, or when another cause is suspected (Table 4.9). Management The important elements in management are the avoidance of, or reduction in exposure to, the allergens and the use of nasal steroid inhalers, with or without oral antihistamines. The latter are particularly useful in young children, who may find the use of inhalers difficult. For perennial symptoms caused by house dust mite patients need to be advised on how to reduce exposure by modifications to floor coverings, bedding, and cleaning and laundering procedures. There is increasing evidence that effective control of nasal
TABLE 4.9 Differential diagnosis of rhinitis Allergic (aeroallergens) Drug induced (decongestant sprays, cocaine, antihypertensive) Vasomotor Infectious Irritant Vasculitis Hormonal (pregnancy) CSF rhinorrhoea
97
allergy in asthmatic patients can improve their overall airway disease. Desensitization is returning to clinical practice for grass and house dust mite allergy, but only specialist units should undertake it.
Urticaria/angioedema Clinical features Urticarial lesions are raised red itchy weals (often described as 'like nettle stings') caused by epidermal mast cell activation. Angioedema is non-itchy, non-dependent swelling which occurs in the deep dermis. Activation of the kinin system is important in causing angioedema. It is common for both symptoms to occur in the same patient. However, when angioedema occurs in the absence of urticaria, hereditary or acquired deficiencies of Cl-esterase inhibitor (Cl-INH) should be considered. A number of specific triggers for both urticaria and angioedema may be identified (Table 4.10), but in the majority (89-90%) of cases referred to clinics no specific allergic cause is identified. If symptoms persist for more than 6 weeks, this is defined as chronic idiopathic urticaria/angioedema. The natural history is quite variable, with many patients experiencing prolonged remissions between relapses. Investigation A thorough clinical history is essential to determine the pattern of symptoms and any associated trigger factors. Screening tests for allergy are not recommended; however, the wide variety of disorders associated with combined urticaria/angioedema (Table 4.10) may justify further investigation, including thyroid function tests, full blood count, CRP and complement levels. Skin biopsy is helpful in confirming urticaria pigmentosa and urticarial vasculitis. Management If an associated medical condition is identified (e.g. hypothyroidism, infection), the urticaria should respond to management of that disorder. In other patients, if attacks are only infrequent oral short-acting antihistamines (e.g. acrivastine 8mg t.i.d.) will be adequate. In most cases, however, daily non-sedating antihistamines are necessary (e.g. fexofenadine, loratadine and cetirizine). If necessary a sedating antihistamine can be added at night (e.g. hydroxizine hydrochloride). Experience with oral disodium chromoglycate has been disappointing, with the possible exception of urticaria pigmentosa, in which it has an important role in management. H2 antagonists (cimetidine and ranitidine) are often tried for refractory cases, as is doxepin (an antidepressant with potent antihistamine effects). Urticarial vasculitis often responds to NSAID therapy. The relapsing, remitting nature of urticaria makes it difficult to be certain of the efficacy of some of these interventions,
1
98
Fig. 4.14
TABLE 4.10 Causes of urticaria/angioedema Idiopathic Allergic (foods, drugs, hymenoptera venom, contact) Physical (pressure, heat, solar, aquagenic, vibratory) Cold induced (autosomal dominant, cryoprotein) Cholinergic (exercise or heat induced) Adrenergic (stress induced) Vasculitis (hypocomplementaemic urticarial vasculitis) Autoimmune (SLE, antibodies to lgE/FceR1/C1q) Infection (hepatitis B, Helicobacter pylori, EBV, Lyme's disease, cutaneous larva migrans, larva currens) Insect bites (papular urticaria) Drug induced (aspirin, ACE inhibitors, opiates, muscle relaxants, and radiocontrast media) Hypothyroidism Urticaria pigmentosa Systemic mastocytosis Angiodema/deafness, urticaria (Muckle-Wells syndrome) Malignancy
and it is essential that once regular therapy is commenced the dose is periodically reduced or withdrawn to determine whether continued treatment is necessary. Food allergy IgE-mediated allergy to food has been described since the 1920s but remains a source of controversy. This is probably because there are exaggerated claims made for both the prevalence and the effects of food allergy, and the diagnostic tests that are available have not been reliable. There is also confusion between food allergy (an IgE-mediated phenomenon) and food intolerance, which may have many causes. For patients in whom food allergy is suspected a double-blind placebo controlled food challenge (DBPCFC) is the only reliable investigation, but this is available in only a few specialist centres at present. Selfreporting of food allergy is common. In one large study the self-reported prevalence was 20%, but actual prevalence was only 1-2% when confirmed by DBPCFC. Food allergy is often invoked as a potential cause for complex multisystem disorders or obscure symptoms. This is unlikely to be the case, and in the absence of clear evidence of allergy patients should be encourage to eat a normal diet. IgE-mediated food allergy may cause symptoms including urticaria, angioedema, rhinitis, asthma, oral allergy syndrome, anaphylactic reactions and some gastrointestinal symptoms (chiefly acute vomiting and/or diarrhoea). Common food allergens include milk, eggs and seafood. Affected children typically become tolerant to these foods by mid-late childhood. Currently, the most important food allergy is to peanut - a relatively unknown condition until the late 1980s, the prevalence of which has increased considerably. Among the UK preschool population it is now estimated to be as high as 1:50-100. Nut allergy is different in many important respects from other food allergies:
• It appears to develop in very young children. • Reactions characteristically cause angioedema, often affecting the larynx, with airway restriction. • Anaphylactic reactions may result from exposure to even trace amounts of nut. • Indirect exposure may cause life-threatening reactions in highly sensitive individuals. • Nut allergy appears to be a lifelong problem in the majority of cases. Nut allergy is a major challenge facing the medical profession and others who look after children. Successful management requires the complete avoidance of all nut-containing foods, and teaching family, friends and school staff the symptoms and signs of allergic reactions. An emergency medication kit should be available which includes both oral antihistamines and injectable adrenaline (epinephrine) (for life-threatening reactions), and patients are encouraged to wear a medical warning bracelet. Nut allergy has now overtaken bee/wasp sting allergy as the most common cause of anaphylactic reactions occurring outside hospital.
Development of autoimmunity The occurrence of hypersensitivity reactions directed against self-antigens implies a breakdown in the body's normal tolerance mechanisms. A number of factors are implicated in the development of autoimmune reactions, including infection, drugs and chemical exposure and HLA type. The influence of the hormonal state is undoubted and is exemplified by the increased autoreactivity seen in women and the effect of hormonal change (pregnancy and lactation, hormone replacement therapy) on the clinical manifestations of disease. Several cellular and molecular mechanisms are recognized as contributing to autoreactivity. These include 'cross-reactivity', where a pathogen is sufficiently similar to self-antigen that it induces an autoimmune response, e.g. group A B-haemolytic streptococcus cross-reacts with cardiac muscle, causing acute rheumatic fever: 'Molecular mimicry', wherein a short genetic sequence of a pathogen is identical to a selfantigen, has long been postulated as a mechanism for autoimmunity. Mathematical modelling, however, suggests that molecular mimicry is likely to be so common as to be the rule rather than the exception, and thus unlikely to be important in disease aetiology. 'Provision of foreign T-cell epitopes' implies that foreign antigens containing T-cell epitopes bind to host proteins and stimulate an autoimmune response. This may be one of the mechanisms through which drug and chemical exposure causes autoimmune reactions. The important HLA disease associations have been summarized in Table 4.3. It should be remembered that T cells learn to differentiate self from non-self antigens during their maturation in the thymus; thus the occurrence of autoreactive antibodies or lymphocytes represents a breakdown in the normal mechanisms of selftolerance. One of the crucial mechanisms for eradication of self-reactive T cells is through programmed cell death
or apoptosis. Patients deficient in the Fas antigen, an essential signalling molecule in normal apoptosis, develop characteristic clinical features dominated by lymphoproliferation and autoimmunity,1 emphasizing the importance of central (thymic) deletion of autoreactive cells.
4
Autoimmune diseases: classification and diagnosis Human autoimmune diseases are classified according to whether predominantly a single organ is affected (organ specific) or whether there is multiple organ involvement (non-organ specific). As with any classification system, some conditions fall between these two extremes. Table 4.11 lists some common autoimmune diseases in these two categories. Autoantibody detection is frequently requested in the investigation of suspected autoimmune disease. Autoantibodies may be primary and directly cause disease (e.g. antiglomerular basement membrane antibodies in Goodpasture's syndrome, antiacetylcholine receptor antibodies in myasthenia gravis and anti-TSH receptor antibodies in Graves' disease), but more commonly they are secondary and are formed as part of the disease process itself (e.g. antinuclear, anti-dsDNA, antismooth muscle, antimitochondrial antibodies). Detection of a secondary autoantibody does not necessarily indicate that the patient has an autoimmune disease. 'False positive' autoantibodies are associated with, for example, infection, female gender, increased age and surgical procedures. Determining the significance of autoantibody results requires careful clinical assessment. It is also important to know the exact pattern of autoantibody detected, its titre (or strength) and
TABLE 4.11 Autoimmune diseases and their associated autoantibodies Disease
Autoantibodies directed against
Hashimoto's disease Graves' disease Pernicious anaemia
Thyroid peroxidase TSH receptor Intrinsic factor Gastric parietal cells Steroid-secreting cells of adrenal cortex Islet cell Smooth muscle Acetylcholine receptor Voltage-gated calcium channel
Addison's disease Type 1 diabetes mellitus Chronic active hepatitis Myasthenia gravis Lambert-Eaton myasthenic syndrome Pemphigus Goodpasture's syndrome Sjb'gren's syndrome Primary biliary cirrhosis Systemic lupus erythematosus (SLE) Rheumatoid arthritis
Desmosomes Basement membrane Nuclear antigens (Ro/La) Mitochondria Nuclear antigens (ds DNA, Ro/La, Sm) Phospholipid IgG (rheumatoid factor-IgM class)
99
CASE STUDY 4.2 ACUTE ONSET OF SWELLING A 15-year-old girl presented to her local accident and emergency department with an acute onset of swelling that affected her face. Her eyes were closed, she had swelling of the lips, but neither tongue swelling nor difficulty in breathing (Case Fig. 4.2.1). She reported eating a chocolate bar that contained peanuts 4 hours earlier, and a provisional diagnosis of nut allergy was made. She was immediately treated with i.v. chlorpheniramine and hydrocortisone. Adrenaline was not administered but she was admitted for observation and remained in hospital for 4 days, until her symptoms had completely resolved. She was discharged home with an adrenaline (epinephrine) selfadministration kit and told to read the package insert to explain its use.
Questions 1. How common is peanut allergy in the UK? 2'. Was her presentation typical of nut allergy? 3. If she did have peanut allergy was her treatment optimal?
Further history Her GP referred her for further investigation as he felt that she might have more than just nut allergy. A detailed history revealed that she had suffered recurrent swelling of her hands since the age of 4 years. She also had been investigated for intermittent abdominal pain and painful knees. She had eczema affecting her face and wrists, mild asthma and hay fever. She had previously had positive skin-prick tests to house dust mite and dog and cat dander. She was unable to wear cheap jewellery as this caused a rash. On examination she was obese, she 100
Further investigation The disparity between the low C4 and normal C3 levels prompted measurement of Cl-esterase inhibitor levels. These were normal (Clesterase inhibitor 0.52 g/L (0.28-0.5)); however, functional assessment of Cl-esterase inhibitor activity was 0% (70-140), indicating a functionally defective molecule and confirming a diagnosis of Cl inhibitor deficiency (type II).
CASE FIG. 4.2.1 Facial angioedema that is preventing the patient from opening her eyes or speaking had eczematous patches at her right wrist, marked dermographism, and respiratory examination confirmed scattered inspiratory wheeze. Investigations indicated: total IgE 731 kU/L, specific IgE to house dust mite (strongly positive), grass pollen (moderately positive), peanut (negative). Autoantibody screen negative, rheumatoid factor negative, C3 1.38g/L (0.7-1.7), C4 < 0.1 g/L (0.13-0.43), CRP 1.5mg/L (<6mg/L).
Questions 4. How does this further history affect the differential diagnosis? 5. Do the investigations rule out nut allergy? 6. What other condition(s) should be considered? 7. Do any of these have significantly different therapeutic implications?
Discussion This case demonstrates an important differential diagnosis that must be considered in anyone presenting with angioedema. Although the common causes of urticaria/angioedema are as listed in Table 4.10, Cl-esterase inhibitor deficiency (Cl-INH deficiency) typically causes angioedema but not urticaria. This presentation is typical in a number of respects of the experience with ClINH-deficient patients. She was symptomatic as a child, with some hand swelling and prominent abdominal pain. In her case this was diagnosed as abdominal migraine, but the more likely cause was Cl-INH deficiency-related abdominal pain, which is thought to be caused by angioedema affecting the bowel wall. The development of facial swelling as a teenager is also typical. Attacks commonly become more frequent and severe after puberty (and during pregnancy), the explanation for this being the relative changes in hormonal balance affecting Cl-inhibitor synthesis from the normal allele. Interestingly, however, the patient did have an atopic background with eczema and asthma, as well as a history of nickel sensitivity. On examination she also had dermographism. Thus she was demonstrating conditions characterized by types 1 and 4 hypersensitivity reactions, and this undoubtedly contributed to the initial
4
CASE STUDY 4.2 CONTINUED clinical diagnosis in the A&E department of probable allergic angioedema. The importance of the complement investigations in angioedema cannot be overestimated. Cl-INH deficiency, cryoglobulinaemia or genetic deficiency of C4 usually explains the finding of very low C4 despite normal C3. Thus measurement of complement levels is an extremely useful investigation, and a normal C4 during an attack of angioedema virtually excludes the diagnosis of Cl-INH deficiency.
The treatment of acute lifethreatening angioedema in this condition is very different from that required for allergic angioedema. Life-threatening attacks commonly occur after dental work that precipitates laryngeal angioedema and respiratory obstruction. Emergency treatment consists of 1000-1500 units Cl-INH concentrate intravenously, with close clinical observation in hospital. Prophylactic therapy is also considered for patients with frequent attacks. In this
whether it is of the IgG or the IgM isotype. For example, a significant antinuclear antibody (ANA) would be of high titre (>1:80) and IgG class. If the ANA pattern was not homogeneous (e.g. speckled or nucleolar) this might indicate specific subsets of connective tissue disorders (mixed connective tissue disease, systemic lupus erythematosus, scleroderma). Once an antinuclear antibody is detected, specialist immunology laboratories will further characterize it according to which nuclear antigen is targeted (Table 4.11). Again, this is helpful in the subcategorization of connective tissue disorders and the recognition of susceptibility to specific complications (e.g. anti-Ro antibodies and neonatal congenital heart block).
Diseases associated with type IV hypersensitivity Contact eczema The most common clinical example is nickel hypersensitivity. Affected individuals develop an eczematous reaction to nickel-containing jewellery, watches, buttons etc. that are in prolonged contact with the skin. The reaction is usually confined to the area of contact. Although sometimes referred to as 'nickel allergy', IgE mechanisms are not involved in the pathogenesis of this condition. Nickel is absorbed directly through the skin and binds to selfproteins (haptenization).This stimulates CD4+ T cells, which are recruited to the area, and there is associated oedema of the epidermis. This reaction occurs over 24-48 hours and is artificially recreated during 'patch testing', which is widely used to investigate type IV hypersensitivity. Granulomatous hypersensitivity Granulomatous reactions represent the full development of type IV hypersensitivity reactions, in which antigen persists and a focus of inflammation is established. The tuberculin reaction is a modified, self-limiting form which occurs, for example, with the Mantoux and Lepromin tests.
case the patient was commenced on cyclokapron 500 mg q.i.d., in preference to androgenic steroids, because of the potential virilizing effects of the latter. She was also provided with a warning bracelet that gave details both of her diagnosis and the necessary treatment in case of an emergency. Family studies confirmed that her biological parents were not affected and that this was one of the significant minority of cases caused by a new mutation.
These involve the intradermal injection of M. tuberculosis and M. leprae extracts. The local skin reaction is characterized by an area of induration and swelling which is mediated by sensitized lymphocytes. CD4+ lymphocytes predominate and accumulate, along with macrophages around blood vessels, with a maximum infiltration at about 48 hours. This reaction is focused at the site of foreign antigen in the dermis and is self-limiting, as antigen is progressively degraded and removed. Where antigen persists, however, granulomatous features can develop. Granulomas are collections of macrophages, some of which form giant cells; others appear as epithelioid cells. A cuff of small lymphocytes surrounds these. Granulomas may develop in response to foreign antigen (Mycobacterium infections) or as part of a presumed autoimmune response (Wegener's granulomatosis, sarcoidosis or CVID). The clinical effects of granulomas depend on the underlying cause, and the number, size and location of the lesions. They may cause significant destruction and morbidity, e.g.TB in the lungs, or they may be an incidental finding, e.g. in CVID in the liver. In mycobacterial infection it is recognized that the immunoregulatory Thl/Th2 response influences the degree of granuloma formation and indeed the individual's clinical manifestation of infection. If the response is predominantly of the Thl phenotype, with activated T cells producing IFN-y and IL-2, there is marked granuloma formation and, in the case of leprosy, the clinical pattern is tuberculoid. Tuberculoid leprosy is characterized clinically by localized granulomatous lesions which may be asymptomatic and which contain few viable organisms. In lepromatous leprosy there are widespread skin lesions containing numerous bacilli but few lymphocytes. These patients have a predominant Th2 phenotypic response to the organism (Th2 cells secrete IL-4, IL-5 and IL-10) and no clear granuloma formation. Consequently, M. leprae are able to proliferate and disseminate more freely in lepromatous leprosy, and the patient suffers the systemic effects
101
of the infection. Host response in the form of hypersensitivity may therefore be advantageous under certain circumstances, and modification of the response by the administration of exogenous cytokines (e.g. interferon-y) can change the pattern of disease. 1
IMMUNOSUPPRESSION The rapid development of organ transplantation has been dependent on the availability of effective immunosuppressant drugs. An ideal immunosuppressant would be antigen specific and free of side-effects, but none of the currently available drugs meets these criteria. The clinical use and relative merits of the major immunosuppressant drugs are outlined below, as are some newly emerging immunomodulatory strategies. Corticosteroids These drugs have been widely used in the treatment of autoimmune diseases, malignancy and graft rejection for many years. The immunosuppressant action is difficult to separate from other potent anti-inflammatory actions of steroids. In humans it is mediated mainly through an inhibitory action on monocytes and macrophages, with reduced phagocytic function and diminished IL-1 secretion. Although in animals there is a marked lymphocytotoxic effect, in humans this is only significant against abnormal lymphocytes, for example in lymphoproliferative disorders, and when used at very high doses. Corticosteroids are potent immunosuppressants but their major disadvantage is multiple side-effects; these include weight gain, hirsutism, hypertension, diabetes mellitus, recurrent infection, growth retardation, osteoporosis, and reduced response to physiological stress. The appropriate dose of corticosteroid is determined by the individual clinical situation. For the long-term control of autoimmune disorders an oral dose of <10mg/day prednisolone would be appropriate. In the acute management of autoimmune haemolytic anaemia, acute glomerulonephritis or immune thrombocytopenic purpura, l-2mg/kg/day is indicated. In very severe life-threatening situations, such as systemic vasculitis, pulsed high-dose regimens of l0mg/kg are used (maximum 1000mg).
CYTOTOXIC DRUGS (see Chapter 6) This group of drugs kills cells capable of self-replication and they were initially introduced in the treatment of cancer. Their introduction into the management of trans1
102
MCQ 4.4
2
Case 4.2
3
MCQ 4.5
plantation and autoimmunity enabled reductions in the doses of corticosteroids required (in this situation they are often referred to as 'steroid-sparing agents'). The major complication of long-term use is myelosuppression and immunosuppression, and a long-term increase in susceptibility to malignancies. Azathioprine Azathioprine is an analogue of the cytotoxic drug 6mercaptopurine (both are thiopurines) and was originally introduced in the 1950s for renal transplant recipients. It now has a major use as a steroid-sparing agent in the management of many autoimmune disorders. Thiopurines block the synthesis of inosinic acid, the precursor of adenylic and guanylic acids, and thus impair DNA synthesis. Their major cytotoxic effect is on developing T and NK cells, and thus there is a delay before clinical onset of action. The most important side-effect is bone marrow suppression. Weekly monitoring of full blood count (FBC) is advised during induction, with 3-monthly FBC during maintenance therapy. The patient must be warned of potential susceptibility to infection, and any unexplained illness or clinical suggestion of infection requires thorough investigation and, potentially, withdrawal of treatment. The usual maintenance dose range is l-3mg/kg daily. 2 Cyclophosphamide This is one of the most widely used drugs in cancer chemotherapy and is now frequently used in combination with corticosteroids in the management of severe autoimmune conditions, especially systemic vasculitis. As an alkylating agent it acts by cross-linking DNA strands, thereby preventing normal mitosis. It is particularly toxic to B cells. Side-effects include a dose-dependent neutropenia and lymphopenia, alopecia and infertility (especially in males) and, infrequently, haemorrhagic cystitis. Cyclophosphamide is typically used in combination with prednisolone in either oral or intravenous protocols to control severe systemic vasculitis. Dosage is determined by disease severity and according to renal function, bone marrow function and the patient's age. Mycophenolate mofetil Mycophenolate mofetil is used in combination with corticosteroids and ciclosporin in the prophylaxis of renal transplant rejection. Mycophenolic acid (MPA) is the active metabolite and is rapidly produced by hydrolysis after ingestion of the drug. MPA selectively inhibits inosine monophosphate dehydrogenase (IMPDH), which prevents lymphocyte purine biosynthesis. The inhibition of IMPDH causes a depletion of guanine nucleotides, inhibition of DNA synthesis, and prevents clonal expansion of both T and B cells. Close monitoring is necessary with weekly full blood counts (FBC) for the first month of treatment, 2-weekly for the next month, and monthly for the first year of treatment. Its use is currently limited to specialist transplantation units.
Methotrexate This drug is used in maintenance treatment of childhood leukaemias and is increasingly used in the control of a number of inflammatory diseases, including rheumatoid arthritis, polymyositis, psoriasis, Reiter's syndrome and graft-versus-host disease following bone marrow transplantation. It also appears to have a role in steroiddependent asthma, although the exact mode of action in this condition is unclear. Methotrexate inhibits dihydrofolate reductase, thus preventing the conversion of folic acid to its active form, tetrahydrofolate. This prevents normal thymidine synthesis and cell division. Side-effects include bone marrow suppression, megaloblastic anaemia, pneumonitis and mucositis. Long-term drug toxicity is increased in hepatic impairment. Acute side-effects are partially reversible by the administration of folinic acid.
NON-CYTOTOXIC IMMUNOSUPPRESSION Ciclosporin This relatively recently introduced drug has revolutionized the management of post-transplantation patients and is also finding a place in the management of some autoimmune disorders. A fungal metabolite with a cyclic undecapeptide structure, it acts to selectively inhibit T-cell activation. The drug binds to cytosolic proteins, called cyclophilins, which prevent calcium-dependent activation of the IL-2 gene. IL-2 transcription is a crucial event in T-cell activation and thus cyclosporine is a relatively selective immunosuppressant. Ciclosporin does not cause myelotoxicity but does cause a dose-dependent reduction in renal function that must be carefully monitored and differentiated from renal transplant failure or rejection. Monitoring of therapeutic plasma levels is essential. Other side-effects include hirsutism, gingival hyperplasia and seizures. In common with other immunosuppressants there is an increased long-term risk of lymphoma and skin neoplasia. Tacrolimus (FK506) This macrolide is not chemically related to ciclosporin but has a similar mode of action. Its use is currently limited to hepatic and renal transplant patients, although there is evidence to suggest it will have significant clinical impact in autoimmunity. Tacrolimus binds to the cytosolic FK506binding protein (FKBP), preventing IL-2 gene activation. It has a similar range of side-effects to ciclosporin. 3
NEWER IMMUNOSUPPRESSIVE STRATEGIES In addition to the pharmacological immunosuppressive drugs, a number of new immunological therapies are emerging in clinical practice.
Plasma exchange has been available for many years and continues to be of value in the acute management of some severe autoimmune conditions, including Goodpasture's syndrome, myasthenia gravis and rhesus disease, in which autoantibodies are demonstrated to be pathogenic. Plasma exchange allows the removal of these autoantibodies acutely but has no proven role in the long-term management of these conditions. High-dose ivIg therapy (l-2g/kg) is of proven benefit in autoimmune thrombocytopenia and Kawasaki's and Guillain-Barre syndromes. Its mode of action is incompletely understood, but may involve blockade of Fc receptors, disturbance of anti-idiotypic networks, or suppression of macrophage and/or T-cell activation. This therapy has specific side-effects, including aseptic meningitis, acute haemolysis (when ivIg is uncross-matched) and acute deterioration in renal function. It should therefore only be used for conditions in which clinical benefit is proven by properly controlled studies. Monoclonal antibody (moAb) therapy has shown encouraging results in a number of areas of clinical practice. CAMPATH-1 is a humanized mouse anti-CDw52 moAb, an antigen which is present on all leukocytes. It has proved to be of particular value in the treatment of acute graft rejection and graft-versus-host disease following bone marrow transplantation. More specifically, anti-CD25 moAb (basiliximab), which prevents T-cell activation, has been introduced for the prophylaxis of acute renal rejection. Antitumour necrosis factor (anti-TNF) moAb has recently shown promising results in the control of disabling rheumatoid arthritis (RA) and in severe inflammatory bowel disease, especially Crohn's disease. TNF is believed to have a central role in the pathogenesis of these diseases. Future clinical developments in this area may follow from current preclinical studies. 'Biological immunosuppressive agents', including antibodies directed against cell surface molecules of T, B and antigen-presenting cells, are being studied in models of transplantation and autoimmunity. These models may indicate new modalities for controlling undesirable immune responses through modulation of the function of the cell surface signalling molecules. Antibodies directed against gp39 (CD40 ligand) and CD28 have been demonstrated to overcome renal allograft rejection in a primate system. Human clinical trials (phases I and II) of these agents are currently under way. Anti-LFA-1 moAb has also been used to control transplant rejection. The cell surface molecule CTLA-4, which is known to downregulate T-cell responses, also has the potential for therapeutic manipulation. CTLA-4 linked to immunoglobulin molecules (to prolong its half-life in the circulation) has been successfully used in clinical trials to treat psoriasis. In respiratory medicine, IL-8 receptor antagonists are being evaluated in airway disease, and antiIL-5 moAb is under investigation in the treatment of asthma. These experiences of 'biological immunosuppression' suggest that this will be a major area of therapeutic development in the coming years, with novel drug devel-
4
103
opment for a wide range of disorders associated with inappropriate or excessive immune activation.
FURTHER READING Chapel H M 1994 Consensus on diagnosis and management of primary antibody deficiencies. British Medical Journal 308:581-585. Chapel H, Heaney M, Misbah S, Snowden N 1999 Essentials of clinical immunology, 4th edn. Blackwell Science, Oxford. Conley M E, Notarangelo L D, Etzioni A 1999 Diagnostic criteria for primary immunodeficiencies. Clinical Immunology 93(3):190-197.
104
Janeway C A, Travers P 1997 Immunobiology - the immune system in health and disease, 3rd edn. Churchill Livingstone, Edinburgh. Primary immunodeficiency diseases. Report of an IUIS scientific group. 1999. Clinical and Experimental Immunology 118 (suppl l):l-28. Reeves W G, Todd I 1996 Lecture notes on immunology, 3rd edn. Blackwell Science, Oxford. Rosen F S, Cooper M D, Wedgewood R J P 1995 The primary immunodeficiencies. New England Journal of Medicine 333(7):431-440. Stites D P, Terr A I, Parslow T G 1997 Medical immunology, 9th edn. Appleton and Lange, Connecticut.
5
Nutrition in Clinical Medicine Michael E J Lean
Food and its use 105
Overweight and obesity 128
Assessment of nutritional status 115
Nutrition support 132
Dietary intake assessment 117
Nutrition as a cofactor in disease and in therapy 136
Nutrition and feeding practices for growth 119
Food sensitivity and intolerance 140
Malnutrition 120
Nutrition in health promotion: current diet and proposals for change 141
Vitamin deficiencies and excesses 122 Trace elements 127
FOOD AND ITS USE FOOD CHOICE AND FOOD COMPOSITION There is no doubt that diet has profound influence on human health, at all ages and affecting all medical subspecialties. Defining and influencing nutritional status is, however, very complicated. Although we customarily summarize the diets of individuals and populations in terms of nutrient exposure, there are many steps in establishing this exposure, each subject to substantial variability, both within individuals over time and between population subgroups. The general scheme (Table 5.1) may seem mostly self-evident, but indicates the scope for error in research and the need for clarity of thinking. The source of variability which may affect the evaluation of the diet of an individual or a population extends well beyond those that can be established either by retrospective questionnaires (depending on memory) or by prospective food records (depending on representativeness). Most of these influences are beyond the control of individuals, and so may tend to confound efforts to change diets.
As well as variations within the population, many of the components in Table 5.1 are also subject to fluctuations over time. Meal and snack patterns have changed dramatically over the last 10-20 years, with 'grazing' now being the norm in young people. Likewise, a generation has now emerged without experience of traditional meals or home cooking, using almost exclusively pre-prepared foods eaten in 'non-meal' situations - e.g. in front of the television, or on public transport. Increasingly homes do not have conventional kitchens, and people rely on microwaves and freezers. Although daily food shopping is still usual in Mediterranean countries, where fresh foods predominate, the steady trend in UK is towards weekly shopping, and this has profound effects on the need for long-life foods and preservatives. Retailers have progressively selected smaller ranges of foods, for shelf-life, appearance and taste, but disregarding nutrient composition. The dominance of major multiples (supermarkets) has significantly reduced biodiversity and driven farmers to produce highly stylized products. The 'added-value' food processing industry is now the major profit source, such that the most heavily advertised and promoted foods are those with the poorest nutritional value. Individual food choice is very complicated, but essentially demands a mix of the known and safe with a little of something new. Over recent decades there have been progressive trends to increase the sweetness and saltiness of foods. This has created a taste expectation, such that home-prepared foods can taste unpleasant if they contain less (i.e. normal amounts) sugar or salt. On a more positive note, the quest for 'health' by consumers is becoming a major driver for food choice and for reformulation of products. Globalization and sophisticated trading and transport have introduced unfamiliar foods, but also a new layer of uniformity which makes change difficult. The influence of season has all but disappeared, to the extent that many people are suspicious of seasonal foods - even locally grown ones, such as soft fruit. The nutrient composition of foods, catalogued in food tables and databases, is drawn up from analyses of a few examples of each food. One or two (e.g. potatoes) take account of seasonal variations in composition, but not the other factors outlined above. These tables provide only a broad guide as to the nutrient composition of the foods consumed by an individual or in a particular survey. Dietary analysis is imprecise, with scope for serious error. For some foods, similar varieties can contain up to 100-fold differences in specific nutrients, e.g. flavonols in lettuces. One way to resolve this is to assess diets, and to construct dietary advice, in terms of food groups consisting of broadly interchangeable foods - bread/cereal/pasta/rice; fruit and vegetables; spreading fats and oils; meat/cheese/ eggs; sweets, cakes and confectionery. This type of grouping has some limitations, but serves to remind us that diets, and foods, are consumed in meals. The meal is the smallest unit of nutrition, and it is the 'eating episode' which provides a focus for individual planning.
a
105
TABLE 5.1 Influences on diet composition and nutrient exposure with food choice and variability Diet composition
Source of variability
Meal and snack pattern Meal structure Cooking methods Home food storage methods Shopping and catering patterns Food choice of individuals Purchasing policies of retailers Farming methods Seasonal
Age, ethnicity, culture Culture, occupation, family Family structure, housing Housing, finance Socioeconomic, ethnic Age, gender, socioeconomic Profit-driven, convenience Profit-driven, subsidies Latitude, transport Analytical rigour
Nutrient composition of food groups Nutrient composition of specific food varieties
Plant breeding, health concerns
NUTRITION AND NUTRIENTS Nutrition is the process by which food is eaten and utilized by the body. More broadly, the principles of nutrition nutrient supply, storage, requirements, consumption and metabolism - can be applied at many levels. Nutritional balance, which incorporates all these factors, should therefore be considered at the levels of the cell, of organs, of the whole body and of populations. For all the processes that define nutritional balance, there are ranges within which balance can be achieved at a level compatible with health. Outside these ranges malfunction and disease will result from deficiencies, toxicity or competition between nutrients. Within 'normal ranges' of nutrition, research is beginning to define levels which may determine optimal long-term health, and which may differ between individuals according to genetic background. In the presence of disease, nutrient requirements, supplies and metabolism are altered. Nutritional status may be a cause, or part of a cause, of disease, and may in turn be altered by disease. This chapter is concerned with the ways in which nutrient supplies - especially energy - are utilized, and how dietary factors and deficiencies may produce specific clinical syndromes or contribute to the development of disease.
DIETARY REQUIREMENTS AND REFERENCE VALUES
106
Defining the nutritional requirements of individuals, or of groups or populations, is one of the most important aims of nutritional science. Information of this kind is essential for designing food supplies, and therefore it has major economic and political implications.
Certain nutrients are essential, i.e. they are necessary components or precursors of human biological pathways, that cannot be synthesized by humans. Essential nutrients include energy (provided by carbohydrates, fat and protein, together with oxygen and water), essential amino acids and fatty acids, and vitamins and essential trace elements. Foods also contain large numbers of other biologically active compounds which can modify metabolism and function. These are not 'essential', but may have beneficial actions for current or long-term health. Finally, there are compounds in foods which are not nutrients. These include environmental contaminants and inert or non-absorbable compounds. They may still affect health through toxic or allergic mechanisms, so the quantity present in foods may be important. Living cells require a continuous balanced supply of nutrients. However, food and nutrient supply is intermittent, and the body must also accommodate periods of nutrient deprivation, whether through famine or illness. The relationship between storage and tissue requirements determines survival time during nutrient deprivation. For oxygen (with only limited local capacity for anaerobic respiration and no storage), survival is measured in minutes. For carbohydrates and water, a clinical problem may occur in hours or a few days. For most water-soluble vitamins and some minerals (e.g. zinc), nutrient status also declines in days of deprivation. In contrast, in the case of the fatsoluble vitamin B12 and iron, full stores can permit many weeks of dietary deprivation. Traditionally, dietary nutrient requirements have been established for the essential nutrients on the basis of the amount per day which is sufficient to prevent a clinical deficiency syndrome developing, with a margin between 30 and 100% to produce a recommended daily amount, or RDA. This safety margin will depend on the nature of the nutrient. Fat-soluble vitamins, which tend to accumulate in the body and can be toxic, have a lower safety margin than water-soluble vitamins, which are rapidly excreted if consumed in excess. For many nutrients, deficiency syndromes develop slowly and isolated deficiencies are rare, so it has been hard to define RDAs. The 'safe intake' is often quoted. These are intakes which are customarily consumed by apparently healthy people. However, there are variations within the range of intakes in the general population. At a cellular level, most nutrients required for normal metabolism are synthesized. In some situations - in illness when supply is limited or demand is increased - there may be a conditioned deficiency of 'non-essential' nutrients which take on the role of 'conditioned essentials'. It appears that, for some nutrients (notably the antioxidant vitamins), there are levels of intake, well above those needed to prevent deficiencies, which are associated with optimal long-term health. Higher intakes than the RDA of vitamin E, for example, appear to have some protective effect against heart disease and some cancers. The RDA for folate, sufficient to prevent folate deficiency, is insufficient to prevent neural tube defects in susceptible women. Furthermore, within the recommended or 'normal' range
a
FIG. 5.1 Dietary reference values - definitions 95% of people would be adequately nourished if they consumed the RNI, and 95% would be deficient at LRNI.
FIG. 5.2 Dietary intakes and risk of deficiency with and without adaptation The risk of clinical deficiency is reduced when there is adaptation to low intake as it falls below the LRNI.
TABLE 5,2 Criteria for defining dietary reference values of folate intakes there is an inverse correlation with plasma homocysteine, a risk factor for heart disease. For most vitamins and minerals the average intakes in western countries are well above the RDAs, but some - e.g. iron, thiamine, folate, vitamin D, vitamin E - are marginal in certain population groups In 1991, the UK Committee on Medical Aspects of Food Policy, published a new approach to dietary reference values for a total of 40 nutrients. The reference nutrient intake (RNI) is defined as 2SD (standard deviations) above the estimated average requirement (EAR), and the lower reference nutrient intake (LRNI) as 2 SD below it (Fig. 5.1). Thus 95% of people would be adequately provided for by consuming the RNI and, assuming no adaptation to low intakes, 95% would be deficient if they consumed the LRNI (Fig. 5.2). The exception to this general rule is the energy requirement. Assuming the need to maintain a constant weight, only an EAR is quoted. The evidence used included not only the classic clinical deficiency evidence, but also data on blood or tissue saturation and on nutrient-dependent enzyme function (Table 5.2). For a number of nutrients adequate scientific data are still not available, and so 'safe intakes' are quoted. The questions surrounding optimal intakes for future health are still unresolved, apart from fatty acids, which follow the recommendations for cardiovascular health. Dietary reference values (DRVs) are determined for healthy people, and assume normal status for other nutrients. The factors affecting requirements are summarized in Table 5.3.
• • • • •
Amount taken without deficiency developing Amount needed to cure deficiency Amount needed to maintain blood or tissue concentration Amount needed to maintain enzyme saturation Amounts associated with appropriate biological marker of adequacy
TABLE 5.3 Factors which affect requirements of nutrients 1. 2. 3. 4. 5. 6. 7. 8. 9. 10.
Size Age Growth Sex Physical activity Pregnancy Lactation Availability from specific foods Illness Deficiencies of other nutrients
ENERGY Energy, utilized over time to produce work or build body tissues, is expressed as kcal or kJ (1 kcal = 4.18kJ). It is supplied by fat (9kcal/g), ethanol (7kcal/g), protein (4kcal/g),
107
carbohydrates (3.75kcal/g) and dietary fibre (2-3kcal/g). Because energy cannot be created or destroyed, energy intake always equals energy output, plus or minus changes in energy stores. The body stores some energy as carbohydrates, in the form of glycogen (mainly in the liver), which provides a source of glucose. Total glycogen stores contain about 250 g, or 1000 kcal. The remaining energy stores are as triglycerides in adipose tissue. An average person with 20kg of adipose tissue has energy stores of 20 x 7000 = 140 000 kcal, enough to provide for 70 days' starvation at 2000 kcal/day. Carbohydrate cannot be synthesized from fatty acids. There are no specific stores of protein, but during starvation protein is metabolized from the destruction of muscle and connective tissue. This, and the glycerol from triglycerides, provides some glucose for organs dependent on glucose. Energy is necessary for the maintenance of all metabolic processes, physical activity and growth. Most dietary energy is needed to maintain oxygenation, blood supply and ionic gradients across membranes in all tissues. This is termed the basal metabolic rate (BMR). Energy expenditure can be measured by indirect calorimetry, usually in the early morning in a resting state, the subject having last eaten the previous evening. This resting energy expenditure (REE) is close to the BMR. BMR can be estimated with reasonable accuracy from the sex, age and body weight (Table 5.4). More recent 'doubly labelled water' methods measure energy expenditure in free-living adults using the different excretion rates of the stable isotopes deuterium (3H) as water, and 18O as water and CO2, to obtain an estimate of CO2 production and hence total energy expenditure (TEE). The difference between TEE and BMR measures the energy expenditure in association with feeding and from physical activity (Table 5.5). The energy requirement of an individual subject, which is equal to TEE if weight is to remain constant, depends primarily on body size and composition. Age, physical activity, environmental temperature and physiological state (whether pregnant, lactating or suffering from sys-
SUMMARY 1 Factors affecting basal metabolic rate and total energy expenditure Factors affecting basal metabolic rate • body weight • age/gender
relative proportion of lean body mass to adipose tissue recent weight change or energy imbalance
• thyroid function
108
Factors affecting total energy expenditure • basal metabolic rate • physical activity and body weight (work output) • diet composition (carbohydrate, protein, fat proportions) • inflammatory conditions, altitude
TABLE 5.4 Equations for estimating basal metabolic rate (BMR) BMR (MJ/d)
Males
10-17 yr 18-29 yr 30-59 yr >60yr
BMR = 0.074 W + 2.754 BMR = 0.063 W + 2.896 BMR = 0.048 W + 3.653 BMR = 0.049 W + 2.459
SEE = 0.44 SEE = 0.64 SEE = 0.70
Females
10-17 yr 18-29 yr 30-59 yr >60yr
BMR = 0.056 W + 2.898 BMR = 0.062 W + 2.036 BMR = 0.034 W + 3.538 BMR = 0.038 W + 2.755
SEE = 0.47 SEE = 0.50 SEE = 0.47
W = body weight (kg), SEE = standard error of estimate
TABLE 5.5 Calculated physical activity level (PAL) of adults at three levels each of occupational and non-occupational activity Occupational activity Light
Non-occupational activity Non-active Moderately active Very active
Moderate
Moderate/Heavy
Male
Female
Male Female Male
1.4 1.5 1.6
1.4
1.6
1.5
1.5
1.7 1.8
1.6 1.7
1.6
1.7 1.8 1.9
Female
1.5 1.6 1.7
temic infection) are also important. BMR is determined by the size and metabolic activity of organs in a resting state, and so it has a major component from organs such as the heart, lungs, kidneys and brain. Skeletal muscle is relatively less important in determining BMR than it does in TEE. TEE has a very close relationship to body weight because the energy cost of physical activity depends closely on weight. Variations in BMR for a given weight can reflect metabolic factors such as thyroid function. Energy expenditure may be considerably increased in situations of metabolic stress, such as pyrexia and burns. The factors that control metabolism physiologically and modify it in disease include catecholamines, thyroid hormones, insulin, cortisol and cytokines (e.g. tumour necrosis factor-a). Energy requirements are highest - on a body weight basis or per unit 'lean body mass' - in infants and young children. Energy expenditure starts to fall in the 20s and declines steadily thereafter into old age, principally because of declining physical activity, with consequent reduction in muscle mass. Because the factors affecting energy requirement vary considerably between individu-
TABLE 5.6 Average daily energy expenditure In various lifestyles
a
24-hour energy expenditure in kcal (MJ) Occupation (age in years)
Men
Retired elderly (65+) Housewife (25-45) Office worker Laboratory technician (20-50) Factory worker (20-45) (heavy industry) Labourer (20-45) (heavy physical work)
2300 2500 2800 3200 3600
Women (9.5) 1900 2200 (10.4) 2100 (11.7) 2200 (13.2) 2400 (14.8)
(7.8) (9.0) (8.6) (9.0) (9.9)
TABLE 5.7 Average energy expenditure of an adult in various degrees of physical activity Degree of activity
Expenditure (kcal/min)
Minimal (e.g. sitting, slow walking) Moderate (e.g. walking, gardening) Intermediate (e.g. swimming, brisk walking) Heavy (e.g. digging, squash, running)
1 5 7 10
als, it is impossible to give an exact ideal nutrient intake, but there are clearly differences in daily energy expenditure between adults with different lifestyles (Table 5.6) and at different ages (Fig. 5.3). The energy expenditure for physical activity depends on body size, so it is convenient to express the energy costs of different activities as functions of BMR. Table 5.7 shows the energy required for various physical activities. As the total time in each 24 hours spent in strenuous activity is often rather short, significant increases in energy expenditure are difficult to sustain. Weight reduction by increasing physical activity is therefore hard to achieve. In adults the main indicator of energy balance (and often of overall nutritional status) is change in body weight. Weight varies by up to 1-2 kg from day to day in healthy adults, and is more affected by fluid balance over the short term. Weight change due to altered energy balance is usually accounted for by fat stores, at 9000kcal/kg (75% of weight change), and lean body mass, at l000kcal/kg (25%). Thus each 1kg change in adipose tissue reflects about 7000 kcal shift in energy balance. Although metabolic rate is governed principally by body weight, the alterations in metabolic rate from weight changes are relatively small: a 1kg weight change alters metabolic rate (and thus energy requirement for weight stability) by only about 15kcal/day. In children energy is required for growth, and measurements of weight gain or height gain are useful indicators
FIG. 5.3 Estimated average requirements for energy intake [A] at different ages, and B during pregnancy and lactation for women.
of dietary insufficiency. During the first few weeks of catchup growth from severe malnutrition, the energy cost of weight gain is about 5kcal/g. Thereafter, it becomes more energy expensive to lay down tissue, as fat rather than lean tissue is laid down. Energy balance can be maintained from a wide range of nutrient origins. In the UK, fat and carbohydrate each provide between 40 and 50% of dietary energy, whereas in developing countries the proportion from fat may be less than 15% and from carbohydrates more than 75%. Protein provides 10-15% of energy in most diets, in both western and developing countries.
109
Dietary energy deficiency is that amount which results in negative energy balance. This results in immediate mobilization of energy stores from glycogen and fat. As underfeeding continues a greater proportion comes from protein, principally through muscle atrophy. Excess energy intake will be stored as glycogen if the limited capacity of the liver permits, or as fat in adipose tissue. Gross excess will lend to storage in tissues such as liver, impairing liver function. Minor imbalances of energy balance occur between meals and from day to day. Energy imbalances insufficient to be detected in body weight will have metabolic effects, e.g. on insulin sensitivity and serum lipoprotein.1
PROTEIN Most major human foods include protein, in an amount equivalent to 5-50% of food energy (Table 5.8). Mixed diets usually supply 10-20% of energy as protein. The requirement for dietary protein is determined by tissue growth and repair. The healthy body is efficient in the utilization of amino acids. Total body protein in an adult is about 16kg, which has accrued over 15-20 years of growth. Healthy protein is constantly being broken down and resynthesized in the process of protein turnover, but the amino acids are mostly reutilized. Losses from skin, hair and gut mucosa contribute to an absolute requirement of about 0.6g/kg/day for adults, or about 8% of dietary energy. Although humans cannot incorporate inorganic nitrogen, colonic bacteria can. It is therefore possible for some nitrogenous waste in the bowel to be rescued by bacterial amino acid synthesis and subsequent absorption. There are no body stores of protein or amino acids, but periods of low intake can be tolerated by metabolism of tissues such as muscle, gut mucosa and skin. However, atrophy of these tissues is more likely to reflect total energy deficiency, not specifically protein. The maximal protein requirement for optimal growth in infancy is about 1.5g/kg/day. This is amply provided by human milk, whose protein content is 130g/L, 7.5% energy.
SUMMARY 2 Protein requirements in health • • • •
Protein deficiency impossible with normal food provision Most dietary protein is metabolized like carbohydrate Minimum safe consumption (about 8% dietary energy) Requirements for essential amino acids virtually always met by 1 g/kg/d (= 10% dietary energy)
1
110
MCQ 5.1
TABLE 5.8 The protein content of some foods which are often major protein sources Protein source Cassava Cooked bananas (plantains) Sweet potatoes Human milk (4.1 % fat) Rice (brown or white) Millet flour Potatoes (old, main crop) Maize (sweetcorn kernels) Wheat flour (wholemeal) Groundnuts (peanuts) Cows' milk, full fat (3.9% fat) Beans and peas Lentils
Eggs Cows' milk (skimmed) Fish (fatty) e.g. mackerel Soya (tofu) Meat (lean) (beef) Fish (white)
Proportion of energy as protein (%) 2 3 5 7 7 7 11 15 16 18 19 31 34 34 40 42 45 50 94
It is assumed that human milk contains the amino acids required for growth in optimal proportions, and this is likely to be similar for other milks, and eggs. There are nine amino acids which are not synthesized in the body, and are thus 'essential' nutrients. Others are needed in the diet to optimize utilization, although they are not technically essential. The ability to synthesize specific amino acids may be compromised during illness, such that 'conditioned essentiality' may develop, e.g. for glycine in infants. The metabolic requirement for amino acids is a separate consideration from dietary requirement. Essential amino acids thus form a small part of metabolic requirement, whereas non-essential amino acids (normally readily synthesized in the body) may be required in large amounts. To some extent alterations in colonic bacterial amino acid synthesis may modify essentiality. Because certain foods are deficient in essential amino acids (cereals, for example, are deficient in tryptophan, methionine and cysteine) an optimal amino acid balance can only be achieved by combination with other foods (such as legumes, which are rich sources of tryptophan and methionine). Thus a diet based on maize and beans is consumed by millions of healthy people all over the world. Most mixed diets contain much more protein than is required for health, and the excess is metabolized, mainly as carbohydrates, allowing the correct balance of amino acids to be extracted for protein synthesis. Protein is absorbed in the small intestine as amino acids and small
peptides, after the action of luminal peptidases such as trypsin. Isolated dietary protein deficiency is extremely rare outside famine situations. Low-protein foods such as cassava or plantains are not otherwise eaten in isolation. Even when intakes of ethanol or fat and sugar are extreme, protein requirements in western societies are usually met. There is considerable debate as to how much protein we require. The usual calculation, which has been applied to all nutritional states, is expressed as nitrogen balance - the difference between the dietary intake and the losses of nitrogen in the urine, faeces and sweat. A positive balance is achieved when intake exceeds losses, such as occurs in normal infant and child growth, or during recovery from malnutrition in adulthood. Negative balance occurs when losses exceed intake, as in systemic infection or diarrhoea, or when dietary intake is reduced. The greatest requirements for protein (relative to body weight) occur in young infants. Those less than 3 months of age require about 2.5 g protein/kg body weight/day, and the older infant (9-12 months of age) requires 1.5g protein/kg body weight/day. Children need less than infants but more than adults. Rates of protein synthesis vary with age, being highest in the newborn and declining with time (Table 5.9). Unfortunately, nitrogen balance measurements are difficult to conduct, particularly in the ill or deprived. The main problem is that they depend on having a complete 24-hour urine collection to estimate output. If urine collections are incomplete, as is very common, the results are biased towards an apparently positive nitrogen balance. Thus, improbable claims of positive nitrogen balance have even been made for subjects on very low-calorie diets and evidently losing weight. Nitrogen balance in adults to some extent changes with the customary diet. There is adaptation to low intakes, so that nitrogen balance has apparently been achieved with 0.2g/kg/day after several weeks. However, it is not certain that this is indefinitely sustainable in health. During illness, both protein synthesis and protein degradation are increased, so that total protein turnover is elevated non-specifically and irrespective of whether total body protein content changes. In general, there is net protein loss during disease, with wasting of muscle, and the losses are restored during recovery. The 'ebb and flow'
TABLE 5.9 Variation in rate of protein synthesis with age Age group
Body weight (kg)
Newborn (premature) 2.0 Infant 9.0 Young adult 70.0 Elderly 55.0
Total body protein synthesis (g/kg body weight/day) 15.0 7.0 3.0 2.0
phases of energy and protein balance after metabolic stress relate to the release of metabolically active compounds such as cytokines, and cannot be corrected by increasing the supply of amino acids or dietary protein. There is no simple biochemical test to estimate amino acid or protein status. Plasma amino acids and proteins all reflect stress non-specifically. Serum albumin falls with any stress or inflammatory condition - e.g. myocardial infarction, malignancy or infection - and is not a marker of nutritional status. Serum albumin may, however, be of some value in distinguishing disease-related cachexia from starvation. Low albumin in the presence of starvation is a worrying prognostic sign, usually indicating the presence of infection. This is the case in oedematous malnutrition (kwashiorkor).
a
CARBOHYDRATES There are three major groups of carbohydrates in the diet: sugars, starches, and the plant wall materials that comprise 'dietary fibre'. All carbohydrates are polymers of monosaccharides, with the common formula (CH2O)n. They are almost completely absorbed from the gut, either as monosaccharides in the small intestine after hydrolysis by amylases and mucosal disaccharidases, or (5-10%) as short-chain fatty acids following fermentation by large bowel bacteria. The main absorbed sugars, glucose and fructose, are ultimately metabolized in the Krebs cycle to release energy through oxidation. Each carbon atom combines with two oxygen atoms to produce H2O and CO2 and release 3.75 kcal/g. Of relevance to the management of diabetes and hyperlipidaemia is the 'glycaemic index' of foods. This is the incremental rise (i.e. subtracting this baseline value) in blood glucose over 3 hours after eating 50 g carbohydrate from a food, expressed as % of the rise after 50 g carbohydrate from bread, which is used as a standard. It is possible to predict the glycaemic index of a whole meal from those of its component parts. Low glycaemic index foods, reflecting the content of fat and dietary fibre, consistency, cooking or processing and other undefined factors, are associated with lower blood glucose and insulin (i.e. increased insulin sensitivity) and with improved serum lipoprotein profiles. • Sugars. Sucrose and its components glucose and fructose are the sugars most used as sweeteners. Lactose (glucose-galactose) is the main sugar in milk. Fructose is the sweetest. The monosaccharides glucose, fructose and galactose are readily absorbed at the jejunal surface. The disaccharides sucrose, maltose and lactose are equally well absorbed as the monosaccharide component parts, provided that there has been effective hydrolysis by the intestinal disaccharidases. Sucrose intolerance and lactose intolerance, leading to watery diarrhoea, may occur during starvation or any diarrhoeal disease, as a result of mucosal atrophy and secondary
111
disaccharidase deficiency. This is a strong argument for maintaining gut function by enteral feeding in postoperative and intensive care patients. • Starches. These comprise a group of polysaccharides containing large numbers of glucose units linked together to form branched chains. They are variably hydrolysed as a result of cooking, and are then further hydrolysed within the intestine. The commonest are the dextrins amylose and amylopectin. About 90% of starch is rapidly hydrolysed and absorbed in the small intestine. The remainder (some altered by processing or cooking to become hydrolysis resistant) passes with non-starch polysaccharides to the colon. • 'Dietary fibre' - non-starch polysaccharides. Plant walls contain a range of lignins, celluloses and hemicelluloses that are not digested in the intestine, and which are variably degraded by intestinal bacteria in the colon. Dietary fibre can be measured in a variety of ways in foods, but its function in maintaining healthy colonic flora - an essential function - can be performed differently by the different subclasses, and by other compounds, such as lactose in breastfed infants. Different dietary fibres have important physiological functions in influencing the absorption of sugars and the regulation of serum lipoproteins (soluble and gum-forming fibre from vegetables, fruits, legumes and oats) and in contributing to intestinal bulk and large bowel health (cereal fibre such as bran). Dietary reference values for carbohydrate are shown in Table 5.10. 'Extrinsic' sugars are those outside intact cells in foods. Several varieties of non-sugar sweetener exist. Sorbitol is a sugar alcohol; however, its energy value is similar to that of other carbohydrates. Saccharine has no chemical or nutritional relationship to sugars and provides no energy; it is about 500 times as sweet as sucrose. Aspartame is an amino acid-based non-nutritive sweetener. EU regulations control the amounts of sweeteners that are permitted in foods. None have been shown to be hazardous to humans, but the recommended limits can be exceeded by individuals with unusually repetitive food habits, and by diabetic children who consume large amounts of highly sweetened foods. Very high consumers should vary the types of artificial sweeteners used.
FAT
112
Fatty acids provide the chief store of energy in the body. They are important in the development of all cell membranes and some tissues, and are essential components of some hormones. Dietary fatty acids are mainly supplied as triglycerides. These are esters of glycerol and three fatty acids. Fatty acids are characterized by the chain length, expressed as the number of carbon atoms (short chain C2-C4, medium chain C6-C12, long chain C20-C24), and by the number and position of double bonds (one double
TABLE 5.10 Dietary reference values as percentage of total energy* Population average Saturated fatty acids cis-polyunsaturated fatty acids of which essential fatty acids
10(11)
cis-monounsaturated fatty acids frans-fatty acids Total fatty acids Total fat Non-milk extrinsic sugars Intrinsic and milk sugars and starch Total carbohydrate
12(13)
33 (35)
Non-starch polysaccharide (g/d)
18
6 (6.5) 3(3)
2(2)
30 (32.5)
10(11)
37 (39) 47 (50)
*The average percentage contribution to total energy does not total 100% because figures for protein and alcohol are excluded. Protein intakes average 15% of total energy, which is above the RNI. It is recognized that many individuals will derive some energy from alcohol, and this has been assumed to average 5%, approximating to current intakes. However the Committee on Medical Aspects of Food (COMA) allowed that some groups might not drink alcohol and that for some purposes nutrient intakes as a proportion of food energy (without alcohol) might be useful. Therefore average figurers are given as percentages both of total energy and, in parentheses, of food energy.
bond monounsaturated, two or more polyunsaturated). Most unsaturated fatty acids are cis isomers, but some, mainly synthetically hydrogenated, are trans isomers. Vegetable oils have a greater proportion of polyunsaturated fats and are more fluid than the more saturated fats from animal sources, which are often hard at room temperature (Fig. 5.4) although liquid at body temperatures. Fish oils need to remain liquid at temperatures down to freezing point, and so contain large amounts of long-chain n-3 fatty acids. Dietary fats are normally almost 100% absorbed as they pass through the small intestine, after emulsification through the action of bile salts, and de-esterification of triglyceride by pancreatic lipase. Most dietary triglyceride is absorbed as monoglyceride and free fatty acids. The triglyceride is thus reassembled by re-esterification in the mucosal cell, and secreted by the mucosal cell with the addition of a lipoprotein as chylomicron. Most reaches the circulation via the chyle and the thoracic duct. Some, particularly short-chain fatty acids, are preferentially released discretely into the portal vein. Dietary reference values are included in Table 5.9. Phospholipids - esters of glycerol with two fatty acids are important for the stability of cell membranes, and deficiency may affect satisfactory psychomotor development. Cholesterol is the most important sterol. It is the precursor of the bile acids (which are essential for mixed micelle formation in the intestinal absorption of fat) as well as of adrenal and sex hormones and vitamin D.
FIG. 5.4 Fatty acid composition of some major sources of saturated, mono, and polyunsaturated fatty acids
of carotenoids (the precursors of vitamin A found in vegetables) and other fat-soluble vitamins. The position is more serious when there is intestinal malabsorption of fat (Chapter 15), as fat-soluble micronutrients are excreted in the faeces, dissolved in the malabsorbed fat. In this situation the dietary fat requirement to maintain dietary needs is greatly increased and may need massive supplemental dosages of essential nutrients. Fats provide over twice as much energy per unit weight as protein or carbohydrate, as each carbon atom of the (CH2) chain combines with three oxygen atoms to produce CO2 and H2O, and 9cal/g. Fats are thus useful sources of energy in diets designed to increase the rate of weight gain, e.g. in malnourished children. Conversely, a reduction in the fat content of the diet is a relatively efficient way to lose weight and to maintain weight loss. The intestinal lipase inhibitor drug orlistat utilizes this principle by introducing malabsorption of 15% of dietary triglyceride. With a low-fat diet (<30% energy) this degree of malabsorption is usually asymptomatic. Long-term use permits maintenance of 12-15% weight loss in the 40% of patients who respond to this drug. These findings remind us that patients may lose weight as a result of asymptomatic fat malabsorption from conditions such as coeliac disease or chronic pancreatitis.
a
ALCOHOL Lipoproteins are the chemical complexes, formed by the triglycerides, phospholipids and cholesterol with apoproteins, that circulate in the blood and which transport cholesterol and other fat-soluble compounds such as tocopherol. Lipoproteins can be separated by electrophoresis or according to density on ultracentrifugation, to demonstrate the classes (chylomicrons, VLDL, LDL, HDL) and their subtractions, which are familiar through their roles in atheroma formation. Triglycerides enter the bloodstream via the lymph, as chylomicra, and are converted in the liver muscle and adipose tissue to VLDL and LDL (see Ch. 17). The body is efficient at synthesizing triglycerides, sterols and phospholipids. Many populations whose diet provides only 15% of total energy as fat are able to lay down good stores of subcutaneous fat, reflecting the high capacity for synthesis of fatty acids from carbohydrate (lipogenesis) in liver, muscle and adipose tissue. Lipogenesis occurs whenever a meal provides more carbohydrate than can be stored immediately, but net lipogenesis is relatively unusual with the relatively low carbohydrate intakes in western diets. Most fat storage is from fat. Requirements for essential fatty acids are rather low (under 3% total energy) and deficiency is therefore uncommon. When diets are low in fat the high carbohydrate and protein content satisfies appetite more effectively. This may limit dietary intake and contribute to weight loss and the thinness of populations with lowfat diets. Low-fat diets may also limit the availability
There is no physiological requirement for dietary alcohol (ethanol). However, most adults have sufficient enzymatic capacity to absorb and metabolize much larger amounts than would have been met during evolutionary adaptation. Alcohol contributes 7kcal/g and tends not to satisfy appetite or to stimulate its own oxidation, and so energy from alcohol tends to be additive to the energy balance of the other proximate nutrients (fat, carbohydrate, protein). Alcohol has obvious immediate effects on the central nervous syndrome: it is a diuretic; in excess, alcohol alters lipoprotein metabolism to produce hypertriglyceridaemia; it inhibits folate absorption; and, in excess, supplants other energy sources, leading to multiple micronutrient deficiencies. The most important is thiamine (vitamin B1) deficiency. This constitutes the only true nutritional emergency. Without thiamine, disordered carbohydrate metabolism leads to Wernicke's encephalopathy and Korsakoffs psychosis (Chapter 24 p 1439). Alcoholics are also prone to scurvy because of neglect of their diet.
MICRONUTRIENTS There are large numbers of bioactive compounds in foods. A small number of these have been found to be essential for humans, who lack the ability to synthesize them. This is the basis for the definition of vitamins and essential trace elements. It is not known why nutrition has evolved in this
113
CASE STUDY 5.1 ALCOHOLIC DIETARY DEFICIENCY A 42-year-old professional violinist is admitted following a witnessed grand mal seizure in a hotel bar following a performance. He gives a history of some weight loss, with anorexia and diarrhoea for 10 days. He is a smoker and admits to intermittent heavy drinking, including over the last months. There is no previous history of seizures, but some altered sensation in the feet for several months. A CT scan is reported as normal. A relative expresses concern over excessive and prolonged drinking since the death of his father 18 months previously, related to impaired performance and loss of employment.
Questions 1. What biochemical abnormality could explain the seizure? 2, What emergency nutritional therapy should be initiated on admission?
3. What is the cause of altered sensation in the feet? 4. What long-term management is appropriate?
Discussion The seizure threshold is lowered in alcoholics for several reasons, including head injuries, B vitamin deficiencies and cerebral atrophy, presumed to be a toxic effect of ethanol. In this case 10 days' diarrhoea is likely to have depleted magnesium status as a cause of seizures. There are no body stores of magnesium, which is plentiful in many foods, particularly cereals. Serum magnesium gives a good indication of magnesium status. Low levels block the secretion of parathyroid hormone and thus cause hypocalcaemia. Thiamine replacement should be
way. Humans have the genetic potential to synthesize ascorbic acid (in common with most other species), but the genes are not expressed. Certain micronutrients, e.g. metals such as iron, or fat-soluble vitamins, can be toxic in excess, and their absorption and transport are highly regulated. The absorption of metallic trace elements is generally low (15-30%), but can increase through adaptation to low intakes, or when requirements increase in pregnancy. Dietary reference values for mineral micronutrients are shown in Figures 5.5a and b and 5.6a and b, and 'safe intakes' for those whose true requirements are not known in Table 5.11. Deficiencies of individual vitamins result in specific biochemical and clinical responses, but vitamins are also involved in metabolism in more general ways. Folate, for example, is necessary for cell division and the transfer of
1
114
MCQ5.2
started without waiting for biochemical confirmation of deficiency. Thiamine is particularly rich in cereals and grains, but not in alcoholic drinks. Peripheral neuropathy is a feature of several B vitamin deficiencies, but also of ethanol toxicity with inadequate antioxidant status, and of secondary diabetes when alcoholinduced pancreatic damage is severe. It seldom responds well to B vitamin replacement. Alcoholics are prone to multiple micronutrient deficiencies. Weight loss, often reflecting loss of lean body mass, indicates reduced total food consumption and may point to other chronic complications, e.g. tuberculosis. A multivitamin prescription is appropriate, but most preparations contain insufficient thiamine, and virtually none contain adequate folic acid. Alcoholics may benefit from greater intakes of antioxidant vitamins (C and E) than healthy people, but evidence is lacking.
methyl groups in protein synthesis; thus, a deficiency may impair tissue repair or growth, even if dietary energy and protein are adequate. Thiamine is important in carbohydrate metabolism, and lactic acidosis may occur in deficiency states and result in the brain damage of Korsakoff s psychosis. Ascorbic acid deficiency leads to scurvy, but it is also one of the hierarchy of antioxidant defences, so low vitamin C status reduces defences against free-radical damage (e.g. from smoking) without any signs of scurvy. A number of trace elements, such as zinc, are important in protein metabolism; deficiency of zinc is associated with an increased energy requirement for deposition of lean tissue. Children receiving nutrient supplements for proteinenergy malnutrition grow more slowly relative to the number of calories given, if they are not also supplemented with zinc. Severe individual micronutrient deficiencies may have recognizable clinical features, but even marginal deficiencies may affect metabolism of protein and energy, and the immune system. A variety of non-essential bioactive nutrients are relevant to human health. For example, flavonoids in fruits and vegetables are potent antioxidants, and may contribute to protection against coronary heart disease and cancers.
a
FIG. 5.5 Reference nutrient intakes for consumption of minerals These amounts will be sufficient for the needs of 95% of people.
Some related flavones in legumes are oestrogenic, and may modify the risks of heart disease, osteoporosis and breast cancer. Dietary carnitine may become important in facilitating fatty acid oxidation if carnitine synthesis is impaired during illness. Caffeine and theobromine in coffee, tea and chocolate have several properties, including central nervous system stimulation and diuretic actions.1 NON-NUTRIENT DIETARY COMPONENTS Within foods there are some compounds which are either not absorbed (e.g. the fat substitute olestra) or which are absorbed but not metabolized (e.g. the sugar inulin). Occasionally the presence of such compounds leads to an important difference between the chemical analysis and the nutritional value of a food. It is important to consider the nutrient availability of foods, as well as their chemical composition. Certain plant sterols, particularly stanol esters, inhibit the absorption of dietary cholesterol, although they themselves are not absorbed. These compounds are marked for cholesterol lowering, on average by about 10%. ASSESSMENT OF NUTRITIONAL STATUS BODY COMPOSITION In weight, the composition of the body is about 16% protein, 10-25% fat in men (15-30% in women), 5% min-
TABLE 5.11 Safe intakes of micronutrients where dietary reference values cannot be defined. Nutrient Vitamins Pantothenic acid adults infants Biotin Vitamin E men women infants Vitamin K adults infants Minerals Manganese adults infants and children Molybdenum adults infants, children and adolescents Chromium adults children and adolescents Fluoride (for infants only)
Safe intake
3-7 mg/day 1.7 mg/day 10-200 jig/day above 4 mg/day above 3 mg/day 0.4mg/g polyunsaturated fatty acids 1 ug/kg/day 10 ug/day
1.4mg (26(umol)/day 16ug(0.3umol)/day 5-400 ug/day 0.5-1.5ng/kg/day 25ng(0.5nmol)/day 0.1-1 .0ug (2.20 nmol)/kg/day 0.05mg(3umol)/kg/day
115
Functional measures, such as grip strength, are valuable to complement measures of muscle bulk. Given the wide ranges of normality, changes in repeated measures are more valuable (for example by showing falls, or a reduction in growth velocity in children). Estimation of body composition is a critical factor in human nutrition, both in clinical situations and when the nutritional status of populations is considered. A large number of indirect methods are available, varying in cost and complexity. The situation is complicated by the lack of any true 'gold standard', even for major components such as fat or muscle. For research purposes, estimates can be made from MRI, CT scanning or dual-energy X-ray absorptiometry (DEXA). These approaches can also characterize the physical distribution of tissues. Total body water (found only in non-fat tissues) can be accurately measured from dilution of deuterium-labelled water, and this is probably the most reliable guide to fat mass. Estimation of fat mass or lean body mass in clinical practice and epidemiology has to rely on well-conducted anthropometric measurements (skinfold measurements and waist circumference), either for static measurement or for detecting changes over time. These methods have been validated against underwater weighing (employing the principle of Archimedes) as an independent reference method. A variety of commercially promoted methods (e.g. bio-impedance) generally perform less well than simple anthropometry in estimating body composition.
Anthropometry
FIG. 5.6 Reference nutrient intakes for dietary vitamin consumption These amounts will satisfy the requirements of 95% of people.
116
erals, 1% carbohydrate and the rest water (about 60%). This total body water is either in the cells (intracellular water, 35%) or in the vascular system and tissues (extracellular water, 25%). The most important static measures to assess nutrition are the height, weight, body fat content (usually expressed as percentage of body weight) and fat distribution (specifically the intra-abdominal fat mass). Lean body mass (bones, muscle, brain and other organs) is estimated by difference between weight and body fat.
The key measurements for anthropometry are height and weight, measured under standard conditions (e.g. fasting, without shoes, in light clothes and with an empty bladder). Height and weight are combined in the body mass index (BMI: weight (kg)/height2(m)) as an estimate of body build or fatness which does not depend on height. The 'normal range' for adult BMI is 18.5-25 kg/m2, with BMI <18.5 indicating chronic energy undernutrition and BMI >25 usually indicating increased medical hazards from overweight. The conventional cut-off of BMI >30kg/m2 is used for epidemiological classification of obesity. The normal range of 18.5-25 kg/m2 applies at all adult ages, although the medical hazards change. These criteria do not apply to children under 16, whose BMI is usually much lower than that of adults. Mid upper arm circumference reflects both muscle mass and subcutaneous fat and has been widely used to indicate overall nutritional status. Mid upper arm circumference below 23cm in men or 22cm in women is a guide to the possibility of chronic energy undernutrition. A variety of anthropometric approaches have been used to predict body fat (and hence, by difference, lean body mass). The simplest approach, which gives a high prediction and low error through bias, is measurement of the waist circumference at the level between the lowest ribs and the iliac crest when the patient is standing.
5
TABLE 5.12 Influence of inflammation on biochemical nutritional analyses Analytes
Reference range
Minor inflammation (CRP<15mg/L)
Iron Zinc Selenium Copper Vitamin A Vitamin E Vitamin C Vitamin Eh Vitamin B2 Vitamin B6 Vitamin B12 Folate Lycopene B-carotene a-carotene Lutein
8-30umol/L 12-18n.mol/L 0.8-2.0 umol/L 11.5-23.5 umol/L 1.0-2.8 umol/L 15-40umol/L 10-115nmol/L 280-540 ng TDP/gHb <70% activation* 18-135nmol/L (PP) 188-1059 pg/mL 3.5-16.0 ng/mL 100-300 ug/L 92-312 ug/L 14-60ug/L 82-202 ng/L
Decreased by 40% Decreased by 10% Decreased by 10% Increased by 10-15% Decreased by 30-40% Negligible No data No data No data No data No data No data Decreased by -50% Decreased by -50% Decreased by -50% Minimal change
Major inflammation (CRP~ 100-200 mg/L)
Comments
Decreased by 60-90% Decreased by 40-60% Decreased by 40-60% Increased by 30% Decreased by 30% Decreased by 20-30% Minimal to >75% dec. No change No change Decreased by 40-50% No change No change Decreased by >90% Decreased by >90% Decreased by >90% Decreased by >70%
Liver uptake Liver uptake ? Redistribution ? Liver extraction Probable redistribution More data needed More data needed More data needed More data needed More data needed More data needed More data needed More data needed More data needed More data needed More data needed
An approximate guide to the extent of change seen in analytes with different degrees of inflammation. The figures quoted are collated from disparate sources and the effects of diverse factors in different pathophysiologies may be important. TDP = thiamine diphosphate: * = of red cell glutathione reductase; PP = pyridoxal phosphate.
Body fat percentage (men) = (0.567 x waist in cm) + (0.101 x age in years)-31.8 Body fat percentage (women) = (0.439 x waist in cm) + (0.221 x age in years) - 9.5 Because the waist circumference incorporates a measure of the internal fat mass as well as of total body fat, it has recently found a place in health promotion to alert people to the need for weight management. Health risks start to develop when the waist circumference exceeds 80cm (32 in) in women or 94cm (37 in) in men. Cardiovascular risks are approximately tripled, and most subjects have symptoms from overweight when the waist exceeds 88cm (35 in) in women or 102cm (40in) in men. Waist circumference does not depend on height.
Biochemical nutritional assessment Biochemical measures are of relatively limited value in nutritional assessment. Blood or plasma is seldom the appropriate compartment to detect functional nutritional abnormalities, and extracellular fluid nutrient contents give only a crude (and sometimes misleading) indication of nutrient status. For some nutrients, e.g. zinc or amino acids, the plasma concentration may actually increase in starvation, reflecting tissue destruction. Abnormal plasma vitamins or trace elements are most frequently found when there is clear clinical evidence of malnutrition. An exception to this generalization is the measurement of haemo-
globin and the nutritional haematinics - transferrin iron, folate and vitamin B12 - where subclinical deficiencies are relatively common and demand treatment. Clinical biochemistry services now offer assays for vitamins (commonly vitamin A and carotenoids, B1, B2, B6, B12, folate, C, D, E) and trace elements (e.g. iron, copper, zinc, selenium). These are used mainly to confirm clinical suspicion of deficiency, and to monitor artificial feeding. Results always have to be interpreted in relation to clinical condition, and to indicators of stress or acute-phase reaction, such as C-reactive protein. Many vitamin measurements, e.g. vitamin C, are strongly influenced by inflammatory states (Table 5.12). Several proteins produced by the liver may be used in association with nutritional assessment, namely albumin, prealbumin, transferrin, retinol-binding globulin and thyroid-binding globulin. Plasma levels are of limited value on their own because they are affected more by short-term energy intake and by stress or inflammation.
DIETARY INTAKE ASSESSMENT Estimation of dietary intake, both of individuals and of groups or populations, is critically important to ensure health. It should not be considered an assessment of nutritional status but it complements nutritional status assessment. Dietary intake can be assessed in terms of eating
117
pattern, foods, food groups and nutrients. All of these elements are important to different aspects of health by reference to standard recommendations or to dietary prescriptions for individuals. The dietary assessment of individuals is a specialized activity which needs to be conducted by trained dietitians.
Dietary intake of individuals The habitual eating pattern of an individual undergoes great variation from day to day. It is therefore usually inadequate to base any judgement on the eating habits of a single day, or even a small number of days. Certain foods are often consumed on only one day per week or less (e.g. fish on Fridays in some communities, carrots as the major contributor of B-carotene on Sundays, and liver as the major source of vitamin A much less frequently). The dayto-day variability of major nutrients is often of the order of 30-50%. Two dietetic approaches are used:
118
• Retrospective dietary assessment This approach relies on the skill of the dietitian in establishing eating habits, depending on the memory of the subject. Retrospective approaches are sometimes used for a single 24-hour period or for a week, or through questionnaires to estimate habitual intake over a much longer period, perhaps 1 year. As a general rule, the more questions asked and the longer the interview, the more foods are remembered and a greater value is obtained for food intake. Cross-check questions should be employed in the dietary history in order to remind subjects of foods that may have been omitted (for example, asking how often milk is purchased may show a disparity from the answers to a question about the amount of milk consumed). The latter approach, which gives some indication of the nutritional quality of the diet, is usually employed to express the fat, carbohydrate and protein intake as percentage calories. Retrospective dietary assessment has a place in clinical practice when there is an interest in the consumption of individual foods, and learning about an individual's meal patterns is often more valuable than attempting to establish nutritional adequacy, which can often give misleading results. Patients currently referred for dietary intake assessment are mostly overweight or obviously undernourished. In both contexts misreporting is common. Overweight people, and those with restrained eating, systematically under-record or underreport by up to 50%. Brief questionnaires attempting to estimate the intake of individual nutrients, e.g. calcium, have been developed, but give rather poor results compared to fully quantitative methods. • Prospective dietary assessment. This approach does not rely on subjects' memories but does rely on a high degree of cooperation over several days, during which they are asked to complete a full inventory of all foods and drinks consumed, together with details of cooking methods and portion sizes, which may be weighed using food scales or again related to household measures.
The 'gold standard' for dietary intake assessment is the 7-day weighed intake. This approach is often impossible to apply to children, to busy working people, to the confused or demented, and to those who are socially deprived or have literacy problems. For this reason, dietary assessment is often problematic in sectors of the population where nutritional problems are most prevalent. Records over 3-4 days, including weekends and weekdays and appropriately adjusted to estimate 7-day intake, are often used. A dietitian compiles a list of foods consumed by the individual and then makes some assessment of the portion sizes and quantities eaten, usually by reference to simple household measures. Standard food tables (for example McCance & Widdowson's Composition of Foods) are now available on computer databases, so the foods can be identified by code number, and the nutrient composition per 100 g is then available for 40-60 nutrients. Nutrient intake data can be extracted in absolute amounts (in g or mmol per 24 hours), or in nutritional terms, expressed as % energy mg or mmol per l000kcal of food energy. It is helpful to be able to evaluate nutrient intake by meal type, in order to identify meals (e.g. lunches) which are the cause of suboptimal total diet composition.
Dietary assessment of populations and groups Several levels, of differing complexity, cost and precision, are available. The best plan is usually to use more than one approach and to check that the results corroborate each other. • Food disappearance rates. The food and agriculture organization of WHO compiles food balance sheets for each country annually. If the total food supply (commercial production, home production, importation) and the population base are known, then an estimate can be made of food consumption per head of population and therefore of nutrient consumption. Data of this kind are often incomplete, particularly with reference to home food production. A number of assumptions have to be made about the ways in which foods are used, wastage in preparation and cooking, etc. This approach gives no guide at all to the intake of individuals or of population subgroups which may be of concern. On the other hand, broad generalizations about dietary adequacy can be made, and comparisons between countries with different disease patterns. • Household food purchasing. The National Food Survey of the United Kingdom, established in 1945, set up a model which has been employed in many countries: a random selection of households is taken every year and their total food purchases surveyed for 1 week. Analysis requires a knowledge of the numbers of individuals within the household. Knowledge of the social setting may also be of value in establishing the eating patterns
of population subgroups. Assumptions still have to be made about the uses to which food purchases are put. The biggest problem in the past has been that household food surveys have not included any measure of foods purchased and eaten outside the home, or of home food production. Therefore, for a number of nutrients diet intakes are spuriously low. This applies particularly to nutrients such as fat and saturated fat, which are present in high concentrations in foods consumed as meals and snacks outside the home. • Food frequency questionnaires. A number of questionnaires have been validated to estimate the food and therefore the nutrient consumption of groups by enquiring about the frequency of consumption of a range of foods. In the computer analysis, standard portion weights are applied to enable estimation of per capita nutrient consumption. Food frequency questionnaires are not sufficiently precise to be used in the assessment of food intakes of individuals, but they are relatively cheap to use. Inevitably, they address only a limited range of major foods and will therefore tend to underestimate food intake, particularly in individuals whose range of food choices is wider. • Prospective dietary intake. Epidemiological approaches have employed the same prospective weighed intake methods used in the assessment of individuals. Although arguably the most reliable approach, this is an expensive and professionally intensive method, and problematic to more deprived sectors of the population. In clinical practice, all methods of dietary intake assessment tend to underestimate the habitual food intakes by 20-50%, particularly those who are overweight. The reason for this is uncertain and there may be selective misreporting (e.g. for high-fat foods). During the assessment period of prospective methods, overweight people tend to cut down on their usual food intake. There is also an element of self-deception and an unwillingness to reveal true eating habits. It is interesting that in many cultures high social status is associated with a denial or minimization of a number of vegetative and physical bodily functions, including food intake.
NUTRITION AND FEEDING PRACTICES FOR GROWTH Standards for child growth - compiled from subjects living in a clean environment with an abundance of food - show a considerable range in rates of gain in weight and stature. There are also differences in dietary intake in such children, which is also true in healthy adults who are not excessively over- or underweight. A man in his 30s who continues to eat the same amount of food that he ate in his late teens is likely to become overweight. In each case, the difference in nutritional status is the result of the balance between energy intake and energy expenditure.
Early infancy In the young infant nutritional requirements are particularly high in relation to body weight. Breast milk certainly provides enough energy and appropriate nutrients for at least the first 4 months, and has psychosocial and immunological advantages over artificial formula feeds. Recent evidence also points to better brain development in breastfed infants, related to essential fatty acid intake. Artificial formulae are frequently dangerous when prepared under unhygienic conditions, as in the homes of many poor families in the developing world. Cows' milk contains a dangerously high sodium content and should not be given before 1 year. Weaning should be gradual from 4-6 months: overfeeding in infancy may programme an excessive appetite.
a
Later infancy and early childhood Nutritional requirements are also high in infants over 4 months of age, when children can begin to receive solid foods in addition to breast milk. In developing countries the growth rate frequently falters at this stage, either because the energy given is not sufficient (the energy density of weaning foods in traditional societies is often low) or because of gut infection, so that food is not so well absorbed. Specific nutrient deficiencies (e.g. zinc, amino acid, folate) may also play a role. Cows' milk consumption in young children has been associated with bleeding into the bowel and anaemia, leading to the development of 'follow-on' formula feeds for use in the first year of life. There is very weak evidence that exposure to common dietary allergens in infancy may provoke allergies so foods with low allergenic potential (e.g. rice rather than wheat) are preferred.
Later childhood and adolescence Nutritional requirements for protein and energy are usually met in older children, but micronutrient deficiencies (e.g. of iron, folate and zinc), which may lead to anaemia, impaired intellectual performance and short stature, are relatively common even in western populations, and easily go unnoticed.
Pregnancy The nutritional stress of pregnancy is created by the need to produce both an infant and a placenta, plus some maternal fat stores. A 12.5kg weight gain in pregnancy would require a total of about 7000kcal (Table 5.13). There are also increased demands on maternal stores, especially of iron, zinc and folate. On the other hand, carefully conducted studies have not shown a greatly increased food intake in pregnancy. For some nutrients, e.g. calcium and iron, the efficiency of intestinal absorption is increased during pregnancy. Energy intake often falls in the first trimester, and then needs to increase to about 200kcal/day
119
above non-pregnant intakes. The additional energy requirements of pregnancy are met from reduced physical activity and greater resting in the later stages. Fetal growth certainly depends on maternal nutritional status, both from starting weight and from weight gain, and may be specifically reduced by physical exertion in late pregnancy. Intriguingly, it has recently been shown that food deprivation in late pregnancy leads not only to smaller babies, but also to these offspring having smaller babies themselves. Good fetal growth is important for later, adult, health (to protect against diabetes, heart disease, stroke), and so maternal nutrition is doubly important. The Institute of Medicine recommends that, at term, women with BMI <19.8 should have gained 12.5-18 kg, those with BMI 19.8-26, 11.5-16kg, and those with BMI 26-29, 7-11.5kg. A BMI 28kg/m2 is a reasonable target at term. Table 5.13 summarizes the extra nutrient requirements of pregnancy, and suitable sources.
Lactation Babies should be exclusively breastfed for 4 months, and according to WHO recommendations breastfeeding should be continued for 12-24 months. The need to produce breast milk (up to 800kcal/day) for many months has obvious nutritional implications. Some of this can be provided from maternal stores laid down in pregnancy, but an additional 500kcal intake and extra protein are often
TABLE S.13 Summary of special nutrient requirements in pregnancy 1. Energy - an increase of 200kcal/day is required in the 3rd trimester. Aim to reach BMI 28 kg/m2 at term (2310kcal for women aged 15-18) (2140kcal for women aged 19-50) 2. Protein - an increase of 6g per day throughout pregnancy (51 g per day) Two small/moderate portions of protein-rich foods, plus milk, bread, pulses, etc. 3. Iron - 14.8mg per day required throughout adulthood. No extra routinely needed during pregnancy: absorption increases 4. Calcium - 100mg per day (19-50) 800 mg per day (15-18) No extra routinely needed during pregnancy: absorption increases Throughout life - half a pint of milk daily as a good insurance 5. Vitamin D-10ug per day Supplement. Encourage women to go outdoors Use fortified foods, e.g. margarine, and vitamin D rich foods, e.g. oily fish 6. Folic acid - supplement from before conception up to first 12 weeks (0.4 mg routinely, 4mg if previous neural tube defect) 7. Vitamin C - increase intake by 10mg to 50mg per day More fruit and fruit juice 8. Vitamin A - increase vegetables, increase intake by 100ug to 800jag
120
9. Dietary fibre - to avoid constipation of pregnancy, increase by 10g/day More vegetables, wholemeal bread
recommended. Many women are able to produce adequate volumes of breast milk despite poor dietary intakes. However, when maternal nutritional status is severely decreased, there is a corresponding decrease in the volume and nutritional content of the milk. It is thus essential to improve the diet and lifestyle of women in developing countries if breastfeeding is to be promoted. When there has been substantial fat accumulation during pregnancy, as is usual in western countries and where obesity is more of a problem than undernutrition, prolonged breastfeeding (4-12 months) helps with weight loss.
MALNUTRITION MALNUTRITION IN CHILDREN The term protein-energy malnutrition (PEM) was used historically to describe a variety of clinical syndromes believed to result from a diet inadequate in both energy and protein. The term is misleading, since dietary protein deficiency is virtually never seen, and low serum proteins in malnutrition are not caused by dietary protein insufficiency. Undernutrition of energy is often accompanied by micronutrient deficiencies, electrolyte imbalance and metabolic disorders. When it occurs in the UK it is usually precipitated by a severe illness (e.g. gastrointestinal disease, surgery). In developing countries it is the result of a poor diet, often exacerbated by the added stress of infection (especially diarrhoea and measles). The term malnutrition/infection syndrome may be used to describe this situation. Classification of the severe clinical syndromes (Table 5.14) depends on the child's weight calculated as a percentage of the median international standard for a child of the same age. Milder grades of malnutrition also exist according to weight/age. Undernourished children may be further classified according to whether, or to what degree, they are short for their age (stunting); alternatively, they may be underweight and thin, i.e. a low weight/height (wasting) (see Table 5.14 and Fig. 5.7). The inference is that children who are stunted are likely to be chronically
TABLE 5.14 Classification of stunting and wasting Degree
Malnutrition (weight/age)
Stunting (height/age)
Wasting (weight/height)
Normal
Over 80%
Over 95%
Over 90%
Mild Moderate Severe
60-80%* Less than 60%*
87.5-95% 80-87.5% Less than 80%
80-90% 70-80% Less than 70%
* Defined as kwashiorkor if oedema present
FIG. 5.7 Growth chart of a severely malnourished child A Start of nutrition rehabilitation. B After discharge from nutrition rehabilitation.
infected or have been deprived of an adequate diet, usually for many months (sufficient to cause linear growth retardation). The child who is wasted but not stunted has usually lost body tissues because of a recent infection or poor diet, for example due to harvest failure.
Marasmus In marasmus (weight for age <60% without oedema), which is usually seen in older, fully weaned children, there is loss of both lean tissue and subcutaneous fat, with characteristic wrinkling of the skin. This is sometimes difficult to differentiate from dehydration. The child is usually very cachectic, and has long eyelashes and lanugo hair on the forearms despite loss of hair on the head. However, the child is generally alert and keen to eat. The plasma albumin is usually maintained, but plasma sodium and potassium levels are often low. Marasmus describes the result of dietary energy shortage, but specific nutrient deficiencies commonly coexist, as in anorexia nervosa.
Vitamin A becomes sequestered in the liver because of insufficient synthesis of the transport protein, retinolbinding protein, and patients are consequently more prone to infection. Plasma albumin is low, as are plasma sodium and potassium. The low plasma potassium indicates a reduction in the total body potassium, owing to the loss of muscle mass. The low plasma sodium, however, is misleading, as it is due to an excess of body water: the total body sodium is in fact elevated. Several factors contribute to the development of oedema. A decrease in plasma albumin decreases colloid osmotic pressure, whereas an increase in the generation of free radicals by infection (from systemic or intestinal pathogens, or toxins, such as aflatoxin) can damage the capillaries sufficiently to cause them to leak fluid into the tissues. The deleterious effects are greatest in children with impaired scavenging mechanisms for free radicals, owing to a relative excess of iron and copper but a deficiency of vitamins C, E and carotenoids.
5
Associated deficiencies Zinc deficiency is common in severe malnutrition, and may account for the skin lesions and impaired cellular immunity. Vitamin A deficiency is frequently precipitated by malnutrition, probably because of lack of synthesis of retinol-binding globulin by the liver, and anaemia often occurs as a consequence of folate and/or iron deficiency and systemic infection (especially malaria). Cellular immunity is frequently depressed, permitting infections such as tuberculosis to become rampant. Antibody production is also impaired, but to a lesser extent, so that even severely malnourished children generally produce satisfactory levels of antibodies following immunization. However, the general reduction in immunity is a key factor in the development of bacterial overgrowth syndromes in the intestine, pneumonia and septicaemia. The decreased heat production in malnutrition is often severe enough to cause hypothermia and prevents a pyrexial response to infection.
Specific organ changes Kwashiorkor The main feature of kwashiorkor, which usually affects infants at the time of weaning, is oedema, which conceals the loss of lean tissue. There is little evidence that dietary differences explain why some children develop kwashiorkor and others become marasmic; kwashiorkor is often precipitated by measles and intestinal and other infections. These children are ill and anorexic, and have very high mortality. Weight for age <60% indicates marasmic kwashiorkor. The oedema usually starts in the legs but may extend to the trunk and head. There is often an associated scaly cracking of the skin, and some children have discoloured or orange hair (caused by associated zinc deficiency). The liver is sometimes enlarged, as it becomes infiltrated with fat which cannot be removed because of inadequate production of lipoproteins (see Ch. 19).
There is atrophy of all organs, including alimentary tract mucosal atrophy, which causes hypochlorhydria and flattening of the intestinal villi with secondary malabsorption. Nearly all children are heavily colonized by intestinal parasites and bacteria. Renal function is often impaired, leading to difficulties in excreting sodium and water. Experimental studies show effects of childhood malnutrition on brain size and psychomotor development, but longitudinal studies of severely malnourished children show that the social environment is more important than nutrient deficiency in determining subsequent intellectual achievement.
Management The following principles should be followed:
121
TABLE 5.15 Predicted rate of weight gain* in malnourished child weighing 7kg Total intake (kcal/day)
Excess (kcal/day)
Weight gain (g/day)
Days to gain 300 g
0
0
-
760
60
10
300
820
120 240
20 40
150
480 960
80 160
700
940 1180 1600
75 38 19
* Assuming maintenance requirements of 100kcal/kg/body weight
• The child requires resuscitation for dehydration and electrolyte restoration (in most cases using oral rehydration therapy). • Antibiotics (this is still an indication for chloramphenicol) should be given for systemic infections, together with treatment for malaria where appropriate. It is wise to assume that all children with severe malnutrition have bacterial infections, tuberculosis and intestinal infestation, even when classic signs of infection are absent. • Nutritional therapy, which depends on the introduction of special feeds providing maintenance requirements (100-150kcal/kg body weight, including 10% energy as protein, and avoiding lactose), should be accompanied by mineral mixes (especially potassium and zinc). In children with kwashiorkor, maintenance requirements are given until the oedema is cleared and then energy intakes are increased. In marasmic children the intake can be increased earlier until, ideally, about 200 kcal/kg body weight/day are given (Table 5.15).
CACHEXIA AND MALNUTRITION IN ADULTS Cachexia of dietary origin, or malnutrition in adults, is surprisingly common in medical and surgical practice. A recent survey in the UK found that 13% of admissions to general medical and surgical wards had malnutrition according to BMI criteria. Higher figures have been found using other criteria. Malnutrition was only recognized in a small proportion, and most patients lost more weight during their admission without any nutritional action being taken. Inadequate intake is the most important cause,
owing to psychological factors (such as depression, isolation or anorexia nervosa), immobility and social deprivation, pain, oral or intestinal cancer, arthritis, nausea/ vomiting, liver metastases, chemotherapy, gastrointestinal disease, fever or postoperative complications (which often cause anorexia). Nutrient intakes are often reduced drastically in those who can only take fluids. 1 Requirements may be considerably increased by sepsis. Energy expenditure increases by at least 10% for every 1°C rise in body temperature, and muscle protein is mobilized to provide amino acid precursors for the inflammatory response. Infection also increases the production of acute-phase proteins such as C-reactive protein, but levels of plasma albumin may decrease as a result of decreased synthesis by the liver and increased catabolism of circulating albumin. Any cause of malabsorption may cause a serious decrease in absorption of protein and energy. Disease of the lower small intestine and colon may cause serious leakage of endogenous protein and protein loss from blood. To produce cachexia, these factors must be chronic, or relapsing without adequate periods of remission, and often more than one factor is operating at any time. The classic causes of malnutrition in adults are cancers, tuberculosis and gastrointestinal problems, including short bowel syndrome and fistulae. Depression is another important cause, but organic disease should always be excluded. More recently AIDS and chronic obstructive airways disease (COAD) have become familiar as causes of apparently intractable cachexia. The most consistent finding is the dominance of anorexia during acute infective episodes, leading to stepwise weight loss. In HIV, as in inflammatory bowel disease, there is also a background of steady weight loss through malabsorption diarrhoea. Elevation of metabolic rate in these conditions plays only a small part in producing weight loss. The most important single manoeuvre in preventing and managing malnutrition is to have good measurements of the weight of every patient at every contact with health services (inpatient and outpatient). The diagnosis must be recorded, as it has profound medical implications, and failure to diagnose malnutrition might incur medicolegal problems. Dietetic intervention, social support and artificial feeding where necessary are much more effective if used early in the process of weight loss. Even with AIDS or COAD, effective nutritional interventions which lead to weight gain will improve muscle function, improve quality of life and reduce susceptibility to infection. Correction of malnutrition takes time, so management started in hospital must be continued after discharge. ©
VITAMIN DEFICIENCIES AND EXCESSES 1 Fig. 5.1 122
0 Case 5.1
A checklist for the methods of assessment of vitamin deficiencies is given in Table 5.16. The important food sources
SUMMARY 3 Vitamin deficiency syndromes Vitamin Syndrome A Thiamine Niacin Riboflavin Pyridoxine Folate B12
C D K
Night blindness, xeropnthalmia Wernicke's encephalopathy, Korsakoff's psychosis Pellagra Mucosal lesions Glossitis, neuropathy Megaloblastosis, villous atrophy Megaloblastosis, neuropathy Scurvy Rickets, osteomalacia Hypoprothrombinaemia
TABLE 5.16 Assessment of nutritional deficiencies: vitamins* Vitamin
Method
Comment
A
Clinical
Infections common Night blindness is a good indicator Corneal lesions are very late-stage findings
• Plasma carotenoids • Plasma retinol Thiamine
Clinical • HPLC • Erythrocyte transketolase
Sensitive indicator of liver stores but reduced in infection Neuropathy and optic atrophy are late-stage findings Specific Sensitive but rapidly altered by amount of dietary thiamine
of the various vitamins are shown in Table 5.17, and their roles in the body in Table 5.18. A table of recommended daily intake of vitamins is given in Table 5.19.
Riboflavin
Clinical • Erythrocyte gluthathione reductase
Mouth lesions are non-specific Assay related poorly to clinical state
VITAMIN A DEFICIENCY
Niacin
Clinical • Urinary n-methylnicotinamine/creatine excretion
Glossitis, stomatitis, dermatitis Sensitive. Difficult assay
Folate
• Serum folate • Erythrocyte folate
Marked changes after dietary intake Sensitive assay of body stores
B12
• Plasma vitamin level
Sensitive assay of body stores
C
Clinical • Plasma or leucocyte ascorbate (HPLC)
Specific but occur at late stage only Sensitive. Rapid response to diet, Falls non-specifically in illness
D
Clinical • Plasma alkaline phosphatase • Plasma 25hydroxycholecalciferol • Bone marrow histology
Rickets, osteomalacia Non-specific. Sensitivity may be improved by isoenzyme analysis Very specific
E
• Plasma or erythrocyte tocopherol (HPLC)
Sensitive and specific. Must be corrected for plasma LDL
K
• Prothrombin time
Non-specific, as it is influenced by hepatocellular dysfunction
Vitamin A (retinol) can be synthesized within the liver from several carotenoids (cc-carotene, B-carotene, lutein) which occur in a variety of vegetables and certain fruits. Vitamin A deficiency leads to night blindness and xerophthalmia (damage to the conjunctiva, the major cause of blindness in children). It also affects the immune system - increasing the severity of respiratory infections and diarrhoea - and the formation of epithelium in the sweat glands, lung and gut. It contributes to the high rates of child mortality in certain populations, particularly among poor communities, where dietary intakes of carotene are low and where the availability of the nutrient may be further reduced by intestinal parasites and diarrhoea, and where undernutrition suppresses the synthesis of retinol-binding protein, preventing utilization of hepatic retinol stores. Vitamin A deficiency sometimes complicates inflammatory bowel disease, coeliac disease and cirrhosis. Measles is an important contributory factor in xerophthalmia because of its direct effect on the conjunctiva, where it increases the local requirement for vitamin A to repair the damaged conjunctiva, and also by its effect on synthesis of retinol-binding protein, which normally carries vitamin A from the liver stores to the eye. Supplementation with vitamin A reduces the mortality from measles in malnourished children, even when their liver contains vitamin A (because its transport to other tissues is inhibited). Night blindness alone is easily reversible, but xerosis (the dry appearance of the conjunctiva) and Bitot's spots (heaped-up desquamated cells causing flecks on the conjunctiva) are signs that, unless treatment is started soon, the lesion may progress to irreversible corneal ulceration. In areas where dietary vitamin A intake cannot be increased by horticulture and nutrition education pro-
5
Specific
* Pyridoxine is omitted as this is not a routine assay
grammes, the administration of vitamin A capsules (100 000 IU every 4 months) will largely prevent xerophthalmia. In established xerophthalmia, retinol palmitate (100 000 IU) is given intramuscularly. Vitamin A should not, however, be given to pregnant women because of its teratogenic effect. Breastfeeding tends to prevent vitamin A deficiency.
123
TABLE 5.17 Vitamins and their important food sources
TABLE 5.18 Major roles of vitamins in the body
Vitamin
Food sources
Vitamin
Function
A
Carotenoids (esp. p-carotene), in carrots, dark green leafy vegetables, pumpkin, mango Preformed vitamin A in fish oils, liver, eggs, margarine
A
Maintenance of mucosal surfaces; production of mucus; immune system and retinal function; fat soluble
Thiamine (B1)
Thiamine (B1)
Fortified wheat flour (much of the thiamine in flour is removed by milling, but is then replaced in most flours), fortified breakfast cereals, milk, eggs, yeast extract, fruit
Metabolism of carbohydrate to provide energy; maintenance of cardiac muscle and peripheral nerves
Riboflavin (B2)
Control of intracellular oxidation; maintenance of skin, especially around the mouth
Riboflavin (B2)
Milk, cheese, eggs, fortified breakfast cereals, liver, kidney, whole grain cereals
Nicotinic acid
Utilization of energy from food; maintenance of skin, especially in light-exposed areas
Niacin
Liver, kidney, milk, cheese, eggs, beef, chicken, pork, yeast extract, instant coffee, peas, beans
Pyridoxine (B6)
Metabolism of amino acids, especially tryptophan to nicotinic acid
Pyridoxine (B6)
Liver, meat, fish, whole grain cereals, milk, peanuts
Folate
Cell multiplication, in the blood and mucosa
Folate
Liver, kidney, green leafy vegetables, peas, beans, oranges, bananas
Cobalamin (B12)
Cell multiplication, especially blood cells; control of fatty acid synthesis in myelin sheaths of nerves
Cobalamine (B12)
Liver, kidney, fish, beef, pork, lamb, eggs, cheese
Ascorbic acid (C)
Ascorbic acid (C)
Oranges, lemons, potatoes, green vegetables, fortified fruit drinks
Maintenance of connective tissue; stimulates iron absorption
D
D
Fortified milk (e.g. evaporated), fatty fish, fortified margarine, eggs, liver
Maintenance of calcium and phosphate levels in the blood; control of absorption of dietary calcium and movement of calcium between blood and bone; fat soluble
E
Vegetable oils, wholegrain cereals, eggs, margarine
E
K
Vegetables, peas, beans, liver
Contributes to antioxidant capacity of body; important in maintenance of erythrocyte membranes in neonates; fat soluble
K
Control of blood clotting; fat soluble
Thiamine deficiency
124
Thiamine is an essential factor in many glycolytic pathways and is especially important for normal function of the peripheral nervous system and the heart. Deficiency can cause a peripheral neuropathy, especially in the legs, ataxia and optic atrophy. Most cases in the UK occur in malnourished alcoholics. Such patients may develop two additional syndromes. In Wernicke's encephalopathy nuclear or supranuclear ophthalmoplegia occurs with nystagmus, pupillary abnormalities, aphasia and mental confusion. In Korsakoffs psychosis a permanent confused state, characterized by short-term memory loss and confabulation, develops (see Chapter 24, p. 1439). In beriberi, a highoutput cardiac failure develops (wet beriberi) and may accompany the peripheral neuropathy (dry beriberi). Deficiency is more common in populations which change to eating highly milled rice, as this process removes the thiamine. Curiously, Korsakoffs psychosis does not seem to occur commonly in populations prone to beriberi, suggesting that in alcoholics an additional factor may be acting. Diagnosis is usually made on clinical history and examination, but subclinical thiamine deficiency should always be suspected in alcoholics, and supplements given prior to feeding carbohydrates. If carbohydrate (e.g. dextrose infusion) is given without thiamine, then lactic acidosis can
rapidly lead to brain damage. Elevated levels of erythrocyte transketolase activity and blood pyruvate occur. Thiamine (100 mg) should be given intravenously (a multiple B vitamin parenteral infusion is appropriate), followed by repeated doses of 20 mg three times daily. Cardiac beriberi and ophthalmoplegias improve rapidly, but Korsakoffs psychosis tends to recover only partially. Many routine vitamin supplements do not contain enough thiamine to correct a deficiency. Long-term oral thiamine supplementation is a reasonable preventative strategy for alcoholics.
Niacin (nicotinic acid and nicotinamide) deficiency Nicotinic acid occurs in many plant and animal foods and can also be synthesized from tryptophan. Nicotinic acid deficiency tends to occur in those who eat a monotonous maize diet (which is low in tryptophan), such as is often supplied to refugees. The resulting deficiency syndrome is pellagra. Pellagra often starts with either a sore mouth, mild diarrhoea or confusion. The full clinical syndrome of 'dermatitis, diarrhoea and dementia' is not common, except in well-established cases. The skin lesions are initially erythe-
TABLE 5.19a Reference nutrient intakes for vitamins Males over 11 years Thiamin (mg/d) Riboflavin (mg/d) Niacin (nicotinic acid equivalent) (mg/d) Vitamin B6 (mg/d) Vitamin 812 (ug/d) Folate (ug/d) Vitamin C (mg/d) Vitamin A (ug/d)
1.0 1.2
17
Females over 11 years
Lactation (0-4 months)
0.8 1.1 14
1.4
1.2
1.5
1.5
+0.2 +0.5
+2
+0.5
200
+60
40
40
+30
700
600
+350
* no increment
TABLE 5.19b Reference nutrient intakes for minerals (SI units)
Calcium (mmol/d) Phosphorus (mmol/d) Magnesium (mmol/d) Sodium (mmol/d) Potassium (mmol/d) Chloride (mmol/d) Iron (umol/d) Zinc (umol/d) Copper (umol/d) Selenium (umol/d) Iodine (umol/d)
Females over 11 years
Lactation (0-4 months)
25
20
+14.3
25
20
+14.3
12.3
12.0 70
70 90 70 180 140
16 0.9 1.0
+2.1
90
* *
70 260**
* *
140 16 0.9 1.0
a
*
200
Males over 11 years
thus accompany general malnutrition or alcoholism and is especially liable to occur during pregnancy. The main lesions are mucosal dryness and cracking around the mouth, ears and eyelids, with the genital region also affected. Red blood cells are affected, causing a normochromic anaemia. Diagnosis is usually on clinical grounds but can be confirmed by reduced glutathione reductase activity in red blood cells. Lesions respond rapidly to riboflavin (6mg daily).
+90
+5 +0.2
*
*no increment ** 160 for females over 50 years
matous, but dry, cracked appearances then occur, especially in areas exposed to the sun, producing 'Casal's necklace' around the neck. There may be villous atrophy in the small intestine and malabsorption. If untreated, later-stage deficiency may cause severe encephalopathy and spasticity. Pellagra is rare in the UK, but may occur in malabsorption syndromes such as coeliac disease, in patients treated with isoniazid, in Hartnup's disease, in the carcinoid syndrome, in patients with very low-protein diets, or in conditions giving rise to considerable loss of protein such as the nephrotic syndrome. Deficiency responds rapidly to daily doses of nicotinic acid (500 mg).
Riboflavin (vitamin B2) deficiency Riboflavin deficiency occurs when a diet is continually deficient in legumes, pulses and animal products. It may
Pyridoxine (vitamin B6) deficiency Pyridoxine deficiency occurs in malabsorption syndromes, alcoholism and secondary to drug toxicity (especially isoniazid), but rarely as a primary deficiency disorder. Clinically, there is mental confusion, glossitis, dry skin lesions and peripheral neuropathy. Pyridoxine deficiency has rarely been associated with infantile convulsions and sideroblastic anaemia. Pyridoxine deficiency is popularly believed to be a cause of premenstrual syndrome but there is little evidence for this. Treatment of deficiency in adults is by 5-20 mg daily. Excess intake can lead to neurotoxicity.
Folate deficiency Folate deficiency occurs in those whose diet lacks fresh vegetables, or in which the vitamin is destroyed by cooking or lost through canning. It may also occur secondary to upper small bowel malabsorption, in situations of increased requirements (i.e. pregnancy or haemolytic conditions), or in patients taking anti-folate drugs (e.g. methotrexate, trimethoprim). Alcohol inhibits the absorption of folate, then aggravating the effect of poor diet in alcoholics. Clinical features, diagnosis and treatment are described in Chapter 23. As well as the megaloblastic anaemia and pancytopenia, depression has been consistently associated with folate deficiency. Folic acid supplementation 400ng/day is recommended for all women who may become pregnant, to prevent neural tube defects (spina bifida, anencephaly). This is not to treat a deficiency, but a pharmacological effect to overcome defects in folate metabolism present in a minority of women. Availability of folate from foods is lower than that of folic acid from supplements.
Vitamin B ]2 deficiency Vitamin B12 deficiency is described in Chapter 23. Dietary deficiency is rare, but can occur in strict vegans.
Vitamin C deficiency The clinical features of scurvy have been identified as part of general malnutrition for centuries, but the specific features of scurvy and its cause only became apparent after it decimated crews on long-distance sea voyages after the discovery of America. In the 18th century, Lind carried out a controlled trial, treating two cases of scurvy with oranges
125
and lemons and using mouthwashes of dilute vinegar or sea water for four other patients. Complete recovery occurred in the treated patients but none in the other patients. Today, deficiencies occur in the elderly - especially those on 'tea and toast' or 'tinned spaghetti' diets - in alcoholics and in food faddists. It may also occur in young children when requirements are high, and in smokers, as ascorbate is consumed in removing the free radicals from smoke. Low ascorbate levels are found in diabetic patients. The clinical features of tiredness, hyperkeratosis of the hair follicles, petechial haemorrhages and bleeding gums are only present in severe deficiency; bleeding gums are more usually due to poor oral hygiene than to vitamin deficiency. The classic features of infantile scurvy - irritability, pain on moving the legs, and tenderness and enlargement of costochondral epiphyses, together with megaloblastic anaemia - are now rarely seen. Diagnosis is by measurement of plasma ascorbate or leukocyte ascorbate content. Ascorbic acid is the antioxidant vitamin whose plasma concentration correlates best with diet. Low concentrations are very common in hospitalized or ill patients, and this is in part an acute-phase response. Ascorbic acid 100 mg three times per day is rapidly effective in clinical deficiency. There is limited evidence that large doses of vitamin C may reduce symptom severity in common cold but this does not point to an underlying nutritional deficiency.
Vitamin D deficiency Vitamin D deficiency occurs in those who fail to produce enough in their skin (from the precursor 7dehydrocholesterol in response to UV light), or who have inadequate dietary intake. In the UK, the high-risk group is immigrant vegetarian Asians, who tend not to expose themselves to the limited sunlight available. Although they do eat fatty fish (a good source of vitamin D), their consumption of vitamin D-fortified foods, e.g. margarine, is low, and the high phytate content (in chapatti flour) of the diet decreases its bioavailability. The result of vitamin D deficiency is rickets (in children) or osteomalacia (in adults) (see Ch. 18, p. 962). 1
Vitamin E deficiency Vitamin E deficiency can occur in low-birthweight infants and in children with malabsorption syndromes (especially cystic fibrosis). It is very rare in adults but has been reported on inadequate total parenteral nutrition, following gastroplication surgery for obesity and in abetalipoproteinaemia, as tocopheral absorption and transport depend on low-density lipoprotein (LDL). Deficiency
1
126
Fig. 5.2
2
Fig. 5.3
permits free radical damage to a number of membranes, such as red blood cells (causing haemolytic anaemia) and nerve cells (causing ataxia and peripheral neuropathy, which is usually permanent). These conditions are exacerbated if extra nutrients, such as linoleic acid and iron, are given without vitamin E. There is no consistent scientific evidence of any effect of vitamin E on athletic success, sexual potency or atheroma. The only indication for therapy is if the level of plasma tocopherol is shown to be low in an appropriate clinical setting. Plasma concentration needs to be adjusted for LDL concentration for interpretation. Deficiency can be treated by 200 mg daily doses in adults, but much larger doses (parenterally) are needed to overcome the effects of abetalipoproteinaemia.
Vitamin K deficiency This may occur in neonates because placental transfer is limited and breast milk is often deficient. It also occurs in obstructive jaundice and certain malabsorption syndromes. The result is hypothrombinaemia and bleeding, which is rapidly reversed by injections of vitamin K (phytomenadione). The prolonged prothrombin time associated with liver disease seldom responds to extra vitamin K.
Fluoride deficiency Dental enamel has a specific requirement for fluoride, whose deficiency in drinking water (under Ippm) is the main cause of dental caries in children. Where fluoride consumption is high - e.g. from tea in Ethiopia - dental caries is rare even with high sugar consumption. Fluoridecontaining toothpaste virtually abolishes the problem in areas of fluoride deficiency. To reach children who do not brush their teeth, successful strategies include fluoride normalization of water supplies to 1 ppm, or fluoridization of salt (Switzerland). Most of the UK is fluoride deficient.
VITAMIN EXCESS SYNDROMES Toxicological syndromes associated with vitamin excess (Table 5.20) are mainly found with fat-soluble vitamins (A, E, D, K) which accumulate in the body.
Vitamin A Toxicity occasionally occurs acutely in children given large doses (e.g. 200000IU) of vitamin A intramuscularly. It takes the form of irritability, and even convulsions, as a result of increased intracranial pressure. Recovery occurs within a few days. Excessive self-medication is the usual cause. Levels of vitamin A in the livers of farmed animals have risen in recent years because of feeding practices. It is quite possible to consume, in a single meal containing liver, much more than the maximum permitted of 10000IU per day for
TABLE 5.20 Main consequences of vitamin toxicity Vitamin
Symptoms of toxicity
A
Headache, convulsions, muscular stiffness, hepatomegaly, teratogenic effects Not described Not described Vasodilatation Peripheral neuropathy Not described Not described Increased urinary oxalate Hypercalcaemia, renal failure Nausea Hyperbilirubinaemia
Thiamine (B1) Riboflavin (B2) Nicotinic acid Pyridoxine (B6) Folate Cobalamine (B12) Ascorbic acid (C) D E K
a woman during pregnancy. Large doses of vitamin A are associated with an increased prevalence of craniofacial abnormalities in the infant. For this reason it is recommended that pregnant women do not eat liver, which used to be encouraged for pregnant women to provide iron and other nutrients.
Pyridoxine (vitamin B6) Pyridoxine toxicity has been occurring more frequently in recent years owing to its use - successful or otherwise - in attempts to alleviate premenstrual syndromes (depression and fluid retention). A peripheral neuropathy is likely if the daily dose exceeds 500 mg, and has been reported at lOOmg/day. Some cases have neurological abnormalities which persist even after stopping the drug.
Vitamin C Toxicity occurs among those who take enormous doses of vitamin C in the unfounded belief that it will prevent the common cold or cancer. Doses above 2g/day may cause abdominal discomfort and osmotic diarrhoea. There is increased urinary oxalate excretion - which may dispose to oxalate stones - and some evidence of damage to the intestinal epithelium.
Vitamin D Vitamin D toxicity occurred in the UK after World War II in some children given too much fortified milk. (The quantities added are now more strictly controlled.) Mild forms of vitamin D toxicity are characterized by weakness, weight loss and growth failure. Severe forms cause nephrocalcinosis, radiological changes in the epiphyses and mental retardation.
TRACE ELEMENTS
a
The clinical relevance of trace elements in health is limited, but zinc deficiency appears important. Zinc, and probably also copper, is important in protecting cell membranes against free radical damage. Zinc is a cofactor in over 100 enzymes, and there are no body stores. Absorption from the diet is about 30%, but adapts to needs in health. Deficiency is seen most clearly in the congenital disorder aerodermatitis enteropathica, which is characterized in infants after weaning by a scaly skin rash, secondary bacterial and fungal infection, diarrhoea and severe growth faltering. All are rapidly reversed by zinc therapy. Deficiencies are also seen in children with severe malnutrition, and were formerly seen in patients receiving parenteral nutrition without sufficient trace element mixes. © Selenium deficiency can cause a cardiomyopathy, although its main role is as a cofactor in the antioxidant enzyme glutathione peroxidase. The selenium content of plasma falls during stress or illness as part of the acutephase response.
Iodine deficiency Most iodine deficiency is due to low levels in the soil and water. There are many regions in the world, e.g. Nepal, Peru and Bangladesh, where iodine intakes are so low (<50-75 mg/day) that thyroid function is impaired. There is a high prevalence of cretinism in neonates in these regions, which may present as deaf-mutism, mental retardation and ataxia, with the characteristic morphological features of thickened facial appearance, stunted stature and enlarged tongue. The brain damage is irreversible if not treated early. It is now also realized that the poor intellectual performance and deafness (without any unusual morphological features) found in many children in iodine-deficient areas is due to marginal iodine deficiency. This may be partially reversible. In some areas an already limited iodine availability is made worse by the consumption of goitrogens, e.g. in certain brassicas, cassava or soya beans. The extent of the problem can be assessed by measuring the prevalence of goitre (enlargement of the thyroid gland), which is particularly common among adolescents and pregnant women. Measurements of urinary iodide and iodine/ thiocyanate levels can determine whether the problem is primary dietary iodine deficiency (low iodine) or the result of a dietary goitrogen. Richer people in goitrous areas generally obtain enough iodine by eating food (e.g. fish) brought in from other areas, but the main strategy is to iodize salt. Where this is impractical, injections of iodized oil (lipiodol) may be given, especially to women of childbearing age. A single dose (5ml) will usually last for up to 5 years. Oral doses (400 mg) of iodine preparations may provide enough to last for 2 years.
127
OVERWEIGHT AND OBESITY Obesity is the accumulation of excess fat with multiple organ-specific pathology. The disease and its clinical consequences are obviously progressive, but for epidemiological purposes cut-offs of BMI 25 and 30kg/m2 are used, corresponding with the clinical hazards increasing and becoming frequent. Alternatively, waist circumference can be used as a simple indicator of total body fat, which is largely independent of weight.
Causes Obesity is due to an interaction between genetic constitution and the environment. The genetic component is clear, as is shown in studies of families and twins. The genes involved are not identified but are probably multiple, and they provide only the predisposition to more or less rapid weight gain. They may affect appetite regulation or metabolic efficiency. Together, genetic factors account for about 30% of predisposition to weight gain. The remainder comes from environmental influence - food attractiveness and availability, need for exercise etc. The fat accumulation itself can of course only come from excess energy consumption above needs over a prolonged period. 1 Obesity may be precipitated by an obvious decrease in energy expenditure due to a change in lifestyle (e.g. to a more sedentary job), or an injury or arthritis which limits mobility. However, in most obese individuals it seems that intake and expenditure problems occur together. Many people admit to eating excessively. A sympathetic request for a confidential 2-week diary of everything the patient eats may be very revealing, but most obese people underestimate their intake. Depression and psychosocial problems are common, so a brief history in the outpatient clinic will usually fail to give an accurate assessment. The metabolism of food energy has been studied in detail over the last 20 years, and the evidence gives some clues as to how some individuals are more prone to weight gain than others with a similar energy intake. • People with a high fasting respiratory quotient (RQ) (CO2 production divided by O2 utilization) are most prone to weight gain. • When volunteers are given extra calories, some put on weight faster than others. • Dieting leads to an adaptive decrease in energy expenditure, and this may vary between individuals. • Obese people have a decreased thermogenic response to stimulation by noradrenaline (norepinephrine) or food, and this persists even when they have lost weight.
1 128
Figs 5.4, 5.5
2
Fig. 5.6
There are well-described genetic obesities in experimental animals, but the mechanisms appear to be different in humans. To cause obesity there needs to be an increase in appetite without a compensatory rise in energy expenditure. The ob gene codes for a peptide hormone, leptin, which is released from adipose tissue as a long-term signal of fat storage. Leptin signals satiety via hypothalamic receptors modifying neuropeptide Y activity, and as a signal to other functions, such as the onset of puberty, and tends to downregulate energy expenditure. Overweight humans have high circulating leptin concentrations and may therefore be resistant to it, although a complete absence of leptin, usually from a very rare defect in the ob gene, results in colossal childhood obesity. Several other genetic obesities are known, such as the Prader-Willi syndrome, with a defect on chromosome 15. No common gene defect has yet been discovered in the general population of obese patients. Studies of families, twins and adoptees all point to a strong genetic influence, accounting for about 30% of variability in weight gain. Multiple genetic factors are involved, with no single common pathway controlling energy balance yet identified.
Consequences It is often overlooked that overweight people start to develop symptoms (Table 5.21) as BMI increases above 25kg/m2. Most people with BMI >30kg/m2 are chronically troubled by symptoms, including tiredness, breathlessness, sweatiness, low back pain, and hip and knee pain. Depression is a common complaint but is unlike typical endogenous depression, and is probably due in part to fatigue. Obesity is associated both with functional difficulties in simple domestic activities and with discrimination in every walk of life. This poor quality of life is only exceeded by the worse quality of life for an obese patient on a protracted diet without visible results. The metabolic effects of overweight, leading to increased risks of heart disease (hypertension and hyperlipidaemia) and cancers (related to increased adipose tissue aromatase and increased free sex hormone) are well documented. These metabolic hazards of being overweight are exaggerated in those who also have a central (appleshaped) fat distribution, with a high intra-abdominal fat
TABLE 5.21 Symptoms of overweight • • • • • • •
Tiredness Sleeping poorly Sweating Breathlessness Snoring Low back pain Hip and knee pain
• Hirsutism • Menorrhagia • Amenorrhoea • Stress incontinence • Angina • Depression • Infertility
TABLE 5.22 Medical consequences of overweight and obesity Physical symptoms
Metabolic problems
Social problems
Anaesthetic/surgical problems
Endocrine problems
Psychological problems
Tiredness Breath lessness Varicose veins Back pain Arthritis Oedema/cellulitis Sweating/intertrigo Stress incontinence
Hypertension NIDDM Hepatic steatosis Hyperlipidaemia Hypercoagulation IHD and stroke
Isolation Agoraphobia Unemployment Family/marital stress Discrimination
Sleep apnoea Chest intections Wound dehiscence Hernia Venous thrombosis
Hirsutism Oligomenorrhoea/ infertility
Low self-esteem Self-deception Cognitive disturbance Distorted body image Depression
Metromenorrhoea Oestrogen dependent cancers: breast, uterus, prostate
a
IHD, ischaemic heart disease; NIDDM, non-insulin dependent diabetes mellitus
mass shown by high waist circumference. Table 5.22 shows the range of metabolic and mechanical consequences of being overweight. They have an impact in virtually every branch of medical practice. © The extra medical costs of the overweight are estimated to account for an astonishing 2-80% of total health service budgets. For this reason the UK Government Health of the Nation White Paper made the prevention and correction of obesity one of the highest priorities for the health service in the 1990s. Most Local Health Authorities have programmes for weight management. The World Health Organization has included obesity as a worldwide epidemic needing coordinated preventive measures, as well as a disease in its own right which requires treatment to relieve distress.
Criteria for treatment The management of weight problems should address the process of weight gain. Many people say they want to lose weight: most are able to do so using a variety of approaches, but many are not prepared to adopt the permanent lifelong change in diet and lifestyle needed to prevent regain. The groups of patients who need professional (medical) weight management are those who are unable to control a weight problem using self-help methods, who are prepared to make substantial lifestyle and diet changes for relatively modest cosmetic gains, and those who should be advised on medical grounds to lose weight. People with BMI below 25kg/m 2 cannot be considered overweight, and so weight loss is usually inappropriate. A request for help from these people may indicate an underlying eating disorder, such as anorexia nervosa. There may be patients with BMI a little under 25 when some weight loss could be valuable, for example those with metabolic syndrome or non-insulin dependent diabetes. Advice on weight management should be offered to all patients whose BMI exceeds 25kg/m2, aiming first at restricting further weight gain and second at a period of weight loss, followed by a period of supervised weight maintenance. Between BMI 25 and 30, the principal aim
should be the further weight gain. Those who wish to lose weight or those who have a high risk (e.g. through family history) of developing diabetes, heart disease, hypertension or hyperlipidaemia, and those who already have these conditions, should be given advice on how to lose weight. Above BMI 30, where disease risks are high, weight loss will bring benefits in relation to metabolic and cardiovascular problems and, more importantly in older patients, from the point of view of symptoms and impairment of quality of life. With a view to health promotion for the general public the waist circumference provides more accessible criteria for treatment. Above waist 80cm (women) or 94cm (men) the risks are increasing and people should avoid further gain. Above 88cm (women) or 102cm (men) health impairment is almost universal, and professional help should be offered (Table 5.23).
WEIGHT MANAGEMENT Recognizing the aetiology of obesity, and its major medical consequences, it is vital that doctors take a leading role in advising patients about the need for and methods of weight management. The skills of several professional groups can be valuably employed, including nurses, dietitians, clinical psychologists, physiotherapists, and even commercial slimming and exercise clubs. Weight management is best conducted in the primary care and community environment, but up-to-date training should be provided for all those involved. All patients with weight problems require assessment for other related and compounding risk factors, such as smoking, blood pressure, lipids and blood glucose. Although many smokers gain some weight when they stop, this weight is usually lost over the subsequent year or so and the gain can be prevented by simple dietetic advice. The medical hazards of smoking are only equalled by weight gain equivalent to a doubling of body weight, but the combination of smoking and overweight has multiply
129
TABLE 5.23a Waist watchers - Men Action level 2 Action level 1 <94cm >102cm 94-102 Increasing health High health risk Green zone risk -aim for - seek advice - no need to green zone to lose weight lose weight Prevalence (%) of Type 2 diabetes Cardiovascular risk factors Shortness of breath Poor physical functioning Chronic low back pain
0.6
1.8
26.0 10.4
47.4
4.5 64.2
17.1 10.2
31.5 17.5
19.5
21.1
4.8 14.1
TABLE 5.23b Waist watchers - women Action level 1 Action level 2 <80cm 80-88 >88cm Green zone Increasing health High health risk - no need to risk - aim for - seek advice lose weight green zone to lose weight Prevalence (%) of Type 2 diabetes Cardiovascular risk factors Shortness of breath Poor physical functioning Chronic low back pain
0.4 13.6 17.4 7.1 16.5
active effects on risks. Serum y-glutamyl transferase (y-GT) should be checked, as alcohol consumption is often an important component of weight gain in men, and it is often difficult to identify overweight drinkers. It should be remembered that y-GT will be elevated in untreated non-insulin dependent diabetes mellitus or metabolic syndrome with fatty liver. Serum TSH is useful, as subclinical hypothyroidism is common and greatly impairs ability to lose weight. Treating hypothyroidism does not automatically lead to weight loss.
Diet modification
130
A first step towards weight management is healthful balanced dietary advice. Many of the features of current health promotion dietary advice are highly appropriate to weight loss or weight maintenance. Even during slimming, patients should eat at least five portions of fruit and vegetables daily. Extra helpings, and even snacks of vegetables, can be encouraged. This will help to reduce fat intake. Fat is the nutrient with the highest energy content (kcal/g), so its major dietary origins need to be restricted, particularly full-fat milk and dairy products, processed meat products such as sausages and pies, and biscuits and baked
0.5 26.0 25.5 10.0 18.0
2.7
42.5 39.4 19.7 24.1
food. Bulky and relatively nutritious foods such as bread, potatoes and pasta can still be taken in reasonable amounts to satisfy appetite; it is the spreads or sauces that go with them that tend to contain unnecessary calories. The style of eating recommended for weight management should be continued for life. It should be explained to patients that they have a metabolic profile which will present a problem if they revert to eating a diet high in fat. Alcohol contains 7 kcal/g, so alcohol restriction is directly valuable, but alcohol consumption rapidly leads to non-compliance with diets. It is best avoided during periods of weight loss, particularly by drivers.
Eating behaviour Many patients with weight problems have a rather undisciplined eating pattern, often skipping meals such as breakfast, and even lunch, and then eating large amounts later in the day and at night. A useful management strategy is to concentrate on shopping, to advise patients not to buy what is not needed. It is helpful to plan eating patterns in advance, based on three meals a day and complete avoidance of all snacks. A breakfast which is filling and nutritious but low in calories, such as porridge, is effective.
SUMMARY 4 Practical advice for weight management • • • •
Become a non-smoker (top priority) Eat at least five portions fruit and vegetables daily Eat fish at least twice a week 20-30 minutes moderate activity daily (to breath hard or break sweat) • Avoid future weight gain (before and after loss) • Achieve weight loss 5-10 kg in 3 month stages • Feel proud to have done each of these
Porridge and 'breakfast cereals' are useful as standbys for energy-saving evening meals, and are preferable to lowcalorie commercial meal replacement products, which are often expensive and unpalatable. Individual strategies can be discussed, negotiated and used with patients. 'Rules', such as only eating off a plate, never eating with the fingers, or never eating with the television on, may be helpful.
Physical activity It is extremely difficult to lose weight simply by increasing exercise and physical activity. Each kilogram of adipose tissue (fat) contains about 7000 calories, so 7kg (a stone) contains 50000 calories. Sustainable increases in physical activity would need to be maintained for well over a year to lose this amount of weight. On the other hand, physical activity can be enormously valuable in improving quality of life and helping people to feel better, and in reducing blood lipids, blood pressure and the risks of diabetes. Increased physical activity is vital for weight maintenance to avoid regain, and it is essential to protect muscle from wasting during weight loss. Regular physical activity may help regulate appetite. The metabolic rate of a patient who has lost 7kg (one stone) will be reduced by about 120kcal/day. This can be matched by 20-30 minutes of brisk walking daily if the patient were to continue to eat the previous intake. It is useful to advise the patient to trade food at snack time for activity, even of a very limited extent. Negotiated plans should be agreed, for example to walk all journeys which are less than one mile. Organized physical activity is helpful for many patients but seldom conducted on a daily basis. For those unable to take some exercise daily, it is acceptable to undertake longer blocks of exercise less frequently (e.g. 1 hour three times a week). In addition to taking specific exercise, the avoidance of complete inactivity is important. Television watching (average 29 hours per week in the UK) relates closely to weight gain and to difficulty in slimming, even in people who take some exercise.
Drugs The main function of drug therapy for obesity is to restrict long-term weight gain below the untreated rate. Weight loss is a brief (3-6-month) phase, but no available drug can produce major weight loss alone, and a drug that did would
be dangerous. Initial weight loss is probably most efficient using a very low-calorie diet, under supervision, with drugs for the long-term maintenance phase. No drug therapy can achieve weight loss or maintenance at a lower level without dietary and physical activity changes, and so drugs should not be prescribed unless patients are achieving success with dietary and lifestyle modification as an indication of motivation. One of the main aims of using drugs for weight management is to reduce the need for drug therapy for complications of obesity, such as antihypertensive drugs or hypoglycaemic agents, lipid-lowering drugs and analgesics. These preparations are usually taken indefinitely and often in combination. There is no place in weight management per se for the use of diuretics: oedema is usually a local problem, not the result of sodium retention, and responds poorly to diuretics. Thyroxine does not produce weight loss except in large doses with dangerous cardiac side-effects, and should not be used for obesity. With recent recognition of the extent of pathology and healthcare costs attributable to obesity, there has been intense research interest in developing new drugs for weight management. Drugs may affect appetite or satiety and energy intake, or energy expenditure. Because of the physiological complexity of energy balance, no single drug is likely to have profound effects, and responsiveness varies widely between subjects. Ideally, to reduce body weight, energy intake must fall and energy expenditure must rise. Most effective agents have some effect on both sides of the energy balance equation, but pharmaceutical management will always rely on dietary restraint. The old appetite suppressant drugs, based structurally on amphetamines and sharing noradrenergic releasing activity (e.g. phentermine), have fallen out of favour, largely because of the historic association with amphetamine, despite their lacking addictive or mood-altering actions. They were never subjected to long-term clinical trials, but undoubtedly led to substantial weight loss in patients otherwise unable to achieve it. These drugs are still available in the USA and elsewhere. Sibutramine, available in most of America and Europe, has both noradrenaline and serotonin reuptake inhibition activity. Patients who respond (2 kg weight loss in 4 weeks) can expect to lose about 10 kg on average over 3-6 months, and to maintain the differences from placebo for at least 2 years. Greater weight loss, achieved by an initial period on a very low calorie diet can also be maintained. The main side effects are increase in pulse rate and in blood pressure. In patients who fail to lose weight blood pressure tends to rise, but blood pressure falls with weight loss on sibutramine, particularly in hypertensive patients. About 10% of patients do not lose weight with sibutramine. They were included in the clinical trial results, but should be identified early in a therapeutic trial in routine practice. Orlistat aids weight loss and maintenance by inhibition of intestinal lipase, leading to 30% fat malabsorption. Patients who lose 5% body weight after 3 months treat-
131
ment, together with a 30% fat diet, can expect 10-15% weight loss, maintained for 2 years. However, only 30-40% of patients are able to pass this hurdle. The main sideeffects are symptoms of fat malabsorption if patients eat too much. The drug is not absorbed. A wide variety of other weight loss agents are prescribed in other countries, or sold over the counter in pharmacies and supermarkets. For none of these is there evidence of safety or efficacy, with the possible exception of an ephedrine and caffeine combination, widely used in Europe, but not in UK.
Surgery In patients with BMI above 35kg/m2 and where metabolic or other complications are crippling or life-threatening, surgery is sometimes justified. The most widely used, operations at present are vertical banded gastroplasty and laparoscopic gastric bonding which reduce the size of the stomach to only about 50ml. Gastroplication requires the backup of a high dependency unit, but has a relatively low complication rate in experienced hands. Following operation, patients need to follow a liquid-only diet for 3 months, otherwise the staple line is likely to rupture and the surgery will be ineffective. It is a good plan to insist that all patients spend 3 months on the liquid-based diet before operation; during this time they should be expected to lose approximately 15kg in weight. Supplementation with iron and vitamins is necessary, and long-term medical nutritional and dietetic supervision is required. This form of operation usually results in a deranged eating pattern for life. For this reason psychiatric or psychological assessment and subsequent supervision should be available. Weight loss of 30-100 kg can be achieved but because regain after 2-3 years is so common gastric bypass with Roux-en-Y is becoming preferred. Long-term weight loss is more assured, but at the cost of chronic loose stools.
1 kg of fat in a week through strict dieting, but to gain the same amount temporarily from water, and this can be demoralizing.
Weight maintenance Very few patients can continue to lose weight beyond 3 months, and it is unreasonable to ask them to attempt more. Any result other than weight gain should be regarded as successful at 3 months, and then a weight maintenance programme introduced to prevent regain. This follow-on programme should include active support and lifestyle and psychological counselling for a further 3 months. Commercial and lay slimming groups may provide valuable support. Where the medical risks of weight gain are specially high (e.g. active, or family history of diabetes, hypertension, coronary heart disease), long-term medication may be considered. 1 2
NUTRITION SUPPORT Malnutrition delays wound healing and the recovery of muscle tone after an injury or operation, and may increase susceptibility to infection. Adults with a BMI below 16 have three times the postoperative mortality of betternourished patients. The striking changes in body composition from partial starvation in illness are shown in Figure 5.8. It is better to avoid malnutrition than to treat it, and it is essential to make a nutritional assessment of every patient. If the patient is already underweight, or if there is weight loss and the clinical condition gives concern, some form of nutrition support - such as dietetic supplements, enteral feeding or parenteral feeding - can be used to prevent further deterioration (Table 5.24). Every hospital should have a nutritional assessment and support policy, with a nutrition team comprising a physician and/or sur-
Expected rate of weight loss Many patients, and indeed health professionals, have unrealistic expectations during weight loss. Following a strict dietary restriction of 500 calories a day below normal maintenance, patients will lose about 0.5kg (1 Ib) per week or 7kg (1 stone) in about 3 months. More restricted diets and faster weight loss can only be achieved by a minority and for a fairly short period. More rapid weight loss may be dangerous, as it implies excessive loss of muscle or other body tissues. Weight loss of 0.5-1 kg per week should be expected and encouraged. Patients should not weigh themselves more often than every 2-4 weeks, as bathroom scales give a poor guide to body weight. It is also possible to lose
1
132
Case 5.2
2
MCQ 5.3
FIG. 5.8 Body composition of a man in health and after partial starvation
TABLE 5.24 Examples of conditions in which nutrition support may be necessary Illness associated with nausea and abdominal pain Gastrointestinal disease Malignancy Chemotherapy
Inability to eat Coma
Weakness Bulbar/pseudobulbar palsy
facing malnutrition, a formal prescription process for nutritional supplements may be as important as that for drug administration.
a
Intestinal disease
Enteral feeding Maiabsorption Inflammatory bowel disease Fistulas Thoracic duct damage Ischaemic colitis Short bowel syndrome Increased requirements Burns Sepsis Trauma
geon with special experience in clinical nutrition, a nutrition nurse/technician and a dietitian, together with strong support from the pharmacy, biochemistry and pathology laboratories.
Food and sip feed supplements Many patients find hospital food unappetizing even when they feel relatively well. In such cases, it may be possible to increase energy and nutrient intake by snacks provided by the diet kitchen between main meals. Attractive food and company can contribute greatly to maintaining nutrition; impersonal meal delivery and having to eat in bed have negative influences. If solid food is not well accepted, it is often possible to give liquid feeds for sipping but energy intake can be compromised. Semi liquid feeds can be prepared for patients with swallowing difficulties. A considerable range of commercially prepared feeds are available, presented as 200ml cartons. Some are complete feeds, containing a balance of all essential nutrients in proportion to requirements; others are incomplete, such as flavoured sugar solutions. Palatability is very variable. Sip feed supplements and enteral feeds are available in a vast range of compositions. For virtually all patients, the macronutrient contents should be similar to that of a healthy balanced diet, i.e. about 10-15% energy from protein, 50-60% from carbohydrate and 30-40% from fat. There is no clinical indication for high protein feeds: preparations with up to 40% energy as protein are available but should not be used as they suppress appetite and may lead to impaired renal function. Evidence is very limited to justify the use of 'elemental' feeds containing pre-digested peptides or oligosaccharides, or for feeds enriched with particular amino acids such as glutamate. Sip feed supplements should be served chilled and their volumes recorded accurately. They must be taken as supplements to an optimized food intake, not used as meal replacements. Patients often need a nurse to help and encourage supplement consumption. For patients
If oral intake is not satisfactory usually because of swallowing problems, a fine-bore silastic nasogastric tube may be passed. Because the enteral route should always be used when the gastrointestinal tract is intact, surgeons should also be encouraged to place a feeding nasogastric or nasojejunal tube at the time of any upper gastrointestinal surgery, or to leave a feeding jejunostomy. Even very limited enteral feeding after surgery or in the ITU nourishes the intestinal mucosa, reducing bacterial overgrowth and translocation, and permits more rapid weaning on to full enteral feeding. Enteral feeding solutions are passed down the tube at controlled rates. Small battery-operated pumps can control the exact flow rate, but they are not essential. The feed should be started in small volumes, and no more than 1000 mL given in the first 24 hours, otherwise diarrhoea may develop. The volume is then increased to the desired amount (probably a maximum of 2500mL/day). When patients are beginning to take food, the feed should be stopped for 1 hour before meals. Overnight enteral feeding may usefully supplement a limited oral intake, but care must be taken to avoid aspiration of gastric contents. A semirecumbent position is advisable. A large range of commercially available enteral feeds are available, made up from a variety of protein sources, including casein, soya and mixtures of amino acids, with glucose polymers and triglycerides added to increase the energy content. Most feeds provide about Ikcal/mL and have an osmolality of 280-420 mmol/kg. Low-lactose and cows' milk-free feeds are available. The commercial preparations have micronutrients in amounts that match dietary reference values, and so additional vitamins and minerals may be needed for patients whose micronutrient status is poor, or who have increased losses, utilization or malabsorption. Biochemical monitoring is required. Energy provision should match the metabolic rate, measured by indirect calorimetry or predicted from standard equations (Table 5.4) (BMR x 1.3 for a bedbound patient, plus 10-50% according to degree of illness or need for weight regain). It is impossible to overcome the increased metabolic rate of an ill, infected patient and to promote muscle regrowth at the same time. Protein should account for 10-15% of energy, the remainder coming in approximately equal amounts from carbohydrates and fat. The use of oligosaccharides or polydextrose may reduce the osmotic effects of glucose delivered enterally, but the evidence for using expensive peptide feeds is scanty. Enteral feeding can be performed at home; the reservoir bottles and lines should be changed every 24 hours to avoid the risk of contamination of feeds, but the silastic tubes can remain in situ for several weeks. Even so, complications of enteral feeding occasionally occur and should be anti-
133
cipated. Some patients prefer to use enteral feeding intermittently and become expert at introducing nasogastric tubes. Oesophagitis caused by the tubes is rare with modern silastic tubing, but the tube may be misplaced and a clinical check (aspiration of gastric fluid, or detection of bubbling with a stethoscope) should be carried out before feeding is commenced. When enteral feeding needs to be continued beyond a few weeks, gastrostomy feeding is usually easier and more acceptable to the patient. Percutaneous endoscopic gastrostomy is now a simple and safe procedure, increasingly used in a range of medical conditions, including pseudobulbar palsy following stroke, advanced multiple sclerosis or other neurological disorders. The most common complications of enteral feeds are diarrhoea, abdominal distension and pain, all of which relate to excessive infusion; the volume infused should then be decreased. More protracted diarrhoea can be controlled by codeine phosphate (30-60 mg t.d.s.) or imodium (2-4mg t.d.s.). Aspiration pneumonia is relatively frequent in debilitated patients (especially those with swallowing disorders) receiving enteral feeding when lying flat. Such patients should be fed sitting, if possible.
Parenteral feeding If enteral feeds cannot be given, parenteral feeding is an option; however, the dangers of infection, thrombosis and metabolic problems with this method are considerable. Enteral feeding should be commenced as soon as possible (even if very limited) to prevent mucosal atrophy. Parenteral feeds are ideal culture media for bacteria. They must be made up under sterile laminar flow conditions by specialist pharmacists (the vitamin and mineral preparations have limited stability, so feeds must be made up shortly before use). A dedicated intravenous line must be inserted under sterile conditions and only handled by trained staff. -Long-term parenteral nutrition requires a central line, as the high osmolality (often l000mmol/L) causes thrombosis in slow-flowing peripheral veins. For shorter-term feeding (up to 10-14 days), perhaps before it is ascertained that long-term parenteral nutrition will be required, peripheral veins can be used. Sterile techniques should still be used, and blood flow can be increased by a distal GTN patch. A lower glucose content allows reduced osmolality and so reduced thrombosis: a limited energy supply is often acceptable for 10-14 days for peripheral line feeding. Some commercial peripheral feeds are incomplete in terms of micronutrients, and so monitoring is important. The energy requirement for a malnourished patient receiving nutritional support is often difficult to assess. For long-term feeding, energy requirements can be estimated from standard equations published by the WHO (Table
1
134
MCQ 5.4
5.4). For ill patients and the malnourished, measurement of resting metabolic rate by indirect calorimetry is valuable, largely to avoid overfeeding, which causes a fatty liver. The amino acid content should be 10-15% of energy, and the remainder given as glucose or lipid emulsion (which permits a lower volume and lower osmolality than with glucose alone). A standard single 24-hour bag (2-3 L) containing 1500-2500 kcal is available. Parenteral feeds can be given either continuously over 24 hours, or over 12-18 hours to allow a daytime period off feeding, when the line is sealed and the patient can be mobile. Micronutrient requirements depend on clinical condition. All the essential nutrients (amino acids, fatty acids, vitamins, trace elements) are required. The matching of provision to need is more critical than with enteral feeding, because the 'buffering' influence of absorption in the gut does not apply. If the patient is malnourished and tissue growth is required, a greater than normal provision of phosphate, potassium and zinc will be needed to avoid 'refeeding syndrome' deficiencies. Because it is difficult to exclude subclinical vitamin B1 deficiency, extra thiamine should be given to patients when starting parenteral nutrition. For some, the intravenous delivery results in more rapid renal excretion, and so greater than normal dietary amounts are needed. Many patients receiving parenteral nutrition have tissue damage, and renal failure is relatively common, demanding special consideration. A number of metabolic complications may occur in patients receiving parenteral nutrition: • Hyperglycaemia is common in patients with severe surgical stress (e.g. burns and intravenous trauma) and sepsis, but plasma glucose can be controlled with carefully monitored insulin, adjusted to maintain plasma glucose 4-8mmol/L. Rebound hypoglycaemia may occur if intravenous feeding is abruptly halted. • Metabolic acidosis is rare if fructose and excessive quantities of amino acids are avoided. • Parenteral feeding, especially with lipid solutions, may cause hepatic abnormalities. The commonest reason is overfeeding, leading to fatty liver, which responds to a reduction of energy in feeds. However, most patients receiving parenteral feeding have many other potential causes for hepatic damage, and there is rarely any indication for parenteral nutrition to be stopped on account of mild biochemical changes. • Fat is metabolized more favourably than glucose by patients with sepsis. • Patients with respiratory failure should not receive large glucose loads because of their impaired ability to excrete the extra CO2 produced. • Mineral and electrolyte abnormalities occur variously according to the underlying disease processes. Fortunately, deficiencies can be made up relatively easily during preparation of the bag that contains the feeding solutions. • The stability of feed constituents is precarious, and problems have arisen with 'home-made' feeds and with
CASE STUDY 5.2 POSTOPERATIVE MALNUTRITION A 54-year-old man, height 1.75m, weight 65kg (BMI 21kg/m2) underwent a revision of a mitral valve replacement. His postoperative course was complicated by mediastinal wound infection and he had an episode of pneumonia, hypotension and acute renal failure, necessitating prolonged ventilation. During recovery the question of his nutritional status, complicated by 7 days of infection is raised at a caseconference, 10 days postoperatively, at which stage feeding had not been commenced. His weight has fallen to 60kg. Questions 1. What nutrient deficiencies are likely to be present? 2. How could management be optimized? Discussion Failure to eat for 10 days postoperatively, when metabolic rate is elevated about 50%, will have resulted in negative energy balance of about 10 (days) x 1.5 (increased metabolic rate) x 1600 (minimum daily requirement) = 24000k/cal. This would be equivalent to almost 4kg adipose tissue, but excess lean tissue is lost in infection, at about l000kcal/kg. The weight
measurement is likely to be seriously confounded by oedema, and changes in fluid balance (which may not be dependent). The patient's 'true' BMI may therefore be as low as 16kg/m2, making death from malnutrition likely. Specific deficiencies of many micronutrients are likely. Blood biochemistry is likely to be difficult to interpret owing to acute changes in protein and electrolyte balance. Deficiencies of nutrients which do not have body stores will be particularly depleted (e.g. vitamin C, B complex, magnesium, zinc, selenium). Preoperative status of thiamine, selenium may have been marginal thereby potentially impairing cardiac function. Immune function may have been impaired by a variety of nutritional factors, including a deficiency of essential fatty acids, vitamin A and zinc. Preoperative nutritional assessment and optimization should be routine. Common hazards with late, and inexperienced, nutritional support include inadequate thiamine to overcome a deficiency state, and the overprovision of energy. During illness the capacity to utilize nutrients and to synthesize body tissues is reduced, partly from cytokine action, partly from secondary nutrient deficiencies and altered nutrient essentiality. Excess energy supply
storage. Micronutrients should be added shortly before infusion. Home parenteral nutrition is occasionally necessary for patients with postsurgical short bowel syndrome and other conditions. It represents an enormous undertaking, but with family, social and medical support can be continued satisfactorily for many years. Commercial organizations exist to deliver supplies and to provide nursing and pharmacy support. In many cases total parenteral nutrition is not necessary - more limited feeding, e.g. 3 or 4 nights per week, may be sufficient. 1
Monitoring nutrition support The measurements available for monitoring support are shown in Table 5.25.
nutrition
leads to acute hepatic steatosis and impaired liver function. Measurement of metabolic rate is possible using a ventilated hood calorimeter, but it is more difficult when the patient is on a ventilator. Using estimated BMR is usually adequate. At this stage this patient requires assessment and management by a multidisciplinary Hospital Nutrition Support Team (including representation from specialist trained nursing, pharmacy, dietetic, biochemical and clinical staff). Biochemical nutritional data should be assessed at least weekly, with daily weight and assessment of state of hydration and for oedema. If the GI tract is accessible and intact, then this route is preferable to intravenous feeding. Because of mucosal atrophy after 10 days without feeding, enteral feeding will need to commence at low rates, increasing to approach energy requirement after 2-5 days. A nutritionally complete feed is required. Evidence does not support enrichment with individual amino acids. An approximate breakdown of energy 15% protein, 55% carbohydrate, 30% fat is appropriate. If increased CO2 production is clinically problematic, then higher fat, lower carbohydrate feeds might be considered.
a
TABLE 5.25 Measurements for monitoring nutrition support • Anthropometric: weight, mid-arm muscle circumference (MAC) • Minerals and electrolytes: uric acid, phosphate, sodium, potassium, zinc, magnesium, iron • Resting metabolic rate • Plasma vitamin concentrations • Nitrogen balance: corrected 24 hour urinary urea excretion • Glucose
Regular measurements of weight are necessary but are difficult to perform in the very sick without special bed balances. Changes in body weight may indicate alterations in fluid balance rather than an increase in lean body mass.
135
Skinfold thicknesses and mid upper-arm circumference are valuable but affected by oedema. Plasma proteins (CRP, albumin) are useful indicators of progress in treating the underlying disease processes. Glucose should be measured regularly. Plasma phosphate and potassium levels may decrease rapidly and even precipitate cardiac arrhythmia if nutrition support is given rapidly in large quantities to a severely malnourished subject who has previously received very little dietary intake. Most modern amino acid solutions, however, have sufficient phosphate to avoid this. A low plasma sodium is often present in severely malnourished subjects. Total body sodium, however, is often high, and extra sodium should only be given with great caution. An approximate assessment of urinary nitrogen loss can be obtained by measurement of the 24-hour urinary urea excretion, corrected according to the formula: Nitrogen (g/24h) = urinary urea (mmol/L) x urine volume (L) x 0.028 x 6/5 This formula allows for the conversion of mmol of urea to g of nitrogen, and corrects for the fact that urea accounts for approximately five-sixths of total urinary nitrogen loss. Parenteral feeding solutions are ideal culture media. The previously high prevalence of infection has been reduced by the single-bag system, but a high standard of nursing and medical care of the lines is essential if sepsis is to be prevented. Different types of intravenous catheters are available - the best are those that are tunnelled subcutaneously. The feeding line must not be used for any other purpose. If other infusions are required a multilumen Hickman line may be used, keeping one lumen sterile for parenteral feeding. Hickman line insertion requires skill and experience. Complications include pneumothorax, central vein thrombosis, nerve injury, haematoma and arrhythmias. Similarly, only staff trained in the care of central venous feeding lines should be allowed to touch them, and the need for aseptic changing of sets and meticulous care of the catheter entry site should be emphasized. Feeding line infection should be suspected if fever develops, and is confirmed by cessation of fever when feeding is withheld and by a drawback blood culture (conducted under sterile conditions). Infected feeding lines can often be rescued by stopping feeding and by infusing vancomycin for 4-5 days. Central vein thrombosis can be treated by streptokinase infusion, but complete sterility must be maintained if the line is to be reused for feeding.
Refeeding syndrome
136
A lesson learned from work in the developing world, and now applicable in western hospitals, is that refeeding of severely malnourished and ill patients can often precipitate rapid decline and death. The 'refeeding syndrome' relates to the dynamic changes induced by introducing nutrition support. Metabolism is reactionary to rapid shifts from
extra- to intracellular spate of potassium, magnesium, zinc and phosphate. Low plasma levels can then lead to cardiac and central nervous system problems. These shifts need to be anticipated, and clinical problems can be avoided by careful monitoring and extra provision of these nutrients during early refeeding.
NUTRITION AS A COFACTOR IN DISEASE AND IN THERAPY
Hypertension There are direct relationships between BMI, sodium intake and blood pressure. Humans evolved on very low-sodium diets. The main effect seems to be a programming effect from exposure to high sodium intake in infancy. Most patients with 'essential hypertension' are in fact obese, and the increased sodium intake is secondary to increased food intake. There is a threshold effect of additional salt in adult volunteers, with those on very high doses showing an increased blood pressure. However, there are also important cofactors, including family history, stress, obesity and potassium, calcium and magnesium intakes, which may obscure the relationship in an individual. In the UK the average daily salt intake in adults is 5-10 g, i.e. sodium intake (150-250mmol). This is more than twice the amount associated with lower rates of hypertension experimentally, and 10 times more than is required daily. Salt restriction and weight loss should always be the first steps in hypertension management. Halving sodium intake to 80-100 mmol/day has an effect similar to that of routine antihypertensive drugs (5-10mmHg) in hypertensive patients, but without the side-effects. This reduction would lower blood pressure by 25mmHg immediately for normotensive people, and would prevent a l0mmHg rise 30 years later. A weight loss of 5-10 kg will also reduce blood pressure by 3-5mmHg. Greater effects are seen during acute energy restriction, but blood pressure tends to return to pre-weight loss figures over a period of years.
Atheroma International comparisons of mortality rates from coronary heart disease (CHD) show that these are highest in populations with the highest saturated fat intakes. This is true even when the effects of obesity, hypertension, cigarette smoking, diabetes, stress and family history are allowed for. The dietary factors leading to coronary heart disease are shown in Figure 5.9. The major lipid risk factors for the development of atheroma are high levels of plasma cholesterol and lowdensity lipoproteins (LDL), and low HDL. The pattern of high triglycerides, small dense LDL and low HDL is particularly atherogenic, and is associated with insulin resistance and non-insulin dependent diabetes in the 'metabolic syndrome', characterized by a high waist circumference
Environmental factor
Metabolite or process affected
Pathophysiological change
Pathology
Disease
FIG. 5.9 Factors leading to coronary heart disease
and intra-abdominal fat accumulation. Consumption of saturated fatty acids is particularly likely to increase both LDL and cholesterol. Diets low in saturated fatty acids lower these levels. Saturated fats are prominent in butter, lard, sausages, meat pies, pastries and chocolates, whereas unsaturated fats predominate in oils or margarines prepared from olives, rape seed, maize, sunflower or soya. Not all margarines are unsaturated - those that contain coconut oil (used in many hospital canteens in the UK), for example, are highly saturated. Synthetically hydrogenated fats
contain high amounts of trans isomer fatty acids, which behave like saturated fats. Plasma cholesterol mainly indicates the production of cholesterol by the liver. Cholesterol-containing foods (such as eggs) do not necessarily increase the synthesis of cholesterol in the liver. Cholesterol absorption can be reduced 10% by plant sterols (sitosterol and sterol esters) used in non-functional foods. Dietary antioxidants (e.g. vitamins A, C, E, flavonoids in fruits and vegetables) reduce atheroma by protecting LDL from oxidation. Fibrinogen is elevated in the overweight, as are coagu-
137
lation factor VII and plasminogen activator inhibitor (PAI-1). These are all predictors of thrombosis, and other dietary factors also have an influence (e.g. dietary fat on factor VII). Certain n-3 polyunsaturated fats - such as eicosapentanoic acid, present in cod liver oil, mackerel and pilchards - tend to inhibit thrombosis and should be particularly encouraged. People who eat a lot of fish have less heart disease. Major dietary changes in the population of Finland between 1970 and 1990, increasing fruit and vegetables and fish, and reducing sodium and saturated fat, together with reduced smoking, have been accompanied by 60-70% reductions in CHD. Intentional weight reduction in overweight or obese subjects, particularly in diabetic patients, is followed by a reduced risk of mortality from CHD and an increased life expectancy.
Diabetes Insulin-dependent diabetes is not principally linked to diet in its aetiology, although prolonged breastfeeding seems to be protective. The major need in management is to provide regular meals and snacks, every 2 hours or so, to match the profile of insulin action and to avoid hypoglycaemia. Alcohol impairs glucose release from the liver and thus potentiates any risk of hypoglycaemia. Non-insulin dependent diabetes (type II) is closely linked to diet. In nearly every society, those who are overweight and whose diet is high in fat and low in soluble dietary fibre have a significantly increased risk of diabetes. The greatest risk is in those who were born small for dates and show poor growth in the first year of life. They seem specially prone to weight gain and diabetes. The major hazard in non-insulin dependent diabetes is premature heart disease and stroke. Weight loss improves the prognosis for the overweight, and physical activity probably plays a major part. For all patients with diabetes, the need to follow a low saturated fat diet, with a high fruit and vegetable intake, is even more pressing than for people without diabetes. Sugar avoidance is no longer considered necessary, but general recommendations for a healthy diet apply (Table 5.26). There is sufficient circumstantial evidence to urge high intakes of antioxidant-rich fruits and vegetables to protect against microvascular disease. There is no benefit from the use of so-called 'diabetic' foods, which exploit a vulnerable group.
The metabolic syndrome
138
The 'metabolic syndrome' describes a clinical context which predisposes to premature CHD and stroke by a variety of coexisting abnormalities, including hypertension, dyslipidaemia (low HDL, high triglycerides, high small dense LDL), type 2 diabetes and hypercoagulability. The clinical syndrome is characterized by a predominantly central fat accumulation (intra-abdominally) even in those
TABLE 5.26 Summary of nutritional recommendations for people with diabetes compared with current average UK diet Approximate content of usual UK diet
Recommendations for diabetes
Energy
maintains BMI 25 kg/m2
to approach BMI 22 kg/m2
Carbohydrate (% energy) Added sucrose or fructose (g/day) Dietary fibre (g/day) Total fat (% energy) Saturated fatty acids Monounsaturated fatty acids Polyunsaturated fatty acids Protein (% energy) Salt (g/day) normotensive hypertensive So-called 'diabetic' foods
45 50-100
50-55* <25
19-25 40
>30g 30-35* <10 10-15 <10 10-15
17 11
6 12-15
10 -
None
<6 <3 None (avoid)
* Lower amounts of energy from carbohydrates and up to 35% from fat may be acceptable provided that most of the fat derives from monounsaturated fatty acids such as olive oil in 'Mediterranean-style' diets.
who are thin - with a high waist circumference. The unifying biochemical feature is probably early insulin resistance, at least in tissues other than the intra-abdominal fat mass, and there seem to be a reduced activity of PPAR (peroxisome proliferator-activated receptor-y) enzymes. The metabolic syndrome is at least partly genetic, but is precipitated by weight gain and physical inactivity, by smoking and by high alcohol consumption. Another key element is related to poor fetal and infant growth (low birthweight and size at 1 year of age). This may relate to under- or imbalanced nutrition at critical stages of fetal organ development the 'Fetal programming' hypothesis.
Cancers It is estimated that malnutrition and cachexia play a part in 70-80% of all cancer deaths, and diet contributes to 35% of all cancer development. Obesity is associated with the development of colonic cancer and also the sex hormonerelated cancers (breast, endometrium and prostate). The WHO produced a summary of dietary influences on different cancers, revealing a rather consistent pattern among major cancers of associations with dietary fat and alcohol, and with protection from fruits and vegetables. There is some suggestion that high intakes of meat perhaps burned meat containing cyclic hydrocarbons may be hazardous. It is not certain which factors in fruits
and vegetables are protective, but antioxidants probably play a part. It is possible that vitamin E supplementation may help reduce cancers. On the other hand, studies with P-carotene supplementation have actually shown increases in lung cancer in smokers, especially if they are also heavy drinkers. Vitamin tablets should therefore not be taken, or prescribed, in doses far exceeding healthy dietary intakes. It is better to promote fruits and vegetables, which also contain other bioactive compounds, such as carotenoids and flavonoids, that probably also help to protect against cancer when consumed throughout life. Advice for cancer prevention is thus essentially the same as for reduction in heart disease.
Gallstones The deposition of cholesterol to form gallstones depends on the relative concentrations of total bile salts, lecithin and cholesterol. The fine balance between these is affected by obesity and low dietary fibre intake, but the precise mechanisms of the imbalance or of the formation of gallstones are not clear. Rapid weight loss may precipitate biliary colic.
Liver disease The most important association between dietary factors and liver disease is that between alcohol and cirrhosis. However, mycotoxins may also affect the liver: aflatoxins, which are widely prevalent in cereals kept under poor storage conditions, may be a factor in causing primary liver cell cancer and may also contribute to the development of the fatty liver in kwashiorkor. Malnutrition in children does not account for the high prevalence of cirrhosis in developing countries: hepatitis B infection seems to be the major cause.
Pancreatic disease Chronic pancreatitis is frequently found in populations where malnutrition is rife. Periods of undernutrition may cause stasis of the exocrine juices within the pancreas, leading to acinar cell destruction and loss of digestive function. Pancreatic calcification often follows, with secondary diabetes. However, in western societies alcohol excess seems more important than undernutrition as a cause of chronic calcific pancreatitis.
Respiratory disease Being overweight, and particularly having a central (intraabdominal) predominance of fat, causes breathlessness, and also aggravates symptoms in patients with COPD. Sleep apnoea and hypoxia is a potentially serious consequence, with snoring as an early symptom. Weight loss is very effective. A proportion of patients with COPD and chest bellows disease become severely cachectic. The chest problem is
aggravated by wasting of the respiratory muscles, and by malnutrition-related immunosuppression. The main cause is suppression of appetite by recurrent infection exacerbations. Hypermetabolism is a lesser factor. Weight gain is extremely hard to achieve by dietetic means, but can improve respiratory function: appetite is poor, and the effort of feeding worsens hypoxia. Starvation ultimately leads to death by pneumonia in most cases, and it has been suggested that malnutrition may contribute to the development of emphysema.
5
Renal disease Patients with renal failure accumulate potassium, phosphate and nitrogenous products from protein catabolism. Traditional conservative management included a diet restricted in protein potassium (limited meat, dairy products, fruit and vegetables). Former advice to avoid fruit and vegetables is now tempered by anxieties about reduced antioxidant status, as the main cause of death is cardiac disease. A daily limit of three items of fruit and two portions of vegetables (or vice versa) is acceptable for most patients. Most patients with advanced renal diet have poor appetites and tend to undereat. The dietetic emphasis should probably be on increasing starchy carbohydrates, rather than on restricting foods. During dialysis, small molecules including vitamin C are removed, and supplements should be given afterwards. Nephrotic syndrome and proteinuric diabetic neuropathy are aggravated by high protein intakes. Restriction to about 0.8-1 g/kg/day (10% energy) is appropriate and will still allow nitrogen balance. This amount is much less than usual in UK diets.
Dental caries Fluoride is an essential nutrient, required to form healthy dental enamel. Much of the UK, particularly Scotland, has a fluoride-deficient water supply (below Ippm). Dental caries occurs when Streptococcus viridens adheres to teeth with fluoride-deficient enamel and metabolizes sugar into lactic acid. This lowers the pH acutely and erodes the enamel. Low-pH foods can be similarly damaging. All sugars can act as substrate; thus 'natural' sugars such as fructose are just as cariogenic as sucrose. The most important factor is the length of time that sugar-containing foods remain in contact with the teeth; adhesive foods and sugary drinks given in bottles to infants are particularly damaging. The low pH of many fruit drinks and colas leads to rapid enamel loss. There has been a marked decrease in dental caries among children in certain social groups in the UK over the last 20 years, but increased social division within the population reveals very high rates in deprived areas and groups. The fall in caries has been associated with an increase in the use of fluoride (in toothpaste, in drinking water or as tablets), and possibly also an increased prevalence of teeth cleaning. Perhaps paradoxically, sugar con-
139
sumption has increased over this period, although very recently low-sugar products have become more prevalent.
TABLE 5.27 Foods associated with food Intolerance* Food
% of cases
Urinary calculi
Milk
Calcium or oxalate stones are sometimes precipitated in the urinary tract as a result of increased dietary intake. Oxalate stones are those most frequently associated with dietary factors, occurring most commonly in populations with high phosphate intakes. In Thailand, for example, oxalate calculi occur most commonly in the rural populations, where the high phosphate intakes, associated with a predominantly vegetarian diet, contrast with the lower phosphate intakes of the better-off urban families. Oxalate stones may also be precipitated by dehydration in extremely hot climates, and by excessive vitamin C consumption. 1
Egg
25 22
Nuts/peanuts Fish/shellfish Wheat/flour Chocolate Artificial colours Pork/bacon Chicken Tomato Soft fruit Cheese (but not milk)
12 12
6 5 3 3 3 3 3 3
*From. Truswell AS 1986 ABC of nutrition
FOOD SENSITIVITY AND INTOLERANCE
The clinical importance of food allergy is difficult to assess as little is known of the scientific basis for hypersensitivity to food, there have been few controlled clinical trials of exclusion diets, and the mechanisms by which they work are not understood. A variety of foods have been implicated in food intolerance (Table 5.27). There has been considerable public interest in peanut allergy. Reports of food allergy can lead to needless anxiety. Parental concern can lead to poorly designed exclusion diets and nutrient deficiencies. The great majority of self-diagnosed food allergies or food intolerances turn out to be erroneous when professionally assessed. However, dramatic, even life-threatening allergies do occur. The major clinical symptoms associated with food sensitivity are shown in Table 5.28. A number of food allergies are associated with immunological reactions - usually an IgE response. A radioallergosorbent test (RAST) may detect antibodies in plasma against a specific food protein, but there is little correlation between the clinical features and the results of a variety of RAST tests. Skin tests of purified antigens may detect an urticarial response within a few minutes of intradermal inoculation, but positive skin tests do not correlate well with sensitivity reactions in other organs, such as the lungs and the gastrointestinal tract. In short, there is as yet no defined mechanism in most cases of food sensitivity, and very few laboratory tests are of any use. Management therefore depends on careful history-taking and a critical approach to elimination diets.
1
140
MCQ 5.5
TABLE 5.28 Symptoms in 100 patients with food intolerance* Symptom
Number of patients affected
Asthma Gastrointestinal Eczema Urticaria Rhinorrhoea Angioedema
58 41 37 35 31 8
* From: Truswell AS 1986 ABC of nutrition
Eczema Exacerbations of eczema are frequently associated with reactions against eggs and milk. Infantile eczema is sometimes improved by withdrawing eggs and cows' milk products; families with a strong history of eczema are advised to breastfeed as long as possible and to delay the introduction of eggs and cows' milk. Dietary manipulation in older children and adults is also worth trying but is often disappointing, and must be supervised to ensure nutritional adequacy.
Gastrointestinal symptoms The best-defined gastrointestinal hypersensitivity syndrome is to gluten in coeliac disease (see Ch. 15). Onset is sometimes precipitated by a gut infection, especially in children. Transient gluten intolerance following mucosal damage from giardiasis or rotavirus infections may occur in other patients. Secondary lactose intolerance may occur
in untreated coeliac disease through mucosal atrophy and loss of lactase. A more frequent problem is cows' milk protein intolerance. Here, mucosal damage permits access to mucosal lymphocytes, which become sensitized to the dietary protein. Subsequent exposure then produces a severe response in which lymphokines are released, damaging enterocytes. Villous atrophy occurs and malabsorption develops. There is also some evidence of exacerbation of the symptoms of ulcerative colitis by cows' milk; it is sometimes suggested (though reliable evidence is lacking) that infantile colic is caused by dietary factors transmitted in breast milk or contained in cows' milk. Early exposure to cows' milk in infancy has been related to gastrointestinal blood loss and anaemia, but the mechanism is obscure. The principal carbohydrate in milk is lactose. The expression of lactase in intestinal mucosa varies widely in adults, and in some races (particularly eastern) it is virtally absent, leading to lactose intolerance. Fermented milk products are preferred and are less liable to be malabsorbed. The very rare genetic fructose intolerance syndrome is usually identified by patients who develop symptoms after sweet foods.
Management of suspected food sensitivity If the patient suffers a reaction each time exposure to the allergen occurs, the latter should be easily identifiable. However, in the case of the general systemic symptoms described above, identification of the allergen is more difficult. There are two approaches:
5
• Exclude a suspected allergen for at least 4 weeks and then reintroduce it (this is mostly satisfactory where the condition is mild); or • Work out an elimination diet (one based on lamb, rice and pears is a classic starting point) as advised by a dietitian which ensures full nutritional adequacy. Then reintroduce a potential allergen every 2 weeks and observe the response. It is important to monitor body weight regularly and be alert to the possibility of an underlying eating disorder. Multiple food 'allergies' are less likely to have organic origins, and multiple exclusion diets can be dangerous. Restricting food choices for growing children is particularly hazardous, and needs careful supervision and counselling.
Migraine Migraines sometimes appear to be precipitated by foods such as chocolate, cheese, red wine, nitrates, cows' milk and wheat. Some of these contain amines or stimulate histamine release, which may produce an effect on cranial arteries.
NUTRITION IN HEALTH PROMOTION: CURRENT DIET AND PROPOSALS FOR CHANGE Health promotion
Respiratory tract responses Respiratory tract responses - including excessive production of tears, nasal secretions, sneezing and asthma are usually related to environmental factors, e.g. chemical sprays, cosmetics and food or plant pollens, but eggs, cows' milk and chocolate may also precipitate symptoms. Recent studies suggest that a variety of food preservatives, including tartrazine and sulphur dioxide, may also be responsible.
Urticaria and angioedema Most cases of urticaria or angio-oedema do not have dietary orgins. Acute or chronic urticaria may occur in response to eggs, nuts, fish (particularly shellfish) and cows' milk, as well as certain fruits, wine and cheese. Angioedema is a feared and potentially lethal complication.
Neurological and behavioural symptoms A range of syndromes of 'hyperactivity' in children and tiredness in adults are commonly attributed to intolerance, especially to tartrazine. Although some cases may occur, social factors are probably more important.
The promotion of good health (physical, psychological and social) incorporates an increasing emphasis on disease prevention through dietary change. Many of the major disabling illnesses and causes of premature mortality in western societies - heart disease, stroke, cancer - are progressive, not amenable to cure by drug therapy, and to a substantial extent preventable through dietary change. Two approaches are possible: • High-risk screening strategy. This approach requires a screening procedure to identify individuals at high risk, who then receive specific dietary advice and professional follow-up. The screening procedure must have very high sensitivity and must be able to reach high-risk groups, such as those in deprived areas and communities. It is dependent on high levels of professional input and therefore expensive. Such a programme must be sustained indefinitely, as there will always be new individuals entering the high-risk categories. Although this type of approach has been heavily promoted for cholesterol lowering, the principles outlined above cannot in fact be met. In particular, the sheer numbers who would require to be screened and followed up would make the system impractical (almost half the UK population has undesirably high blood lipids), and
141
the low sensitivity and specificity of cholesterol screening means that among those with low serum cholesterol the commonest cause of death is still ischaemic heart disease. The high-risk strategy approach is therefore more suited to less frequent conditions that require specific advice, such as phenylketonuria identified by a Guthrie test at birth, or the identification of women who have had a child with neural tube defect, who need high-risk folate supplementation (4mg daily) in the periconceptional period to prevent a recurrence. • Population-directed strategy. This approach does not involve screening but requires, by a combination of health education and modification of food supply, a change in the nutrient consumption of the whole population or of targeted subgroups. Examples include the abolition of marketing of high-sugar bedtime drinks for infants, as a way of reducing dental caries, and the healthy eating food and health policies designed to reduce major diseases such as ischaemic heart disease, diabetes, cancers and osteoporosis, which have been urged by many governments and umbrella organizations such as WHO. Population-directed programmes do not demand major health service inputs, although high-risk strategies may operate alongside for special groups. Because the diet of the whole population will be modified, it is essential that the changes promoted should be advantageous or safe for everybody. Given the very limited resources of health promotion agencies, effective population-directed nutritional policies must include cooperation from the food production and supply industries.
142
The average dietary intakes in western countries, including the UK, have changed substantially over the last 50 years, with greatly increased intakes of foods of animal origin, and declining intakes of fruits and vegetables and starch-rich staple foods (cereals, potatoes). There is now little scientific argument in opposition to health-directed measures aimed at reducing intakes of total fat (particularly saturated fat), reducing sodium and some increase in potassium and calcium consumption, while promoting increased consumption of fruits and vegetables and, to some extent, unsaturated fats, particularly those from oilrich fish. Although the benefits to any individual from dietary change are relatively small, the burden of disease to whole populations would be reduced substantially, particularly through reductions in heart disease, stroke and diabetes, and in the prevention of obesity and osteoporosis. A comprehensive package of quantitative proposals for dietary change have been made for Scotland, a country which has a very high burden of preventable disease (Table 5.29). To some extent .this has been influenced by the observational evidence from countries such as Norway and Finland, where long-term programmes of dietary change have resulted in major reductions in heart disease, stroke and cancer. It is important to recognize that nutrient tar-
TABLE 5.29 Intermediate nutrient and dietary targets for Scotland for the year 2005 Dietary component Vegetables and fruit excluding potatoes (g/d) Carbohydrates: total % E Starch (% E) Non-starch polysaccharides (g/d) Extrinsic non-milk sugars (% E) Fatty acids (% E): Cis-monounsaturated Cis-polyunsaturated (Total) n-6 n-3 Saturated Trans Total fat (% E) Sodium consumption (mmol/d) Potassium consumption (mmol/d) Alcohol consumption* (g/d) Men Women Dietary cholesterol (mg/d)
1989-91 intake
Targets
181
>400
25.3
>40
10.5 16.3
>16 <10
12.6 6.3 5.2
<10
0.8 16.6
13 <8.8 >1.2
2.1
<11 <2
40.7
<35
163
70
62
80
34.5 11.1*
<24*
-
-
<16*
f
Current intakes relate to estimates derived from a variety of sources. % E signifies the proportion of the nutrient as a percentage of total food energy, i.e. excluding alcohol. Changes in vitamin intakes are those expected from the dietary changes; women of child-bearing age have been recommended to supplement their diet with 400 ug folic acid, * Alcohol is specified for consumers only, intakes from Adult Survey, maximum intakes proposed by Royal College of Physicians (1987).
gets can only be met if there are changes in food choices, and that these must be matched by changes in food supply. Successful intervention programmes thus require multidepartment government action over a long period. For some of the nutritional consequences of dietary change, the benefits would be seen principally in those who are currently consuming very poor diets; however, it is likely that there would be some improvement even for groups with better diets at present. Extensive studies have shown no appreciable health disadvantage in the changes proposed. In particular, the effects of cholesterol lowering, which were disputed for many years, have now been shown clearly not to be harmful. The benefits from sodium restriction had been difficult to quantify because of the variety of research addressing different groups with different levels of blood pressure and different levels of sodium intake. Large meta-analyses have clarified that a major reduction in sodium intake should be made. This would partially benefit those who already have relatively high blood pressure and would be likely to reduce the development of hypertension in younger people.
RECENT ADVANCES IN HUMAN NUTRITION Recent years have seen an important expansion of research in human nutrition, stimulated by recognition that the major sources of illness and premature mortality in the world, and specifically in highly developed Western countries, will not be amenable to cure by drug therapy. If these problems (cancers, heart disease, stroke, diabetes, osteoporosis) are to be alleviated, the answer must lie in prevention, and diet plays a major role. These are the themes that underlie the application of modern nutritional science to medicine. Most diseases develop as a result of interaction between genetic factors peculiar to the individual, and environmental exposure or conditions. Thus within human nutrition the concept of 'gene-nutrient interactions' has emerged. It is very difficult for people to change their diets, and satisfy targets to maintain good health. The science of food choice, which relates closely to food science in the context of functional foods, designer foods and therapeutic foods or diets, has become of major importance. Dietary and nutritional influences operate over a very long timespan in modifying health and disease. Longterm observational follow-up studies from cohorts of relatively young people, are already demonstrating new dietary influences on health in periodic followup surveys. A number of recent advances in human nutrition can be identified as arising from these new understandings: • Importance of fetal nutrition and development for later health: poor fetal growth predicts diabetes, hypertension, heart disease, stroke. • Folic acid supplementation in the perioconceptional period overcomes metabolic abnormalities that prevent neural tube development. • Dietary folate reduces serum homocysteine, a risk factor for CHD. • Antioxidants - vitamins C, E, carotenoids and phenolics - have the potential to be involved at several stages against development of cancers (free radical DNA damage) and coronary heart disease (protection against LDL oxidation). • Vitamin supplements given unphysiologically as tablets may have different effects from giving foods which contain these vitamins. Foods contain many other related bioactive compounds such as flavonoids, carotenoids, etc. This balance is likely to be important for health. • Specific fatty acids have different effects on plasma lipo-proteins and coronary heart disease risk. For example stearic acid, although saturated, does not elevate cholesterol. Trans-fatty acids, found mainly in synthetically hydrogenated fats such as margarine and in baked foods, elevate LDL cholesterol and are linked to heart disease prevention in the same way
as saturated fatty acids. Individuals with different apolipoprotein E subtypes respond differently to dietary fatty acids. • The human placenta can probably transfer fatty acids to the fetus and there may be specific fatty acid transfer proteins. • Immune function appears to be determined to some extent by the balance of fatty acids in the diet. New non-absorbable drugs (e.g. orlistat) or novel food products (e.g. sitosterols and sterol esters) modify fat absorption and consequent health. • The two-way interaction between nutritional status and disease may lead to 'conditioned essentiality' for specific nutrients during illness, e.g. for amino acids such as glycine or glutamine, which are not essential during health.
Some of the dietary changes required to improve health demand action principally from individuals, to select more appropriate foods and to cook and prepare them in more healthy ways. Thus an increased consumer demand for fruits and vegetables and for lower saturated fat food can be encouraged to help health promotion, and is likely to be met by increased provision from the food industry. To reach other nutrient targets, however, there will need to be greater emphasis on programmes of change within the food manufacturing and catering industries: for example, about 80% of sodium intake derives from foods that have had salt added during manufacture or processing. A programme of stepped small reductions in the salt content of common foods is likely to be acceptable and beneficial to consumers. The composition of many foods could be modified with health benefits and without impairing palatability or commercial success. Examples of effective national nutritional policies are available from countries such as Norway and Finland, where substantial changes in average diet composition over a period of 10-20 years have been accompanied by major reductions of the order of 60-70% in ischaemic heart disease and cancers before the age of 65. There are far greater effects that could be achieved by lipid lowering or other drug interventions. The three dietary components with the greatest impact are reduced saturated fat as a proportion of energy, reduced sodium consumption, and substantially increased fruit and vegetable consumption. The success of these programmes has depended on the activities of committed health professionals prepared to take on public positions and to interact with national and local governments and with the food supply industries. Responsible and well-educated media involvement, which does not seek to promote mavericks and sensationalists, has been influential. High levels of general education and minimization of social deprivation are critical for the effectiveness of health promotion.
a
143
FURTHER READING Department of Health. Nutrition: A core curriculum for nutrition in the education of health professionals. London: HMSO, 1994. Department of Health. Nutritional aspects of the development of cancer. Report of the Working Group on Diet and Cancer of the Committee on Medical Aspects of Food and Nutrition Policy. Report on Health and Social Subjects No. 48. London: HMSO, 1998. Dietary reference values for food energy and nutrients for the United Kingdom. Report on Health and Social Subjects, 41 1991. Department of Health COMA. London: HMSO, 1991. Garrow J S Obesity and related disorders. Edinburgh: Churchill Livingstone, 1988. Holland B, Welch A. McCance and Widdowson's compositions of foods, 5th edn. Cambridge: Royal Society of Chemistry. 1991: See also supplements dated after 1991. James W P T, Garrow J S Human nutrition and dietetics, 10th edn. Edinburgh: Churchill Livingstone, 2000.
144
Mann J, Truswell A S. Essentials of human nutrition. Oxford: Oxford University Press, 1998. Manual of dietetic practice, 2nd edn, Oxford: Blackwell Science, 1994. National Institutes of Health (NIH) obesity guidelines. Available online at http://www.nhlbi.nih.gov/guidelines/obesity/ob_home.htm The Scottish Office Home & Health Department. The Scottish diet: Scotland's health - a challenge to us all. Report of a Working Party to the Chief Medical Officer for Scotland, 1994. Scottish Office Department of Health. Scotland's Health - A challenge to us all. Eating for health - a diet action plan for Scotland, 1996. Truswell A S ABC of nutrition, 2nd edn. London: British Medical Association, 1992. WHO Diet, nutrition and the prevention of chronic diseases. Technical Report Series 797. Geneva: World Health Organization, 1990.
6
Cancer Medicine Robert L Souhami
Incidence and epidemiology 145 Aetiology 146 Tumour growth and development 149 Pathology 151 Clinical features 151 Staging and investigation 155
Supportive care in cancer management 165 New approaches to management 167 Trials of treatment 167 Care of the dying 168 Alternative therapy 168
Principles of cancer management 157
Each year in the UK there are approximately 220000 new cases of cancer. Almost one-third of the population will develop cancer during their lifetime, and of these 70% will die of the disease - 150000 deaths a year. As a cause of mortality, cancer is second only to cardiovascular disease. It is most common in the elderly: the age-specific incidence rates for men and women are shown in Figure 6.1. The frequency of cancer and the increasing complexity of management mean that every clinician must have a firm grasp of the principles of diagnosis, investigation and management. In recent years, the approach has been changing rapidly as a consequence of fundamental advances in cancer biology, the isolation of genes responsible for hereditary disposition to cancer, increasing accuracy in diagnosis and staging, and major developments in the use of radiotherapy and chemotherapy. At the same time, clinicians have developed a better awareness of the problems faced by patients who are incurable, and professional attitudes have changed in the direction of more open discussion with patients. Cancer medicine therefore demands a combination of a high degree of technical competence and a sympathetic insight into the feelings of the patients. It is this double challenge that makes it a most rewarding part of medical practice.
INCIDENCE AND EPIDEMIOLOGY Incidence means the proportion of a defined population developing a disease in a stated period of time; prevalence
is the proportion which has the condition at a single point in time. Crude incidence or prevalence rates refer to a whole population and specific rates to selected groups, for example those defined by age or sex. The age-specific incidence rates of some cancers are shown in Figures 6.2 to 6.4. It can be seen that adenocarcinomas in women have quite different age-specific incidence rates. Cancer of the breast increases rapidly in incidence before the menopause, and at a slightly slower rate thereafter (Fig. 6.2). Uterine and ovarian cancer also show an increasing incidence premenopausally, but the rate does not rise in later life. Gut cancers (Fig. 6.3), on the other hand, show no relation to the menopause but rise rapidly in incidence in old age in both sexes. The biphasic age-specific incidence of Hodgkin's disease (Fig. 6.4) contrasts markedly with the findings in adenocarcinoma. Lung cancer is at present more common in men, but the incidence in women is rising rapidly, approaching that of breast cancer. Cancer is the second main cause of death in childhood, with acute lymphoblastic leukaemia accounting for nearly half the deaths. The commonest sites of cancer in the west are the lung, skin, large bowel, prostate, stomach and rectum in men; and the breast, large bowel, skin and lung in women. The mortality rates are, however, different from incidence rates (Fig. 6.5), with skin cancer having a low mortality rate and lung cancer a very bad prognosis. However, the relative incidence of cancers is changing with time. For example, the incidence of lung cancer has been rising rapidly since the mid-1960s, especially in women, whereas that of stomach cancer has been falling for both men and women (Fig. 6.6). The rise in incidence of lung cancer is undoubtedly due to smoking, but the reason for the decline in stomach cancer is not clear. Cancer incidence varies in different countries (Table 6.1), and this variation may provide insights into aetiology. Carcinoma of the oesophagus has a high incidence in an area extending from the Caspian Sea to Central Asia and the Far East; it is also more common in the Transkei. In these areas it has an incidence 200 times that found in the UK. In Japan, gastric carcinoma is 30 times more common than it is in the UK, but pancreatic cancer is much rarer. The reasons for these variations are as yet unknown, but dietary and nutritional factors are suspected to play a part. The migration of populations has helped to determine how much of the geographical variation is genetic and how much is environmental. When Japanese people settle in the USA, the incidence of cancers in their offspring resembles that of the adopted country: the high incidence of gastric cancer falls, and the lower incidence of cancers of the breast, colon, ovary and prostate rises. These findings suggest that environmental, rather than genetic, causes account for most of the observed differences between countries.
6
145
FIG. 6.3 Age-specific incidence of adenocarcinoma of the colon FIG. 6.1 Age-specific incidence of cancer (England)
FIG. 6.4 Age-specific incidence of Hodgkin's disease
FIG. 6.2 Age-specific incidence of carcinomas of the breast, ovary and uterus Note change in rate of increase at the time of the menopause.
AETIOLOGY Evidence suggesting aetiological factors in cancer has come from epidemiological and laboratory investigation. 1 It is probable that, for many types of neoplasm, an inter-
1
146
MCQ 6.1
FIG. 6.5 Incidence and mortality of common cancers in men and women in England and Wales Note that whereas skin cancer is common, its mortality is low. Cancer of the lung is common and accounts for a large number of total cancer deaths.
6
FIG. 6.6 Cancer of the lung and stomach A Cancer of the lung: age-standardized death rate/10000 in age group 65-74,1905-85 in the UK. B Cancer of the lung: mortality 1941-91 for different age groups. C Cancer of the stomach: change in mortality in England and Wales and in Japan, 1940-1990.
TABLE 6.1 Geographical Incidence of cancer Cancer
High incidence
Low incidence
Ratio (high Mow)
Oesophagus
Iran, Transkei, Kazakhstan Australia Mozambique Far East (China) UK Japan Europe, USA
Holland
200:1
India UK Europe Nigeria UK Japan
200:1 100:1
Skin Liver Nasopharynx Lung Stomach Breast
100:1 35:1 30:1 6:1
action of genetic and environmental factors is responsible for the development of a cancer (Fig. 6.7).
CHEMICAL CARCINOGENS
The frequency of scrotal carcinoma in chimney sweeps was noted by Sir Percivall Pott in 1775, and the high incidence of bladder cancer in dye workers in 1895. The mechanisms
of action of chemical carcinogens have been intensively studied. There are several classes of experimental carcinogens (Table 6.2) which are possible causes in humans: • Polycyclic hydrocarbons are formed from combustion of organic compounds. They are present in cigarette smoke, soot, car exhaust fumes and some foods. Dibenzanthracene was one of the first to be shown to be carcinogenic. The carcinogenic effect results from reaction with bases in DNA. • Aromatic amines and azo dyes, such as B-naphthylamine and benzidine, are metabolized to an active form. (3Naphthylamine is glucuronated in the liver. Glucuronidases in the urine liberate the carcinogen in the bladder. • Nitrosamines are formed when nitrites in food are converted to nitrates, which react with amines in food. The substances can cause stomach cancer experimentally. • Alkylating agents, such as those used in cancer management, bind to DNA. Use of these drugs in cancer treatment has been associated with the development of secondary malignancies, the most important of which is secondary leukaemia, which may also be caused by treatment with etoposide, a widely used anticancer agent.
147
FIG. 6.7 The sequence of genetic events contributing to invasive cancer
TABLE 6.2 Chemical carcinogens Class
Example
Source
Polycyclic hydrocarbons Aromatic amines Azo dyes Nitrosamines Toxins Alkylating agents Chromates Asbestos
Dibenzanthracene
Smoke, cigarettes
p-Naphthylamine Dimethylaminobenzene Dimethylnitrosamine Aflatoxin Melphalan
Aniline dyes Butter yellow ?Food Aspergillus flaws Drug treatment of cancer Industrial exposure Insulation and heating installations
• Organic toxins include the best-studied example, aflatoxin, produced by the mould Aspergillus flavus growing on grain. This substance has been suggested as an aetiological agent in liver cancer in Africa. • The most important occupational carcinogen is asbestos, which causes cancer of the pleura, lung and peritoneum in workers exposed to the dust. When carcinogens act on a cell they may cause a permanent change which predisposes to cancer, a process known as initiation. Other agents can then produce transient changes which with continued exposure lead to cancer; this is known as tumour promotion. This multistage process has been shown in some experimental cancers, where mutagens act as initiators and hormones or dietary constituents act as promoters. The more prolonged the exposure to a carcinogen, the more likely the tumour is to develop. Several genetic events in sequence are necessary for the tumour to develop.
IRRADIATION
148
The carcinogenic effect of ionizing irradiation was indicated by the skin cancers that developed on the hands
of early radiologists, and by the increased frequency of acute and chronic leukaemia, breast and thyroid cancer in Hiroshima during the 30 years after the atom bomb was dropped. The mechanism of carcinogenesis is probably related to the chromosomal damage caused by X-rays. It seems likely that 'background' ionizing irradiation does not contribute greatly to common cancers in humans. Therapeutic irradiation may give rise to bone and soft tissue sarcoma (after a latent period of 10 years), and possibly to lung cancer. Ultraviolet light probably plays a role in the development of skin cancers. This is seen most clearly in the autosomal recessive disorder xeroderma pigmentosum, where a defective DNA repair mechanism is associated with the early development of skin cancers on skin exposed to sunlight. Malignant melanoma and other skin cancers are uncommon in black people but are particularly frequent in fair-skinned Celts. In Australia, skin cancers are common among the non-indigenous population and increase in incidence in the north nearer the Equator.
VIRUSES Ribonucleic acid (RNA) viruses can cause a variety of cancers in animals. These viruses contain a gene which codes for the enzyme reverse transcriptase, which is produced in the infected cell and results in the cellular synthesis of DNA complementary to the viral RNA and thus to the production of more viruses. For this reason they are called retroviruses. Tumours caused by these viruses include avian erythroblastosis, rat sarcoma, feline leukaemia and murine leukaemia. The insertion of the viral genome into DNA leads to malignant transformation. A growth-factor receptor is encoded by the erythroblastosisB virus (v-erb B), and a phosphokinase by Rous' sarcoma virus (sis). RNA viruses are involved in the development of some forms of T-cell leukaemia and lymphoma (human T-cell leukaemia virus, HTLV types 1 and 2). The human immunodeficiency virus (HIV) is the cause of the acquired
immune deficiency syndrome (AIDS), in which there is a greatly increased frequency of skin sarcoma and B-cell lymphoma. These tumours are probably not caused by the virus but are a consequence of oncogenesis in patients with greatly reduced immunity. Hepatitis C is an RNA virus which is implicated in the high incidence of hepatoma in chronically infected patients. Research into RNA viruses led to the discovery that the viral oncogenes had homologues in normal cellular DNA. These cellular proto-oncogenes appear to code for products very similar to those produced by the equivalent virus. These findings have led to the search for increased expression of cellular oncogenes in human cancers, for the gene products, and for the link between carcinogenesis and oncogene activation. There is strong circumstantial evidence implicating DNA viruses in the pathogenesis of some malignant neoplasms. For example, Epstein-Barr virus (EBV) causes proliferation of normal human B lymphocytes; EBV-coded proteins are found in Burkitt's lymphoma cell lines; and African children with the lymphoma have high titres of antibody to viral antigens. Worldwide, hepatoma is one of the commonest cancers. Infection with hepatitis B virus (HBV) is associated with its development both in Africa and in Europe. Hepatoma is particularly likely to occur in chronic active hepatitis associated with HBV and hepatitis C, and in alcoholic cirrhosis where there is evidence of previous HBV infection. Cancer of the uterine cervix is increasing in frequency in young women. There is strong evidence that human papillomavirus is associated with this disease, possibly as a result of sexually transmitted infection.
GENETIC FACTORS Numerous inherited genetic abnormalities predispose to the development of malignancy (Table 6.3). These syndromes include examples of autosomal dominant and recessive inheritance, and X-linked disorders. Inherited chromosomal abnormalities may also predispose to cancer (Table 6.3). The most common is Down's syndrome (trisomy 21), where there is an increased incidence of acute leukaemia. In some cases the relationship between the genetic abnormality and the induction of cancer has become clearer. In hereditary retinoblastoma the retinoblastoma gene (Rb) acts as a growth suppressor gene. Inherited loss of this gene is followed by mutation in the other allele, which sets the scene for malignant transformation. Germline mutation, followed by loss of heterozygosity of the p53 gene, occurs in the Li-Fraumeni syndrome, in which the families of children with sarcoma show an excess of other cancers. It has become apparent that there may be an important inherited genetic component to many other common cancers. Very recently, two genes responsible for familial breast cancer have been isolated. The first, BRCA1, is prevalent in Ashkenazi
RECENT ADVANCES IN GENETIC DIAGNOSIS OF FAMILIAL CANCER, SCREENING, CANCER PREVENTION
6
The cloning of two breast cancer genes that are responsible for early-onset and aggressive breast cancer, the identification of the genes responsible for hereditary colon cancer, and the likelihood that other genes are responsible for some cases of testicular, lung and prostate cancer, will lead to increasing demand for genetic testing for cancer risk. In satisfying this demand it will be necessary to provide counselling and advice to patients and their families. The identification of individuals at especially high risk may allow screening services to be directed more efficiently towards those who have extra need and in whom considerable expenditure will be fully justified. It is now feasible to consider the use of drugs which may prevent cancer developing in those at high risk. An example of such intervention is the use of tamoxifen as a preventative agent in breast cancer.
Jewish women and has an early age of onset. A wide variety of mutations have been detected. BRCA2 predisposes to both breast and ovarian cancer. In hereditary nonpolyposis colorectal cancer the syndrome arises as a result of mutation in one of a family of DNA mismatch repair genes. Acquired genetic abnormalities are frequently found in cancer cells, with mutation, transposition and deletion of genetic material. These abnormalities are sometimes consistent, such as the translocation from chromosome 22 in chronic granulocytic leukaemia, and the reciprocal translocation involving chromosome 8 in Burkitt's lymphoma. In many tumours (lung cancer, leukaemia, hepatoma) there is mutation of the p53 gene, which codes for a growth regulatory transcription factor. In colon cancer a cascade of genetic events is responsible for the transformation of polyps to invasive cancer.
TUMOUR GROWTH AND DEVELOPMENT Some tumours exhibit properties which imply that they have arisen as a result of clonal expansion caused by an oncogenic event in a single cell. Lymphomas, for example, usually show restriction to one type of surface immunoglobulin light chain; and studies in individuals who are heterozygotes for the enzyme glucose-6-phosphate dehydrogenase have shown that tumours contain only one form of the enzyme. Whether all cancer are monoclonal in origin is not known, and the development of some
149
carcinomas in a polyclonal field of premalignant change remains a possibility. Even if most tumours are monoclonal, heterogeneity of structure and function arises during the course of tumour growth. Cells from a tumour are diverse with respect to resistance to damage by irradiation or cytotoxic drugs, surface antigen expression, growth rate, and expression of biochemical markers such as embryonic proteins or peptide hormones. This diversity is due to genetic instability in the cancer cells. Heterogeneity within tumours presents a formidable problem for treatment. In normal tissues, self-renewing stem cells replenish a proliferating population of cells which follow a pathway of differentiation resulting in a mature tissue (Fig. 6.8). Cell death is balanced by the formation of precursors, and the tissue is static in size or else grows and diminishes in response to such external controls as hormonal environment. In cancers the restraint on growth is disrupted, so that sustained expansion of the tumour occurs. For clinically detectable cancers, the kinetics of growth appear to be exponential and the rate of tumour volume doubling varies widely. In Burkitt's lymphoma, the doubling time of visible tumour may be as short as 1-2 days, in contrast to 100-400 days for some squamous carcinomas and adenocarcinomas. It seems unlikely that growth is exponential from the beginning of the cancer, as this would imply very long subclinical growth periods for some tumours (Fig. 6.9). Cancers are clinically apparent after about 32 doublings, and lethal after 36-38. It is possible that tumours grow more rapidly when they are very small and slow progressively as they enlarge (gompertzian growth). If true, this may have implications for therapy, as the more rapidly dividing small tumour might be more susceptible to chemotherapy. During growth, the tumour becomes vascularized and lymphatic drainage is established. Cells more than 150 um from a capillary are relatively hypoxic and resistant to radiotherapy. They are also exposed to a lower concentration of cytotoxic agents. The vascularization may be insufficient to sustain viability, and areas of necrosis and haemorrhage are frequently found in large cancers. The process of vascularization allows tumour cells to penetrate blood and lymphatic channels, and thence to metastasize to regional lymph nodes and distant sites.
Metastasis Metastasis is a remarkable process and one which is still very poorly understood. The risk of metastases increases as tumours become larger. The cells must survive tissue invasion, circulation, passage across the capillary wall, and establishment in tissues. The process of tissue penetration
1
150
Figs 6.1, 6.2
Table 6.3 Inherited genetic abnormalities and malignancy Inherited disorder Skin disorders Neurofibromatosis (AD) Tylosis palmaris (AD) (keratosis of palms and soles) Peutz-Jeghers syndrome (AD) Immune deficiency X-linked agammaglobulinaemia (XLR) Wiskott-Aldrich syndrome (XLR) Ataxia telangiectasia (AR) X-linked lymphoproliferative syndrome (XLR) Gut disorders Polyposis coli (AD) Gardner's syndrome (AD) Hereditary non-polyposis Colotectal cancer (AD) Neurological disorders Tuberous sclerosis (AD) Retinal/cerebellar angiomatosis (von Hippel-Lindau syndrome) (AD) Other syndromes Bloom's syndrome (AR) (short stature, telangiectasia) Hemihypertrophy Fanconi's anaemia (AR) (skeletal abnormality, patchy pigmentation, mental retardation) Multiple enchondromata (S) (Oilier syndrome) Chromosomal abnormalities Down's syndrome (trisomy 21) Klinefelter's syndrome (47.XXY) Aniridia - Wilms' syndrome (11pMosaicism (45,XO/46,XY) 13q- (multiple malformations)
Cancer
Sarcoma, phaeochromocytoma, medullary carcinoma of thyroid Oesophageal cancer Intestinal and ovarian cancer
Lymphoma Lymphoma Lymphoma and stomach cancer Lymphoma
Colonic carcinoma Colonic carcinoma Duodenal carcinoma Colonic carcinoma
Glioma Hypernephroma, ependymoma, phaeochromocytoma
Leukaemia Many other cancers Wilms' tumour, hepatoblastoma Acute leukaemia
Chondrosarcoma
Acute leukaemia Breast cancer Wilms' tumour Gonadoblastoma Retinoblastoma
Hereditable component of other cancers Breast cancer BRCA1 BRCA2 Breast cancer Unknown (recessive?) gene Testicular cancer p53 mutation Sarcoma in children Breast and other cancers AD Autosomal dominant AR Autosomal recessive
XLR X-linked recessive S Sporadic
• sarcomas, which arise from mesodermal cells making up bone and connective tissue; • leukaemias and lymphomas, which arise in cells of the bone marrow and immune system.
FIG. 6.9 Diagrammatic representation of exponential and gompertzian growth
FIG. 6.8 Diagrammatic representation of cellular proliferation in a tumour A Pluripotent self-renewing stem cell. B Proliferative compartment in which cell number increases but gradually loses reproductive potential. C Mature tissue.
appears to be by secretion of enzymes known as metalloproteinases (such as collagenase). Inhibitors of tissue metalloproteinases are now in early trials as anticancer agents. The precise location of a metastasis is probably due in part to chance. Nevertheless, clinical patterns of bloodborne metastasis are apparent: gut cancers spread through the portal venous system to the liver; ovarian cancers seed into the peritoneal space; breast cancer has a predilection for bones of the axial skeleton; sarcomas characteristically spread to the lungs.
PATHOLOGY The major categories of malignant tumour are: • carcinomas, which arise from ectoderm or endodermal cells;
6
The distinction between benign and malignant neoplasms is based histologically on the cellular pleomorphism, frequent mitoses and tissue invasion that are characteristic of malignancy. The clinical manifestations of malignancy are tissue infiltration and lymphatic and bloodborne metastases. The degree of differentiation of a tumour is often an important guide to prognosis, and therefore to therapy. Poorly differentiated carcinomas have a worse prognosis than well-differentiated tumours. This is due in part to an association with a more rapid growth rate and more early and widespread metastases. About 5% of cancers present as metastases where the primary site of the tumour is unknown. The histology is usually a poorly differentiated carcinoma, often with features suggestive of adenocaicinoma, but the pathologist may find the tumour difficult to classify. The development of monoclonal antibodies has led to a greater precision in diagnosis by using immunocytochemical methods. Many anaplastic tumours can now be diagnosed as epithelial tumours, melanomas or lymphomas by using antibodies against epithelial antigens, or antigens associated with melanoma, leukocytes or T and B lymphocytes. The correct identification of lymphoma will lead to important changes in management of a patient (Fig. 6.10). Many antibodies will not bind to antigens on formalin-fixed and paraffin-embedded sections, and require fresh tissue. Other specialized investigations can be carried out on fresh tumour tissue - measurement of hormone receptor content (e.g. oestrogen and progesterone receptors) for example, which may be of importance in prognosis and in deciding treatment. Using immunocytochemical techniques, the presence of substances such as oc-fetoprotein can be detected in the tumour. The increasing complexity and versatility of histopathological diagnosis means that it is now essential for there to be close collaboration between clinician and pathologist before specimens are obtained. Ultrasound and CT scanning now allow accurate needle biopsy and aspiration cytology of hitherto inaccessible intra-abdominal and intrathoracic tumours. 1 Cytological diagnosis does have some limitations: in the diagnosis of lymphoma, for example, it may be difficult to distinguish tumour cells from normal reactive lymphocytes. For this reason, histological diagnosis is preferred, especially in situations in which there is clinical doubt about the diagnosis.
CLINICAL FEATURES Cancers cause symptoms due to the local spread of the primary tumour, and as a result of metastasis and of metabolic and remote effects of the malignancy.
151
Metastatic disease in bone causes pain which is often intense and distressing. One characteristic feature of malignant bone pain is that it is often worse at night. Bone pain may occur in the absence of a pathological fracture or vertebral collapse, but becomes worse when this occurs. In the liver, metastases cause pain by stretching the capsule. Cerebral metastases give rise to raised intracranial pressure, fits, focal signs and symptoms, and mental confusion. Pulmonary spread may cause breathlessness due to large intrapulmonary tumour masses, diffuse lymphatic permeation (lymphangitis carcinomatosa) and massive pleural effusion.
SYSTEMIC SYMPTOMS Primary and metastatic cancer may cause a variety of metabolic and other disturbances which are important causes of symptoms. In general, these are produced in one of three ways:
FIG. 6.10 Section of nasopharyngeal tumour A Staining with anticytokeratin; the epithelium of normal respiratory gland stains strongly but tumour cells are negative. B Staining with antibody to the leukocyte common antigen reveals that the tumour cells are expressing the leukocyte antigen and that the tumour is a lymphoma.
SYMPTOMS DUE TO LOCAL DISEASE
152
The primary tumour is clinically silent either until it becomes a visible painless lump that the patient notices (this is a common presentation of breast cancer and Hodgkin's disease and other lymphomas), or until it impinges on surrounding tissues. Thus, carcinoma of the lung will cause increasing bronchial narrowing, with breathlessness, cough and collapse of the distal lung; colonic carcinoma may present with disturbed bowel habit and obstruction; brain tumours may cause raised intracranial pressure or focal neurological signs; cancer of the head of the pancreas will cause obstruction of the bile duct, leading to jaundice. As the primary tumour gets larger it may ulcerate and bleed. Haemoptysis is a common symptom of bronchial carcinoma, and chronic blood loss leading to iron deficiency anaemia frequently occurs with carcinoma of the colon. The tumour may infiltrate nerves and bone, leading to pain, or pain may arise from stretching of the capsule of an organ - for example pain over the liver with advanced hepatoma. Nerve entrapment frequently occurs with pelvic tumours, such as carcinoma of the cervix. Similarly, carcinoma of the bronchus occurring in the superior sulcus (Pancoast's tumour) may be accompanied by intense pain in the arm, owing to involvement of the brachial plexus.
• As a result of the tumour mass, both primary and metastatic; • As a result of secretion of hormones by the tumour (Table 6.4); • By ill-understood mechanisms which give rise to specific cutaneous, neurological and other syndromes remote from the tumour and not due to metastasis - paraneoplastic syndromes (Table 6.5). The commonest metabolic disturbance associated with advanced cancer is cachexia. This is a state of profound weight loss, muscle wasting and weakness. Many factors contribute to the state, of which anorexia is perhaps the major cause. Loss of appetite occurs early with tumours of the upper gastrointestinal tract, even before metastases have occurred. For most tumours loss of appetite is an accompaniment of advanced disease, particularly hepatic metastases. Anorexia may be made worse by treatment with radiation and cytotoxic drugs, by psychological factors such as depression, and by unrelieved pain. The tumour may promote weight loss by direct metabolic effects. For example, there may be excess lactate production by the tumour which is recycled into glucose (a process wasteful of energy), and an increased glucose consumption at a time when carbohydrate intake has declined. Some tumours may cause malabsorption (carcinoma of pancreas) or intestinal obstruction (colon cancer), which contributes to weight loss. Unlike patients who are starving, many cancer patients have a normal or high metabolic rate but the reason for this is not clear. Fever may accompany cancer and is not always due to infection, although this must always be excluded. Fever is particularly likely to occur with lymphomas, renal carcinoma, sarcomas, and any tumours that have metastasized to the liver. Both fever and anorexia may be due to cytokine production by the tumour.
6
CASE STUDY 6.1 COUGH AND BACK PAIN A 65-year-old retired warehouseman presented with a 2-month history of troublesome cough productive of clear sputum. One week previously he had had a sudden onset of midthoracic back pain while bending to clean the bath. The pain was worse on moving and on coughing. He smoked 20 cigarettes a day and for 2 years had had intermittent pain in his left calf on walking 500 yards. On examination he looked well but had back pain on undressing. BP 145/90, pulse 76 regular. Foot pulses absent except for the right posterior tibial. Both external jugular veins were distended. The heart was normal and there was no peripheral oedema. Chest expansion was symmetrically diminished, with increased anteroposterior diameter of the chest. There was an expiratory wheeze, more marked on the right. He was tender on pressure over T8, with a suggestion of angulation at this site. The rest of the examination was normal.
Questions 1. What is the probable underlying diagnosis? 2. What might be the cause of the venous distension? 3. What is the probable cause of the back pain? 4. What are the most important diagnostic investigations? 5. What should be the immediate treatment?
Discussion The patient is a cigarette smoker who has a history and signs of peripheral vascular disease in his legs. Any new
symptoms in such a patient should raise the question of whether these might be due to the development of a bronchial carcinoma. The local symptoms caused by a bronchial carcinoma depend on the site of the tumour. At the periphery of the lung it may remain silent until it invades the pleura, causing pain or an effusion, or obstructs a peripheral airway, causing breathlessness or infection. When centrally placed, tumours may obstruct an airway, causing severe breathlessness, wheeze, or an exacerbation of cough. The tumour, or associated lymph node masses, may expand in the superior mediastinum and cause superior vena cava obstruction (SVCO). Bronchial carcinoma typically metastasizes to liver, bone and brain. About 50% of cases present with symptoms or signs of metastasis. Metastasis to bone typically causes pain that may not be alleviated by rest - indeed, it is often troublesome at night. Presentation with pathological fracture may occur. One of the most important sites of bone metastasis is the cervical and thoracic vertebral column, because at this site there is a grave risk of spinal cord compression. In this case the worsening cough might equally be due to an exacerbation of the obstructive airways disease from which smokers suffer. The back pain after minor exertion raises the possibility of a vertebral collapse and therefore of metastasis to the vertebral column. Physical examination further increases the suspicion that there might be an underlying malignancy. The wheeze is more prominent on the right, suggesting a unilateral cause, and there is tenderness over
Anaemia may be due to blood loss, malabsorption, or dietary deficiency of iron or folate. The most common mechanism is a failure of release of iron (stored in macrophages) into the plasma - the anaemia of 'chronic
the spine of the eighth thoracic vertebra. The distended external jugular veins, in the absence of signs of heart failure, may indicate the early onset of SVCO. Investigations are therefore directed to establishing the diagnosis and the cause of the back pain. A chest X-ray may show appearances suggestive of a carcinoma and indicate if this is centrally placed. If a mass is present the involvement of the SVC can be further investigated by CT scan. Sputum cytology may reveal malignant cells. If negative, a bronchoscopy will be necessary provided that the clinical condition permits. A bone scan will show increased uptake in the thoracic spine if there is a vertebral metastasis, and a lateral X-ray may show vertebral collapse. The appearances will be further delineated by a thoracic CT scan. This will also give an indication of incipient pressure on the spinal cord which is the greatest threat to this patient. Routine full blood counts and biochemistry are unlikely to add to the diagnosis but will be helpful in indicating if other complications of malignancy are present, such as liver metastases or hypercalcaemia. The essential initial treatment is relief of early SVCO and treatment of the vertebral metastasis, if present. To some extent the method of treatment will depend on the histological type of lung cancer. Chemotherapy is rapidly effective in relieving SVCO if the tumour is small cell carcinoma. Other types of lung cancer will require radiotherapy treatment. The vertebral metastasis should be treated with radiotherapy, whatever the histology, especially if the CT appearances suggest that the cord may be in danger.
disease' (p. 1226). This anaemia is unresponsive to iron therapy. Chemotherapy and radiation both depress bone marrow function and contribute to anaemia. The hormonal syndromes that accompany cancer (Table
153
TABLE 6.4 Hormonal syndromes in non-endocrine cancers
TABLE 6.5 Paraneoplastic syndromes
Hormonal syndrome
Tumour
Mechanism
Syndrome
Hypercalcaemia
Squamous carcinomas Carcinoma of kidney
Parathyroid hormone related peptide
Neurological Neuropathy (usually sensory)
Hyponatraemia
Small cell lung cancer Lymphoma Pancreatic carcinoma
Ectopic ADH produced by tumour
Small cell lung cancer Bronchial and thymic carcinoids
Ectopic ACTH produced by tumour
Gynaecomastia
Teratoma Hepatoma Large cell bronchial cancer
Excess oestrogen activity
Hyperpigmentation
Small cell lung cancer
Ectopic MSH produced by tumour
Cushing's syndrome
Cerebellar degeneration Eaton-Lambert syndrome Musculoskeletal Clubbing Hypertrophic pulmonary osteoarthropathy Dermatomyositis
Polyarthritis Haematological Multiple venous thrombosis
6.4) are important because they are a cause of symptoms which are frequently treatable. In many patients hypercalcaemia is due to bone destruction by metastases, but some cancers produce hypercalcaemia by a hormonal mechanism. In these cases the calcium level falls if the tumour is removed. The tumour elaborates a peptide (parathormone-related peptide) and other factors (such as growth factors) which can mobilize bone calcium. Hypercalcaemia associated with cancer can be very severe, requiring urgent management (see Ch. 18). Hyponatraemia, caused by the production of antidiuretic hormone (ADH) by the tumour, is a frequent accompaniment of small cell lung cancer. Malaise, fatigue leading to fits, and coma may result. The condition can be reversed by demeclocycline and water restriction (Ch. 21). Adrenocorticotrophic hormone (ACTH)-like peptides may also be produced by small cell lung cancer. In this disease the high levels of ectopic ACTH produce profound metabolic disturbances, with proximal muscle weakness, hyperglycaemia and hypokalaemic alkalosis. These symptoms can be reversed by management of the tumour. The paraneoplastic syndromes (Table 6.5) can cause diagnostic difficulty in two ways. First, the syndromes must be distinguished from other diseases causing a similar clinical picture. For example, the peripheral neuropathy accompanying cancer may be clinically indistinguishable from other causes. Second, the underlying carcinoma may not always be clinically apparent. Tumours such as carcinoma of the ovary or pancreas may be associated with multiple migratory venous thromboses at a time when the primary disease is not detectable. The diversity of symptoms caused by primary and
0 Case 6.1
154
O Fig. 6.8
0 Figs 6.3-6.6
Q Fig. 6.7
Erythrocytosis
Disseminated intravascular coagulation
Associated tumours
Small cell lung cancer Cancers of breast and ovary Small cell lung cancer Small cell lung cancer
Carcinoma of the lung (particularly squamous cell) Lung cancer Oesophageal cancer Other cancers Adenocarcinomas of breast, gut and ovary
Pancreatic cancer Other adenocarcinomas Renal carcinoma Hepatoma Cerebellar haemangioblastoma Uterine cancer Mucinous adenocarcinomas
metastatic cancer, together with the hormonal, metabolic and paraneoplastic syndromes that accompany many malignant tumours, mean that a diagnosis of cancer must be considered in any unexplained illness, particularly in a middle-aged or elderly patient.
METASTASIS FROM AN UNKNOWN PRIMARY SITE From 2 to 5% of patients with cancer present with a metastasis, in lymph nodes, bone, liver, brain or lung, the primary site not being clinically apparent. Usually the histological appearances are of adenocarcinoma or poorly differentiated cancer. This common clinical problem is a considerable test of medical skill, because the patient is understandable extremely anxious and it is probable that only limited treatment will be available if the primary is discovered. The site may suggest the source of the metastasis. Lymph node metastasis in the head and neck will suggest a head and neck or lung cancer. Metastases in the liver commonly arise from the gut. An axillary node containing adenocarcinoma 1 may be due to a primary in the breast. Detailed histological analysis may be necessary to rule out important and curable cancers such as germ cell tumours or poorly differentiated lymphomas. Investigation is directed towards discovering a treatable primary source, for example in breast or prostate, where hormone therapy
may be effective. Multiple invasive investigations seldom produce information that will affect management. In 20% of cases the primary site is never discovered. Empirical treatment with chemotherapy may be given, but the risk of toxicity is considerable and the response rates are poor.
STAGING AND INVESTIGATION Once a diagnosis of cancer has been established, further investigation is usually needed to establish the degree of spread of the primary tumour and to determine whether metastasis has occurred. It has been known for many years that the prognosis of a patient depends, among other things, on the size of the tumour and the presence of metastases. Our ability to locate the tumour and distant metastases accurately has improved immeasurably in recent years with the introduction of radionuclide and ultrasound scanning, CT scanning and magnetic resonance (MR) imaging. These techniques have shown that in many patients the cancer is metastatic at the time of presentation. This realization has led to a greater emphasis on systemic treatments such as hormone therapy and chemotherapy and, in some cases (e.g. breast cancer), a tendency towards less radical surgical procedures for the primary tumour. The determination of the degree of spread at presentation is generally known as staging. The international acceptance of staging systems has meant that, in treatment trials, comparable groups of patients can be treated allowing a comparison between different methods.
TNM CLASSIFICATION
A generally accepted system which is applicable to some (but not all) cancers is the TNM (Tumour, Nodes, Metastases) classification. 0 The T component defines certain characteristics of the primary tumour, such as its size, site or depth of invasion; the defining criteria will be different with each type of cancer. N refers to the presence or absence of involved nodes; the degree of node involvement may be designated as NO (no involved nodes) and Nl, N2, N3 etc. as more nodes are involved. If no metastases are present the designation is MO, and Ml if they are detected. Clearly, the TNM stage assigned to a tumour will depend on the thoroughness of the clinical and radiological investigation, and this will change as new techniques are invented and perfected. The TNM stages can be grouped into categories which have prognostic significance. These categories or 'stage groups' have been of great value in the design of treatment trials. The TNM stages and related stage groupings for carcinoma of the kidney are shown in Table 6.6 and the prognosis related to the stage grouping in Figure 6.11.
TABLE 6.6 Renal carcinoma TNM staging and stage
grouping Stage
Definition
T1 T2 T3 T4
T stage Small tumour surrounded by normal kidney Large tumour with kidney deformity Perinephric infiltration or renal vein extension Invasion of local structures (e.g. abdominal wall)
NO N1 N2 N3
N stage No nodes involved Ipsilateral nodes involved Contralateral nodes involved Fixed nodes
M1
M stage No distant metastases Distant metastases
Stage I Stage II Stage III Stage IV
T1 T2 T3 T4
M0
6
Stage grouping NO NO NO-2 NO-3
MO MO MO M1
The stage grouping refers to the worst prognostic feature of the case: e.g. a T1 N1 tumour would be stage III
The TNM system is not applicable to some tumours and is of limited value in others; it is clearly inappropriate, for example, in acute leukaemias, and prognostic factors in these diseases are based on other criteria (see Ch. 23). Nevertheless, staging classification is possible and useful in diseases such as chronic lymphatic leukaemia and myeloma. The criteria have nothing to do with a TNM system, but are related to tumour mass. In lung cancer the TNM system is useful and widely used in squamous carcinoma, but is of considerably less value in small cell carcinoma. In this disease, a rough categorization is made into limited disease (confined to one hemithorax) and extensive disease (spread beyond one hemithorax, including metastases). There is a clear difference in prognosis in these two categories (Fig. 6.12).
STAGING INVESTIGATION Much information can be obtained from a chest X-ray. © As techniques are developed, the sensitivity (ability to detect an abnormality if it is present) and specificity (ability to distinguish a metastasis from other pathologies) of the investigations changes. At present, radionuclide bone scanning is the most sensitive method of detection of bone metastases (Fig. 6.13A). 4 CT scanners are better than,
155
FIG. 6.12 Prognosis of small cell carcinoma of the lung related to the disease extent at presentation
Limited disease = disease confined to one hemithorax. Extensive disease = more widespread local extent or metastasis.
CT has proved of value in detecting lymph node enlargement in the thorax and the abdomen. Unfortunately, nodes can be replaced by secondary tumour and yet not be enlarged. Lymphography - in which contrast material is injected into lymphatics in the dorsum of the feet can show filling defects in normal size nodes, as well as node enlargement. For tumours that spread transperitoneally, such as carcinoma of the ovary, laparoscopy (peritoneoscopy) is the most sensitive method of detecting spread of tumour if a laparotomy is not carried out. Although invasive, this procedure can also be used to obtain liver biopsy material under direct vision.
TUMOUR MARKERS 4
FIG. 6.11
A Carcinoma of the left kidney. T = degree of local spread; N = involvement of adjacent lymph nodes; M = metastasis to bone or other sites. B Prognosis according to stage grouping.
or at least equal to, ultrasound scanning in the detection of hepatic metastases (Fig. 6.13B), 1 but ultrasound is much cheaper and can be repeated regularly to assess response. CT is the best method of detecting pulmonary metastases and is able to demonstrate metastases of 2-3 mm in size (Fig. 6.13C). MRI is superior to CT in detecting deepseated brain tumours, especially in the brainstem and spinal cord, and is the preferred method for showing brain metastases (Fig. 6.13D). 2 MRI is of great value in demonstrating cord compression (Fig. 6.13E) 0 and the soft tissue extent of tumours such as sarcomas (Fig. 6.13F).
156
1
Fig. 6.9
4
MCQ 6.2
0 0
Fig. 6.10
0 Fig. 6.11
Figs 6.9-6.11
Tumours may secrete substances into the blood which can be used both diagnostically (to detect the presence of disease) and in therapy, to monitor the effects of treatment. A variety of biochemical disturbances may be induced in the body by a tumour, such as the rise in alkaline phosphatase caused by liver or bone metastases, but these are crude and insensitive guides to the effect of treatment. The markers in common clinical use (Table 6.7) are oncofetal antigens, placental products, isoenzymes, ectopic hormones and some cellular antigens, usually derived from the cell membrane. Ideally, the tumour marker should always be produced by the cancer in question. In choriocarcinoma, human chorionic gonadotrophin (hCG) is produced in over 95% of cases; and 75% of germ cell tumours secrete either oc-fetoprotein (AFP), hCG or both. Carcinoembryonic antigen (CEA) (a glycoprotein produced by colonic mucosa) is found in the serum in 65% of cases of colorectal cancer. With some markers, e.g. hCG, AFP and placental alkaline phosphatase (PLAP), the serum level of the marker is a reasonably accurate and sensitive reflection
6
FIG. 6.13 Scanning 0 5] Isotope bone scan showing multiple areas of increased uptake in a patient with bone metastases from lung cancer. B Ultrasound scan of liver showing several metastases (arrowed) in a patient with colorectal cancer. C CT scan of thorax showing a solitary subpleural metastasis in the left lung. D MR scan of the brain showing a left-sided frontal metastasis with some associated oedema. The patient had non-small cell lung cancer. E MR scan of the thoracic vertebrae. A large paravertebral mass is invading the left lateral T9 vertebra. The tumour passes through the intervertebral foramen and is displacing the spinal cord to the right. This was a round cell sarcoma of the chest wall. F MR scan showing a large intraosseous tumour arising in the right tibia. The associated soft tissue mass is clearly shown. This was an osteosarcoma.
of the tumour mass in an individual patient, and can therefore be used as a guide to therapy. Prostate-specific antigen (PSA) is a sensitive marker of early prostate cancer which is now widely used in screening. This has led to considerable controversy over the treatment of early, screen-detected, prostate cancer. The antigen is a serine protease produced at low levels in non-malignant prostate disease. The serum marker may be a valuable guide to tumour recurrence and, in most cases of germ cell tumours (such as teratoma of the testis), is a more sensitive indicator of tumour recurrence than any other technique. There is, of course, little value in knowing when relapse is occurring if there is no effective treatment. However, in the case of early-stage germ cell tumours, the markers have allowed a policy of observation following initial surgery, as highly effective chemotherapy is available for relapse. An example of the use of tumour markers is shown in Figure 6.14.
The tumour marker may be produced in other conditions: for example, serum AFP is raised in early pregnancy, and CEA may be present in inflammatory bowel disease. AFP is produced in the fetal liver, in the malignant yolksac cells in teratoma, and in hepatoma. It has a plasma halflife of 5-7 days. hCG is produced by the placenta and by choriocarcinoma, and by the trophoblastic elements in teratoma. The plasma half-life is 30 hours.
PRINCIPLES OF CANCER MANAGEMENT Surgery and radiotherapy are the principal methods of treating the primary tumour. For many early-stage cancers - e.g. in cancer of the breast, squamous cancer of the lung, and cancers of the ovary, kidney, testis and gastrointestinal tract - surgery alone has a good chance of cure. Unfortu-
157
FIG. 6.14 Tumour markers in management of testicular cancer A Both hCG and AFP markers are elevated before orchidectomy but fall following operation (hCG more rapidly because of its short half-life). B No evidence of recurrence, followed by a rise in marker levels. C Combination chemotherapy for recurrence is followed by a fall in levels to normal. D, E A further rise in marker levels is treated more intensively and the patient is disease-free at 3 years F.
TABLE 6.7 Tumour markers present in blood Marker Oncofetal antigens oc-fetoprotein
Tumour
Carcinoembryonic antigen Pancreatic oncofetal antigen
Germ cell tumours of ovary and testis Hepatoma Gastrointestinal cancer Pancreatic carcinoma
Placental products Human chorionic gonadotrophin Placental lactogen Placental alkaline phosphatase
Choriocarcinoma Teratoma Choriocarcinoma Seminoma
Isoenzymes Alkaline phosphatase Lactic dehydrogenase Neuron specific enolase
Osteosarcoma Neuroblastoma, many cancers Small cell carcinoma of lung
Ectopic hormones (see Table 6.4) Other cellular antigens (defined by antisera) Ca 125 (aglycoprotein) Ca 19-9 (a carbohydrate) Prostate-specific antigen (pSA)
158
Ovarian cancer (also breast, pancreas and gut) Pancreatic cancer (also gut) Prostate cancer
nately, many patients cannot be cured surgically, either because the tumour is so advanced locally as to make resection impossible, or because investigation has revealed metastases. Advances in radiotherapy technique and the recent developments in combination cytotoxic chemotherapy have meant that, for many patients, a combined approach
to management is needed to achieve the best results. This involves close collaboration between surgeon, radiotherapist and medical oncologist. Before treatment begins, it is essential to decide whether there is a possibility of cure or whether the intention should be palliative. Many factors will influence this decision, including the degree of spread of the tumour locally, the presence of distant metastases, and the patient's age and state of health. It may be very difficult to decide on the best policy if the chances of cure are relatively small and the toxicity of treatment considerable. In a young patient the aim of cure would probably overcome doubts about toxicity, but this might not be the case in the elderly. If the clinical evidence makes it quite clear that there is no hope of cure, then investigations should only be performed if they will alter management. Investigation, as previously outlined, will be necessary in all other patients to determine the degree of spread of the disease before deciding on the treatment plan. The principles of surgical management of cancer are beyond the scope of this chapter, but it is important for all physicians to have an understanding of the basis of management using radiotherapy, chemotherapy and hormone therapy.
RADIOTHERAPY Most radiotherapy treatment involves the use of electromagnetic waves with very high energy and short wavelength - gamma rays and X-rays. Some modern radiotherapy machines use 60Co as a source, which decays to a more stable form with a half-life of 5.3 years. The process of decay (with loss of a neutron) is accompanied by emission of gamma rays with a high energy (1.2MeV). X-rays were first produced by Roentgen, who heated an electrode in a sealed vacuum tube. The electrode produced electrons which bombarded a target, resulting in the emission of
TABLE 6.8 Relative radiosensitivity of tumours
Depth/cm FIG. 6.15 Tissue penetration of different types and energies of radiation
electromagnetic waves which were designated 'X-rays' and whose nature was the same as that of gamma rays. By increasing the voltage, X-rays of shorter wavelength and higher energy are produced which have greater tissuepenetrating power than those produced from low-voltage machines (Fig. 6.15). Modern machines accelerate the electrons almost to the speed of light, resulting in a high-energy beam. These machines (linear accelerators) have become standard equipment in most departments. They provide a sharper beam than that obtained from 60Co sources and greater depth doses. When the target is moved out of the path of the electrons, the high-energy electron beam can be used for the treatment of superficial tumours. The tissue-penetrating power of high-energy X-rays and gamma rays means that normal tissues will be irradiated as well as the tumour. With lower voltage X-rays, the penetrating power is less and more energy is deposited in superficial tissues, especially bone. With electrons, the radiation decays rapidly in tissue, the depth of penetration depending on the energy of the beam (Fig. 6.15). The important site of radiation damage is nuclear DNA. The damage appears to be induced indirectly. The radiation first produces highly reactive radicals, which in turn damage the DNA, impairing the reproductive integrity of the cell. The damaging effects of radiation are less marked in cells which are hypoxic. Some areas of tumour may not be well vascularized and these cells are relatively radioresistant. The mechanisms of resistance are not well understood. The amount of cell death following exposure to irradiation is also proportional to the dose administered. At low doses the damage is sublethal. Nevertheless, radiation administered as a few large fractions may not be as effective as multiple-fraction regimens using smaller daily doses. The latter technique may be more effective because it allows the tumour to shrink and become less hypoxic, may be easier to tolerate, and allows normal tissues to recover at a faster rate than the tumour. In treating tumours, multiple fractions are usually employed and the total dose administered depends on what is known of the radiosensitivity of the neoplasm (Table 6.8). The total dose
Highly radiosensitive Lymphomas Ewing's sarcoma Seminoma Wilms' tumour Myeloma
Relatively resistant Squamous cell lung cancer Hypernephroma Bladder carcinoma Rectal carcinoma Soft tissue sarcoma (adults) Cervical carcinoma
Moderately radiosensitive Breast cancer Small cell lung cancer Ovarian cancer Medulloblastoma Basal cell carcinoma Teratoma
Very resistant Melanoma Osteosarcoma Pancreatic carcinoma
received by the tumour is measured in grays (1 Gy = 1 J/kg) orrad (100 rad = 1Gy). The planning of the radiation field is often a highly complex procedure that has been greatly facilitated in recent years by the use of CT scanning and simulators, which allow the fields to be constructed with precision. In planning the fields, the radiotherapist must therefore consider the localization of the tumour, its probable inherent radiosensitivity, the tolerance of the normal tissues in the path of the beam, and the need to include draining lymph nodes in the treatment. Multiple fields may be necessary to achieve the desired dose in the tumour without damaging normal tissues. The fields may be open (or direct}. Here, the radiation beam is applied directly, usually at rightangles to the skin. Alternatively, if several fields are used, the field may be wedged. These wedges, inserted into the beam, alter the dose distribution so that the tumour dose is homogeneous and problems of irradiation of normal tissue where fields overlap are minimized. An example of a multiple field is shown in Figure 6.16. The treatment area is immobilized and, for some tumours, such as head and neck cancers, moulds and shells are used to ensure accurate and reproducible positioning. The radiation source is mounted in a gantry which moves isocentrically about the patient. Radiotherapy may also be given by placing a sealed source containing a radioactive isotope inside a body cavity or in tissues. This is known as brachytherapy. Examples of such isotopes are 137Cs, which is widely used as an intracavity source of radiation in treating carcinoma of the cervix, and iridium wires, which may be placed in breast tissue to provide interstitial irradiation when radical radiotherapy is used following conservative surgery for breast cancer. Unsealed sources of radioactivity may be taken by mouth, e.g. 131I in the treatment of thyroid cancer, or given intravenously, e.g. 32P in the treatment of polycythaemia rubra vera.
6
159
TABU 6.9 Complications of radiotherapy Complication
FIG. 6.16 Radiation planning for carcinoma of bladder The relationship of the three beams to the tumour and the dose levels (% of maximum) achieved within the tumour and surrounding normal tissue are shown.
The complications of radiotherapy depend on the radiation sensitivity of normal tissues in the path of the beam, and may be immediate or delayed. A summary of some of these is given in Table 6.9.
SYSTEMIC TREATMENTS In the last 40 years there has been a dramatic increase in interest in the use of drugs to kill cancer cells. So many cancers are either disseminated at diagnosis or too advanced locally to resect, that a systemic approach to treatment offers the only chance of remission or cure. The two treatments in general use are cytotoxic chemotherapy and hormone therapy.
Cytotoxic chemotherapy The earliest compounds to be introduced were nitrogen mustards, which were shown to be cytotoxic to lymphoid tissue and then to have activity against lymphomas in humans. In 1948, Farber demonstrated remissions of leukaemia using the antifolate aminopterin, and this led to the development of a wide variety of antipurines and antipyrimidines. Antitumour antibiotics were first developed in 1940 (actinomycin A), with a significant step forward in 1963 with the isolation of anthracyclines. The platinum drugs were introduced in the 1970s and proved to have great activity in germ cell tumours. The epipodophyllotoxins were also introduced at that time. Recently the taxoids have been introduced. There are now about 35 cytotoxic drugs of proven value in routine use, and the
1
160
MCQ 6.3
Tissue
Immediate
Delayed
Skin
Erythema, desquamation
Oral cavity Gut Bone Kidney
Mucosal ulceration Nausea, diarrhoea Bone necrosis Acute nephritis
CNS
Radiation myelitis and encephalitis
Eye
Conjunctivitis
Gonads Bone marrow
Sterility Leukopenia
Fibrosis Telangiectasia Squamous carcinoma Loss of saliva Fibrosis and stricture Loss of bone growth in children Chronic nephritis Hypertension Demyelination Possible alteration of personality and intellect Dry eye Cataract formation Sterility Suppression of haemopoiesis in area irradiated
RECENT ADVANCES IN NEW METHODS OF ADMINISTERING RADIOTHERAPY The advent of CT scanning has meant that precise three-dimensional images of the tumour can now be obtained. The radiation can now be channeled with considerable accuracy using new methods of directing the beam ('beam's eye view'). A further development has come from the knowledge that repopulation of tumours with new cells occurs rapidly. This has led to the development of hyperfractionated schedules of radiation, in which two or more treatments are given each day. This, and conventional fractionation, may now be given at the same time as cytotoxic chemotherapy in an attempt to improve local control and to prevent interruption of systemic treatment. These complex procedures are likely to play an increasing part in modern cancer management.
increasing complexity of medical treatment of cancer has led to the development of medical oncology as an important specialty in cancer management. Mechanisms of action Cytotoxic drugs produce their effect mainly by damaging the capacity of the cell to divide, and also by interfering with synthesis of essential proteins. For many of these agents the most important toxicity concerns DNA, with impairment of DNA synthesis, reaction with the DNA helix or damage to DNA repair mechanisms. During cell division there is a phase (G1) which precedes the phase of DNA synthesis (S). Following the S phase
SUMMARY 1 Common chemotherapeutic agents Alkylating agents Nitrogen mustard Melphalan Cyclophosphamide Ifostamide Busulphan Chlorambucil Nitrosoureas Cisplatin
Plant alkaloids Vinca alkaloids Epipodophyllotoxins Taxoids Antibiotics Anthracyclines Doxorubicin Daunorubicin Bleomycin
Anti-metabolites Methotrexate 5-fluorouracil 6-mercaptopurine 6-thioguanine Cytosine arabinoside
there is a postsynthetic phase (G2), which is followed by mitosis (M). The daughter cells then either enter into the cycle of division or remain in a non-reproductive stage (Go). Because of their action on DNA, most cytotoxic drugs exert their maximum effect on replicating rather than resting cells. If, after damage to DNA (e.g. by alkylation), the cell does not divide, there will be time for DNA repair mechanisms to excise the attached alkyl groups and to repair strand breaks. Rapidly proliferating cells are thus more susceptible to cytotoxic damage, but this is not the only determinant of susceptibility since, as with radiation, different tissues and tumours show inherent differences in susceptibility, the biochemical basis of which is poorly understood. Alkylating agents are very reactive compounds which exert their effect by linkage of the alkyl group to DNA bases, particularly guanine. If the drug is bifunctional (having two alkyl groups), inter- and intrastrand crosslinks will form. Nitrogen mustard, phenylalanine nitrogen mustard (melphalan), cyclophosphamide, busulphan and chlorambucil are commonly used alkylating agents. Cyclophosphamide itself is inactive but is metabolized by the liver to 4-hydroxycyclophosphamide, which is transported to the tissue and there releases the active alkylating compounds. Nitrosoureas and cisplatin probably act mainly as alkylating agents. Methotrexate inhibits dihydrofolate reductase, thus preventing the formation of tetrahydrofolate, which is necessary for thymidine synthesis. Other antimetabolites include 5-fluorouracil (5FU), which also blocks thymidine formation; 6-mercaptopurine (6MP), which interferes with purine nucleotide biosynthesis; and 6-thioguanine, which has a similar mechanism of action to 6MP. Several plant alkaloids have anticancer activity. The vinca alkaloids interfere with the formation of the mitotic spindle by blocking the assembly of tubulin. The taxoids interfere with disassembly of the microtubules that constitute the mitotic spindle. The epipodophyllotoxins damage
DNA through topoisomerase II. This enzyme normally allows the unwinding of DNA during DNA replication. Anthracycline antibiotics intercalate between DNA bases, as does actinomycin, which has the additional action of interfering with RNA synthesis. Bleomycin causes DNA strand breaks.
6
Testing a new drug When a new drug has shown activity in the laboratory, it is tested in patients with cancer. At first, it is given in gradually increasing doses to patients with advanced drugresistant cancer. These trials are called phase I studies: the aim is to monitor toxicity and to study metabolism and distribution of the drug, as well as to note any activity. In phase II studies, patients with a wide range of tumours are then treated in order to determine the spectrum of activity of the drug. Later, phase HI studies are performed in which the drug is tested, usually in previously untreated patients, either alone or in combination with other drugs, and often as part of a randomized comparison. Combination chemotherapy In recent years it has become standard practice to use cytotoxic drugs in combination. The aim is to produce a variety of different biochemical lesions in the tumour, if possible without increasing toxicity. It quickly became apparent that quadruple therapy in, for example, advanced Hodgkin's disease, produced a far higher complete response rate (disappearance of all symptoms and signs of the tumour) than did single-agent therapy. Furthermore, many of these complete responses were sustained, about 40% of patients being disease free between 5 and 10 years later. This had not been observed with single-agent therapy. Similar results were reported with non-Hodgkin's lymphoma and, later, with testicular teratoma, Ewing's sarcoma and other childhood tumours. In the common tumours of adults (such as cancer of the breast and small cell lung cancer), an increased response rate is also obtained with drugs in combination, but most of these responses are partial (>50% reduction in size) and not sustained for long. Most of the regimens used today have been derived empirically by oncologists with knowledge and experience. There are, however, some general principles governing selection of the drugs (Table 6.10). Using these general principles, combination chemotherapy has been introduced into the treatment of many cancers and forms the mainstay of management in an important minority of uncommon tumours. Unfortunately, most of the common adult cancers are only moderately sensitive to these drugs, and some are very resistant (Table 6.11). Cancer is a disease of the elderly and many patients are not fit enough to risk the toxicity of chemotherapy, especially if the intention is to palliate rather than cure. Complications of chemotherapy 1 There are both immediate and long-term complications of chemotherapy. Many patients greatly fear chemotherapy
161
TABLE 6.10 General principles governing the selection of drugs used in combination therapy • The drugs are known to be effective when used as single agents. • Where possible, drugs with differing modes of action are combined. • The major toxicity of each drug should be as different as possible from that of other agents. • Pulsed intermittent treatment is used to allow recovery of the gut and bone marrow. • If possible each drug should be used in its optimum dose and schedule, although in practice some reduction in dose is nearly always necessary. • There should be no known synergistic toxicity.
as they have often been told lurid stories about toxicity. However, with many regimens toxicity is very mild. The drugs are not equally toxic and it is incorrect for inexperienced physicians to give patients the impression that they are. Immediate The most troublesome immediate side-effects of some chemotherapy regimens are nausea and vomiting, mucosal ulceration, bone marrow depression and alopecia. Nausea and vomiting are probably initiated by a centre in the medulla. Intravenous alkylating agents tend to produce nausea at 12-18 hours, and cisplatin and doxorubicin typically produce nausea about 6 hours after administration. Many other drugs produce very little nausea. Nausea is often accompanied by vomiting, and the symptoms usually last 12-24 hours. These symptoms can be very troublesome but are tolerated by the majority of patients. Skilled, meticulous and flexible use of antiemetics is essential. 5HT3 antagonists have been a big advance in controlling nausea and vomiting, and are now the mainstay of antiemetic treatment. The most widely used agents are ondansetron and granisetron. These are the antiemetics of first choice for chemotherapy which regularly produces troublesome vomiting,
SUMMARY 2 Complications of chemotherapy Long-term Impairment of fertility Secondary cancers Pulmonary fibrosis Cardiomyopathy Nerve damage Loss of hearing Renal impairment
Immediate Nausea and vomiting Mucosal ulceration Bone marrow depression Immune suppression (opportunistic infection) Alopecia
1
162
Case 6.2
2
Figs 6.12-6.15
3
MCQ 6.4
TABLE 6.11 Relative chemosensitivity of tumours Highly sensitive tumours (which may be cured by chemotherapy) Teratoma of testis Hodgkin's disease High grade non-Hodgkin's lymphoma Wilms' tumour Embryonal rhabdomyosarcoma Choriocarcinoma Acute lymphoblastic leukaemia in children Ewing's sarcoma Moderately sensitive tumours (in which chemotherapy may sometimes contribute to cure and often palliates) Small cell carcinoma of lung Breast carcinoma Low grade non-Hodgkin's lymphoma Acute myeloid leukaemia Ovarian cancer Myeloma Relatively insensitive tumours (in which chemotherapy may sometimes produce palliation) Gastric carcinoma Bladder carcinoma Squamous carcinoma of head and neck Soft tissue sarcoma Cervical carcinoma Resistant tumours Melanoma Squamous carcinoma of lung Large bowel cancer
such as cisplatin (Table 6.12). Piperazine phenothiazines (e.g. prochlorperazine) are of some help when given in full dose, but aliphatic phenothiazines (e.g. chlorpromazine) have less antiemetic effect. Metoclopramide is of some value, and its effect may be increased by giving it in high dosage. Benzodiazepines enable the patient to sleep during the period of maximum nausea. Mucosal ulceration in the mouth and gut is a complication of chemotherapy which is particularly likely to occur following methotrexate and anthracyclines. It is dose related, but some individuals are especially susceptible and the dose may then need to be lower than usual. Alopecia is very common with many drugs especially doxorubicin and cyclophosphamide, and is caused by damage to the proliferating cells of the hair follicle. Although the hair regrows when treatment is finally stopped, many patients find this a distressing side-effect. With anthracycline the hair loss can be minimized by scalp cooling during drug administration. The patient must be warned of the likelihood of hair loss, and a wig ordered if desired. Bone marrow depression results in acute leukopenia
TABLE 6.12 Commonly used antiemetic agents Drug
Usual dose
Side-effects
5HT3 antagonists Ondansetron Granisetron
0.15mg/kg 3mg i.v.
Constipation, headache Constipation, headache
12.5mg i.m. or as suppository
Drowsiness Dyskinesia
Benzodiazepine Lorazepam
1-2 mg p.o, or i.v.
Sedation, dizziness, hypotension
Steroids Dexamethasone
6-8 mg i.v.
Restlessness
Phenothiazines Prochlorperazine
10mg p.o. or i.v., Metoclopramide or 1-2mg/kg i.v. (5HT3 and dopamine antagonist)
Dyskinesias, diarrhoea
and thrombocytopenia and the slower onset of anaemia (because of the greater lifespan of red cells). The nadir of the leukocyte count often comes at 7-9 days after intravenous chemotherapy, and it is at this time that the patient is most susceptible to serious infection. 1 Increasingly, oncologists are adjusting the dosage in each cycle of very myelosuppressive regimens according to nadir counts, even though this involves an extra blood count between visits. Patients must be forewarned of their susceptibility to infection and bleeding, so that they can report symptoms promptly. The commonest infections are of the respiratory and gastrointestinal tracts. Immune suppression is cumulative. Patients become increasingly susceptible to opportunistic infection. These are typically pulmonary (aspergillosis, Pneumocystis), oral and oesophageal Candida, and herpes zoster 2 and simplex, which can be severe, confluent and disseminated. Long-term The long-term sequelae of cancer chemotherapy are now becoming better defined as more children and adults are surviving previously incurable cancers. One in 1000 adults now has been cured of cancer in childhood or adolescence. Although complications may be an inevitable risk of regimens that are potentially curative, they are a reminder of the risks attached to increasing the intensity of treatment. Cytotoxic drugs impair fertility in adults. In men, complete and irreversible loss of fertility occurs with many regimens, particularly those that include an alkylating agent or procarbazine. Prepubertal boys do not become infertile, but Leydig cell function may be impaired and testosterone levels may fall. It is important to inform adolescent boys and men of this risk and to arrange sperm storage before chemotherapy begins. Curiously, in Hodgkin's disease, where there is greatest experience of
this problem, patients are often subfertile even before chemotherapy begins. For women, the problem is more complex. Amenorrhoea is common during chemotherapy, especially if an alkylating agent is used. Menstruation will usually return when treatment is finished, although subfertility is common. Chemotherapy may, however, induce the onset of menopause; this is more likely to occur in older women who are nearer the natural menopause. Even in younger women the period of reproductive life may be reduced. It is essential to discuss this potential problem. In both sexes, patients who are receiving chemotherapy should be advised of possible short-term teratogenic effects and to use a contraceptive during treatment. Second cancers are increasingly recognized as a longterm consequence of chemotherapy, particularly in ovarian cancer or Hodgkin's disease. In both cases the risk is especially of acute myelomonocytic leukaemia. Second cancers are also more common in patients receiving immunosuppressive therapy with cytotoxic drugs, and in these patients there is an increased incidence of brain lymphoma, cervical carcinoma and skin cancer. Pulmonary fibrosis is a complication of treatment with busulfan (e.g. for chronic myeloid leukaemia), and acute pneumonitis leading to fibrosis is a dose-related complication of bleomycin. Other cytotoxic agents rarely produce lung damage, although pulmonary fibrosis is a long-term complication of cyclophosphamide and nitrosourea treatment. Anthracyclines such as doxorubicin cause a cardiomyopathy, the risk being dose related. Above a total dose of 400mg/m2 of doxorubicin about 50% of patients will have measurable impairment of cardiac function, but only 5% will develop cardiac symptoms. Established cardiomyopathy leads to cardiac failure, which is irreversible on stopping the drug. Vinca alkaloids cause damage to peripheral and autonomic nerves. The earliest symptoms are of tingling paraesthesiae. There is loss of tendon reflexes and, later, sensory loss and motor weakness. Autonomic neuropathy produces ileus and postural hypotension. Vincristine and vindesine are particularly likely to produce neuropathy, and vinblastine less so. The neuropathy is usually reversible, is totaldose related and is more common and severe in the elderly. Cisplatin may cause irreversible loss of hearing, particularly of high frequencies, and peripheral neuropathy. Renal impairment is also common and irreversible. These toxic effects are a reminder that the treatment of cancer with cytotoxic drugs is a matter requiring skill and judgement if the benefits are not to be outweighed by the disadvantages. Nevertheless, the improvement in prognosis in some cancers as a result of cytotoxic drug treatment fully justifies the acute and long-term risks involved.
6
Hormone therapy3 The growth of many normal tissues is under hormonal regulation, and the cancers that arise in them often retain
163
sensitivity to changes in the hormone environment. Hormone therapy is an essential part of management of cancers of the prostate, breast and endometrium. In these cases, the steroid hormone binds to a hormone-binding molecule (receptor) in the cytoplasm and the receptor/ hormone complex is transported to the nucleus, where it modifies the activity of DNA. There is an increase in RNA polymerase activity, resulting in increasing production of cytoplasmic proteins followed by cell division (Fig. 6.17). In some cases the hormone provokes the increased synthesis of receptors for other hormones; oestrogen, for example, increases the synthesis of progesterone receptor in breast epithelium. Response to hormone therapy is strongly associated with the presence of cytoplasmic hormone receptors. In advanced breast cancer, the presence of oestrogen receptors is associated with a 60% response to hormone therapy but only a 5% response if the cancer contains very low levels of receptor. Response is also strongly associated with the presence of progesterone receptors. The following general approaches are taken in hormonesensitive tumours. Blocking the action of circulating hormones In breast cancer, the use of tamoxifen has been a major advance. It appears to exert most of its effect by binding to the oestrogen receptor, thereby preventing the activity of circulating oestradiol. Paradoxically, the drug is effective in postmenopausal women whose tumours are receptor positive, but in whom circulating levels of oestrogen are likely to be low. A direct growth-regulatory effect of the drug may be responsible. Reduction in concentration of circulating hormones Until recently, this was the mainstay of hormone therapy and was usually accomplished surgically. In breast cancer, oophorectomy was performed, or in premenopausal
164
women a radiation menopause induced. In those who showed an initial response but then relapsed, further responses could be obtained by adrenalectomy, which prevented sex hormone synthesis in the adrenal, and by hypophysectomy which produced a similar effect. The advent of aromatase inhibitors has led to a decline in frequency of these operations. Androstanedione is converted in peripheral tissues (and in the breast itself) to oestradiol by enzymes known as aromatases, and several powerful aromatase inhibitors can now be used to prevent oestradiol formation. In prostate cancer, luteinizing hormone-releasing hormone (LHRH) agonists cause a spurt of LH release followed by a profound fall, which reduces plasma testosterone levels to those seen after castration. Prostate cancer is usually very sensitive to a fall in testosterone levels. LHRH agonists are therefore a widely used medical alternative to orchidectomy.
Addition of hormones The hormonal environment can be altered by the administration of hormones which are judged to provide an unfavourable environment for the tumour. Stilboestrol has for many years been used to produce regression in carcinoma of the prostate, and androgens, glucocorticoids and progestogens may all slow the growth of the tumour in breast cancer. Progesterone derivatives will also produce regression in about 20% of carcinomas of the endometrium. In advanced breast cancer, endocrine therapy has the great advantage of low toxicity and low cost compared to chemotherapy. Tumour responses are often more complete and more durable than those achieved with cytotoxic drugs. On the other hand, the proportion of responding patients is lower (30% with endocrine therapy, 60% with chemotherapy). For these reasons, many physicians prefer to start treatment with hormone manipulation, moving to chemotherapy when the disease becomes unresponsive and progresses.
FIG. 6.17 The mechanism of oestrogen action on cell growth Tamoxifen acts by binding to the oestrogen receptor and blocking its action.
Adjuvant chemotherapy and hormone therapy There are many situations in which a cancer has been removed surgically or treated with radiotherapy, but the risk of local or systemic recurrence is high. Examples include breast cancer, where there is involvement of axillary nodes; gastric and other cancers, where the regional nodes are involved; or Ewing's sarcoma of bone, where the tumour is highly sensitive to radiotherapy but the risk of metastasis is very great. In these situations, advances have been made by the use of cytotoxic drugs or hormones in an attempt to delay or prevent recurrence. Even if these treatments are not very effective against advanced cancer (of the stomach or breast), they may be more so when the residual tumour mass is small, when the penetration of the drugs may be better and the degree of cell kill may lead to cure rather than temporary tumour regression. Many large-scale trials have been undertaken to assess the value of adjuvant cytotoxic or endocrine therapy. For the results to be accepted with confidence, there must be both sufficient numbers of patients in the study, and prospective randomization of the allocation of the treatment policy. (The difficulties involved in these trials are discussed below.) In patients with stage II breast cancer, both adjuvant endocrine therapy (using tamoxifen) and cytotoxic therapy (using drug combinations such as cyclophosphamide, methotrexate and 5-fluorouracil) have been shown to give a survival advantage of about 7% at 5 years and 10% at 10 years (Fig. 6.18). A follow-up overview of all randomized trials now shows that patients with stage I disease also benefit from chemotherapy if they are premenopausal, and from hormone therapy after the menopause. Adjuvant drug therapy after surgery or irradiation has become an essential part of management in most childhood tumours (rhabdomyosarcoma, Wilms' tumour, osteosarcoma, Ewing's sarcoma), and in a number of adult tumours, such as breast cancer, ovarian cancer, and in Duke's C colon cancer. There are many other tumours (gliomas, gastric carcinoma, operable lung cancer) in which adjuvant chemotherapy has not yet been adequately evaluated. As the survival benefit is likely to be small, it will only be demonstrated in very large-scale trials, which are still to be undertaken or in patients data-based metaanalyses. Even a 5 % improvement in survival in colorectal cancer is worthwhile, as the disease affects 1 million people a year in eastern and western Europe.
SUPPORTIVE CARE IN CANCER MANAGEMENT Patients with cancer need supportive care for both the psychological impact of the disease and the physical effects of the tumour and its management. Even if there is no
6
FIG. 6.16 Radiation planning for carcinoma of bladder The relationship of the three beams to the tumour and the dose levels (% of
prospect of cure, the patients' quality of life can be greatly improved by the attitude of the medical staff and by meticulous attention to the management of pain, anaemia, infection, nausea and anorexia.
Psychological support The last 20 years have seen an increasing readiness on the part of doctors to discuss the diagnosis of cancer with their patients and to explain the principles of management. Indeed, the complexities of modern cancer management make it difficult to withhold the facts of the diagnosis, even if it were desirable to do so. Nevertheless, the manner in which the diagnosis is explained and the words used are of great importance, and must be carefully judged in each case. Cancer is the only word that conveys the nature of the complaint accurately; other words used are often misinterpreted by patients as implying a less, or even more, serious condition. The problem is that in the mind of many patients cancer is invariably fatal. Explanation of the diagnosis must therefore be accompanied by an unhurried and easily comprehended account of management and the possibilities of cure. It is nearly always wrong to offer no hope of either cure or a period of normal life. Usually, the physician will need to talk to the patient on several occasions, as their understanding of the problems may be incomplete at the beginning. Time taken in unhurried, private conversation is always well spent and greatly appreciated. One of the advantages of having specialized oncology units in hospitals is that all members of the medical team - nurses, doctors, social workers and counsellors - become familiar with the problems that are associated with malignant disease and skilful in dealing with them. It is important that all members of this team know what has been said to the patient in the way of explanation, in order to avoid conflicting advice. A relapse of the disease or the appearance of a new symptom will often cause a slump in morale and confidence which will require more explanation and reassurance. The emotional demands of this aspect of cancer
165
medicine are considerable, and are one reason why some doctors have been reluctant to spend time in discussion with their patients. Nevertheless, the patient will need the help and support of the doctor at these difficult times. It is an essential aspect of cancer medicine and one of the most rewarding.
PAIN RELIEF This is a very important aspect of management, particularly in patients with widespread disease who are terminally ill. No single analgesic will suit all patients all of the time. A patient will need to change from one to another, depending on the severity of pain. A brief classification of some of the most useful analgesics is given in Table 6.13. When using opiates, the dosage should be adjusted to the patient's requirements. A wide range of dosages is encountered. Long-acting morphine and heroin are especially useful and should be given regularly, rather than 'as required'. The constipating effects of opiates can be partly relieved by regular laxatives. If pain is at a particular site, it may be possible to give relief by local measures, such as radiotherapy to a bone metastasis, a nerve block or a coeliac plexus block. The advice of colleagues specializing in these forms of pain relief is often helpful, and the procedures may allow a reduction in dosage of opiate.
Nutritional support
166
Patients lose weight because of the local effects of the tumour (especially if this is in the alimentary tract), metastases, and as a result of treatment. Successful treatment of the primary tumour (e.g. by surgery) will be accompanied by a return of appetite and weight gain. During radical treatment with surgery, radiotherapy and intensive chemotherapy, weight loss is common. Calorie supplements can be given both in the form of oral supplements and intravenously to patients undergoing cancer treatment. However, the value of nutritional support is difficult to demonstrate. It is usual practice to consider total parenteral (intravenous) nutrition in patients undergoing exceptionally intensive treatment, such as high-dose chemotherapy or total-body irradiation with bone marrow transplantation, or during the intensive phases of chemotherapy for acute leukaemia, where there is prolonged hypoplasia. At these times, mucosal ulceration, nausea and diarrhoea make it difficult to feed the patient by mouth, and nasogastric tubes may produce monilial infection or exacerbate acid reflux and oesophagitis. Parenteral nutrition is also used for patients undergoing extensive surgery, particularly gut resection. The aim is to maintain the patient's weight and nutritional status so that recovery is more rapid, allowing further treatment with chemotherapy or irradiation to begin as soon as possible. There is no evidence that additional enteral or parenteral feeding is of value in the management of advanced
TABLE 6.13 Useful analgesics Drugs Mild analgesics Aspirin Paracetamol Indole derivatives (e.g. indomethacin) Propionic acid derivatives (e.g. ibuprofen)
Duration of action (hours)
4-6 2-4 6-8 4-6
Moderate analgesics Codeine (and dihydrocodeine) Pentazocine Dipipanone Oxycodone
4-6 3-4 6 8
Strong analgesics Morphine sulphate Diamorphine Dextromoramide Pethidine Methadone
4-6 (up to 12 with sustained-release forms) 4-6 4-6 3 12-30
cancer where cure is impossible. It is, however, important to encourage the patient to eat by giving food that appeals (often in the form of smaller, more frequent meals), by controlling nausea with drugs such as metoclopramide, and by the careful use of corticosteroids which improve wellbeing and stimulate the patient's appetite.
Tumour lysis syndrome In some very sensitive untreated cancers, chemotherapy may produce massive tumour breakdown when treatment is first given. This process may be accompanied by severe metabolic disturbances, which constitute the tumour lysis syndrome. The syndrome is usually associated with the early phases of treatment of lymphoma and leukaemia in children and, less frequently, in other chemosensitive childhood tumours. In adults the syndrome is infrequent but may occur with treatment of lymphoma, especially if there is impairment of renal function (such as ureteric obstruction by lymph nodes), which diminishes renal excretion of the tumour products. Tissue destruction releases large amounts of urate, phosphate and potassium. The urate may be deposited in the renal tubule, causing reversible renal failure, which in turn diminishes further urate excretion. Severe hyperuricaemia and renal failure may necessitate dialysis. This complication can be largely avoided by using the xanthine oxidase inhibitor allopurinol (100-200 mg 8-hourly) before and during the early phase of treatment, and by establishing and maintaining a diuresis during the first 24-48 hours.
Hyperkalaemia may be severe, particularly if renal failure occurs, and may need treatment with glucose and insulin (see Ch. 21). Hyperphosphataemia can be partly prevented by hydration and diuresis before and during the initial treatment.
NEW APPROACHES TO MANAGEMENT Progress in cancer treatment is slow, and results usually improve after many small refinements in therapy, rather than by sudden steps forward. Since the late 1970s only modest progress has been made, and the search for new drugs and new approaches continues.
Haemopoietic growth factors (see also Ch. 23) The production of haemopoietic growth factors by recombinant technology has allowed their use in chemotherapy to reduce the period in which the white count is low. Proven advantages are a modest reduction in the period of neutropenia and somewhat diminished antibiotic use. It is possible that the intensity of chemotherapy may be increased by avoiding dose reductions. It has yet to be proved that the routine use of growth factors increases the cure rate of cancer by allowing increasing dose of chemotherapy. They are used if the dose of a curative treatment would otherwise have to be reduced but can be maintained if growth factors are given. Granulocyte colony-stimulating factor (GCSF) is most widely used. It is given for 7-10 days subcutaneously following chemotherapy. It may cause fever and bone pain. It is expensive and should only be given if there is a clear indication, and not if treatment is palliative.
High-dose therapy Allogeneic (from one individual to another) bone marrow transplantation was introduced for the treatment of acute myeloblastic leukaemia in the early 1970s. Allogeneic marrow was infused after an attempt had been made to eradicate the leukaemia by total-body irradiation and high-dose cyclophosphamide. The results (Ch. 23) showed that the leukaemia might be eradicated. This finding led to the consideration of total-body irradiation in the management of other disorders, such as lymphomas and myeloma. More recently, attempts have been made to eradicate leukaemia, lymphoma and some solid tumours with very high-dose chemotherapy (rather than total-body irradiation) using autologous (taken from, and reinfused into, the same individual) bone marrow, harvested just before treatment, as a means of preventing life-threatening myelosuppression. These approaches are based on the assumption that increasing doses of chemotherapy will eradicate residual disease when multiple conventional doses will fail.
This approach has been revolutionized in the last few years by the finding that the haemopoietic progenitor cells appear in large numbers in the peripheral blood following chemotherapy and the use of haemopoietic growth factors. These cells can be 'harvested' by a leukopheresis machine and used, instead of bone marrow, to reconstitute the blood count following high-dose treatment. This is called a peripheral blood stem cell (PBSC) transplant. High-dose therapy and PBSC transplant has now become a safe and much cheaper treatment allowing further exploration of the value of high-dose therapy.
6
Monoclonal antibodies to cell surface antigens Many tumours express oncofetal or differentiation antigens not usually found in the normal tissue from which the cancer is derived. An example are the antigens found on the surface of both acute lymphoblastic leukaemia cells, lymphomas and normal lymphatic progenitor cells. The development of monoclonal antibodies of defined specificity has resulted in the production of monoclonal reagents, which bind preferentially to antigens on the surface of some tumour cells (and to those normal cells that express the antigen). Cytotoxic drugs, radioactive isotopes, and enzymes capable of converting an inactive cytotoxic agent to an active one, can be attached to such antibodies with the aim of selectively destroying the tumour. There are considerable difficulties with this approach: heterogeneity of antigen expression within the tumour; variable uptake and distribution of antibody in normal and malignant tissue; and the production of antibodies by the patient against the foreign (usually mouse) protein. Nevertheless, there are interesting future possibilities for therapy and tumour localization using this approach.
TRIALS OF TREATMENT Many cancers have a long and unpredictable natural history: cancer of the breast, for example, is associated with an excess mortality for over 25 years after diagnosis. If survival is the endpoint of treatment, assessment of therapy in this disease will mean prolonged periods of observation. In small cell lung cancer or acute myeloblastic leukaemia, on the other hand, a majority of patients are dead within 2 years, and relapse in those who survive is less frequent beyond that point. Treatment trials will therefore give answers quickly. In assessment of therapy of a cancer (such as breast cancer), there may be more than one endpoint to be considered: does the treatment give effective local control: does the treatment influence the onset of metastasis; is the proportion of survivors at 5 and 10 years or longer increased? Comparison of a treatment with historical controls is very unreliable, as diagnostic and staging criteria are changing constantly and selection of cases is thereby
167
altered. Randomized prospective studies are now regarded as the only reliable way of making a comparison between two treatments. Such studies must include sufficient numbers of patients to allow the questions to be answered with confidence statistically. The studies require careful documentation and prolonged observation of the patient groups. The treatments being compared must be justifiable ethically and the design of the study capable of giving a clear answer to the central question. These considerations mean that treatment trials in cancer are complex and usually demand collaboration between many different centres: even, in the case of rare tumours, between different countries. To detect a 5 % difference in survival with confidence may require many hundreds or even thousands of patients in a study. Nevertheless, a 5% difference in long-term survival in breast cancer, if achieved by a non-toxic hormonal means, would mean 1000 lives saved a year in the UK alone - more than the number of patients cured of Hodgkin's disease. However, a 5% difference achieved by means of toxic chemotherapy might be regarded with less enthusiasm. At present, because progress in cancer management is slow and achieved only by small improvements, large-scale clinical trials are the only reliable way of validating new treatments.
CARE OF THE DYING
168
Many patients with cancer die from their disease; it is the responsibility of the oncologist to be sure that aggressive management of the tumour is not thoughtlessly continued beyond the point at which cure is possible. This does not mean that treatment is discontinued, but that the aim of management becomes palliative rather than curative. In skilled hands palliative treatment can often give the patient a period of happy life free from distressing symptoms. Palliation may require radiotherapy, e.g. for painful bone metastases or bronchial obstruction; chemotherapy at low dose to suppress constitutional symptoms in lymphoma; aspiration of ascites or pleural effusion; or surgical pinning of a bone weakened by metastasis. There is more to palliative management than pain relief. Nevertheless, relief of pain, control of nausea and treatment of depression become increasingly important as the disease progresses. The most important component of management at this stage is the psychological support of the patient and his or her family. Support comes from the nature of the relationship that the patient has established with the medical team throughout the illness. Extra help may be needed from domiciliary nursing teams, which are increasingly providing expert and readily available advice on symptom control to patients in their own homes. Many patients prefer to remain at home in the last few weeks of life, and the family doctor and specialist nurses can often make this possible. Alternatively, the patient's wishes or family circumstances may make admission to a hospital or hospice necessary.
The nursing practices and the approach to symptom control that have been developed in hospices are now being incorporated into hospital practice. In some hospitals, nurse specialists have been appointed to advise on these aspects of management. The gradual awareness of death produces many different reactions. The patient may become angry and direct this at the medical or nursing staff. Feelings of apathy, hopelessness and fatigue are common, and depression may be severe enough to need treatment with antidepressants. The support of relatives and friends is essential. Meticulous attention to detail and a willingness to take time to talk to the patient are just as important at this stage in management as during the early stages when the intention may have been curative. Even though active management of the cancer has finally failed, this does not mean it was not worthwhile, nor is it a reflection on the abilities of the medical or nursing staff. The fact of treatment failure leads some doctors to avoid seeing their patients at this stage. This is bad practice and increases the patient's feeling of isolation and helplessness. Many non-medical agencies are able to help the patient and his or her family. Patients with religious beliefs may gain great comfort from their clergyman and other members of their local religious community. Counselling and support groups have been set up in many towns to provide help during the illness and to the bereaved relatives afterwards.
ALTERNATIVE THERAPY A multitude of unorthodox approaches to management of cancer have been offered to patients over the years. These usually have echoes of current medical practice. Serotherapy was used after antitoxins were introduced for infectious disease; tooth extraction was practised, based on the interwar notions that dental sepsis was responsible for chronic inflammation. Nowadays, psychological ideas are translated into visualization therapy, and concern over pollution and diet are transmuted into strict vegetarian or fatfree diets. The uncritical assumption that answers will be found in nature has led to a wide range of herbal remedies, some of which (e.g. laetrile) are somewhat dangerous. As with many chronic diseases, the practitioners of homeopathy and faith healing offer their remedies. Most of these approaches share certain recognizable characteristics. These include a tendency to borrow the jargon of medicine without its science; a belief that all tumours can be treated by the same or similar remedies; a tacit or explicit assumption that there exists a medical conspiracy to conceal the truth about the remedy in question; and a complete failure to adopt any of the proven methods of validation of the results of treatment. What these approaches offer distressed and anxious patients is a feeling that they can themselves do something to combat their disease, a glimmer of hope that they might
be cured, and relief from the side-effects of conventional treatment if this is abandoned. These benefits are often a reflection of inadequacy in the relationship of the patient and doctor, rather than a clearly held view by the patient and family. The damaging aspects of these approaches are that they may induce the patient to abandon a worthwhile treatment, weaken the relationship between doctor and patient, and impose unpleasant constraints on the patient's life, such as rigid dietary control. These disadvantages should be discussed with the patient and, if patients are thinking of abandoning a potentially curative treatment, every attempt should be made to persuade them not to do so. Nevertheless, the doctor's role in management is to offer help, advice and expertise; the patient has the right to choose what to do. In many cases no great harm will be
done, and an experienced doctor will make it clear that the patient is welcome to continue under his or her care now and in the future.
6
FURTHER READING DeVita V T, Hellam S, Rosenberg S 1997 Cancer: principles and practice of oncology, 3rd edn. Lippincott, Philadelphia. A comprehensive cancer textbook. Souhami R L, Tannock I, Hohenberger P, Horiot J C 2001 Oxford textbook of oncology, 2nd edn. Blackwell, Oxford. A comprehensive textbook of oncology. Souhami R L, Tobias J S 1997 Cancer and its management, 2nd edn. Blackwell, Oxford. A medium-sized text covering most aspects of cancer treatment.
169
This page intentionally left blank
7 Ageing and Disease Peter W Overstall
Theories of ageing 172
Altered reactions to disease 189
Sociological aspects 173
Clinical approach 191
Special features of disease in old age 174
Investigation in the elderly 193
Autonomic dysfunction 178
Assessment of fitness for operation 196
Nutrition and ageing 179
Prescribing for the elderly 197
Balance and falls 180
Cholesterol lowering in stroke 200
Urinary incontinence 185 Faecal incontinence 187 Sleep and insomnia 187
Rehabilitation 201 Community care and long-stay care 202
Sexual function 189
Most ill health in developed countries now occurs in elderly persons. Not only are the elderly more prone to illness, but the proportion of elderly people has increased considerably in the last 100 years. The response of an individual to growing old depends more upon the previous pattern of life than upon anything in the ageing process itself, so that one of the features of old age is increased differences between individuals.
LIFE EXPECTANCY Life expectancy is the average observed years of life from birth, or from any stated age. Since 1900, life expectancy at birth in the UK has increased from 49 to 75 years for men and from 52 to 80 years for women (Fig. 7.1). This is mainly the result of reductions in infant mortality from the major
1 MCQ 7.1
infectious diseases. Tuberculosis, acute rheumatic fever, smallpox, diphtheria, tetanus and poliomyelitis now account for less than 2% of the ill health they caused in 1900. These changes are largely due to improvements in nutrition and to public health measures which have reduced water- and food-borne diseases. The influence of immunization and treatment on mortality is comparatively much smaller. Life expectancy may also deteriorate sharply. In the former Soviet Union and eastern bloc countries male life expectancy has fallen since 1980 from 62 to 58 years. This has been blamed on the disruption caused by the transition to market economies and the resulting poverty, unemployment, homelessness, excessive drinking and smoking. Life expectancy in sub-Saharan Africa has also fallen since the 1980s because of HIV/AIDS. Much interest was aroused by early studies in industrialized countries which suggested that there was a connection between income inequality and life expectancy, implying that income inequality is bad for the whole population. It has now been shown that there is no association at the population level, although household income has a powerful effect on mortality. In the UK life expectancy at birth for daughters of semiskilled and unskilled manual workers is 3 years less than for those born to professional and managerial classes. For their brothers there is a 5-year class divide.
CHANGES IN THE ELDERLY POPULATION The age structure of a population is affected by infant mortality and by fertility rates, late-age mortality and migration. Demographic ageing, i.e. a shift towards a larger proportion of elderly people in the population, began in Europe in the early 20th century, as a result of falling fertility. This change has already occurred in the UK, so that during the 1990s there was very little overall change in the population aged 60 years and over, but a rapid expansion of the over-85s. After 2001, the cohort of the post-1945 'baby boom' reaches retirement and there will then be a further rise. The proportion of elderly in the population will not increase thereafter unless there are further substantial falls in both fertility and late-age mortality. Fertility rates are declining worldwide and we can anticipate the most rapid changes in age structure of the population to be in the developing world (Fig. 7.2). Note the narrowing of the base of the pyramids during the 21st century due to lower fertility rates. The population pyramids in Europe and the western Pacific are starting to invert. Already over 60% of older people live in developing countries, and by 2020 this will reach 70%. Absolute numbers of elderly in the world will increase from 385 million now to 1.5 billion in 2050. Most of this increase will occur between 2025 and 2050, as children bom in the 1960s reach the oldest population cohorts. 1
171
FIG. 7.1 Life expectancy at birth (both sexes) in WHO regions (weighted by population)
SUMMARY 1 Epidemiology of ageing • In the UK, the increase in life expectancy at birth seen in the early part of the 20th century was due largely to a decrease in infant mortality. • The rising percentage of elderly in the population is due to falling fertility and lower mortality rates, particularly in the very old. • During the 1990s there was a pause in the overall growth of the elderly population in the UK, but the over 85s increased by onethird. • Developing countries face a growing number of elderly in the first half of the 21st century.
FURTHER READING ON LIFE EXPECTANCY Mackenbach JP 2002 Income inequality and population health. BMJ 324: 1-2. FIG. 7.2 Population pyramids of WHO regions
THEORIES OF AGEING
172
Ageing is a complex process resulting from intrinsic and extrinsic damage to the organism at a rate dependent on each particular individual's genetic background and environment. The resulting disability is not fixed or inevitable. For example, high-tone deafness and high blood pressure are common in elderly Britons, but are absent among
elderly persons in the Easter Islands. Osteoporosis is common in western Europe and the USA but rare in China. Thus descriptions of physical decline are too variable to be useful for defining ageing. A better approach, which allows populations to be compared and so highlights differences in environmental or intrinsic ageing factors, is to define ageing
as a process which brings about an ever-increasing age-specific mortality (i.e. the older the individual becomes the more likely he or she is to die). In the UK mortality is at its lowest around puberty, and ageing can be said to begin at this point, rising progressively throughout adult life. There is general agreement that ageing is at least partly genetically determined. Each animal species has a specific lifespan: the maximum recorded longevity of Marion's tortoise, for example, is over 152 years, for man 122 years, and for golden hamsters 2 or 3 years. In species of Drosophila, the Fl hybrid has a greater longevity than either parental strain. Female sex also generally confers increased longevity in a number of different species. Individuals whose parents live to the age of 75 years or more live longer than those whose parents died before the age of 60, and siblings of centenarians have a four times greater chance than average of surviving to their early 90s. The mean difference in longevity in dizygotic twins is twice that of monozygotes. Current theory sees the ageing process as non-adaptive, with ageing evolving as a late by-product of processes that benefit the individual during its earlier, more fecund lifespan. With limited energy resources, an organism has to strike the right balance between investing in bodily maintenance and repair, and producing and rearing its young. Oxidative metabolism plays a key role in cellular ageing. Over the years free radicals cause increasing damage to enzymes, structural proteins, and nuclear and mitochondrial DNA. Mitochondria are the main intracellular source of free radicals, and with increasing age more free radicals are generated while at the same time antioxidant production declines. This suggests that defective mitochondria are central to the process of ageing. The only proven way to delay ageing in higher animals is to eat a low-calorie diet. A 50% calorie diet restriction increases the lifespan of mice from 38 to 56 months. Whether humans would show a similar gain is unknown, but restricting calories by onethird results in lower blood pressure, cholesterol, glucose and white blood cell counts.
FURTHER READING ON THEORIES OF AGEING Kirkwood T 1999 Time of our lives: the science of human ageing. London: Orion Publishing.
SOCIOLOGICAL ASPECTS Retirement age is an administrative measure without relation to the capacity of individuals. Most people at retirement can expect good health for several years, and for developed countries the World Health Organization has introduced a new demographic indicator of 'life expectancy without incapacity'. At age 65 this is estimated to be between 8 and 11 years for men, and between 9 and 12 years for women. People in developed countries are main-
taining better health in later life than ever before, and severe disability in older people is declining at 1.5% per annum. For example, it is anticipated that in the USA the number of severely disabled elderly will halve between 2000 and 2050. The notion that the older you get the sicker you get has been challenged by the finding that centenarians appear to have lived most of their lives in good health, with a relatively rapid terminal decline. This suggests that the older you get the healthier you have been, and promises a potential reduction in morbidity and disability as people approach the limits of their lifespan. None the less, medical costs are four times greater in the first decade of retirement than during working life, and by the second decade of retirement they are nine times as great. The top diagnostic categories for healthcare costs for the over-70s are dementia, stroke, musculoskeletal disorders and falls.
7
ATTITUDES TO THE ELDERLY In Europe the falling birth rate, increased longevity and trend to early retirement has reduced the workerpensioner ratio. In 1901 4.7% of British citizens were aged 65 or over; today this figure is 15.6%. This striking change had occurred by the 1980s (since when it has levelled off) and was not accompanied by undue economic strain or intergenerational strife, despite concerns in the 1960s and 1970s about 'dependency ratios' (the ratio of non-working people to those of working age). Discrimination against elderly people springs from three main impulses: a fear of death and dying, a social belief that falsely associates success with productivity, and misconceptions about the inevitability of senility. There is, in fact, little or no sign of a significant decline in happiness or life satisfaction with age. Over 80% of elderly people maintain independent house-holds, three-quarters of those over 85 can wash all over unaided, 95% can go to the toilet alone, and only 5% of people over 75 have significant dementia. It is true that institutionalization rates for the very old have increased considerably in the last 30 years owing to a decline in the amount of family support available to the elderly. Women aged between 45 and 60 have carried the brunt of community care, and since 1900, when there were 83 women in this age group for every 100 people over 65, there are now only 45. None the less, families do still care for their elderly relatives and indeed provide far more support than is available from health or social services. Family support ratios compare the relative sizes of older and younger generations and indicate the availability of family support for the elderly (Fig. 7.3).
RETIREMENT Retirement is now a well established part of life in developed countries and is starting to appear in developing countries among government employees and urban
173
FIG. 7.3 Parent support ratio in WHO regions (weighted by population) The increase in the parent support ratio (population aged over 80 divided by the population aged 50-64) is most marked in developed countries, particularly Japan (increase in ratio from 8 to 41 between 1975 and 2025).
174
workers (Fig. 7.4). Most people no longer see it as a traumatic event marked by major losses to the individual, but instead prepare for it as a normal and expected part of the life-cycle and welcome it as a time of opportunity and increased leisure. The rate of early retirement is, therefore, rising. Since 1975 there has been a decline in the UK of about one-third in the number of men aged 60-64 in fulltime employment. Of course, not all of these early retirements are voluntary, and there has been a noticeable trend for businesses in economic difficulties to make their older rather than their younger workers redundant. The period of active retirement, in which many take up part-time or voluntary work, ends when the person becomes disabled by declining physical or mental health. The difference between these two stages of old age depends on functional capacity, not on chronological age. Some people do find that retirement produces troublesome stresses. The most frequent problem is adjustment to a lower level of income. Some suffer from a loss of selfesteem, others fear the onset of ill health, or are distressed by their idleness. Most of these problems fade as the new pattern of activity is taken up, and serious depression is not a particular feature of retirement. Claims of large numbers of super-centenarians living in certain geographical regions - such as Vilcabamba in Ecuador, Hunza in Pakistan and Abkhasia in Georgia have been shown to be exaggerated. However, it is true that the inhabitants of each of the above areas are relatively long-lived, and in each case the esteem and merit enjoyed by a person increases with age. There is no retirement age
FIG. 7.4 Percentage of the population aged 65 years and over that is economically active worldwide The developed countries have still to find a satisfactory role for their unemployed elderly.
and old people continue to play an active role in the economic and social life of their communities.
FURTHER READING ON SOCIOLOGICAL ASPECTS Grundy E 1996 Age, 'dependency' and intergenerational relationships. Rev Clin Gerontol 6:303-304.
SPECIAL FEATURES OF DISEASE IN OLD AGE Measurement of physiological functions in healthy young adults gives fairly uniform results, with a narrow range between the upper and lower limits of normal. From about 30 years of age, a functional decline in performance can be detected in most organs and body systems (Fig. 7.5). However, the organs and systems age differentially, so that the variation both within and between individuals increases with age. The chronological age of an old person may therefore bear little relation to his or her functional age (Fig. 7.6), and the response of an old person to the stress of illness will be more unpredictable than that of a young adult. Degenerative changes occur throughout the body with increasing age, but these may become sufficiently marked to constitute a pathological process. The distinction between this and normal physiological ageing is often difficult to make, and there is increasing recognition that so-called normal ageing is the result of occult pathology. These changes have an important bearing on the management of the patient, as will be seen in the examples that follow.
TABLE 7.1 Good practice guidelines in osteoporosis 1. Frail housebound elderly should be prescribed calcium and vitamin D, assessed and managed for falls risk and considered for hip protectors.
7
2. Patients with osteoporosis risk factors should have their bone mineral density measured (DXA at the hip). If their T-score is above -1 they can be reassured. If between -1 and -2.5 they should be given lifestyle advice and osteoporosis treatment if there is a history of a previous fracture. If the T-score is below -2.5 they should have lifestyle advice and osteoporosis treatment.
30
40 Age (years)
3. Patients with a previous fragility fracture should have routine investigations (blood count, ESR, bone and liver function tests, serum creatinine, serum TSH) and, because they are at high risk for a further fracture, should be started on osteoporosis treatment and given lifestyle advice.
FIG. 7.5 Age decrements in physiological functions in males A Fasting blood glucose; B resting cardiac index; C maximum breathing capacity; [6] maximum work rate.
cause of visual impairment is age-related macular degeneration. This is untreatable, but about 80% of patients can improve their reading performance with simple magnifying devices and brighter illumination.
THE AGEING EAR
FIG. 7.6 The relation between resting cardiac output and age in men without circulatory disorders Note that several men over the age of 70 have values similar to men in their 30s.
Impaired hearing increases with age and can contribute to poor health, social isolation, depression and (probably) paranoid psychosis. About 30% of the elderly regard themselves as having a hearing impairment, but audiometric testing reveals a much higher prevalence (60%) in those aged over 70. Presbyacusis is age-related loss of high-frequency hearing, but this cannot be reliably distinguished from the effect of ototoxic drugs, diuretics or vascular disorders. Some of the hearing loss usually regarded as an inevitable part of old age may be due to our noisy environment.
OSTEOPOROSIS (See Table 7.1)
THE AGEING EYE The force required to focus the eye increases considerably at about 40 years of age and, by 45 or 50, accommodation will be so poor that for most persons small print can be read only at arm's length (presbyopia). This is a result of both a reduction in elasticity of the lens capsule and a thickening of the lens, which prevents it adapting its shape to focus on near objects. Opacities and general yellowing of the lens, together with an age-related meiosis, cut down the amount of light entering the eye and reduce visual aculity. A loss of cells in all regions of the visual pathway affects perception and contrast sensitivity. About 20% of those aged 75 and over have a visual acuity of less than 6/12. With continuing advances in the management of cataracts, glaucoma and diabetic retinopathy the main
Postmenopausal (type 1) osteoporosis results from accelerated bone loss due to oestrogen deficiency. There is mainly a loss of trabecular bone, typically resulting in fractures of vertebral bodies and the distal forearm in women in their 60s and 70s. Senile (type 2) osteoporosis is a slower, age-related bone loss that occurs in both sexes. There is cortical as well as trabecular bone loss, which typically results in femoral neck fractures in men and women in their 70s and 80s. These fractures are a serious threat to older people and are associated with a 20% increased risk of either death or institutional care over the following year. Secondary causes of osteoporosis include endocrine (thyrotoxicosis, hypogonadism, hyperadrenocorticism) and gastrointestinal (malabsorption, primary biliary cirrhosis) disorders, rheumatoid arthritis, malignancy, hypertension, and drugs such as corticosteroids and heparin. Other risk
175
factors include a strong family history, inactivity, excessive alcohol and smoking. Unfortunately, clinical risk factor profiles correlate poorly with both bone density and fracture risk, and the most useful way of assessing increased osteoporosis risk is to measure bone density by dual energy X-ray absorptiometry. Ultrasound assessment of the skeleton is a promising alternative method. The predictive value of bone density is similar to that of blood pressure in determining the risk of stroke. The relative risk of fracture increases two to three times for each standard deviation decrease in bone density. Definite indications for bone density measurements include fracture after minimal trauma in previously fit individuals, past history of early menopause (<45 years) in women up to the age of 70 years, underlying secondary causes of osteoporosis and apparent osteopenia on X-ray. There is currently no evidence to indicate that routine population screening is valuable, and instead a case-finding strategy is used. Bone density measurements are not needed in patients at greatest risk, such as those over 80 years who are frail and housebound or institutionalized, those with a previous fragility fracture and patients taking prolonged oral steroid therapy (>7.5 mg prednisolone/day), as they should be treated regardless of their bone density. Prevention of osteoporosis depends on achieving the maximum peak bone mass (regular weight-bearing exercise and dietary calcium intake of 1000-1500 mg/day, between the ages of 15 and 25) and reducing the rate of bone loss by encouraging elderly people to keep exercising, maintain a daily calcium intake of 1000 mg, avoid falls (see p. 175), stop smoking and moderate alcohol intake. These are all worthwhile interventions at the population level. For the individual postmenopausal patient at risk, particularly if she has climacteric symptoms such as hot flushes, the single most effective intervention is hormone replacement therapy (HRT). The greatest benefit is gained by starting treatment soon after the menopause. For current users of HRT there is a 65% reduction in hip fracture risk but 5 years after stopping HRT most of the benefit is lost. For optimal protection HRT should be continued for long periods. Long-term use increases the risk of breast cancer; for women aged 50-70 the risk of developing breast cancer increases from 51 cases per 1000 women to 57. HRT reduces the risk of coronary artery disease but the benefit is not as great as early studies suggested. The risks of developing Alzheimer's disease appears to be reduced. Raloxifene is an alternative to HRT for the postmenopausal patient without climacteric symptoms, which can be exacerbated by raloxifene. It appears to be associated with a lower incidence of breast cancer and does not cause
1
176
MCQ 7.2
2
Fig. 7.1
endometrial bleeding, but, like HRT, it can cause deep vein thrombosis. For the elderly patient HRT is rarely indicated and bisphosphonates or calcium and vitamin D are used instead. The best evidence for efficacy in reducing spinal, non-vertebral and hip fractures is for alendronate and risedronate. Calcitonin has proven efficacy for preventing spinal fractures and is also effective in relieving the pain associated with vertebral fractures. Calcium and vitamin D have proven efficacy in preventing non-vertebral and hip fractures, and it has been argued that these supplements should routinely be prescribed for frail housebound elderly persons. Corticosteroid treatment doubles the risk of fractures of the hip and distal radius and quadruples the risk of vertebral fracture. All patients over 65 years taking prednisolone 7.5 mg a day or more should have treatment to prevent osteoporosis: the first choice is a bisphosphonate1212.
FURTHER READING ON OSTEOPOROSIS Royal College of Physicians, 2000. Osteoporosis: clinical guidelines for prevention and treatment. RCP, London.
DEMENTIA AND NORMAL AGEING Cross-sectional and longitudinal studies consistently demonstrate a decline in cognitive function with increasing age. A decline in cognitive ability is not confined to old age, and tests that measure the ability to solve novel problems rapidly (fluid intelligence) show a fall in performance by the late third and early fourth decades. Age-related changes in cognitive function appear to be related to a general decline in the speed at which information is processed. Thus, highly practised skills, such as vocabulary test scores, alter very little with age, but timed novel problem solving, reaction time tests and the ability to learn new material decline with increasing age. Ill health undoubtedly affects cognitive performance, particularly cardiovascular disease. Congestive cardiac failure doubles the risk of cognitive impairment, and systolic hypertension in middle age increases the likelihood in old age of developing white matter hyperintensities (on MRI) and dementia. Other predictors of cognitive decline are increasing age, 'old age forgetfulness', low educational status, lack of social and physical activities and possession of the ApoE-4 allele. The major cause of intellectual loss in old age is Alzheimer's disease (AD), followed by vascular dementia and Lewy body dementia. There is increasing recognition that vascular risk factors are important predictors of AD as well as of vascular dementia. Severe atherosclerosis carries a threefold risk of developing AD, and the Syst-Eur study showed that treating systolic hypertension halves the likelihood of developing dementia. AD is a distinct entity rather than a mere exaggeration of normal ageing, and prevention strategies
17
pathological decrements in SUMMARY 2 Normal vs physiological performance in old age Normal age-related functional decline
pathological process
Impaired sight (presbyopia)
Cataracts, macular degeneration
Impaired hearing (presbyacusis)
Effects of ototoxic drugs, diuretics or vascular disorders
Bone loss
'Accelerated' osteoporosis
Decline in intellectual function
White matter lesions due to hypertension; Alzheimer's disease
Impaired glucose tolerance
Diabetes
Minor gait slowing and balance impairment (increased sway)
Parkinson's, Alzheimer's or cerebrovascular disease; dementia; vestibular lesions; cervical spondylosis; visual problems
Altered sleep pattern
Insomnia due to nocturia (due to detrusor instability); pain, depression, etc.
need to concentrate on 'cognitive impairment, not dementia' in people aged 65 and over. This has twice the prevalence of all types of dementia combined and is associated with functional disability and the need for institutional care, yet little is known of its natural history.
IMPAIRMENT OF BIOCHEMICAL HOMEOSTASIS Most normal old people can, under resting conditions, maintain their internal environment at levels similar to those in the young. When stressed, however, it is apparent that homeostatic mechanisms in the elderly are impaired. Blood glucose control and osmoregulation are two good examples of this.
The control of blood glucose The average fasting blood glucose level increases only slightly with advancing age. When a glucose load is imposed, however, the rise in maximum blood glucose levels is clearly greater, and the return to resting levels slower, in old people (Fig. 7.7). The upward drift of blood glucose with age produces diagnostic difficulties. If criteria used to diagnose diabetes in young populations were applied to the elderly, there would be a considerable increase in the number of those diagnosed as diabetic from the glucose tolerance test. Thus, elderly patients with an impaired glucose tolerance test (i.e. a 2-hour post-glucose blood sugar of 7-llmmol/L) should probably not be regarded as diabetic if they are asymptomatic, but they do carry a
Minutes FIG. 7.7 Mean blood sugar levels after a 50 g oral glucose load in a cross-sectional population study Known diabetics have been excluded.
higher risk of developing frank diabetes. Recent American Diabetic Association (ADA) criteria propose the use of fasting blood sugar, with 6.1-6.9 mmol/L indicating impairment and 7.0 mmol/L as the new diagnostic cut-off (instead of the WHO fasting criterion of 7.8 mmol/L). The fasting ADA criteria are less predictive than the WHO criteria of cardiovascular risk in the elderly, and for older adults a fasting glucose cut-off of 7.8mmol/L is preferable.
Osmoregulation On average, young adults maintain their blood osmolality in the range 280-295 mmol/kg. Although resting plasma osmolality is unchanged in the elderly, the osmoregulatory response to 24-hour water deprivation is impaired, even in good health. Despite developing higher plasma osmolality and sodium concentrations in response to dehydration, elderly subjects do not respond with appropriate thirst and water intake. They do not drink sufficient water to replenish their body water deficit and return plasma sodium levels to normal. Not only is there reduced thirst and water intake following dehydration, but the old person's kidneys are less able to retain water, due to reduced renal responsiveness to arginine vasopressin (AVP). These changes can predispose even healthy old people to fluid and electrolyte disturbances when there is excessive salt and water loss. They are also at risk of overhydration and hyponatraemia because they are unable to excrete excess water, mainly because of a decline in glomerular filtration rate with age. Particular care is needed with intravenous infusion to avoid overhydration and hyponatraemia. Postoperative patients are at high risk, especially if they have been taking a thiazide diuretic and as a result have mild hyponatraemia. Surgical stress causes inappropriate ADH secretion, which increases the hypona-
177
traemia. Sympathetic blockade resulting from spinal anaesthesia lowers the blood pressure, and if in an attempt to counteract this large volumes of i.v. 5% dextrose/saline are given, serious hyponatraemia ensues, which carries a 20% risk of brain damage or death. Hypotonic fluids must not be given to elderly postoperative patients.
FURTHER READING ON SPECIAL FEATURES OF DISEASE IN OLD AGE Mosekilde L 1998 Aging of bone. Rev Clin Gerontol 8:281-296. O'Neill P A 1997 Aging homeostasis. Rev Clin Gerontol 7:199-211. Sorlie P, Gordan T, Kannel W B 1980 Body build and mortality: the Framingham Study. JAMA 243:1828-1831. Staessen J A, Fagard R,Tuijs L et al 1997 for the Systolic Hypertension in Europe (Syst-Eur) trial investigators. Randomised double-blind comparison of placebo and active treatment for older patients with isolated systolic hypertension. Lancet 350:757-764.
AUTONOMIC DYSFUNCTION This results from a number of factors: a reduction in nerve density and neurotransmitter concentrations in the autonomic nerves; reduced responsiveness of effector organs, such as blood vessels and stretch receptors in arterial walls; and a decline in cellular p-adrenergic sensitivity. Dysfunction may follow central lesions such as cerebrovascular disease, Parkinson's disease, Shy-Drager syndrome, Wernicke's encephalopathy (due to thiamine deficiency associated with alcoholism) and Alzheimer's disease. Peripheral autonomic neuropathy may occur in diabetes mellitus, chronic alcoholism and malignancy. Autonomic dysfunction may also be caused by drugs such as phenothiazines, tricyclic antidepressants and haloperidol. The important clinical consequences are orthostatic hypotension (Table 7.2), bowel and bladder disturbances, impotence and impaired thermoregulation.
AGEING AND THERMOREGULATION
178
Under normal circumstances the body core temperature is about 37°C with, in temperate climates, a skin temperature of 33°C, giving a core-skin temperature gradient of 4°C. Thermoregulatory responses are impaired in old age due to disordered autonomic function. This usually passes unnoticed, but in times of environmental stress the old person is less able to maintain a constant deep body temperature. Surveys of old people living at home in winter show that only 0.5% had frank hypothermia (deep body temperature less than 35°C) but that 10% had a deep body temperature below 35.5°C. The latter had impaired
TABLE 7.2 Orthostatic hypotension • Fall in systolic blood pressure of at least 20mmHg or a fall of 10 mmHg or more in diastolic pressure on standing • Prevalence in elderly between 10 and 24% • Age-related aetiology Impaired baroreceptor response Failure of cerebral autoregulation Increased arterial and arteriolar rigidity Autonomic dysfunction • Cardiovascular causes Low cardiac output (e.g. heart failure) Restricted cardiac output (e.g. aortic stenosis) Absolute hypovolaemia (e.g. blood loss) Relative hypovolaemia (e.g. venous pooling) • Drug causes Centrally acting (e.g. L-dopa, MAOIs, sedatives) Vasodilators (e.g. nitrates, alcohol) Diuretics, calcium channel blockers • Symptoms Typically these consist of faintness, giddiness and blurring of vision, and are precipitated by standing and exacerbated by exertion or a heavy meal. However, if there is a lesion of the parasympathetic system these symptoms may be absent, so that despite a fall in blood pressure on standing there is no warning giddiness. The patient remains upright and experiences symptoms such as profound weakness, falls, confusion and pallor • Management Raise head of bed 15-20°, leg and abdominal compression, 9afludrocortisone 0.1 mg daily initially, increasing by 0.4mg each week. Other drug treatments include mididrone, dihydroergotamine, indomethacin, domperidone (in Parkinson's disease) and octreotide (for postprandial hypotension)
thermoregulation, as shown by a core-skin temperature gradient only half that of normal individuals. The elderly may also suffer impairment of thermal perception. Young persons can detect temperature differences as small as 0.8°C, but old people only perceive differences of 2-5°C. Furthermore, the elderly shiver less efficiently in response to cooling, with little more than half the metabolic heat production seen in young subjects. Old people are thus not only less able to maintain their deep body temperature when subjected to cold stress, but may also be less aware of cold conditions and therefore fail to take the appropriate steps. This may explain why some old people can tolerate cold living conditions without discomfort. Although most British homes now have central heating, hypothermic patients are less likely than controls to have the heating on at the time of collapse. Typically, hypothermia occurring indoors results from a collapse due to illness, when the patient is alone, lightly clothed and not in bed. These conditions cause progressive core cooling. About 80% of the variation in mortality rates throughout the year is associated with changes in temperature
a
FIG. 7.8 Observed and expected deaths in the UK during the cold winter of 1984/5 Note the rise in death rate during the winter months and the excess deaths during the two exceptionally cold periods in early 1985.
FIG. 7.9 Relation of obesity to mortality found in the Framingham study The obesity index is the ratio of the subject's weight to a reference weight obtained from height and frame charts compiled by large insurance studies. Note that the lowest mortality occurs at an obesity index rather above 1.0.
FURTHER READING ON AUTONOMIC DYSFUNCTION (Fig. 7.8). For every degree change in the average winter temperature, the number of annual winter deaths rises or falls by about 8000. Thus, in the UK in the mild winter of 1983/4, about 30000 more elderly people died than during the summer months (a 14% increase). In the cold winter of 1984/5 this figure rose to 46000 (an increase of 20%). However, the majority of these 'excess' deaths are not directly due to hypothermia, but to coronary and cerebral thrombosis resulting from haemoconcentration and hypertension after cold exposure. Over the last 20 years there has been a decline in this excess winter mortality. About half of this decline is the result of non-seasonal factors, such as improved general medical care. The rest is due to improvements in home heating and greater car ownership, which reduces outdoor exposure to cold. The diagnosis and treatment of hypothermia are discussed in Chapter 2, p. 46. The elderly are also less able to cope with excessive heat, and the mortality rate during heatwaves rises with increasing age. In Chicago during the benign summers of 1992, 1993 and 1994 the heat-related mortality was 1, 3 and 9, respectively, but during the exceptionally hot summer of 1995 it rose to 515, with 162 deaths on a single day in July. It has been estimated that on the hottest day of a heatwave there are six extra deaths per 100000 population. There is much unrecognized heat illness and large variations in the mortality rates, as there are no international or even national agreements on the definition of heat-related death. Various criteria have been introduced, such as a core body temperature above 40.6°C at the time of death. Most models of global warming predict an increase in the frequency and intensity of heatwaves. The impact is likely to be greatest in mid-latitude cities with infrequent but extreme heatwaves, so that in cities such as Shanghai and New York there will be several thousand extra heat-related deaths annually by the middle of the 21st century.
Collin K J 1997 Aging, disease and the autonomic nervous system. Rev Clin Gerontol 7:119-126.
NUTRITION AND AGEING At retirement age in developed countries the average person is more likely to be obese than undernourished, but subsequently body weight and nutrient intake fall and, for the very elderly, the main concern is undernutrition. Moderate overweight is not associated with a high mortality in old age (Fig. 7.9), but low body weight is associated with a higher mortality in both fit old people and those admitted to hospital. Nutritional surveys have shown a marked decrease in energy requirements and nutrient intake with increasing age. However, this is due mainly to physical illness and reduced physical activity, which reduce appetite and energy expenditure. With increasing age there is a gradual decline in metabolism at rest, but this is relatively unimportant. For healthy active persons over 60 years of age the energy and nutrient requirements are similar to those of a 30-year-old. Longitudinal studies have shown that nutrient intakes are maintained in old people who remain in good health. Housebound elderly women consume 15% less carbohydrate and 46% less vitamin C than do active age-matched controls.
NUTRITIONAL DEFICIENCIES A survey of old people living at home found that 3% were suffering from malnutrition, including protein-calorie malnutrition, iron deficiency and specific vitamin deficiencies.
179
supplement of 800 IU vitamin D and calcium reduces fracture rates and should be widely prescribed to at-risk patients. 1
TABLE 7.3 Risk factors for malnutrition Unexpected weight change of more than 3 kg Physical disability Lack of sunlight Gastrectomy Mental confusion Chewing or swallowing difficulties Fewer than eight main meals, hot or cold, in a week Absence of fruit or vegetables in diet Food wastage Alcoholism Poverty (receiving financial support from state) Depression or loneliness
BALANCE AND FALLS
In most cases this was the result of some underlying medical problem and was only rarely due primarily to economic or social factors (see Table 7.3). Social factors are, however, likely to be important in cases of subclinical malnutrition. For example, 31% of those living alone had leukocyte ascorbic acid levels below 7.0ug/108wbc, compared to 8% of those living with a spouse. Scurvy remains rare even in the most isolated patients. Almost 10% of acute hospital admissions are seriously malnourished and this is associated with a slower rate of recovery, longer hospital stay and increased treatment costs. Patients should be weighed on admission and questioned about their diet. Megaloblastic anaemia due to a folate-poor diet is rare in old people in the UK. However, low serum folate levels are found in about 8% of elderly hospital patients, and often in patients with physical or mental disorders that interfere with shopping and cooking. Osteomalacia may contribute significantly to the skeletal rarefaction seen in old age (although this is more commonly due to osteoporosis). There are many causes of osteomalacia, but two of the most important are reduced vitamin D intake and low exposure to sunlight - two factors often present together in the elderly. More than half of elderly admissions to a general medical ward have 25-OHD concentrations below 37.5nmol/L and nearly a quarter of these have a level below 20nmol/L indicating severe deficiency. The current UK recommended intake of vitamin D for people aged 65 years and over is 400IU (10 ug) daily, and this is not easily achieved without fortified foods or adequate levels of sunlight. A daily
180
1
MCQ 7.2
0 Case 7.1 3
4
Fig. 7.3
0 Fig. 7.4 6
0 Fig. 7.5
Fig. 7.2 MCQ 7.3
During normal quiet standing balance is maintained when the centre of gravity is kept within the support base provided by the feet. Maintenance of this upright position is associated with body sway, mainly in the anteriorposterior (AP) direction, and this sway may be measured either as degrees of angular movement or, using force platforms, as changes in the pressure over the soles of the feet. Threats to balance are detected principally by vision, lower limb cutaneous sensation and proprioception, and to a lesser extent by the vestibular system. Following a pertubation sensory information is centrally processed and corrective responses, such as muscle stiffening and cocontraction, or protective responses, where one or more steps are taken or an arm is thrown out to catch hold of an external support, are triggered. Disease in any part of this system will impair balance. Loss of a single sensory input is rarely completely disabling because of good overall reserve, but closing the eyes always causes an increase in postural sway and it appears that peripheral vision in particular is necessary for normal balance.
CHANGES IN BALANCE IN OLD AGE Both AP sway velocity and area increase in normal elderly subjects (Fig. 7.10), (i.e. those who report that their balance is normal and who are functionally independent). Further increases in AP sway correlate with spontaneous falls, but a better predictor of falls is increased mediolateral sway. Age-related changes occur in all parts of the postural control system. There is reduced visual acuity, contrast sensitivity, depth perception and dark adaptation. There is decreased cutaneous sensitivity in the feet and proprioceptor loss in the ankles and apophyseal joints in the cervical spine. In the vestibular system there is loss of labyrinthine hair cells and vestibular ganglion cells. Centrally there is an age-related loss of neurons, resulting in slowing of information processing and depletion of neurotransmitters such as dopamine in the basal ganglia. The older person has to pay much more attention to their balance, and loss of concentration contributes significantly to the risk of falling. On the motor side there is an agerelated reduction in muscle strength due to decreases in the size and number of muscle fibres and motor neurons. Loss of strength of the ankle dorsiflexors and knee extensors (i.e. quadriceps) is particularly associated with an increased risk ofgn f There has been a long-running debate on what constitutes normal gait in old age and the cause of senile gait
TABLE 7.4 Risk factors for falls
a
More than one previous fall Lower limb disability (including muscle weakness) © Impaired balance or gait Use of sedative drugs Use of more than four drugs Cognitive impairment (mini mental state examination score <26/30) Impaired activities of daily living 0 Visual deficit
FIG. 7.10 Postural sway (measured as movement in the anterior-posterior plane with the subject standing) increases with age At all ages, women sway significantly more than men. 1 unit = 3.5° of angular movement.
disorder. There are undoubtedly some elderly people who maintain a normal gait even in extreme old age. However, gait laboratory studies show subtle changes even in carefully screened healthy elderly subjects. Gait slowing is due to a decreased stride length and cadence (steps per minute) remains unaltered. Stance time and double support time increase and there is a less vigorous push-off. Whether this represents an early degeneration of the balance control system or an adaptation to make the gait safer is unclear. However, it is now apparent that the senile gait disorder, which is characterized by caution and shorter and more frequent strides and is said to occur in about 20% of the elderly, is not due to age but to underlying neurodegenerative syndromes and subclinical cerebrovascular disease. These patients have a twofold increased risk of cardiovascular death, compared to age-matched subjects with a normal gait. 4 FALLS Although falls are the leading cause of death from injury in people over the age of 75, serious injury only occurs in about 5 % of falls in community-living elderly, and a much more common consequence is loss of confidence, a reluctance to go out of doors and reduced quality of life. Thirty per cent of people over the age of 65 give a history of having had a fall in the previous year, and 50% of fallers do so repeatedly. Incidence rates in nursing homes and hospitals are nearly three times the community rate and the likelihood of an injury is more than doubled. Falls increase with age and fall rates in women are twice those in men. The more risk factors a person has (Table 7.4) the more likely they are to fall. Over 1 year 65-100% of people with three risk factors will fall, compared to 8-12% for those with none. The typical frequent faller usually has multiple defects affecting the postural control system.
Clinical or subclinical disease is a far more important cause of falls than environmental factors such as trailing wires and loose rugs. It is therefore no surprise to find that falls, incontinence and functional dependence all share the same risk factors. Increased fall rates in women probably reflect greater muscle weakness and possibly lower levels of fitness: for example, over 50% of women over the age of 55 are unable to walk at 3 miles per hour on the level, and the average healthy 80-year-old woman has to make a maximum quadriceps contraction to rise from a low armless chair or the lavatory. 7
HISTORY AND EXAMINATION It is important to spend time with the patient (and ideally a reliable witness) getting a precise account of the circumstances surrounding the fall. Was it a simple trip or accident, which carries a relatively good prognosis? Or was it a more ominous spontaneous fall (' I don't know what happened, I just went down') (Table 7.5). Some may say that they felt dizzy (particularly if prompted by the doctor). However, only very rarely does the patient experience true vertigo (a sensation of the surroundings or the inside of the head spinning round). They do not so much feel dizzy as unsteady when standing or walking, and are frightened that they are going to fall over. Some of these patients suffer drop attacks. These are falls which occur without warning: the patient suddenly crumples to the ground and there are no neurological sequelae. As with other spontaneous falls their aetiology is multifactorial, although sometimes a specific cause will be found, such as reflex-mediated syncope, normal-pressure hydrocephalus or Meniere's disease. Specific causes of falls such as these are less common than widespread postural defects (e.g. cerebrovascular disease and a diabetic peripheral neuropathy), which result either in spontaneous falls or a fall following a trivial pertubation because of slowing or even loss of the normal corrective responses. These patients are usually older and more frail, their gait and balance are noticeably impaired and their general health poor. Their mortality is about five times that of non-fallers.
181
TABLE 7.5 Causes of spontaneous falling
TABLE 7.6 Causes of syncope
Patient usually impaired in more than one of the systems concerned with balance control:
Pathophysiology of syncope is complex in older patients. Orthostatic hypotension, carotid sinus hypersensitivity and vasovagal syncope overlap in 30% of elderly with syncope.
• • • • • •
Vision, e.g. impaired depth perception Impaired cutaneous sensation (e.g. peripheral neuropathy) Impaired proprioception, e.g. cervical spondylosis, peripheral neuropathy Vestibular lesions, e.g. Meniere's disease Impaired central coordination, e.g. cerebrovascular disease Unstable support base, e.g. turning quickly, walking downstairs or arising from a chair
If balance is already impaired, falls are precipitated by: • Acute illness, e.g. chest infection, worsening of heart failure • Drugs, e.g. tranquillizers • Occult ill health, e.g. anaemia, hyponatraemia
Reflex mediated (neurovascular instability) Vasovagal Carotid sinus hypersensitivity Orthostatic hypotension Situational syncope (cough, micturition, etc) Cardiac Arrhythmias Obstruction (aortic stenosis, pericardial effusion etc) Neurological Vertebrobasilar insufficiency Subclavian steel syndrome
Rare
Points to note in the history are: • Circumstances of the fall; • If the fall occurred soon after standing up (raising the possibility of orthostatic hypotension) • Loss of consciousness (can the patient remember hitting the floor?). There are only two common causes syncope (Table 7.6) and epilepsy; • Syncope accounts for up to 6% of medical admissions and 20% of elderly patients presenting to A & E with unexplained falls, such as drop attacks. Patients will sometimes deny loss of consciousness, despite unequivocal evidence that it occurred; • Vasovagal syncope may be preceded by the classic symptoms of lightheadedness, sweating and nausea, but in the 'malignant' variety there is no warning, the patient falls unexpectedly, the attack is prolonged with slow recovery and injury, and convulsions and incontinence are common; • Palpitations before the fall, a sense of dizziness or faintness and dimming of vision are important pointers to syncope; • Loss of consciousness, dizziness and faintness are not features of transient ischaemic attacks. These depend for their diagnosis on focal neurological signs (e.g. motor or sensory loss, dysphasia); • The patient's drugs will need to be checked. Sedatives or hypnotics frequently slow the patient down and may precipitate a fall. B-Blockers, certain calcium channel blockers and diuretics may cause orthostatic hypotension or vasovagal syncope; • Acute or chronic medical problems
1
182
Fig. 7.6
SUMMARY 3 Typical features in patients with recurrent falls • • • • •
Have several risk factors, especially lower limb muscle weakness Significantly impaired gait and balance Difficulty in accounting for how they fell Show fear of falling Generally have multiple defects both in the sensory systems concerned with balance control (vision, proprioceptors and the vestibular system) and in central coordination centres
• Mental state should be assessed if there is a suspicion of dementia or depression; • A history of tinnitus, deafness or vertigo should be sought. If present, this may indicate a vestibular lesion, either peripheral (e.g. Meniere's disease) or central (vascular disease in the brainstem or cerebellum). • A sudden onset of severe vertigo suggests a posterior circulation stroke. Episodic vertigo lasting less than 1 minute and provoked by rapid positional change is probably benign positional vertigo, which is confirmed by a positive Hallpike test (for description see p. 183); In the general examination: • The lying and standing blood pressure should be measured (a drop in systolic pressure of more than 20mmHg indicates postural hypotension). • Carefully examine the heart. • The range of neck movements should be assessed. • Watch the patient rise from a chair, walk several paces and return. • Normal old people should not have a positive Romberg test (i.e. closing the eyes when standing should not markedly impair balance). • Check for impaired righting reflexes by tapping the
RECENT ADVANCES IN THE PREVENTION OF FALLS 1. Intervention studies have demonstrated significant reductions in falls. Because falls' are multifactorial broad-based interventions are best. Programmes such as the following reduce the risk of falling by 30%: • Review and adjust drugs • Balance and gait training • Muscle strengthening exercises • Practise transfer skills from bed/chair/toilet • Make home safer. 2. Assessment and appropriate treatment and referral of patients attending an A & E department lowers the risk of recurrent falls, reduces fracture rate by 50% and decreases the odds of hospital admission. 3. The Frailty and Injuries: Cooperative Studies of Intervention Techniques (FICSIT) programme demonstrated that exercise alone could produce a 25% reduction in falls. In particular, Tai Chi appeared beneficial and led to a 47% reduction in falls incidence in elderly women. A home visit by a physiotherapist and the prescription of 30 minutes of strength and balance retraining exercises and an outdoor walk three times a week reduces fall rate and remains effective for at least 2 years. 4. Hip protector pads reduce the risk of hip fracture. They are indicated for frail at-risk patients who are sufficiently well motivated to wear them. 5. Patients with parkinsonism can be taught how to manoeuvre more safely in the home and to walk with a normal stride length using markers on the floor or attentional strategies.
patient lightly on the sternum or giving the shoulders a tug from behind. Be ready to catch them if they fall. • In severe cases there will be manifest anxiety and fear of falling, with the patient reluctant to move without clutching on to furniture or onlookers for support. • Check muscle strength (especially quadriceps), lower limb joints, vision, neurological function (especially lower limb peripheral nerves). In addition to routine investigations: • A 24-hour ambulatory ECG should be obtained for patients suspected of having episodes of cardiac syncope due to an arrhythmia. • Patients with a normal 24-hour tape, but who have symptoms suggesting vasovagal syncope or carotid sinus syncope, require head-up tilt testing and carotid sinus massage (a positive response produces asystole exceeding 3 seconds, a decrease in systolic blood pressure exceeding 50mmHg, or a combination of the two). 1 • An EEG is occasionally helpful, although the diagnosis of epilepsy is essentially clinical (see Ch. 24 p. 1321).
Early morning falls in patients taking a long-acting hypoglycaemic drug (e.g. chlorpropamide) raise the possibility of hypoglycaemia. Patients suspected of having a vestibular lesion can have this accurately localized only by specialist examinations, which include electronystagmography and caloric tests. The Hallpike manoeuvre can be carried out in the clinic and tests for the presence of positional vertigo. The nystagmus of benign positional vertigo occurs after a latent period of 2-20 seconds when the head is reclined and turned to the affected side. To carry out the test the patient is seated at the top end of a flat examination couch and warned that they will experience vertigo. The examiner holds the patient's head firmly and turned 45° to the left or the right; the patient is then carried rapidly backwards until the head is dependent. The patient is asked to keep his eyes open all the time and look at the examiner's nose. The nystagmus of benign positional vertigo is rotatory (torsional) and is directed towards the affected ear when it is undermost (i.e. when the left ear is affected the nystagmus is to the left when the head is hanging to the left.) The nystagmus lasts for up to a minute and coincides with a sense of vertigo, which may be severe. When the patient sits up the nystagmus may reappear beating to the opposite side. With repeat testing the symptoms and signs adapt and fatigue. Central types of positional nystagmus may also be recognized by this test. In contrast to benign positional vertigo the central type of nystagmus appears after no latent period, it persists for longer than a minute, it does not fatigue, vertigo is usually absent, and the direction is variable. The patient's vision, both with and without spectacles, should be noted (depth perception, low contrast, etc.). Low-contrast visual acuity and contrast sensitivity (the detection of large visual stimuli under low-contrast conditions) are better predictors of falls than impaired high-contrast visual acuity.
a
MANAGEMENT Many patients with recurrent falls have multiple postural defects and their balance is precarious. All require a multidisciplinary assessment. Sometimes a minor illness such as a chest infection or a newly prescribed sedative drug can simply prove too much for a frail patient. Identification of precipitating factors enables the patient to be appropriately advised. Culprit drugs should be withdrawn in patients with syncope. Vasovagal syncope may be treated with B-blockers, SSRIs or pacing. Cardioinhibitory carotid sinus syndrome usually needs a permanent pacemaker. Cervical spondylosis should be treated with neck exercises, not a cervical collar, which often makes the patient feel more unsteady. Faulty spectacles should be replaced and everything possible done to improve the patient's vision, including better illumination in the home.
183
CASE STUDY 7.1
FALLS AND 'FY T
An 83-year-old woman, who looks after her 90-year-old husband, gives a 2-year history of increasing difficulty with walking. When standing or walking she feels unsteady, as if she might fall, but there is no sense of vertigo. She goes out for a walk every day with her daughter, who lives nearby, but lacks confidence and does not go out of doors on her own. She has had several spontaneous falls, sometimes going over backwards. She says that her walking has become difficult and that her legs feel 'as if they are in concrete', but they are not painful. Sometimes when she starts walking her legs will not move - 'they seem to be nailed to the floor' - but after a few seconds she is able to get going. She finds a similar problem when she turns: her legs lag behind her upper body, with the feet seemingly stuck to the floor, and she has fallen over twice as a result. She also describes 'funny turns'. These occur about once a week without warning. She has an unpleasant sick feeling in her stomach that rises rapidly to her head. Her daughter says that during these episodes her mother looks vacant. Her eyes are open, but she does not respond to questioning and sometimes makes a funny grunting noise. The episodes last just a minute or two, but she often feels unwell for some hours afterwards. The daughter has also noticed that her mother's
memory has deteriorated. On direct questioning the patient admits to urinary urge incontinence and daytime frequency, sometimes having to pass urine every hour. At night she gets up two or three times. There is no dysuria.
Questions 1, What gait abnormality has the patient described? 2. What is the cause of her 'funny turns'? 3, What is the likeliest explanation for her urinary incontinence?
The patient's description of her feet sticking to the ground when she tries to walk or turn is known as freezing. It is a feature (in order of frequency) of progressive supranuclear palsy, arteriosclerotic parkinsonism, normal pressure hydrocephalus and idiopathic Parkinson's disease. It is rare in multisystem atrophy and very rare in drug-induced parkinsonism. The commonest type of freezing is start hesitation (sometimes called gait ignition failure), but it can also be observed in speech, the eyelids, in handwriting and in tasks such as shaving. Her 'funny turns' are typical of complex partial fits (elderly patients
Peripheral vestibular lesions may be improved with cinnarizine (15 mg t.d.s.) or betahistine (8mg t.d.s.), but these drugs may have troublesome sedative effects. Central vestibular lesions are rarely helped by drugs and these should therefore be avoided if this diagnosis is definitely made. Phenothiazines should not be prescribed for vague complaints of dizziness, because of the risk of drug induced parkinsonism. Benign positional vertigo can be treated by a physiotherapist with the Epley manoeuvre or Cooksey1
184
Case 7.2
0 Figs 7.8-7.9
0 Fig. 7.7
do not have petit mal). There is a steep rise in the incidence of fits in old age and the commonest cause is cerebrovascular disease. She has described urge incontinence and frequency, and the likeliest explanation for this is detrusor instability. Examination of the patient The patient scored 24/30 on the minimental state examination, confirming mild cognitive impairment. She was unable to stand unsupported with her feet together, even with her eyes open. When asked to walk there was start hesitation before she got into her stride. She walked with a broadbased, short-paced gait. Her posture was upright and she swung both arms normally. There was no tremor and tone in her arms was normal. In her legs tone was increased and there was also bradykinesia, shown by marked slowness and frequent hesitations when asked to rapidly tap her heel on the ground. Reflexes were brisk in her legs, but plantars were flexor. The rest of the examination, including PV and PR, was normal. Is this idiopathic Parkinson's disease? Probably not. Despite having three of the four cardinal signs (rigidity, bradykinesia and gait disturbance) the signs are all confined to the legs and this strongly suggests arteriosclerotic parkinsonism
Cawthorne exercises. The Epley manoeuvre is based on the premise that debris moving in the endolymph of the posterior semicircular canal stimulates the hair cells and causes vertigo. The manoeuvre aims to direct the debris out of the canal into the utricle. About 80% of patients experience immediate relief of vertigo and nystagmus after a single session. Cooksey-Cawthorne exercises are suitable for any patient with chronic dizziness. They are performed twice a day and help the patient to develop tolerance to the vertigo and increase confidence. The patient's chair should be at the right height (the seat level with the top of the knee) so that getting out of it is not difficult. A walking frame may initially help both mobility and confidence, but should be removed once the
7
CASE STUDY 7.1 CONTINUED (sometimes known as lower-half parkinsonism). Further support for this diagnosis and against idiopathic Parkinson's disease is the symmetry of the findings, the initial presentation with a gait abnormality, normal arm swing and upright posture, the early appearance of cognitive impairment and the absence of tremor. Management Patients with arteriosclerotic parkinsonism (unlike idiopathic Parkinson's disease) only rarely improve with levodopa. Treatment was started with co-careldopa 12.5/50 one tablet b.d., and gradually increased until she was taking the equivalent of 400 mg levodopa a day. The drug made her feel sick and
shaky and there was no improvement in her walking, and so it was stopped. Gait, mobility and confidence improved with physiotherapy. After an MSU was checked to exclude a urinary tract infection she was started on bladder retraining; after 6 weeks she was no longer incontinent and was managing to hold for 2-3 hours between voids during the day. A CT brain scan confirmed small vessel disease. (Case Fig. 7.1.1) She was checked for vascular risk factors and started on 75 mg aspirin daily. Although hypertension is associated with small vessel disease there is no evidence that lowering blood pressure or taking aspirin slows the rate of progression of the disease.
patient's walking is better. Balance and muscle strengthening exercises and measures to improve confidence and wellbeing are of proven benefit. If the falls have been such as to warrant hospital admission, then follow-up for a few weeks in a day hospital is helpful. In case of another fall, the patient should be taught how to get up off the floor 3 and advised of the various alarm systems that can be installed in the home. An occupational therapist should also visit the home and correct obvious environmental hazards and teach the patient safe transfers. Preventing fractures is important. Patients should be assessed for osteoporosis and treated accordingly (see p. 175). FURTHER READING ON BALANCE AND FALLS AGS/BGS/AAOS Panel on Falls Prevention 2001 Guidelines for the prevention of falls in older patients. J Am Geriatr Soc 49:664-672. Campbell A J, Robertson M C, Gardner M M 1999 Falls prevention over 2 years: a randomised controlled trial in women 80 years and older. Age Ageing 28:513-518. Close J, Ellis M, Hooper R et al 1999 Prevention of falls in the elderly trial (PROFET): a randomised controlled trial. Lancet 353:93-97. Davies A J, Kenny R A 1999 Syncope in older patients. Rev Clin Gerontol 9:117-126. Lempert T, Gresty M A, Bronstein A M 1995 Benign positional vertigo: recognition and treatment. BMJ 311:489-491. Maki B E, Mcllroy W E 1996 Postural control in the older adult. Clin Geriatr Med 12:635-658. Nutt J G, Marden C D, Thompson P D 1993 Human walking and higher level gait disorders, particularly in the elderly. Neurology 43:268-279.
CASE FIG. 7.1.1 CT of the head showing leukaraiosis. This is a radiological diagnosis indicating periventricular white matter hypodensity. It is commonly caused by small vessel disease and is associated with gait disturbance, falls and dementia it may also be seen in normal elderly people.
Province M, Hadley E, Hornbrook M et al 1995 For the FICSIT Group. The effects of exercise on falls in elderly patients. A preplanned meta analysis of the FICSIT trials. J Am Med Assoc 273:1341-1347
URINARY INCONTINENCE Although this is more common in the elderly, the causes and management are similar to those in the young (see Ch. 20). The major difference is that elderly patients are more likely to suffer in silence or even to deny the problem. Doctors must be proactive and should routinely ask at-risk patients whether they have 'any bladder problems'. After a pertinent general assessment (diuretics, mental state, mobility, etc.), examination to exclude prolapse, pelvic mass and prostatic carcinoma and urine tests for infection, blood, glucose and protein, the patient is referred to the continence nurse specialist for initial management. Age has little effect on prognosis and the majority of patients can expect to become dry following treatment.
DETRUSOR INSTABILITY The majority of patients are incontinent because of idiopathic detrusor instability. The cortical centre for this willed control over the hindbrain-sacral reflex lies in the frontal premotor area. In old age these tracts are vulnerable to cerebrovascular disease and Alzheimer's disease. An early sign of detrusor instability in old age is nocturia,
185
TABLE 7,7 Principles of bladder retraining 1. 2. 3. 4. 5. 6.
Explanation of condition Establish baseline micturition pattern using chart Select appropriate time for patient to wait between urinations, e.g. 1-2 hours Provide patient with a suitable pad to wear in case of incontinence Gradually extend interval as patient improves Concomitant relaxation therapy for stressed or anxious patients
which may progress to overactive symptoms of urgency, urge incontinence and daytime frequency. Stress incontinence is usually due to urethral sphincter weakness, but similar stress leakage may be seen in patients with detrusor instability and is due to cough or sneeze raising intraabdominal pressure and triggering an unstable contraction. A cystometrogram is needed to distinguish between the two causes, and patients with genuine stress incontinence can expect good results from pelvic floor exercises and surgery. Whether the detrusor instability is idiopathic or due to cortical damage (e.g. from a stroke), the response to bladder retraining is good provided that the patient can comprehend the instructions and is well motivated. About 80% of patients will be dry after 6 weeks' treatment. Bladder retraining (see Table 7.7) depends on asking the patient to urinate only after a certain fixed time, the underlying assumption being that 'holding' in this way strengthens cortical inhibition over the sacral reflex. If patients are struggling with retraining they may benefit from the addition of tolterodine m/r 2mg o.d. or oxybutyrin m/r 5-30 mg o.d. The modified release formulation is less likely to cause dryness of the mouth. If despite these measures patients continue to wet the bed or have very troublesome nocturnal polyuria, they can be helped by desmopressin tablets 0.1-0.2 mg at bedtime. This reduces urinary output in patients with a high nocturnal diuresis (>0.9mL/min) and is ideal for occasional use, such as a stay in a hotel. Up to 3 weeks treatment is safe; over longer periods blood pressure and serum sodium must be monitored. 12
VOIDING DIFFICULTIES These increase with age and also occur in women. Typical symptoms, such as hesitancy, poor stream, straining to void and a feeling of incomplete bladder emptying, do not reliably distinguish bladder outlet obstruction from detrusor hypocontractility, which may be idiopathic or sec-
1
186
Case 7.3
2
ondary to, say, a cauda equina or peripheral nerve lesion. Neurological and rectal examination and pressure-flow studies are required for an accurate diagnosis. Hypocontractility causing a large residual urine volume carries the risk of recurrent urinary tract infections, and is managed initially by advising the patient how to empty the bladder completely and, if necessary, with prophylactic antibiotics. Long-term management is with intermittent self-catheterization. Patients with benign prostatic obstruction have a choice of treatments: watchful waiting if symptoms are causing little trouble, drugs if symptoms are troublesome and surgery is declined (a-blocker or a 5-a-reductase inhibitor), TURP, or alternatives such as laser prostatectomy or thermotherapy.
POSTOPERATIVE URINARY RETENTION This may happen to any elderly man following surgery. It is commonly assumed to be due to prostatic outflow obstruction, but is much more likely to result from a combination of postoperative pain, preoperative opiates, anticholinergic anaesthetic agents, a bladder overdistended with intravenous fluids, and lying immobilized in bed. If the patient does not respond to an oc-blocker, such as alfuzosin 2.5mg b.d. (beware hypotension and give the first dose at bedtime), then the bladder should be emptied with intermittent catheterization until normal detrusor activity returns.
CATHETERS A permanent indwelling catheter is the last resort for urinary incontinence, but is not necessarily a bad solution. Some patients are very relieved to be clean, dry and comfortable for the first time in years. The gauge should be 14 or 16 Ch and the retaining balloon should contain no more than 5 mL of water to reduce the risk of provoking unstable contractions, which will cause urine to leak out around the catheter. If leakage persists tolterodine or oxybutyrin b.d. should be tried; if this is unsuccessful the best solution is to change to a suprapubic catheter. Catheters always become infected within 2 weeks of insertion. This is rarely a problem if drainage is satisfactory and fluid intake is l-1.5L/day. Catheter specimens of urine should only be sent for culture if there is an unexplained deterioration in the patient's condition or symptoms of system infection. Bladder washouts and prophylactic antibiotics are ineffective (see Table 7.8).
FURTHER READING ON URINARY INCONTINENCE Fig. 7.10
Incontinence. Causes, management and provision of services. London: Royal College of Physicians, 1995.
TABLE 7.8 Good practice guidelines: Urinary incontinence
FAECAL LOADING
Summary of recommendations from Good Practice in Continence Services (Dept. of Health 2000) and US Department of Health and Human Services: Clinical Practice Guidelines: Urinary Incontinence in Adults (1996). The strength of evidence supporting each recommendation is based on the following criteria: A Scientific evidence from properly designed and implemented controlled trials providing statistical results that consistently support the guideline statement; B Supported by scientific evidence from properly designed and implemented clinical series; C Supported by expert opinion.
This is the commonest cause of faecal soiling. Rectal sensation is impaired, probably aggravated by chronic rectal distension, and the patient often leaks before experiencing a call to stool. Problems result not only from a large hard stool in the rectum, but also from a mass of soft stool, which is not readily recognized. The rectum and lower colon should be cleared either with repeated enemas, which are uncomfortable and time-consuming, or a kinder alternative such as oral polyethylene glycol (Movicol). To clear faecal impaction, eight sachets in a litre of water are taken over at least 6 hours on 3 consecutive days. Bran must be used with caution, as it may make the stool consistency too soft and can actually cause faecal incontinence.
In primary and secondary care • All patients require initial assessment, to include a review of symptoms, examination of abdomen and perineum (including pelvic floor contraction) to identify prolapse and excoriation, and rectal examination to exclude faecal impaction and urinalysis (grade B). • Detrusor instability should be treated with bladder training (grade A).and, if necessary, anticholinergic drugs (grade A). Symptoms of stress incontinence are reduced by pelvic floor muscle exercises (grade A). • There is no evidence that oestrogen supplementation improves incontinence in postmenopausal women (grade B). • Colposuspension and sling procedure are more effective than anterior colporrhaphy or needle suspension (grade B). • Appropriate continence aids such as pads need to be provided (grade C). • Existing medications (e.g. diuretics) need to be reviewed (grade C). • Refer immediately to a urologist patients with acute retention of urine, renal impairment, carcinoma of the prostate, haematuria or recurrent infection (grade C). • Refer immediately to a gynaecologist patients with a pelvic mass, vaginal bleeding or a history of previous gynaecological surgery (grade C). • If, after initial assessment and 6 weeks of bladder retraining or pelvic floor exercises patients are not improving, they should be referred for specialist review (grade C).
SLEEP AND INSOMNIA Insomnia is a common complaint in the elderly and there is great pressure on doctors to prescribe hypnotics. The elderly receive more hypnotics than any other age group. It is often assumed that hypnotics are both harmless and effective, but for the elderly neither assumption is true. Elderly patients taking hypnotics regularly rate the quality of their sleep as worse than those not on hypnotics, and more than one in 10 persons aged 70 or over taking nitrazepam (10 mg) at night have troublesome daytime sedation, with confusion unsteadiness and an increased risk of falling. Any patient complaining of insomnia - but particularly an elderly one - needs careful assessment and not just a prescription for a hypnotic.
TABLE 7.9 Causes of faecal incontinence
NORMAL SLEEP
• Secondary to colorectal disease, e.g. infective diarrhoea, carcinoma of the rectum • Idiopathic weakness of the anal sphincter and pelvic floor muscles • Faecal loading • Neurological causes, e.g. dementia, impaired consciousness and rectal instability
A person falling asleep 'descends' rapidly through progressively deeper stages of sleep. Slow-wave sleep - which occupies about 20% of the night in the young - is reduced to only 5% by 70 years of age, and stage four is almost completely absent (Fig. 7.11). The elderly wake more frequently and take longer to fall asleep, so that even for the normal old person sleep becomes increasingly fragmented. Rapid sleep onset is promoted by dilatation of the blood vessels of the hands and feet, which increases distal heat loss. A hot water bottle at the feet rapidly induces vasodilatation and the resulting heat loss is most effective when the ambient temperature is cool. Difficulty falling asleep in old age may reflect an inability to vasodilate owing to impaired autonomic responses. Thus, the doctor needs to decide whether an elderly patient's complaint of insomnia is an unrealistic expectation of what constitutes a good night's sleep. Less physical activity and daytime naps will further reduce the ability to sleep well at night.
FAECAL INCONTINENCE Faecal incontinence is distressing for both patient and carer and is a major reason for care breaking down in the home. The prevalence in the community is less than 1%, rising to 10% in residential homes and 25-30% in nursing homes or on long-stay wards. The causes are given in Table 7.9.
a
187
TABLE 7.10 Advice to patients with insomnia • • • • • •
Avoid daytime naps. Avoid caffeine or alcohol at bedtime (a hot milky drink is better). Ensure that the bed is warm and comfortable. Only go to bed when tired. Do not read or watch television in bed. If not asleep in 20 minutes get out of bed and sit in another room until feeling tired again. • Get up at the same time every morning.
A similar effect can be seen after hypnotics are withdrawn, when the patient complains of anxiety, tension and insomnia. If these withdrawal effects are not understood by the doctor and patient then a hypnotic may be needlessly represcribed.
CHOOSING A HYPNOTIC
FIG. 7.11 Typical hypnograms for young adults and elderly people The elderly wake more frequently and have less deep sleep.
SUMMARY 4 Causes of insomnia • • • • • •
Age-related changes in sleep pattern Nocturia (probably due to detrusor instability) Pain Anxiety and depression Drug induced, e.g. alcohol, withdrawal from hypnotics Specific problems, e.g. sleep apnoea, myoclonus
CAUSES OF INSOMNIA
188
Insomnia may be age related, as discussed above. Nocturia is another common reason for an old person waking up; the condition may be caused by heart failure, renal failure or diabetes, but is most likely due to detrusor instability (especially if associated with some urgency). Pain is also an important cause of insomnia, and the akinetic parkinsonian patient who cannot turn over in bed will find that sleep is disturbed. Anxiety and depression commonly cause sleep disturbances, and are best managed by psychiatric treatment directed at the primary condition. Insomnia may be drug induced. The most familiar example is alcohol which, if taken in the evening, will quickly induce sleep but because of its rapid metabolism results in rebound insomnia with awakening later the same night.
Hypnotics should only be used when insomnia is impairing the patient's daytime performance, and after advice on non-pharmacological measures (see Table 7.10). There should be a clear indication, such as a recent bereavement or impending major surgery, and the prescription should be limited to 7 or 10 days wherever possible. The drug should have a rapid onset of action, particularly if the patient's main complaint is difficulty in falling asleep. There should be no daytime sedation, although this may occur because of the accumulation of long-acting hypnotics and their active metabolites, or because of an age-related alteration in sensitivity to the drug.
Benzodiazepines Diazepam has a half-life in hours approximately equivalent to the person's age, but the constant clearance rate means that its average steady-state plasma level is unaffected by ageing. However, the half-life of its major active metabolite, desmethyldiazepam, is prolonged as a result of reduced plasma clearance. The dose necessary to produce sedation is therefore inversely correlated with age, owing partly to an increased sensitivity to the drug in old age and also to accumulation of the active metabolite. Diazepam (2 mg or 5 mg) may be a suitable hypnotic for anxious old people where a daytime anxiolytic effect is required. Daytime drowsiness, confusion and falls, however, may be a problem. Nitrazepam also produces more sedation in the elderly, probably as a result of increased receptor sensitivity (as the pharmacokinetics remain unaltered). The unwanted daytime sedation is largely dose dependent (Fig. 7.12); 2.5 mg is the maximum dose that should be given to an old person.
Morgan K 2001 Mental health factors in late life insomnia. Rev Clin Gerontol 11:71-81.
7
SEXUAL FUNCTION
FIG. 7.12 Relationship of daily dose (5.0-9.9mg/day and 10.0 or more mg/day) to the frequency of unwanted daytime CNS depression attributed to nitrazepam, with the population stratified according to age
Temazepam has a half-life of only 5-10 hours in young people but may be as long as 30 hours in the elderly. Accumulation therefore occurs and, after a week of continuous dosing at 20mg each night subjects show a significant slowing of reaction times. The effect is likely to be dose related; 10 mg at night rarely causes serious problems. Lormetazepam has a good pharmacokinetic profile for use in the elderly. Although the elimination half-life is prolonged to about 14 hours in elderly subjects, accumulation does not occur and there is no impairment of daytime performance with a nightly dose of either 0.5 mg or 1.0 mg.
Other hypnotics Zopiclone, a cyclopyrrolone, has a half-life of about 8 hours in the elderly; it does not accumulate over 7 days' treatment and psychomotor performance is unimpaired. Treatment should start with 3.75mg. Clomethiazole (chlormethiazole) is valuable in the elderly. Its pharmaco-kinetics are unaltered by age and its short plasma half-life of 3-4 hours prevents accumulation. It is metabolized by the liver, and should be used with caution in patients with cirrhosis of the liver or in alcoholics. One capsule (192mg of chlormethiazole base) may be sufficient but two capsules is still safe. Restless and confused patients are often best sedated with haloperidol (0.5-3mg nocte). Long-term use carries a risk of extrapyramidal side-effects and should be avoided in parkinsonian patients.
In western society sexuality among adolescents and young adults is openly studied and discussed. No such liberal attitude exists towards sex in old age and, unfortunately, the stereotype of the sexless old persists. Although sexual activity does decline with advancing age, much of this is due to ill health or the death of the marriage partner. Old age itself causes very little impairment of sexual enjoyment: 81% of married men and women aged 70-79 are sexually active and find it enjoyable. Overall, it would appear that continued sexual activity in old age depends on the frequency and enjoyment it afforded in middle age, the availability of a suitable partner and (particularly in men) continuing good health. The main physical changes in women result from a lack of oestrogen, which may cause vaginal and clitoral soreness, with reduced lubrication and painful intercourse. Length of orgasm may be reduced but many postmenopausal women report increased desire and arousability. Male fertility is usually maintained into extreme old age, although the volume of prostatic secretions reduces, it takes longer to achieve an erection, orgasm is briefer and the following refractory period is longer. Many doctors are reluctant to discuss sexual practice with their elderly patients and thereby lose the opportunity for helpful counselling. Vaginitis due to oestrogen deficiency responds to topical oestrogen cream and lack of lubrication is helped by over-the-counter products such as K-Y jelly or Senselle. Complaints of impotence in the male should prompt a thorough physical examination, including a blood sugar estimation. Sildenafil is generally safe and effective, but is contraindicated in patients taking nitrates. Many drugs interfere with sexual function and the elderly should be warned about this when they are prescribed. Propranolol and thiazide diuretics may produce impotence. All of the phenothiazines may cause impotence; thioridazine may also cause lack of ejaculation. Haloperidol is free of these problems. Sexuality - or the lack of it - in old age should not be seen in isolation. The need for affection, tenderness and caressing may be more important than intercourse, and counselling as to what is normal and appropriate may dispel fears of inadequacy or embarrassment.
ALTERED REACTIONS TO DISEASE FURTHER READING ON SLEEP AND INSOMNIA Espie C A 1993 Practical management of insomnia: behavioural and cognitive techniques. Br Med J 306:509-511.
In the elderly acute illness frequently presents in a non-specific way, such as with confusion, falls and incontinence.
189
TABLE 7.11 Differential diagnosis of confusion and dementia Differential diagnosis Acute confusional state
Dementia
Onset Clouding of consciousness
Abrupt Yes
Course
Fluctuates, lucid intervals during day. Worse at night Yes (may be intermittent)
Gradual, months or years No (but there may be drowsiness due to sedation) Stable over course of day
Disorientation and cognitive impairment Alertness Hallucinations Duration
Increased or impaired Yes (common) Hours or days
After treatment of any underlying cause, management of the confused patient relies mainly on the correct environment, and sedation should be kept to a minimum. The patient is best looked after in a side-ward so as to avoid disturbing other patients. A relative or nurse should stay with the patient at all times to reassure, comfort and explain what is happening. The light should be kept on in the room at night. Sedation is best avoided but may be needed if the patient is very restless, e.g. haloperidol 1-3 mg q.d.s. by mouth, or 2.5-5mg i.m. (NB the oral and i.m. doses are not equivalent).
Yes
Usually normal Yes (uncommon) Steadily progressive
N.B, None of the clinical features of the acute confusional state is reliable and a confident diagnosis depends on the history.
CONFUSIONAL STATES A toxic confusional state is the ageing brain's response to a number of insults: the stress of a physical illness, a variety of powerful drugs, and alterations in the old person's familiar environment. It tends to occur more commonly in those whose mental state is already impaired, for example by Alzheimer's disease, or who have communication difficulties because of defective hearing and vision. Typically, the onset is abrupt over hours or days. This and the clouding of consciousness are the main points of differentiation from dementia (see Table 7.11). Typically, the acutely confused patient is drowsy; it is difficult to get their attention and there are fluctuations in the level of consciousness. The patient's agitation and confusion are usually worse at night. About 15% of elderly patients admitted to acute medical wards are delirious. One-third die within a month; of the survivors, 80% will have recovered mentally within a month.
Investigations
190
Management
Proper assessment and diagnosis are essential, and require a careful history from a reliable witness. Physical illness, coexisting dementia, recent emotional stress, alcohol abuse, drugs (especially benzodiazepines, antidepressants, antiparkinsonian drugs, analgesics, NSAIDs and steroids), or head injury are important precipitating factors. In hospital, surgery is an important cause of confusional states. Physical examination should concentrate on identifying possible causes. The commonest are cardiac failure, Gram-negative septicaemia and pneumonia.
ABSENCE OF PAIN For reasons not clearly understood, pain due to illness or trauma, which would be expected in a younger individual, is often minimal or absent in the elderly. Thus, myocardial infarction is commonly pain free and the patient presents instead with dyspnoea or non-specific illness. Similarly, abdominal pathology such as gastric ulcers or mesenteric thrombosis may be silent; however, acute appendicitis often has a fulminating course in older patients, with the rapid development of gangrene and peritonitis. Even a fracture of the neck of femur may cause the patient only slight discomfort, evidenced by a disinclination to walk.
MULTIPLE PATHOLOGICAL PROCESSES The explanation of all symptoms, signs and abnormal investigations by one diagnosis is seldom possible in older patients, the usual pattern being one of multiple disorders. Thus, a momentary cardiac arrhythmia which may produce only a slight feeling of dizziness or palpitations in a young person may cause loss of consciousness or even a stroke with hemiplegia in an old patient. Similarly, a chest infection may precipitate heart failure because the cardiac reserve is already impaired by ischaemic heart disease. Common conditions such as obesity, osteoarthritis, diverticular disease, hypertension, diabetes, dementia and presbyacusis may all be present in a single individual, and the aim then is to decide which are causing important functional disability.
UNREPORTED ILLNESS The early identification of disease or disordered function allows treatment to be initiated or social support organized before things have gone too far. Studies in general practice show that an elderly person has, on average, at least three disabilities, and for every one known to the GP there is another that is not. Typically, cardiac, chest and neurological disabilities are known to the GP, but incontinence,
difficulty in walking, painful feet, dementia and depression often go unreported.
FURTHER READING ON ALTERED REACTION TO DISEASE Treloar A 1998 Delirium: prevalence, prognosis and management. Rev Clin Gerontol 8:241-249.
CLINICAL APPROACH When assessing an elderly patient it is generally more useful to think in terms of functional ability than to emphasize the underlying pathology. For example, the distinction between rheumatoid and osteoarthritis in a patient with arthritis of the knees may be largely academic: the fact that the patient has poor mobility is much more important. Emphasis is placed on physiotherapy, walking exercises and possibly surgery to improve mobility and independence.
HISTORY A full history remains the primary investigation. In a confused patient it is necessary to obtain additional information from a relative, community nurse, or someone who knows the patient well. The tempo with which the symptoms have developed is particularly important. Forget fulness gradually increasing over 2 or 3 years suggests Alzheimer's disease (AD), whereas a sudden onset of confusion over a day or two indicates a toxic confusional state and requires a search for underlying physical problems, such as an infection or myocardial infarct. A sudden onset of headaches or a recent change in bowel habit is never normal in old age, whereas gradually failing hearing and vision may be. The history must include a full list of the patient's medications, including details of dose and frequency; details of their functional ability (shopping, cooking, cleaning and personal toilet); and social circumstances. The main carer at home should be identified, as well as additional support that might be provided by family, neighbours and social services.
ASSESSMENT The chances of successfully discharging an elderly, frail person, if his or her homelessness, anxiety and impaired psychological state are ignored, are remote. Seeing the patient as a whole is thus not only good for the patient, it
is essential if limited health service resources are to be used effectively. Recent legislation and guidance place a responsibility on local authorities, health authorities and health providers to work together to assess, plan and meet the needs of people leaving hospital. An overall view of the patient includes assessment of medical, functional, social and psychological status, and usually brings together the professional views from several disciplines. The doctor attends to the physical and mental diagnosis and appropriate treatments. The nurse notes to what extent the patient can wash and feed him or herself or use the lavatory, and also particular problems such as incontinence, pressure sores or nocturnal confusion. The physiotherapist is concerned with whether the patient can get in and out of bed, rise from a chair, balance and walk; and as the patient improves, the occupational therapist assesses how well they can dress, bathe, cook and care for themselves. Discharge planning begins as soon as possible after admission. The social worker or discharge liaison nurse enquires into the patient's social background to find out what circumstances are like at home - whether they are already receiving support from relatives, neighbours, community nurse or social services, and whether this support will be continued or need to be increased once the patient returns home. Whether the patient's needs are simple or complex the social worker, together with the rest of the multidisciplinary team, draws up a care plan before discharge and later reviews this plan as an essential part of the care management process. The aim is to ensure that patients are speedily and effectively treated and returned to their own home in a planned and thoughtful manner, so that the gains resulting from treatment are likely to be maintained. A similar process of assessment can be initiated by family doctors using community staff, for patients living at home.
7
PHYSICAL EXAMINATION An extensive and detailed examination of every system can exhaust a frail patient. However, with practice, the
SUMMARY 5 Assessment of an elderly patient • Main stress is on functional disability, rather than underlying pathology. • Overall view essential: Medical status - manner of onset of symptoms is important. Full drug history required. Functional ability - washing, cooking, shopping etc. Psychological status - depression, anxiety, confusion etc. Social circumstances - support available at home from family and friends. • Involves a multidisciplinary team of doctors, nurses, occupational and physiotherapists and social workers.
191
examination can be thorough, informative and quick if the doctor concentrates on identifying disabilities and assessing loss of function.
General appearance The examination should begin with an observation of the patient's general appearance and clothes, noting any signs of self-neglect. Facial pallor is frequently present and so is a poor indicator of anaemia. Pupil size is often small, with reduced response, and upward gaze is often limited. Angular stomatitis - if not due to ill-fitting dentures - suggests multivitamin deficiency or iron deficiency anaemia, but a black hairy tongue or sublingual varicosities are of no significance.
Skin changes Loose, dry, scaly skin is a common finding, as is senile purpura owing to increased capillary fragility on the dorsum of the hands and extensor surface of the arms. Sunexposed skin should be searched for basal cell carcinomas or actinic keratoses, which are potentially malignant. The incidence of both conditions increases with years of exposure to the sun, and both are common in the elderly. Intertrigo - sore, inflamed patches of skin under the breasts or in the abdominal folds of obese patients - is often the result of poor personal hygiene. A keratinized transverse crease across the abdomen is the consequence of long-standing kyphosis, following osteoporotic spinal wedging. The breasts should be examined for lumps.
of unwanted drug effects (see p. 199). Systolic murmurs usually of the ejection type and present at the left sternal edge and aortic area - are found in up to 60% of the elderly. They are commonly associated with significant disease such as cardiac failure, ischaemic heart disease, arrhythmias and hypertension, and should not therefore be regarded as always benign.
Feet
Bowels and bladder
The ankles and feet should be inspected for signs of peripheral vascular disease (especially in diabetics), oedema and the need for chiropody. 1
A rectal examination is essential: carcinoma of the rectum or prostate is common in the elderly, and there may be loading of the rectum with faeces - a common cause of faecal incontinence. The presence of urinary incontinence should be noted and, particularly in bedridden patients, the pressure areas inspected for sores.
Cardiovascular Abnormalities of cardiac rhythm are frequently present: occasional ectopic beats occur in about one-sixth of elderly persons, but any other arrhythmia should be regarded as abnormal and investigated by electrocardiography. Systolic and diastolic blood pressure increases with age, although there is little change over the age of 65; values up to 160/90 can be regarded as normal. Overviews confirm that treating systolic or diastolic levels above this reduces total mortality as well as coronary and stroke mortality and morbidity in persons up to the age of 85 years (Fig. 7.13), but the value of treatment needs to be set against the risk
FIG. 7.13 Distribution by age of deaths from stroke in England and Wales The single most important risk factor for stroke is hypertension. Lowering the diastolic pressure at any level by 7mmHg halves the relative risk of stroke.
Eyesight and hearing The patient should be asked whether their vision is satisfactory; if it is not, it should be tested with eye charts (Fig. 7.14). Hearing is probably adequate if the patient can hear a normal conversational voice. Examination of the eardrums for wax should be routine, particularly where a hearing aid is worn, as the earpiece may compress wax into a hard, impenetrable lump.
Neurological changes 1
192
Fig. 7.11
Ankle jerks are absent in about 10% of elderly patients. Superficial abdominal reflexes are also often absent, but the presence of extensor-plantar responses is always pathological.
ing the benefits and risks of investigation and treatment. For example, a patient may be having repeated falls associated with loss of consciousness which do not bother them unduly but cause the relatives great stress and anxiety, because they dare not leave them alone in the house. Tilt table testing could be used to detect whether the falls are due to cardioinhibitory carotid sinus hypersensitivity. If they are, then a pacemaker can be safely inserted - even in the very elderly - with the potential for a considerable improvement in quality of life.
7
FIG. 7.14 Causes of visual impairment and blindness in the elderly
Vibration sense in the lower limbs is reduced, and may be absent at the ankles, in up to a half of patients over 75. However, joint position sense is usually normal. Appreciation of pain, temperature and light touch is very variable, but at least one of these sensations is impaired in about a quarter of the elderly. Both the glabellar tap, and primitive reflexes such as the pout reflex (tap the upper lip and the lips pout), grasp reflex and palmomental reflex (the palm is scratched and the chin wrinkles on the same side), can often be elicited in the elderly, particularly in those who have dementia.
Gait and balance Healthy old people show very little change in gait. There may be slight slowing, but a speed greater than 1m per second is still maintained. Nearly a fifth of the very elderly have a normal gait. A variety of pathologies, especially cerebrovascular disease, produce the senile (or cautious) gait typified by a normal to mildly widened base, shortened stride, slowing of walking and en bloc turns. There is mild disequilibrium in response to a light tap on the chest or a flick on the shoulders from behind, and difficulty in balancing on one foot (see section on falls).
WILL THE INVESTIGATION INFLUENCE MANAGEMENT? Before ordering an investigation it is necessary to consider whether the result is likely to usefully influence management. For example, a severely demented patient with an abdominal mass and positive faecal occult bloods could have the presumptive diagnosis of carcinoma of the colon confirmed by a barium enema. However, if surgery is not being considered (because of the patient's poor general condition and inability to cope with a colostomy), there is little point in the barium enema. On the other hand, if the same patient is found to be unable to walk following a fall, the hips should certainly be X-rayed. Repair of a fractured neck of femur will not only relieve the patient's pain: it is also much easier to nurse an ambulant patient than one who is bedridden.
WILL THE DIAGNOSIS AFFECT PROGNOSIS? It is important to consider whether the investigation will establish a diagnosis which significantly affects prognosis. A very frail patient with severe dyspepsia can be treated easily with an H2 antagonist. But if symptoms persist it may be important for the patient and relatives to know if the diagnosis is peptic ulceration or carcinoma of the stomach.
INVESTIGATION IN THE ELDERLY Potentially remediable conditions cannot be ignored simply because the patient is elderly, but it is not good medicine to order invasive, uncomfortable and possibly expensive tests when the potential benefit to the patient is minimal.
OVERALL STATE OF HEALTH Does the patient have the physical and mental capacity to benefit from a proposed treatment? If surgery is an option, would the patient be fit for operation? If the patient is debilitated and being looked after by family at home, then the views of these relatives must be included when assess-
ROUTINE SCREENING Most patients seen in clinic or admitted to hospital will have a full blood count, ESR (or viscosity), urea and electrolytes, glucose and TSH. Urine should be analysed for protein, glucose and blood. All of these tests can usefully detect treatable disease where the clinical diagnosis is unsuspected or doubtful. This is particularly true of thyroid disease, which is found on screening in about 4% of elderly inpatients in whom the classic symptoms and signs of hypoor hyperthyroidism may be absent. The interpretation of thyroid function tests can be difficult in the elderly because of the effects of severe systemic illness, which cause a reduction in circulating T3 often accompanied by a rise in reverse T3. As the illness becomes more severe T4 levels
193
fall, partly due to interference with binding to plasma proteins. TSH immunoradiometric assays can accurately measure the subnormal range and are now widely used as the single first line test of thyroid function. Although TSH measurements are usually reliable, in very severe illness this may not be true with subnormal levels being seen during the acute stage and sometimes a rebound to slightly above the normal range during recovery. A number of drugs can interfere with thyroid function, both lithium and amiodarone commonly cause goitre and either hypothyroidism or hyperthyroidism. In the case of amiodarone the total and free T4 levels are raised and cannot be used to diagnose thyrotoxicosis. A routine chest X-ray is usually taken, as about 5% of patients over 65 admitted to hospital are found to have an unexpected lesion on chest X-ray (such as a tumour, cardiomegaly or TB). It is particularly valuable in patients presenting with falls, immobility, incontinence or deteriorating mental function; nearly a quarter of these have cardiopulmonary disease without classic features. An electrocardiogram is not routine, but is required for patients with cardiopulmonary disease, strokes (quite commonly associated with a myocardial infarct) and falls (which might be caused by a cardiac arrhythmia).
In addition to the routine blood tests, the patient should have the serum B12 level checked and a VDRL test to exclude syphilis. Although it cannot positively diagnose dementia or Alzheimer's disease, a CT scan is a valuable screening test as it can identify multiple infarctions, spaceoccupying lesions and hydrocephalus. However, only 2% of all demented patients could expect an improvement in their mental state from treatment following a CT scan. Thus, CT is only indicated in patients with mild to moderate dementia (i.e. a mini mental state examination score of 10-26/30) of less than 1 year who are fit enough for surgery if a remediable lesion is found. 1
INVESTIGATION OF DEMENTIA
INVESTIGATION OF GASTROINTESTINAL LESIONS
The main concern in the investigation of dementia is not to miss a cause for which there is specific treatment. Although rare among elderly patients referred to a geriatrician or general physician, such reversible dementias are
In the investigation of upper gastrointestinal lesions, both barium meal and endoscopy give accurate results. However, endoscopy has the advantage of providing a tissue diagnosis where a tumour is suspected, and tends to be
relatively common among referrals to specialist neurological centres. Conditions which may respond to treatment include: • • • • • • • •
depression and other psychiatric disorders normal pressure (communicating) hydrocephalus resectable tumours subdural haematoma toxic drug effects thyroid disease pernicious anaemia syphilis.
RECENT ADVANCES IN THE CARE OF THE ELDERLY 1. Comprehensive geriatric assessment with immediate and ongoing specialist multidisciplinary interventions improves functional status and reduces the length of the initial hospital stay and the likelihood of subsequent readmissions. It also reduces the rate of immediate nursing home admissions and delays permanent nursing home placement. 2. Older adults who adopt or maintain a lifestyle with increased moderate daily physical activity derive considerable health benefits. The range of activities of daily living is increased, walking speed and balance improve, and there is a reduced risk of morbidity, institutionalization and mortality. Even social and productive activities involving little or no physical exertion improve survival.
1
194
MCQ 7.4
2
Fig. 7.12
3. The benefit of thrombolysis following myocardial infarction increases with age and is most cost effective in patients 75 years and older. The development of left ventricular failure is a more important determinant of outlook than age. 4. A daily supplement of 200 mg of vitamin E improves T-cell-mediated immune response in healthy elderly people. Vitamin E may also delay the progress of Alzheimer's disease and reduce cardiovascular events. Randomized controlled trials on the use of vitamin E have given conflicting results and its use as a regular dietary supplement is not currently recommended. 5. Hypertension as a risk factor for coronary artery disease, stroke and heart failure has a greater impact on elderly than on middle-aged patients.
RECENT ADVANCES IN THE CARE OF THE ELDERLY (CONTINUED) Lowering blood pressure, particularly systolic pressure, has a marked effect on reducing the incidence of stroke. Isolated systolic pressure greater than 140 mmHg or a diastolic greater than 85 mmHg should be treated, in patients up to the age of 80. No trial has looked specifically at those aged 80 and over, although the Hypertension in the Very Elderly Trial is underway. A meta-analysis of other trials which included very elderly subjects suggests that antihypertensive treatment reduces stroke, cardiovascular events and heart failure, but does not reduce mortality or major coronary events. At present no firm clinical guidelines can be given, but patients over the age of 80 should stay on existing treatment. Treatment decisions in newly diagnosed patients should be based on biological rather than chronological age. Treatment should begin with a low-dose thiazide, calcium antagonist or ACE inhibitor. 6. Non-rheumatic atrial fibrillation is associated with a fivefold increase in the risk of stroke or transient ischaemic attacks. Its prevalence increases with age to 11% in those aged over 75. The absolute annual risk of stroke in patients with atrial fibrillation is about 5% and this is increased in the presence of other stroke risk factors (see below). For primary prevention warfarin prevents 31 strokes for every 1000 patients treated per year, but at a cost of three haemorrhages. In secondary prevention warfarin prevents 80 strokes for every 1000 patients treated per year but at a cost of 21 major haemorrhages. Aspirin is less effective than warfarin in the secondary prevention of strokes in patients with atrial fibrillation, and prevents 40 strokes per 1000 patients treated each year at a cost of seven haemorrhages. Patients with non-rheumatic atrial fibrillation should be considered for warfarin if they are aged 65-75 and have one stroke risk factor, and over the age of 75 if they have two risk factors. Patients with no risk factors should be given aspirin. Paroxysmal atrial fibrillation carries the same risk of stroke as continuous atrial fibrillation, and patients should be considered for warfarin if they have one or more risk factors present. For patients on warfarin the INR should be kept around 2.0 to minimize the risk of bleeding. Aspirin or
better tolerated by a frail elderly patient. It is the investigation of choice but may need to be preceded by a barium swallow (to check if a pharyngeal pouch is present) when investigating dysphagia. For lower bowel disorders the first steps are usually rectal examination, sigmoidoscopy, stool culture, examination of the stool for occult blood and, finally, barium enema and possibly colonoscopy. Colonoscopy is the investigation
7
warfarin is best begun within a few days of the stroke, provided that a CT scan has excluded haemorrhage. If the cerebral infarct is very large there is a risk of haemorrhagic transformation and warfarin should not be started for 14 days. Contraindications to warfarin include cerebral haemorrhage, active peptic ulceration, uncontrolled hypertension, falls, moderate to severe cerebral periventricular small vessel disease and concerns over compliance. It is particularly important for elderly patients taking these drugs to have annual review to reassess the risk-benefit ratio. Treatment with aspirin is simpler and safer than warfarin and should always be considered for patients in atrial fibrillation when warfarin is difficult to control or is contraindicated.
Stroke risk factors • Previous stroke, transient ischaemic attack, myocardial infarct or peripheral arterial thromboembolism • Hypertension • Ischaemic heart disease • Recent heart failure • Diabetes mellitus • Thyrotoxicosis • Echocardiographic abnormalities, e.g. impaired left ventricular function, enlarged left atrium, enlarged left ventricle, intracavity thrombus. 7. Advances in surgical techniques have meant that major cardiac and vascular surgery is now routinely carried out on elderly patients. Thrombolysis and angioplasty allow successful treatment of peripheral ischaemia, and carotid endarterectomy should now be considered for a patient of any age who has a stenosis of greater than 70% and is either having transient ischaemic attacks or has made a good recovery from a cerebral infarct. Patients over the age of 70 years undergoing aortic valve replacement have a survival rate of 95% at 1 year and 75% at 5 years, which is no different from age- and sex-matched controls from the general population. Even in octogenarians undergoing aortic valve replacement the 5-year survival is 65%. By comparison aortic balloon valvuloplasty results are poor. 0
of choice for colonic adenoma, carcinoma or angiodysplasia, as it is more sensitive than barium enema and often better tolerated. Treatment of non-metastatic colonic malignancies gives a good prognosis; vigorous investigation of fit and active elderly patients is therefore justified. In the frailer patient, however, more caution is necessary before ordering a barium enema. Both the preparation (laxatives and sodium citrate enema) and the barium
195
enema itself are uncomfortable and difficult procedures for elderly patients to undergo. Ultrasound scans have the advantages of being non-invasive, quick and relatively cheap, and are particularly useful for investigating jaundice, abdominal masses, pancreatic tumours and possible liver metastasis. In some centres CT scanning of the colon is now established as an alternative to barium enema in frail patients. Investigation of faecal incontinence is described on page 187.
INVESTIGATION OF BACTERIURIA
196
A routine midstream urine (MSU) test in elderly patients admitted to hospital will show significant bacteriuria (bacterial count of more than 100000 organisms per mL) in 20-30% of men and women. Provided the patient is asymptomatic this bacteriuria is best ignored, as it is not associated with excess morbidity or mortality. A better guide to infection is pyuria, and in the presence of lower urinary tract symptoms even a sterile pyuria may be relevant. This is most conveniently detected by the finding of leukocytes on urine dipstick (e.g. Multistix 8 SG), with an MSU being sent for culture and sensitivity if dipstick testing is positive. The cardinal feature of a urinary tract infection is dysuria, but there is increasing recognition that some patients with urinary incontinence have no dysuria yet have a low-grade infection indicated by pyuria, and when this is treated with antibiotics the symptoms improve. Similarly, some patients complain of suprapubic or perineal pain during bladder filling, which may not be attributed to infection if the MSU fails to show a significant bacteriuria (i.e. more than 105 organisms per mL). However, it is possible that this criterion is inappropriate in these patients and bacterial counts of 102 per mL may be relevant. Urine should also be cultured for Chlamydia trachomatis, Trichomonas vaginalis and yeast. In summary, patients with a significant pyuria (positive urine dipstick or more than 10 leukocytes per highpowered film) who have lower urinary tract symptoms should be given a course of an appropriate antibiotic, such as trimethoprim or nitrofurantoin. Some patients require several weeks' treatment before the urine is clear. Patients with recurrent urinary tract infections associated with lower urinary tract symptoms should be considered for continuous low-dose antibiotic prophylaxis. A number of different regimens have been used, but all appear equally effective. Patients with recurrent urinary tract infections should have their postmicturition residual urine checked. If this is increased it is usually the result of detrusor hypocontractility or bladder outflow obstruction, and patients need to be advised on the importance of emptying the bladder completely as a chronic residual urine increases the risk of further infection. Surgery or intermittent self-catheterization may be needed. A group of patients often difficult to manage are those with recurrent episodes of suprapubic or perineal pain
during bladder filling, which is relieved by emptying and associated with frequency and urgency, but no actual urinary incontinence. Repeat urine testing is always unremarkable and antibiotics do not relieve symptoms. These patients usually have idiopathic detrusor hypersensitivity and some improve with bladder retraining. Patients with severe pain or with red cells in their urine should undergo cystoscopy to exclude interstitial cystitis or bladder cancer.
FURTHER READING ON INVESTIGATIONS IN THE ELDERLY Kafetz K 1998 Blood tests in elderly people and their interpretation. Rev Clin Gerontol. 8:305-318.
ASSESSMENT OF FITNESS FOR OPERATION Advanced age is no longer a contraindication to surgery as over the last 40 years the surgical mortality rate for patients over 80 has fallen from 25% to about 5%. In those over 90 mortality is around 10%. This compares with less than 2% for younger patients. This increased risk is only justified if surgery offers a reasonable prospect for improving the quality of the patient's life, or preventing loss of function. Average life expectancy for a 70-year-old male is 11 years and for a female 14 years, and many patients feel that this potential outweighs high surgical risks. Surgery for the relief of severe pain or complete bowel obstruction would probably be indicated even in the most severely disabled patient. However, a patient would need to be relatively fit and active before removal of a non-obstructive malignant bowel tumour, repair of an aortic aneurysm or a coronary artery bypass would be considered. Ageism should not be allowed to cloud the issue and each patient requires careful individual assessment. This is especially true of cancer in old age, which is less extensively investigated and receives less treatment than in younger patients, a difference not wholly explained by appropriate adjustment for comorbidity or frailty. Patients should always have a specialist opinion, as chemotherapy and radiotherapy protocols can be modified in less fit patients. The 1999 report of the National Confidential Enquiry into Perioperative Deaths highlighted the need for senior surgeons, anaesthetists and physicians to be closely involved in the care of elderly patients who have poor physical status and a high operative risk. Patients needing an urgent operation should be given a high surgical priority. The increased surgical mortality in the elderly is due to several factors, which are shown in Table 7.12. The mortality risk must be weighed against the likely final outcome of surgery. Total hip replacement has trans-
TABLE 7.12 Selecting patients for surgery or intensive care Chronological age alone is a poor indicator of outcome: • Good results in the elderly reflect good selection criteria • Consider the patient's previous health, level of physical independence, exercise tolerance and mental state • Patients' and families' views must be considered; they may be much less enthusiastic than the doctor about major surgery Increased mortality is associated with: • The presence of unsuspected heart disease • Reduced pulmonary and cardiac reserve (making a postoperative chest infection or myocardial infarct more likely) • Greater susceptibility to anaesthetic drugs • Greater risk of developing pressure sores postoperatively
is practicable). Many patients will have a minor ECG abnormality which provides a useful baseline measurement for comparing postoperative changes. Preoperative ECG abnormalities do not reliably predict postoperative cardiovascular complications, which can be expected in about one-fifth of elderly patients and consist mainly of heart failure with some cases of myocardial infarction. Cardiovascular disease is the major cause of increased mortality following general surgery in the elderly. Impaired mental function and poor motivation are also barriers to postoperative rehabilitation. If concentration and short-term memory are poor the patient may be unable to grasp the physiotherapist's instructions; episodes of mental confusion and agitation may also occur.
7
FURTHER READING ON SURGERY formed the lives of many old people and is now a routine operation. However, if chronic lung disease or an old stroke has reduced the patient's exercise tolerance to a few yards, the operation is unlikely to be worthwhile unless for the relief of severe pain. Before surgery, heart failure and diabetes should be controlled, dehydration and electrolyte disturbance corrected, and severe anaemia remedied by blood transfusion. A routine preoperative ECG is worthwhile. Its major use is in detecting a recent myocardial infarct, which would mean postponement of surgery for 6 months (if this
Seymour D G 1999 The ageing surgical patient - an update. Rev Clin Gerontol 9:221-233.
PRESCRIBING FOR THE ELDERLY A general rule when prescribing drugs for the elderly is 'not too many and not too much'. Although the elderly make up only 18% of the total population, they receive almost half of all prescriptions issued.
CASE STUDY 7.2 SURGERY IN OLDER PATIENTS A 90-year-old woman was admitted to hospital for rehabilitation following an accidental fall at home. She had a past history of left ventricular failure due to ischaemic heart disease, which was well controlled with drugs. She also suffered chronic osteoarthritis of her hips and 2 years previously she underwent an elective total hip replacement on the left. She lived alone in a house with downstairs bed and toilet. She was fairly independent and mobile around the house with the help of a walking frame. She had home care visits five times a week. She was taking furosemide (frusemide) 40mg o.d., captopril 25 mg b.d., diclofenac 50mg t.d.s., aspirin 75 mg o.d. and co-codamol 2 tablets q.d.s. She weighed 47.6kg.
A few days after admission she had an episode of haematemesis and melaena. Although frail she was alert and haemodynamically stable. Pulse 90 per minute, BP 140/100. Abdominal examination was normal, haemoglobin 8.8g, serum albumin 27 g. The rest of her blood results, chest X-ray and ECG were normal.
Question
1. How would you manage this patient?
She needs a blood transfusion (2 units were given) and an urgent oesophagogastroduodenoscopy (OGD). This showed a duodenal ulcer with a deformed pylorus. CLO
test was negative. The aspirin and diclofenac were stopped and she was given omeprazole 20 mg daily. Over the next few days she made good progress and was eating and drinking well, but she then had a second episode of haematemesis and melaena. Haemoglobin was 10.4 g. The omeprazole was increased to 40 mg daily. Three days later the nurses reported faecal vomiting. The abdomen was distended and tender, but bowel sounds were normal and the rectum was empty. Plain abdominal X-rays showed only gaseous distension with no signs of obstruction. She was treated with intravenous fluids, given nil by mouth, and had a phosphate enema. The nausea and vomiting persisted intermittently for the next few days. 197
CASE STUDY 7.2 CONTINUED A barium enema showed only diverticular disease of the colon. She was referred to the surgeons, who recommended the continuation of conservative management as she was considered unfit for surgical intervention.
Question 2. Do you think that this was the right decision?
The view of the physicians at the time was that this patient should have had surgery. Prior to admission she had been in relatively good health. Her heart failure was well controlled and she had successfully undergone a total hip replacement. All of these factors would point to a relatively good prognosis. The 1999 report of the National Confidential Enquiry into Perioperative Deaths stressed the importance of a team of senior surgeons, anaesthetists and physicians being closely involved in the care of elderly patients who have poor physical status and high operative risk. Furthermore, the experience of the surgeon and anaesthetist need to be matched to the physical status of the elderly patients as well as to the technical demands of the procedure. Following the decision not to operate the patient continued to have
198
nausea and vomiting and steadily deteriorated. Four weeks after the second episode of haematemesis her haemoglobin had dropped to 8.6g and her weight was now 38kg. She declined a repeat OGD and a barium meal showed complete pyloric obstruction. Again she was referred to the surgeons, who remained very reluctant to operate. The opinion of the anaesthetist was sought and he felt that surgery might be considered under epidural anaesthesia. Despite her general frailty the patient was fully alert, and after the available options and surgical risks were explained to her she opted for surgery. She was transferred to the intensive therapy unit where total parenteral nutrition was given for 3 days; by this stage her weight was 32 kg. She then underwent gastrojejunostomy under epidural anaesthesia, which was successful. She had an uneventful postoperative recovery. Three days later nasogastric tube feeding was started and 2 days after that she was swallowing liquids. After another 10 days she was able to start rehabilitation, and 2 months following surgery, by which time she weighed 38 kg, she successfully returned home. Discussion This patient had haematemesis and melaena as a result of peptic ulcer disease, presumably secondary to her intake of non-steroidal anti-
About 75% of those over the age of 65 and living at home are taking some kind of medication, with 15% receiving four drugs or more. However, multiple prescriptions increase the risk of drug interactions and adverse effects, and compliance is likely to be poor. Over 90% of people in residential and nursing homes receive prescribed medicines: many of these are unnecessary. Adverse reactions are two or three times more common in the elderly than in those under the age of 60. This is due primarily to slower rates of inactivation and excretion but also, with some drugs, to increased sensitivity
inflammatory drugs. She developed gastric outlet obstruction due to a deformed pylorus. Conservative management was initially adopted, but without success. Despite the high surgical risk this patient survived, but with hindsight it is apparent that the surgical risk would have been considerably less had the operation been carried out electively 2 or even 3 weeks previously. Emergency surgery for whatever reason in older people increases the surgical risk. Mortality in patients over the age of 70 undergoing emergency surgery is 20%, compared to 1.9% in patients undergoing elective operations. Postoperative complications and morbidity are also higher. Over the last few years surgery has become much safer owing to improvements in anaesthesia and surgical expertise. Age is generally a poor predictor of surgical morbidity or mortality, and certainly a much poorer predictor of outcome than severity of illness. Careful preoperative assessment of a patient's co-morbidities is more important than age in determining risk. This patient's major preoperative risk was associated with her poor nutritional status: weight loss of more than 20% or a serum albumin less than 35 g/L increases mortality. Giving preoperative total parenteral nutrition for severely malnourished patients probably reduces morbidity and mortality, although the evidence is inconclusive.
of the target organ. Thus, many drugs need to be given in lower dosage.
ALTERED PHARMACOKINETICS Drug absorption Changes in gastrointestinal function with increasing age include a rise in gastric pH, decreased gastric emptying time, decreased splanchnic blood flow, and loss of small
bowel mucosal surface area. Although these changes are theoretically rate-limiting for drug absorption, none appears to be important for passively absorbed drugs.
young patients. The drug plasma concentration may have to be measured.
Distribution
ALTERED PHARMACODYNAMICS
There are a number of theoretically important changes that affect drug distribution in the elderly: • A decrease in lean body mass and total body water reduces the distribution of water-soluble drugs. • Increase in body fat results in an increased volume of distribution of lipid-soluble drugs such as lidocaine (lignocaine), chlordiazepoxide and diazepam. • The small decrease in plasma albumin that occurs in the elderly will reduce drug binding and may thus result in an increased distribution of the drug. As it is the unbound fraction that is clinically active, there may be an increased pharmacological effect. This may be important in sick or malnourished patients, who have a greater reduction in plasma albumin concentration. • Conversely, if the drug binds predominantly to a1-acid glycoprotein (e.g. lidocaine (lignocaine) and disopyramide) then protein binding is likely to be normal, or even slightly increased, in the elderly.
Metabolism There is a reduced rate of hepatic metabolism with increasing age. This reduces presystemic metabolism and causes a marked increase in the bioavailability of drugs metabolized by the liver, such as propranolol, labetalol, lidocaine (lignocaine), clomethiazole (chlormethiazole) and verapamil. In the case of propranolol the age differences in plasma concentrations are large, with the mean concentration in the elderly being about twice that found in the young. However, because of reduced sensitivity, the dosage need not be lowered. Age-related effects on drug metabolism are variable, so that even some extensively metabolized drugs, e.g. warfarin or diazepam, may show no change in clearance.
Excretion Advancing age is accompanied by a reduction in both glomerular filtration rate and tubular function. At 60 years of age renal function is about half that at age 30, and will be further impaired by dehydration, cardiac failure and urinary retention, as well as by diseases such as diabetic nephropathy. Normal elderly people may have significant reductions in glomerular filtration rate and tubular function yet have a normal blood urea and serum creatinine. For drugs excreted by glomerular filtration the rate of excretion correlates with glomerular filtration rate. Some of these drugs, e.g. digoxin, gentamicin, lithium, cimetidine and chlorpropamide, have a low therapeutic index and their dosage therefore needs to be carefully chosen in the elderly. In general, a lower dose will be needed than in
7
The most clinically important result of altered pharmacodynamics occurs with drugs acting on the central nervous system. Sedatives and tranquillizers are more likely to produce drowsiness and hangover effects in the elderly. Although nitrazepam and diazepam have similar plasma concentrations in both young and old, psychological testing shows that the elderly make more mistakes and have longer reaction times for 36 hours after a single dose. They also show increased sensitivity to anaesthetic agents such as halothane. A reduced sensitivity to adrenergic agonists is seen in the elderly heart. Sensitivity to propranolol also decreases, so that despite the higher plasma propranolol concentrations seen in elderly subjects the degree of B-blockade is reduced. The dose of warfarin needed to produce anticoagulation in the elderly is reduced, but this is not due to an agerelated rise in plasma warfarin concentration. Warfarin acts by inhibiting the synthesis of vitamin K-dependent clotting factors, and this inhibitory effect is greater in the elderly, resulting in an increased sensitivity.
ADVERSE REACTIONS Whenever a reduction in drug elimination or increase in receptor sensitivity occurs, there is the likelihood of an excessive drug effect and hence an adverse reaction. The risk of these adverse reactions increases with age (Fig. 7.15A). About 3% of all admissions to geriatric units in the UK are due solely to unwanted drug effects; in a further 8% of cases an adverse reaction is a contributory cause. Two-thirds of all reactions are caused by two groups of drugs: • Cardiovascular drugs: diuretics, digoxin and hypotensive drugs • Drugs acting on the central nervous system: antiparkinsonian drugs, antidepressants, hypnotics and tranquilizers. Although more than 70% of patients taking cardiovascular drugs make a full recovery from the adverse reaction, only 46% recover from the ill effects of antiparkinsonian drugs. The risk of an adverse reaction increases with the number of drugs taken (Fig. 7.15B). Elderly people are more likely to have multiple diseases than the young, and the likelihood of polypharmacy is therefore high. Not only is the patient apt to be muddled by a large number of drugs and inadvertently take the wrong dose, but drug
199
FIG. 7.15 Adverse drug reactions A The increase in adverse drug reactions with age; B Prevalence of adverse reactions related to number of prescribed drugs. The risk in a patient taking only one drug is about 11%, but is 27% if six drugs are taken.
interactions lead directly to an increased adverse reaction rate. This is particularly likely to occur when drugs with a low therapeutic index, e.g. anticoagulants, antidepressants, anticonvulsants and antihypertensives, are used in combination. There are a number of important causes of adverse drug reaction in the elderly other than altered pharmacokinetics and pharmacodynamics. Inadequate clinical assessment is perhaps the most common. Dependent leg oedema, for example, is more often due to immobility than to congestive cardiac failure, and a diuretic is thus not an appropriate treatment. Similarly, old people who complain of dizziness are often expressing a sensation of unsteadiness and fear of falling, rather than true vertigo. Prochlorperazine - an effective vestibular sedative - is frequently prescribed in this situation but is quite useless and also carries a serious risk of parkinsonian side-effects. Loneliness and social problems often present as minor aches and pains, unhappiness and insomnia. Although both difficult and time-consuming, it is far better to deal with the underlying problems than simply to issue a number of drug prescriptions.
COMPLIANCE There is no evidence that the elderly are less compliant than the young, but they do make more medication errors. These occur in up to three-quarters of old people taking
1
200
MCQ 7.5
2
Fig. 7.13
drugs, but only about a quarter are potentially serious, usually because of underdosage. Medication errors are more commonly made by patients over the age of 75 who are living alone and are confused. Poor visual acuity often prevents an old person from reading the instructions correctly, and impaired manual dexterity may make it difficult or even impossible to unscrew the cap on the bottle (particularly if it is one of the child-resistant types). Compliance can be improved, and errors in medication reduced, by careful counselling and an explanation of when and how to take the drug. After a single lesson in inhaler technique up to 30% of elderly patients are still unable to use a metered dose inhaler. Further instruction may be needed, or patients can be given a breath-activated device or a large-volume spacer, which they find easier to use and thus prefer. Written instructions or a calendar pack can be helpful. Dosette boxes (devices which organize a week's supply of tablets) can be useful for patients who are motivated to take their drugs but are absentminded. They can be prepared by the pharmacy or by a carer. 1
CHOLESTEROL LOWERING IN STROKE Total and low-density lipoprotein (LDL) peak at around age 65 in males and 75 in females, and thereafter decline. There is probably also a decline in high-density lipoprotein (HDL) after age 65. Thus cholesterol levels measured in old age do not necessarily reflect lifetime levels. There is an inverse relationship between serum cholesterol and haemorrhagic stroke, and a direct relationship with ischaemic stroke. In general the association between cholesterol and stroke is considerably weaker than those reported for blood pressure, diabetes and atrial fibrillation. Systematic reviews indicate that for people with known CHD and cholesterol levels in the mid to elevated range statins significantly reduce stroke risk by approximately 32%. This is probably greater than the relative stroke risk reduction achieved with aspirin therapy (approximately 25%) and compares with the 40% resulting from antihypertensive treatment. The number needed to treat to prevent one stroke over 5 years using statins in patients with CHD is approximately 80-150, compared with 40-70 for treating elderly hypertensives. The best advice at present is that patients up to the age of 75 years with known CHD and total cholesterol >5 mmol/L will benefit from a statin to reduce the risk of a first stroke, and also to reduce the risk of further CHD events. Patients up to the age of 70 with cholesterol >5 mmol/L and no history of CHD, but at high cardiovascular risk, benefit from a statin because of reduced CHD risk. The cardiovascular risk can be assessed using various tables
RECENT ADVANCES IN STROKE REHABILITATION
RECENT ADVANCES IN DYSPHAGIA AFTER STROKE
• The accuracy and completeness of clinical notetaking is improved by using a clerking proforma. Although there is no reliable evidence it is likely that improved assessment leads to improved outcome. Certainly audit is facilitated and, where the process being audited is of proven effectiveness (e.g. the use of aspirin as secondary prevention of ischaemic stroke), it is reasonable to assume that improved performance (i.e. ensuring that all ischaemic stroke patients leave hospital taking aspirin) will lead to improved outcome. • An overview of controlled trials confirms that stroke units reduce early mortality by 28%, disability (measured as an 'activities of daily living' score) is significantly reduced and there is a substantial reduction in the odds of being dead or requiring institutional care 1 year after a stroke. 2 • The characteristics of a stroke unit are: coordinated multidisciplinary rehabilitation with involvement of carers; a specialist interest in stroke disease and rehabilitation; and training and education programmes for both staff and carers. • There is early evidence to suggest that, after discharge from hospital, stroke patients have better outcomes if physiotherapy is continued in their own homes rather than at geriatric day hospitals.
Patients should be routinely tested by asking them to sip some water and observing any tendency to choke, make a gargling sound when asked to say 'aah' or have a 'wet voice'. The gag reflex is unreliable. Patients with dysphagia should take nothing by mouth, be given intravenous fluid, and be assessed by a speech and language therapist. After 48 hours many clinicians start tube feeding, but there is no evidence that early feeding increases the proportion of patients surviving without severe disability, or indeed whether a nasogastric tube or percutaneous endoscopic/gastrostomy (PEG) is preferable. There is an indication from a small trial that a PEG is better tolerated and produces a greater improvement in nutritional state, but the evidence is not strong and there is considerable uncertainty regarding when tube feeding should begin, which is the best method, and, for patients who are able to swallow, whether nutritional supplements by mouth improve stroke outcome. A large international trial (FOOD) is under way to try to resolve these issues.
(e.g. Sheffield table or the New Zealand guidelines) that predict risk based as the ratio of total: HDL cholesterol, age, sex and the presence of hypertension, smoking and diabetes. • Patients who have had a non-haemorrhagic stroke or TIA are at high risk of a myocardial infarction, and a statin is justifiable for the secondary prevention of CHD if total cholesterol is >5mmol/L up to the age of 75.
REHABILITATION The aim of the rehabilitation team is to help restore maximum capability within the limits of the elderly patient's needs and disability.
PRINCIPLES OF REHABILITATION When setting a realistic rehabilitation goal it is important to consider the patient's needs. For a very elderly and frail
amputee wheelchair independence may be perfectly satisfactory, but this would not be acceptable for a fit 65-yearold amputee who is a keen golfer. Although rehabilitation is a core activity of geriatricians it has suffered in recent years as services have had to focus on the increasing number of acute admissions. As a result, rehabilitation goals are often set merely at achieving independence in activities of daily living (ADL), so that patients can be discharged from hospital as quickly as possible, but goals directed towards quality of life, such as driving the car or using public transport, may be just as important to the patient. Rehabilitation does not stop once the patient leaves hospital, and there is increasing interest in the role of rehabilitation as a means to prevent hospital readmission. Programmes of chronic disease management agreed between primary care and the relevant specialist teams improve outcomes and are cost effective. Hospital admissions can be reduced for patients with chronic obstructive pulmonary disease by comprehensive pulmonary rehabilitation (coordinating medical treatment, nutrition and exercise) and for heart failure by nurse-led monitoring and advice. For patients with Parkinson's disease home-based rehabilitation can be particularly effective. Patients can be taught to break up long movement sequences into separate steps and do only one movement in the sequence at a time. They can be advised to avoid doing two things at once, such as carrying a tray of drinks when walking, and to consciously think about each movement before starting to do it. Movement around the home can be improved by the occupational therapist providing visual cues, which are par-
7
201
ticularly useful in overcoming freezing episodes. Cue cards can be placed around the house with instructions such as 'go' or 'step', and strips of adhesive tape on the floor, particularly in confined spaces such as bathrooms or kitchens, can encourage more normal walking patterns. For patients who have had falls it might seem obvious that a home visit by an occupational therapist should concentrate on removing environmental hazards. However, apart from correcting obvious dangers (such as a broken light bulb at the top of the stairs) most studies on environmental manipulation have shown little benefit in the form of reduced rate of falls. However, what the occupational therapist can do is to teach the patient how to cope safely with various everyday activities and to help them regain their confidence. There is some evidence that this type of intervention reduces the risk of falling not only in the home, but outside it as well. The principles of rehabilitation in the elderly are essentially the same as for young patients, but some special features of old age should be noted. Multiple pathology is likely to be present, so that the speed with which a stroke patient can be mobilized is often hampered by shortness of breath due to chronic lung or heart disease. The mental barriers to recovery may also be greater, whether due to dementia or to the increased feelings of passivity and dependence sometimes shown by older people. There may be difficult social problems owing to lack of family support or poor housing. Rehabilitation is concerned with helping the patient to learn to do things for him or herself, and there may be times when it is better to let a stroke patient struggle to feed himself rather than to always rely on feeding by a carer. Patients enjoy exercising their painfully regained skills and it is essential to regain independence before leaving hospital and returning home.
THE MULTIDISCIPLINARY TEAM
202
The most effective approach to rehabilitation is through a multidisciplinary team, with each member contributing their special skills and working together with the patient and family towards an agreed goal. The team meets regularly to discuss the patient's progress and review future plans. With a good team the patient is undergoing rehabilitation all the time and not just during the half an hour a day spent with the physiotherapist or occupational therapist. Although elderly patients can be successfully rehabilitated on a busy general medical ward, there are definite advantages to grouping them together in one ward: the nurses develop greater expertise, the pace of treatment can be better geared to the patients' needs, and it is easier to create an atmosphere of 24-hour-a-day rehabilitation. Correct positioning of a stroke patient is something all nurses and doctors should be aware of (Fig. 7.16). Before discharge, the occupational therapist will take
FIG. 7.16 Positioning the stroke patient A Incorrect; B Correct. The forearm on the affected side should be supported and should point straight forwards with wrist and fingers extended and thumb abducted. The arm must not be allowed to hang from the shoulder in internal rotation. Choosing a suitable chair - with unrestricted view and with arm rests - is important3, C Transferring the stroke patient to a chair. Note the support given to the affected arm.
the patient on a home visit to see how well they cope in familiar surroundings. This also allows assessment of the need for a specific aid, e.g. a grab handle on the wall next to the lavatory, and the opportunity to have it fitted before the patient arrives home. The social worker not only organizes the care package at home or arranges funding for patients going into residential or nursing homes, but also plays a valuable role in providing support and advice. Increasing disability and loss of independence can cause considerable distress to both patient and family, which can be helped by skilled counselling.
FURTHER READING ON REHABILITATION Department of Health 2001 National Service Framework for Older People. Standard 5: Stroke, www.doh.gov.uk/nsf/olderpeople.htm Young J, Brown A, Forster A, Clare J 1999 An overview of rehabilitation for older people. Rev Clin Gerontol 9:183-196.
COMMUNITY CARE AND LONG-STAY CARE The demand for community and long-stay care rises rapidly with age. Of those aged 65-74 only 1 % are living in institutional care and only 6% are receiving visits from a home help. For those aged 85 and over the figures rise to 26% and 36%. In the UK the principal demographic change in recent years has been a one-third rise in the number of those aged 85 and over. The escalating cost of caring for this frail and dependent section of the population (Fig. 7.17) has caused governments of all industrialized countries to think hard about how this need might be met. In the UK the NHS and Community Care Act of
7
FIG. 7.17 Resources required to keep pace with demographic change Demographic change has the most marked effect on spending on long-term care C 1991 = £8 billion: this includes nursing and residential homes as well as NHS long-stay beds. A Hospital and community health services expenditure 1991 = £16 billion B General practitioners and prescription medicine expenditure 1991 =£5.5 billion.
1990 (implemented 1993) coordinates domiciliary, day care and respite services so that the old person can live in their own home for as long as possible; when this becomes no longer feasible they are cared for in private residential or nursing homes. The cost of this is borne by the individual until capital has dwindled to a threshold level (currently £18500), when the bill is then picked up by the local authority. Local social services departments and health authorities have to agree joint policies for providing both residential and nursing home care and arrangements for discharge from hospital to the community. An old person living at home in need of support has a care worker who identifies his or her needs and plans a package of care. This may involve home carers, district nurse, bathing attendant and 'meals on wheels'. Respite care to give the carers a break may be arranged in either a residential or nursing home or the local community hospital. Day care is available at local authority centres, where the needs are mainly social, or at the geriatric day hospital if the needs are medical. Patients in hospital may not be sent home until there is an agreed discharge plan based on a multidisciplinary assessment. If this assessment, whether carried out in hospital or in the community, determines that the patient is no longer able to cope at home then a decision will be made whether to admit them to a residential or nursing home (paid for as outlined above). Patients with complex conditions or multiple problems who need continuing weekly assessments by the geriatric medical team are cared for free of charge in an NHS long-stay hospital bed. These patients now make up only a tiny minority and the
FIG. 7.18 Vicious circle
NHS withdrawal from the long-stay sector has raised important issues about standards of medical care in private institutions. The Community Care Act has brought improvements in the form of a better coordinated, patient-orientated service, but the time patients spend in hospital waiting for transfer to institutional care has increased because of funding difficulties, and there are continuing uncertainties about the eligibility criteria for an NHS long-stay bed. Increasing acute hospital admissions and a declining number of available beds are putting unprecedented pressure on acute medical services. An important response has been to try to find ways of preventing inappropriate admissions of elderly patients to district general hospitals and to speed up the discharge of those whose investigations and treatment is completed. Initiatives include improved community rehabilitation services; hospital at home; rapid response teams to provide short-term support for patients sent home from A & E departments; and increasing use of community hospitals. This range of services is now described as intermediate care. Despite these developments, community services have not been expanded sufficiently to cope with the increased demand resulting from hospital bed closures. Elderly people are being discharged from hospital 'quicker and sicker', and this has two predictable results. The increased demand on social services departments from a few people with a high level of personal care needs means that very many people who require less intense service packages receive no service at all. Secondly, the pressure for earlier hospital discharge results in
203
insufficient rehabilitation, creating a vicious circle (Fig. 7.18). This will only by broken by joint working between the NHS and social service departments to develop better services. It should not be forgotten that in the UK, as in other countries, the unpaid support provided by relatives, friends and neighbours easily outweighs that provided by statutory services. Advising and helping these carers is an important part of the doctor's role. It is also important to remember that the quality of care in long-stay institutions, private or NHS, is crucially dependent on the visiting doctor's vigilance and enthusiasm. This applies not only to ensuring that high-quality nursing standards are maintained, but that the environment for the patients is made homely, pleasant and comfortable. The emphasis should be on educating patients to do as much for themselves as possible, and physiotherapy and occupa-
204
tional therapy may be entirely appropriate for certain patients.
FURTHER READING ON COMMUNITY CARE AND LONG-STAY CARE Black D, Bowman C 1997 Community institutional care for frail elderly people - time to structure professional responsibility. Br Med J 315:441-442. Department of Health 2001 National Service Framework for Older People. Standard 3: Intermediate care. www.doh.gov.uk/nsf/olderpeople.htm Nikolaus T, Specht-Leible N, Bach M et al 1999 A randomised trial of comprehensive geriatric assessment and home intervention in the care of hospitalised patients. Age Ageing 28:543-550. The Coming of Age - improving care services for older people. London: Audit Commission, 1997.
8
Psychological Medicine Jeremy Holmes
Classification and overview 205
Hysteria 235
The causes of psychiatric illness 210
Histrionic personality and related conditions 238
The psychiatric examination 211
Eating disorders 239
Treatments in psychological medicine 212 Anxiety 212
Drug dependence 243 Alcoholism 247
Loss, grief and bereavement 217
Mental handicap or learning difficulties 252
Depression 218
Psychiatry and the law 253
Suicide and parasuicide 223
Mental health legislation 253
Mania and hypomania 226
Medicine and the emotions 255
Schizophrenia 228
Sex and medicine 256
Paranoid states 231
Death and dying 257
psychiatry are psychology and psychoanalysis, child development and sociology. Neurochemistry and neuroimaging, and the new genetics and neo-Darwinism, are making increasingly important contributions to the subject. The central meeting ground for medicine and psychiatry is the doctor-patient relationship. All patients, whatever their illness, have feelings and fears that the doctor needs to understand and know how to handle. The meaning to the patient of a particular symptom - chest pain, for example, whether due to angina or to anxiety in a 40-yearold man whose father died suddenly of a heart attack in middle age - needs to be understood, in order to appreciate its impact on the patient, as well as diagnosed and investigated. Psychiatry is concerned with meaning as well as explanation, and with methods of communication with the patient, as well as the technology of treatment. Despite the inseparability of psyche and soma, many doctors find psychiatry difficult and confusing. This is partly because the subject is inherently complex and multifaceted, but also because psychiatry involves the doctor's own feelings and attitudes in a way that can often be avoided in other branches of medicine. In approaching psychiatry, doctors have to learn to deal not just with the patient, but also with themselves.
CLASSIFICATION AND OVERVIEW A simple classification of psychiatric illness is summarized in Table 8.1. Some aspects of psychiatry of old age are also considered in Chapter 7.
Somatoform disorders 233
MINDS AND BRAINS
Psychiatric disease constitutes a large proportion of disability and illness in society (Fig. 8.1 and Summary 1). The World Health Organization has identified depression as the main cause of disability throughout the world; suicide is one of the commonest cause of death in young people, especially males, in developed countries. Somatization disorders are among the most frequent cause of consultation in general practice. Throughout the western world, most of the large mental hospitals have now closed and acute psychiatric illness is treated in general hospital units and the community, alongside the other medical disciplines. The boundary between general medicine and psychiatry is much less rigid: patients and their illnesses are no longer seen by physicians purely as scientific puzzles to be solved: psychological aspects of physical illness are, through liaison psychiatry, now recognized to be of great importance. Medical science is, in turn, making an increasingly important impact on psychiatric knowledge and practice. The basic disciplines underlying
An eminent neurologist once stated that 'psychiatry is neurology without physical signs'. This would be true if psychiatry were simply concerned with the brain and its disorders; the problem of psychiatric diagnosis and classification would then be no different from that of any other system of the body. A significant part of psychiatry is indeed concerned with diseases of the brain - the organic psychoses, such as confusional states, for example, or the affective symptoms (i.e. disorder of mood) caused by adrenal disorders. The 19th century discovery that the psychosis known as general paralysis of the insane (GPI) was caused by syphilis stimulated one of the founding fathers of psychiatry, Emil Kraepelin, to search for other physical causes of insanity, with the expectation that all mental illness would soon be found to be caused by diseases of the brain. Psychiatry continues, rightly, to try to understand the structural and biochemical correlates of psychiatric disorders, but the Kraeplinian project can never be fully realized, partly because brain research is difficult and at a rather primitive stage, but also because psychiatry is concerned with minds as well as brains.
205
TABLE 8.1 Classification of psychiatric disorders Organic syndromes Delirium Dementia Intoxication and withdrawal syndromes Functional psychoses Schizophrenia Manic-depressive psychosis Paranoid states Neuroses Anxiety Phobias Depression Obsessive-compulsive neurosis Somatoform disorders Conversion Somatization Hypochondriasis
Others Addictions Alcohol Drugs Eating disorders Sexual dysfunction and deviation Personality disorders (Axis II in DSM) (see p. 180) A. Paranoid Schizoid B. Antisocial (psychopathic) Histrionic Borderline C. Avoidant Dependent Obsessive-compulsive
Prevalence Prevalence of psychiatric ill health in the community Prevalence of psychiatric disorder in general practice Prevalence of psychiatric disorder among schoolchildren Psychiatric referral rate from general practice Psychiatric beds as a proportion of all NHS beds Major disorders Severe depression Suicide attempts Suicide Chronic mental illness Severe mental handicap
SUMMARY 1 The prevalence of psychiatric morbidity among adults aged 16-64, living in private households, in Great Britain • 14% of adults have a neurotic health problem. Women are far more likely to suffer this type of problem than men. • The most common neurotic symptoms are fatigue (27%), sleep problems (25%), irritability (22%), and worry (20%). • The most prevalent neurotic disorder is mixed anxiety and depressive disorder (7.7%), followed by generalized anxiety disorder (3.1%). The prevalence of all neurotic disorders is higher among women than men. • Functional psychosis has a prevalence of 0.4%. • The overall rates of alcohol and drug dependence are 4.7% and 2.2%, respectively. Men are three times more likely than women to have alcohol dependence and twice as likely to be drug dependent. Alcohol and drug dependence are most prevalent among young adults, particularly young men aged 16-24.
Mind has three main properties: • The ability to experience emotions • Intentionality (i.e. having desires and goals) • Self-awareness.
206
Although psychiatric diagnosis approaches the mind as if it were an organ, this is often merely an analogy. When we speak of psychiatric illness we may be speaking about a brain disease, e.g. GPI, Alzheimer's disease or (possibly) some forms of schizophrenia, in the same way we speak of pneumonia as a disease of the lungs. On the other hand, although conditions such as personality disorders or agoraphobia are in some ways like illnesses, they also differ in many important respects because they affect the mind. They are best seen as disorders, rather than diseases. This important distinction between mind and brain may
Neurotic disorders Social pathology Chronic alcoholism (identified cases) Chronic alcohol ism (unidentified cases) Juvenile delinquency Problem families One-parent families with children under 15 FIG. 8.1 Epidemiology of psychiatric disorders A Prevalence of, and provision for, psychiatric ill health in the community. B Cases per annum of various psychiatric disorders in a typical British general practice population of 2500.
help to explain the discomfort some feel when confronted with the essentially rather simple issue of psychiatric diagnosis. The categories of mental illness are few and not difficult to memorize. The main problem is philosophical, rather than one of classification. A number of other difficulties may also be encountered on first approaching psychiatry. First, psychiatric diagnoses tend to be at a rather general level. They are symptomatic/syndromic rather than pathological/specific. The diagnosis of anxiety neurosis or schizophrenia is analogous to that of 'heart failure' rather than 'mitral stenosis'. Secondly, with the exception of the organic psychoses, the underlying pathology of psychiatric disorders is usually complex and multifactorial. This follows from the nature of mental phenomena. Just as there is usually no simple reason why an individual chooses medicine as a career, so
there is rarely a single 'cause' of depression. There may be many explanations for a particular symptom or problem. A third difficulty encountered in psychiatric diagnosis is that of deciding what is normal or abnormal, which is sometimes more a political or ethical question than a technical one. The doctor's own standards and feelings are involved in assessing a psychiatric patient. This also leads to two errors commonly made by newcomers to psychiatry: either the student identifies the patient with himself, and so decides there is nothing much wrong, or he identifies himself with the patient and worries that he must be psychiatrically ill! (Note that throughout this chapter 'he' is used to mean 'he or she'.) Two systems of classification are widely used in psychiatry: ICD (International Classification of Diseases), which is favoured in Europe, and DSM (Diagnostic and Statistical Manual), which has been developed in the USA by the American Psychiatric Association. The latter is interesting in that it is a multiaxial classification: Axis I diagnoses classify the psychiatric disorder; Axis II classifies any personality disorder that may or may not accompany the psychiatric illness; and Axis III allows for the diagnosis of any concomitant physical disorder.
FURTHER READING ON MINDS AND BRAINS Fulford K W 1989 Moral theory and medical practice. Cambridge University Press, Cambridge Kendell R 1975 The concept of disease and its implications for psychiatry. Br J Psychiatry 127: 305-315
PSYCHOSIS AND NEUROSIS The distinction between psychosis and neurosis has been and remains fundamental to psychiatric thinking, although neither is easily defined on its own, and some classifications have attempted to do away with the rather vague and blanket term neurosis. The difference turns on four main issues: • • • •
Relationship to reality Severity Relationship to normality Insight.
Relationship to reality The essence of psychosis is that the patient loses contact with everyday reality. This may happen as a result of either hallucinations or delusions, or both. Delusions and hallucinations are not a feature of neurosis. The neurotic's feelings and beliefs about himself may be distorted, but perception and understanding of the external world remains intact.
SUMMARY 2 The distinction between psychosis and neurosis Feature Relationship to reality
Psychosis Loss of contact with reality Delusions and/or hallucinations
Neurosis Perception of external reality intact Problem is with the self
Severity
More severe, more global disturbance
Areas of normal function remain
Relationship to normality
Clear distinction between normal and psychotic experience
Represents extremes of normal difficulties
Insight
Usually lacking
Present
8
Hallucinations A hallucination is a false perception. The patient undergoes a sensory experience in the absence of an external stimulus, for example hearing a voice when there is nobody there. For this to be diagnostic of psychosis it should be clear-cut; hearing an 'inner voice', which the person recognizes as really part of himself, is not a hallucination. An illusion should be distinguished from a hallucination in that it is an elaboration of a real percept, e.g. 'seeing faces in the fire', and is of less, if any, pathological significance. In hallucination, any of the five senses may be involved in the patient's altered perception of reality. Hearing Auditory hallucinations are probably the commonest type of hallucination, found especially in paranoid states, in schizophrenia, and occasionally in psychotic depression. Sight Contrary to popular belief, schizophrenic patients rarely 'see things': visual hallucinations occur most commonly in drug and alcohol withdrawal states, temporal lobe epilepsy and hysterical psychosis. Smell and taste Olfactory hallucinations are usually a sign of organic disease, e.g. temporal lobe seizures. Touch Tactile hallucinations are rare, but can occur in schizophrenia and drug withdrawal. Hallucinations are not always a sign of pathology. After bereavement, visual or auditory hallucinations of the lost loved one are common. Delusions A delusion is a fixed and firmly held false belief. The patient's perceptions are unaltered, but his interpretation of them is, and is at variance with common experience. The patient sees people chatting at a bus-stop and is convinced
207
they are talking about him, saying he is homosexual or a spy, for example. These beliefs may be well concealed and not evident in superficial conversation. We normally assume that our thoughts are private, that individuals are autonomous, that the non-human world is indifferent to our existence, that we are not in any special danger, and that we are not of any particular importance or interest to strangers. The deluded patient (e.g. in schizophrenia) has experiences that conflict with these everyday beliefs. The patient may feel that his thoughts can be interfered with from outside, or that his movements can be controlled by others; he may believe there is some special significance in the number plate of a passing car, that he is in great danger from hostile forces, or that television programmes or public events are caused by, or directed at, himself.
SUMMARY 3 Classification of psychosis Organic Acute (delirium) Chronic (dementia)
Functional Manic-depressive psychosis Schizophrenia
oneself and one's emotions and motives without denial or self-deception. Although insight in this second sense may be desirable, it bears no relationship to the presence or absence of illness. It is possible to be perfectly healthy and yet to lack self-knowledge, or to be profoundly insightful yet mentally ill.
THE PSYCHOSES Severity In general, psychotic disorders are more severe, more disabling and produce greater overall disturbance of mental functioning than neuroses. There are exceptions to this. An obsessional neurosis, for example one in which the individual may spend many hours a day engaged in complicated washing or dressing rituals, can be incapacitating.
Relationship to normality In psychosis there is a clear departure from normality. In contrast, minor neurotic symptoms, e.g. depression, anxiety, obsessional symptoms and hysteria, are common in normal people. The neurotic population is best seen as an extreme end of a normal distribution curve in which quantitative, but not qualitative, change has taken place.
Insight
208
It is commonly stated that the difference between neurosis and psychosis is that the psychotic 'lacks insight'. The psychotic patient attributes his symptoms to reality rather than illness, and cannot be persuaded out of these delusions or hallucinations; the neurotic, on the other hand, can usually see that his view of the world might be mistaken. However, although it is undoubtedly true that the psychotic lacks insight, there are several reasons for giving less prominence to insight than is customary. First, if the psychotic is identified on the basis of a loss of touch with reality, then he will, by definition, lack insight. If the patient knew that his delusions or hallucinations were false, he would not be deluded or hallucinating. Secondly, the patient often tacitly accepts that he is ill by coming for help, despite the apparent illogicality of complaining to a doctor about a delusion. Thirdly, the word 'insight' has two distinct meanings in psychiatry: one, given above, refers to the patient's relationship to reality and his illness; another more literal meaning refers to the ability to look into
Psychoses may be divided by their features and causes into two main groups: organic and functional (or, more accurately, 'of unknown origin'). In organic psychosis there is established biochemical, infective or structural brain disease. In functional psychosis no such disease process can be demonstrated. Organic psychoses can be divided into acute organic psychoses (also known.as acute confusional states, delirium or 'acute brain syndrome') and chronic organic psychoses (also known as dementia and 'chronic brain syndrome') (see also Ch. 24).
Functional psychosis vs. acute organic psychosis It is essential to be able to distinguish functional psychoses from acute confusional states, as the former require psychiatric, the latter medical, treatment. The key difference is the state of consciousness. In functional psychosis consciousness is clear and the patient fully orientated: it is possible to complete a complicated crossword puzzle while suffering from paranoid schizophrenia. In organic psychosis, however, there is almost always some disturbance of consciousness; this is usually variable ('fluctuating level of consciousness') and is often worse at night. Some causes of acute organic psychosis are given in Table 8.2.
Functional psychosis One hundred years ago, Kraepelin divided the functional psychoses into two main groups: manic-depressive psychosis, and schizophrenia (or, as he called it, 'dementia praecox'). Manic-depressive psychosis is primarily a disorder of mood. The patient becomes psychotically depressed or elated ('unipolar manic depression') or experiences episodes of both ('bipolar manic depression'). There are usually periods of normality between episodes of illness. Schizophrenia is primarily a disorder of thinking, and on the whole it produces, a more severe and more general disturbance of mental functioning. The prognosis is less good than for manic depression.
TABLE 8.2 Some causes of acute organic psychosis Cause
Examples
Systemic infection Metabolic disturbance Vitamin deficiency
Malaria, HIV, pneumonia (especially in the elderly) Electrolyte imbalance, renal failure, liver failure Thiamine deficiency (Wernicke-Korsakoff syndrome in alcoholics, and beriberi) Hypoglycaemia, hypothyroidism, steroid administration Anticonvulsants, hypnotics, antidepressants, LSD, amphetamines CVA, subarachnoid haemorrhage, tumour, cerebral abscess DTs, benzodiazepine withdrawal
Endocrine Drug intoxication Intracerebral Withdrawal syndrome
cal health than those who are mentally untroubled. Childhood adversity, for example, is strongly associated with poor physical health in adult life. This link was orginally conceptualized by Freud in terms of 'hysterical conversion disorders' - i.e. the 'conversion' of mental distress into bodily symptoms. The basic themes of hysteria were denial, dissociation, displacement and dependency. The patient denies a painful conflict and thus avoids anxiety or depression, but at a price: she (many hysterical patients are female) dissociates herself from her feelings and displaces the latter into her body instead. Psychic pain is thereby converted into physical symptomatology, and the patient becomes dependent on doctors and others. Although the possibly perjorative and aetiologically loaded term 'hysteria' has been replaced with the more neutral 'somatization' the underlying themes remain.
THE NEUROSES
Obsessive-compulsive neurosis
Unlike psychosis, in neurosis the patient experiences no alteration of external reality. Instead, he is troubled by, and tries to avoid, some unacceptable aspect of himself or of his internal reality. There are four main patterns of neurosis:
Here the patient deals with anxiety - often aroused by fear of his own feelings of aggression, sexuality or wish for power or independence - by an attempt at control. A ritual action or a repetitive thought is repeated over and over again in the magical hope that this will keep some imagined danger at bay. The patient knows it is absurd (thus has insight and is not psychotic), tries to resist, but still has, say, to wash in a particular way every morning in order to feel safe to start the day.
• • • •
Anxiety neurosis and phobia Depressive neurosis Hysteria and somatization Obsessive-compulsive neurosis.
Anxiety neurosis and phobia Anxiety is an almost universal feature of all psychiatric illness. It is the psychic equivalent of pain. Anxiety is normally a response to external threat or unpredictability in the environment. In anxiety neurosis, rather than being alerted and mobilized into action by anxiety, the patient is paralysed or overwhelmed by it. Where anxiety is experienced only in specific situations, the patient is said to suffer from a phobia. In phobic disorders the patient attempts to master anxiety by avoidance (e.g. an agoraphobic patient avoids public places).
Depressive neurosis If anxiety is the psychic equivalent of pain, depression is the equivalent of disability (although anxiety can also of course be disabling, and depression intensely painful). In depression, the patient has lost not a limb or a function but a relationship. It is usually a person who is lost, but the 'lost object' can also be a job or a house, or the patient's own self-esteem. Depression can be seen as an attempt to avoid painful reality by withdrawal.
Hysteria Body and mind are inseparable. There is good evidence that patients with psychiatric disorders have worse physi-
8
PERSONALITY DISORDER Individuals are recognizable not just by their appearance but by their personality which, despite ageing and change, remains relatively constant through time. Personalities can be classified dimensionally or categorically. A dimensional approach is exemplified by Hans Eysenk who, following his intellectual opponent Jung, devised a method for assessing personalities along the dimensions of extrovert (outgoing, gregarious, stimulusseeking) and introvert (inner-directed, shy, stimulusavoiding). The problem of differentiating between normal and abnormal personality is even more difficult than in neurosis. There are undoubtedly individuals whose personalities are very unusual, at least in the statistical sense, but they are not necessarily abnormal. An alternative approach to the classification of personality uses psychiatric categories to describe different types of individual. Someone suffering from schizoid personality, for example, is withdrawn and aloof, preoccupied with material objects or intellectual pursuits rather than people, lacking in close emotional contact, and is defensive and easily hurt. These features may only be a personality trait, and may even be advantageous: many creative people have schizoid tendencies. However, when taken to extremes they become a personality disorder. Here, the individual is so handicapped by
209
SUMMARY 4 Classification of personality Dimensional approaches e.g. extrovert/introvert DSM categorization A. Paranoid Schizoid
B. Antisocial (psychopathic) Borderline Histrionic
C. Avoidant Dependent Obsessive-compulsive
his personality that he seeks, or is brought for, help, e.g. someone with a schizoid personality who suffers from severe social isolation. Unlike psychosis and neurosis, a personality disorder is not an illness. Its features date back to childhood or adolescence, and so there is no premorbid period of normality. However, personality disorder often coexists with, and may predispose to, psychiatric illness (this is an example of 'comorbidity'). Personality disorders are conveniently grouped into three main types. Group A have some of the features of schizophrenia and paranoia, but without any overt signs of psychosis. They may, however, predispose to a psychotic illness, and eventually develop into one. Thus someone with a paranoid personality may, in later life, develop pamphrenia. In group B, sometimes described as 'dramatic', patients experience social difficulties that often bring them into conflict with authority. Many of the patients who present to casualty departments after episodes of deliberate self-harm (see below) suffer from borderline personality disorder, characterized by unstable relationships, substance abuse, chronic feelings of emptiness, and difficulty in regulating emotions. For histrionic personality disorder, see page 238, and for antisocial personality disorder, page 253. Group C are neurotic personalities typified by anxiety, avoidance of threat or challenge, and dependent relationships. An example is that of obsessional personality disorder. Here the individual is meticulous, controlled, orderly and rigid, and may find the sloppiness of others unbearable. Such characteristics may be advantageous in certain circumstances, e.g. the armed forces or the operating theatre, but may also bring the individual into conflict with others when flexibility is needed, e.g. under stress and in intimate relationships.
THE CAUSES OF PSYCHIATRIC ILLNESS
210
The complexity of the interactions underlying psychiatric illness can be confusing. A causal model of the type 'one pathogen-one disease' rarely applies in psychiatry. There are three main types of causal factor in psychiatric illness: genetic/biochemical, developmental, and social. All play at least some role in most psychiatric disturbances, and part of the art of psychiatry lies in assigning the appropriate weight to each factor and identifying which may be
FIG. 8.2 The origins of psychiatric disorder
the most important (Fig. 8.2). Most psychiatric illnesses are genuinely 'multifactorial' in origin. This is not surprising, considering the complexity of brain development and the numerous branching pathways that development can take. The eventual outcome in terms of mental health will depend on genetic inheritance, childhood environment, resistance or vulnerability factors, adverse and healthpromoting experiences, and accidental factors such as loss and trauma. Eliciting this personal narrative or life story is central to psychiatric history taking and provides an essential backdrop to understanding current psychiatric disorder.
Genetic/biochemical ('organic') Occasionally a single genetic defect can determine a psychiatric illness, e.g. the psychiatric manifestations of Huntington's chorea. However, although genetic inheritance may, as in schizophrenia, be a necessary organic cause of illness, it is rarely sufficient. Biochemical, viral, immunological and nutritional factors may well be important in a number of psychiatric illnesses, although few have so far been convincingly demonstrated as a unique cause.
Developmental ('infrapsychic') Each individual is a product of, and in a sense contains and continues, his past. Psychological development, especially that shaped by early childhood experience and family relationships, plays a crucial part in determining personality and ways of reacting to stress in later life.
Social ('interpersonal') Many psychiatric illnesses are triggered by recent social events, such as bereavement, divorce or unemployment. The patient's social and family situation can play a major role in both initiating his illness and helping or hindering his capacity to recover. The quality of family relationships is itself influenced by the personality, which is in turn a product of both genetic and developmental factors.
8
THE PSYCHIATRIC EXAMINATION The psychiatric examination, although similar to the medical examination insofar as it is a systematic gathering and ordering of facts and observations, is unique in a number of important ways. First, it consists of a detailed account of a person's biography and current circumstances. Second, in gathering the history the interviewer uses a much more open style than is usual in the closed-question 'checklist' approach of conventional history-taking. The 'facts' of psychiatry are often feelings, and these are often most effectively elicited by open questions such as 'How do you feel about...?' or 'What was the worst moment .. .?' Third, the interviewer's own reactions and thoughts, rather than being put aside, should be recognized as relevant data to be noted and recorded. The interviewer should maintain a non-judgemental, balanced, compassionate but neutral position. The interviewer should also be gentle but firm and should not avoid eliciting material (e.g. sexual or traumatic) that may be painful for the patient simply because of his own scruples or anxiety. The psychiatric history, which may have to be supplemented by interviewing close friends or relations, should include the following: • Reason for referral. Did the patient ask for help, was he encouraged to seek it, and if so by whom, or was he brought unwittingly or unwillingly to the doctor? Why now? • History of present complaint. A detailed account, as far as possible in the patient's own words, of what he experiences as 'wrong', unusual or bizarre, or would like to change in his life. • Previous psychiatric and medical history.
SUMMARY 5 Psychiatric history and examination History • Reason for referral • History of present complaint • Previous psychiatric history • Previous medical history • Drugs and alcohol • Family history - genogram • Personal history • Personality Examination • General appearance and behaviour • Speech - form and content • Mood • Abnormal beliefs • Abnormal experiences • Cognitive state • Insight • Interviewer's responses
FIG. 8.3 A genogram
Drug and alcohol history. Family history. A detailed description of the patient's 'family of origin' and 'family of procreation' (if they have one) can conveniently be recorded in the form of a family tree or 'genogram' (Fig. 8.3). Personal history. Detailed biography, starting at birth, recording all significant memories and events, including early separations, family atmosphere, school experiences and achievements, work history, psychosexual and marital history. Personality. A person's likes and dislikes, interests, attitudes and aptitudes should be recorded to establish a premorbid stage against which to evaluate the present condition.
MENTAL STATE EXAMINATION This is a systematic compilation of the abnormal phenomena observed and elicited by the interviewer or complained about by the patient. • General appearance and behaviour. How is the patient dressed? How does the patient relate to the interviewer - is he relaxed and friendly, or suspicious and taciturn? Does the patient sit immobile in the chair, or is he fidgety and restless?
211
• Speech. Is the speech normal in form and content, slowed down, or accelerated? Does it follow a logical progression or does it jump from idea to idea ('flight of ideas'); or is there evidence of a disorder of the logical progression of thoughts ('thought disorder')? • Mood. Is the mood normal, depressed or elated? Is the person troubled by feelings of guilt and unworthiness and suicidal thoughts, or is the patient grandiose and overexcited? Is the patient anxious or agitated? • Abnormal beliefs (delusions). Does the patient feel he is being spied on, talked about or got at? Are his thoughts or actions being interfered with? • Abnormal experiences (hallucinations). Has the patient had any bizarre or unusual sensations? Is he hearing noises or voices when no-one is around? • Cognitive assessment (for mini-mental state examination, see p. 1288). What is the general level of intelligence? Is there evidence of impairment of consciousness, immediate memory or recall? Is the patient fully oriented in time, place and person? • Insight. What is the patient's self-appraisal and theory about what is happening to him? • Response of the interviewer. How does the patient make the interviewer feel? Sympathetic? Angry? Irritated? Bored?
212
The examination should be concluded by a formulation containing the salient points of the history and mental state, with a differential diagnosis and some ideas about possible aetiological and precipitating factors. Risk assessment should be considered in each case, with a specific discussion about suicidality ('How suicidal do you feel at the moment', or 'How would you rate your suicidality on a scale of 0-10?'), and consideration of risk to others, based on past history of violence, if any. Example of a psychiatric formulation: 'Mr A is a 22-yearold unemployed man currently living in a bedsit. For the past few months he has become increasingly withdrawn and self-neglectful, and caused worry to his landlord, whom he has accused of spying on him. He has been smoking cannabis on a daily basis since leaving school at the age of 16. He has few friends, and has only held down casual jobs for short periods. In his background his maternal uncle suffered from schizophrenia; his parents split up when he was 8, he has lost contact with his father and does not get on with his stepfather, whom his mother married 2 years ago. On mental state examination he appears mildly depressed and shows evidence of paranoid delusions of being watched, and occasionally hears a voice warning him that he is in danger. There may be some suicide risk, but there is no history of any violence to others. The differential diagnosis includes schizophrenia, cannabis psychosis, depressive disorder, and insidious organic brain disease. A degree of maternal neglect (his delusion could reflect a psychotic expression of his feeling of being unnoticed), lack of a positive male role-model, low self-esteem and underachievement may all contribute to the underlying dynamic of his developing illness'.
FURTHER READING ON THE PSYCHIATRIC EXAMINATION Leff J, Isaacs A 1990 Psychiatric examination in clinical practice. Blackwell, Oxford Sims A 1995 Symptoms in the mind, 2nd edn. WB Saunders, London
TREATMENTS IN PSYCHOLOGICAL MEDICINE Psychiatric treatments are of three types: • physical - psychotropic drugs - ECT • social - housing - day centres • psychological - see Table 8.3
ANXIETY Anxiety, like pain, is an unpleasant necessity. A person unable to feel anxious would be severely incapacitated. Arousal, which may be experienced subjectively as anxiety, leads to an adaptive response to threat: fight or flight.
AROUSAL AND ANXIETY There are three main components of the arousal response: • Psychophysiological • Psychological • Interpersonal.
The psychophysiological component This is mediated by the autonomic nervous system and is accompanied by increased adrenaline (epinephrine),nora-
SUMMARY 6 Manifestations of anxiety Physical Tachycardia Tightness/pain in chest Difficulty in breathing Headache Paraesthesia Muscular pains Muscular weakness Dizziness Difficulty in swallowing Abdominal discomfort Diarrhoea Frequency of micturition
Psychological Irritability Inability to memorize Inability to concentrate Fear of impending death Fear of madness (depersonalization and derealization)
8
TABLE 8.3 Choosing a psychological therapy Principal recommendations
Evidence
• Psychological therapy should be routinely considered as an option when assessing mental health problems (B)
Psychological therapy shows benefits over no treatment for a wide range of mental health difficulties.
• Patients who are adjusting to life events, illnesses, disabilities or losses may benefit from brief therapies such as counselling. (B)
There is evidence of counselling effectiveness in mixed anxiety/depression, most effective when used with specified client groups, e.g. postnatal mothers, bereaved groups.
• Post-traumatic stress symptoms may be helped by psychological therapy, with most evidence for cognitive behavioural methods. Routine debriefing following traumatic events is not recommended. (A)
CBT has been found helpful. Some evidence of efficacy has been shown for other forms of psychological therapy. Single session debriefing appears to be unhelpful in preventing later disorders.
• Depression may be treated effectively with cognitive behavioural therapy (CBT) or interpersonal therapy (IPT). A number of other brief structured therapies for depression may be of benefit, such as psychodynamic therapy. (A)
CBT & IPT effectively reduce symptoms of depression. Benefit has also been found for other forms of psychological therapy.
• Anxiety disorders with marked symptomatic anxiety (panic disorder, agoraphobia, social phobia, obsessive-compulsive disorders, generalized anxiety disorders) are likely to benefit from cognitive behaviour therapy. (A)
CBT effectively reduces symptoms of panic and anxiety. Behaviour therapy and cognitive therapy both appear effective in treatment of obsessional problems.
• Psychological intervention should be considered for somatic complaints with a psychological component with most evidence for CBT in the treatment of chronic pain and chronic fatigue. (C)
Psychological therapies have benefit in range of somatic complaints including gastrointestional and gynaecological problems. CBT found more effective than control in improving functioning in chronic fatigue and chronic pain.
• Eating disorders can be treated with psychological therapy. Best evidence in bulimia nervosa is for CBT, IPT and family therapy for teenagers. Treatment usually includes psychoeducational methods. There is little strong evidence on the best therapy type for anorexia. (B)
Efficacy of CBT and IPT in bulimia has been established. Individual therapies have shown some benefit in anorexia, with little to distinguish treatment types. Early onset of anorexia may indicate family therapy, and later onset, broadly based individual therapy.
• Structured psychological therapies delivered by skilled practitioners can contribute to the longer-term treatment of personality disorders, (C)
Meta-analysis found a number of therapy approaches, both individual, group and milieu show some success, including dialectical behaviour therapy, psychoanalytic day hospital programme and therapeutic communities.
The recommendations are weighted as follows: A. Based on a consistent finding in a majority of studies in high quality systematic reviews or evidence from high quality studies. B. Based on at least one high quality trial, a weak or inconsistent finding in high quality reviews or a consistent finding in reviews that 'high quality'. C. Based on evidence from individual studies that do not meet all the criteria of 'high quality'. D. Based on evidence from structured expert consensus.
drenaline (norepinephrine) and corticosteroid secretion. These result in tachycardia, piloerection, sweating and pupillary dilatation; and subjective manifestations of autonomic activity, including paraesthesiae, giddiness, 'butterflies in the stomach', breathing difficulties, a sensation of painful pressure in the chest, and muscular tension, especially around the head and neck. These symptoms may be mistakenly attributed by both patients and doctors to organic illness.
The psychological component There is a continuum of arousal responses to threat, from alertness and readiness, through mild fear to severe anxiety and incapacitating panic. Effective action depends on an optimal state of arousal: little can be achieved when an individual is either barely aroused or in a state of panic. Examination nerves, if not too great, improve results. During a panic attack the patient experiences a sense of threat, or even of impending death. Chronic anxiety states
not meet all the criteria of
SUMMARY 7 Aetiology of anxiety syndromes Past Genetic factors (predisposition) Faulty learning (as a child) Early childhood relationships (Attachment theory)
Present External threat Relationships to attachment figures Internal conflict
may produce irritability, lack of concentration and a subjective sense of failing memory. Anxious patients fail to habituate to stimuli and so remain chronically overaroused; this can result in extreme sensitivity to sudden noises or movements. In extreme anxiety a state of detachment may supervene in which anxiety suddenly disappears, to be replaced by a feeling of being outside of oneself (depersonalization) and cut off from one's surroundings, which appear unreal and distant (derealizatiori). These
213
TABLE 8.4 Classification of anxiety syndromes Primary anxiety Generalized Situational Agoraphobia Social phobia Hypochondriasis Specific (e.g. spiders) Panic attacks (hyperventilation syndrome)
Secondary anxiety Psychiatric illness, e.g. depression Organic illness, e.g. thyrotoxicosis Alcohol-related withdrawal symptoms Benzodiazepine-related withdrawal symptoms
experiences may be misinterpreted by the patient as signs of 'going mad'.
The interpersonal component A frightened individual 'regresses' (see p. 217) and, childlike, clings to those he loves and on whom he depends. This is part of 'attachment behaviour' and, like anxiety, is adaptive: species survival depends on secure bonding. The dependency and excessive demands on others that so often accompany anxiety states (and which can be trying to both relatives and doctors) can be understood as part of the attachment response to threat.
anxiety syndromes because in a phobia the patient avoids the feared situation and is thus restricted by the underlying anxiety. Situational anxiety syndromes include: • Specific phobias, e.g. snake or spider phobia, or fear of heights. These have a good prognosis, are found in otherwise healthy individuals, and respond well to behavioural treatment (p. 215). • Agoraphobia is named after the Greek agora, or meeting place. In agoraphobia the patient is frightened to leave home unaccompanied, avoids public places such as supermarkets and department stores, and cannot travel on public transport, especially underground railways and aeroplanes (claustrophobia is usually part of agoraphobia). The patient is usually female and may be very dependent on her mother, daughter or husband. The prognosis is less good than with specific phobias, but behavioural therapy is usually helpful. Agoraphobic symptoms may develop as part of a depressive illness (p. 218). • Social phobia, i.e. fear of meeting people in social situations, e.g. parties, canteens. This affects mainly young people and is an extreme form of normal 'shyness'. Patients can be helped by social skills training in groups with fellow sufferers in which they 'role-play' the feared situations. • Hypochondriasis, a morbid fear of illness, leading to a frequent need for reassurance by family, friends and doctors.
ANXIETY SYNDROMES Anxiety may be a primary diagnosis, or secondary to another psychiatric or physical illness. It is a non-specific symptom which occurs in a wide range of psychiatric syndromes, including benzodiazepine withdrawal, depression, alcoholism and schizophrenia. It can also be an important manifestation of organic illness, particularly thyrotoxicosis, paroxysmal tachycardia, carcinoid syndrome, hypoglycaemic attacks, phaeochromocytoma and temporal lobe seizures.
CLASSIFICATION Primary anxiety syndromes may be classified as shown in Table 8.4.
Generalized anxiety Individuals who experience anxiety symptoms, either chronically or intermittently, without a clear stimulus or an obvious focus of fear, suffer so-called 'free-floating' anxiety.
Situational anxiety 214
In situational anxiety there is an identifiable precipitant to which the anxiety is related. Phobias are closely related to
Panic attacks (hyperventilation syndrome) These may be part of a specific syndrome, e.g. agoraphobia, or may occur on their own. They frequently present to physicians as medical emergencies and are usually selflimiting. The patient presents in a state of terror, overbreathing, complaining of chest pain, and often feeling he is dying. The diagnosis can be established by provoking these symptoms with voluntary overbreathing, which are then relieved by rebreathing from a paper bag. Tetany may be a feature. Organic causes (e.g. hyperthyroidism) must be eliminated and a positive psychiatric history should be established (i.e. a history of recent stress/conflict, or a background of chronic difficulty).
Aetiology There is no single cause of anxiety syndrome. Individuals vary in their tendency to become over-aroused: genetic factors may play a part in this. Anxiety may also arise from faulty learning. A child who senses his mother's tension in social situations may become socially phobic himself. Repeated avoidance of a feared stimulus then exaggerates the threat associated with it, as there is no opportunity for mastery through repeated exposure. Attachment theory explains how early childhood relationships may predispose to anxiety in later life. In order
to survive, a developing child must bond to an attachment figure (usually the mother). If the mother is consistently present, reliable in her handling and 'good enough' in her emotional responsiveness, then a bond of secure attachment, or 'secure base', will develop. This enables the child to engage in exploratory behaviour, to deal with new situations without becoming overanxious, and so gradually to separate, safe in the knowledge that the mother is available if necessary. The child builds up an internal image of a good parent, which provides a sense of security. If, on the other hand, the early relationship with the parent is disrupted - by separation or by inconsistent handling, for example - the child may develop a bond of anxious attachment. Rather than being able to explore and become autonomous, the child clings to the mother, at first physically and later emotionally, showing signs of distress when separation is threatened. This childhood experience then acts as a template for separations in later life. Faced with threat, the anxious individual clings to attachment figures • spouse, parent, child or doctor. The following factors should be considered in cases of anxiety: • The nature of the current external threat. This may be obvious, such as major illness in the patient or a close relative. The 'threat' may, on the other hand, appear as trivial and 'normal' as an adolescent leaving home, or a family holiday. For an anxiously attached individual these can be major hurdles. • The relationship to attachment figures, past and present. A pattern of anxious attachment in childhood now repeated in relationship to spouse or children is often found. • 'Internal threat'. Anxious patients often experience an inner conflict between their need for dependency and their feelings about those on whom they depend. The patient is threatened not so much by external circumstances as by himself. A patient who feels angry, for example with an unfaithful spouse, but is unable to express this because of fear of separation and loss, may develop anxiety symptoms. He fears to bite the hand that feeds. The patient is frightened by his own inner impulses: sexual or aggressive feelings, or the wish for independence and autonomy. Anger in particular often coexists with anxiety; the angry individual is often a frightened one, and vice versa.
SUMMARY 8 Management of anxiety syndromes • Exploratory psychotherapy • Cognitive-behavioural psychotherapy
• Psychotropic drugs
Exploration and resolution of underlying conflict. Non-directive. Aims to change patients' behaviour directly through desensitization, and/or to, challenge their underlying assumptions. Antidepressants, minor tranquillizers, B-blockers.
MANAGEMENT
8
Michael Balint, a psychoanalyst who pioneered the use of psychotherapeutic methods in medicine, wrote 'the doctor is a drug: the question is in what dose, and with what frequency it should be prescribed'. The two drugs most commonly prescribed for anxiety are tranquillizers and, via supportive psychotherapy, 'doctor'. Both can be effective in the short term, but can in the long term produce the complication of dependence, and may even exacerbate the symptoms of anxiety.
Exploratory psychotherapy Normal individuals who become anxious are usually relieved of their fears by reassurance, and the ability to reassure is thus an important part of a doctor's skill. Reassurance in neurotic individuals is often ineffective, however, because it deals only with the surface fear and not with the underlying conflict. A man who develops repeated attacks of pain, in which he is convinced that he is about to die of a heart attack, can be reassured that his ECG is normal and that he is a fit man, and be discharged. Yet a few days later he may develop another attack and present again to the doctor. The underlying fear, and the root cause of his anxiety, of which he may be unaware or unconscious, may be that his mother, on whom he is very dependent and who has recently had an illness, will die and that he will be left alone. Only when this fear is exposed and when he has learned to accept the dependent part of his himself, will his panic attacks cease. This kind of exploration is helpful in the evaluation of most cases of anxiety. In some cases it may need to be followed by longer-term psychotherapy. If the patient can learn to resolve his inner conflicts through his relationship with a doctor or therapist, and so move from a position of anxious attachment to one of secure attachment, he will be relieved of the symptoms.
Cognitive-behavioural psychotherapy (CBT) In exploratory psychotherapy the doctor aims to be understanding but is non-directive. In behavioural psychotherapy, on the other hand, the doctor aims to change the patient's behaviour directly. A phobic patient associates the feared stimulus (e.g. a spider or a department store) with unpleasant feelings. The therapy aims to desensitize the patient by gradual exposure to the feared stimulus, often in the reassuring presence of the therapist. An important feature of behavioural treatment for anxiety is relaxation training. Here the patient learns to control anxiety through muscular relaxation and deep breathing, sometimes with the aid of tape-recorded instructions. Physiological measures of arousal - galvanic skin response and pulse rate - may provide objective evidence of anxiety
215
TABLE 8.5 Side-effects of benzodiazepines Tolerance Drowsiness Incoodination, ataxia Emotional blunting Anger and irritability Diminished sexual response (women) Withdrawal syndrome: insomnia anxiety depression (may be profound) irritability muscular pains and twitching perceptual distortion fits
reduction. When self-administered, this is known as autogenie training. Behavioural therapy, as its name implies, works directly with how the patient behaves and acts in the world. The focus in cognitive therapy is on the patient's thoughts, which may themselves be as anxiety-provoking as real-life situations. Indeed, one of the basic principles of CBT is Epictetus' dictum: 'Men are troubled not so much by things as by their thoughts about things'. In cognitive therapy the patient's underlying assumptions and view of the world are challenged: for example, someone with fear of flying is asked to consider rationally the probabilities of an aircraft crashing and to compare them with accident rates for road and rail travel. Their tendencies to catastrophize (i.e. fear the worst) and dichotomize (divide the world into black and white, good and bad) are pointed out, and alternative strategies suggested.
Psychotropic drugs When anxiety is a manifestation of depressive illness, the treatment of depression with antidepressants (many of which are sedative) also relieves the anxiety. Short-term (up to 10 days) prescription of minor tranquillizers such as benzodiazepines is occasionally justified for the relief of stress-related anxiety. Longer-term prescription of tranquillizers should be avoided because of the likelihood of habituation and physiological dependence. B-Receptorblocking drugs relieve the peripheral symptoms of anxiety and may also occasionally be useful. Side-effects of benzodiazepines are common (Table 8.5) (see also p. 23).
DEFENCE MECHANISMS
216
Life is beset with threats. A variety of social and psychological defence mechanisms exist that keep anxiety within manageable limits. Many of these can be observed on
SUMMARY 9 Defence mechanisms against anxiety Denial Dissociation or conversion Splitting Projection
Idealization Regression Obsessional defence Intellectualization
hospital wards, where both patients and staff face the daily threat of illness and death and yet usually manage to remain cheerful and efficient.
Denial 'Everything's wonderful'. One way of dealing with fear or pain is simply to pretend it does not exist. Men are particularly prone to this in everyday life, but false cheerfulness (sometimes known as manic denial) may conceal unvoiced fears or sadness.
Dissociation or conversion 'I'm not worried about anything, doctor, it's just that I keep getting this pain ...'. Akin to denial is dissociation, in which a fear is displaced or converted into a bodily symptom. Patients who have inexplicable and elusive pains, in addition to established physical disease, may well be harbouring unspoken fears and conflicts.
Splitting 'You're wonderful, doctor, not like those terrible doctors at the other hospital.' As Trojans should fear Greeks bearing gifts, so doctors should beware the patient who heaps excessive praise (as opposed to expressing genuine gratitude). The patient may be dealing with anxiety by splitting his world into good and bad, and clinging to the good in the vain hope of absolute security. As with the Trojans, the tables may suddenly turn and we may be seen as bad, and they good. Patients can sometimes split ward staff in this way; physicians and nurses must learn to take both praise and condemnation with equanimity.
Projection 'It's the psychiatrists who are mad, not me'. Closely linked to splitting is projection, in which unwanted feelings are attributed instead to a convenient other.
Idealization 'The doctors here are the best in the world'. The defence of idealization is closely linked to splitting and projection. It is probably best seen as an example of
positive transference, in which past childhood feelings towards one's parents are, under the threat of illness, transferred on to current medical attendants.
Regression
SUMMARY 10 Mourning responses • • • •
Denial Numbness Searching Guilt
8 • Anger • Detachment • Acceptance
'Nurse ... nurse ...'. The sick, like children, are tucked up in bed, fed, pampered and waited on. This sometimes helps the physiology of recovery, but can also lead to helpless behaviour on the part of the patient, who may deal with the fear associated with illness by becoming more and more childlike, regressed and demanding.
Obsessional defences 'I always have my bowels open at such-and-such o'clock, doctor.'
MOURNING The mourning response is divided for convenience into a number of stages, which can be summarized as denial, despair and detachment, but emotional reality does not conform to any such neat sequence. Grief is characterized by surges and cycles of often confused feelings, rather than an orderly progression of recognizable stages.
Denial
The 'malade-d-petit-papief - the patient who presents with a written list of symptoms - is a familiar figure in medical folklore. The obsessional defence is an attempt to deal with fear by control. This may produce feelings of irritation and discomfort in the doctor that mirror the patient's feelings. This is an example of how the doctor's subjective response to the patient (technically known as countertransference} can be a useful guide to what the patient is feeling.
The initial reaction, especially to sudden bereavement, may be denial: 'Oh no .. .'. This attempt to resist the reality of death may persist long after the bereaved have consciously and rationally accepted their loss; they find themselves talking to their lost loved one, or may 'hear' or 'see' them in one of the hallucinatory experiences that not uncommonly occur after bereavement.
Intellectualization
Another early response to bereavement is a complete absence of feeling. The bereaved person may appear to be coping very well because of this emotional shutdown which, like the analgesia of a soldier injured in battle, enables him to get through the initial phase of loss. When this is prolonged, however, it produces chronic impoverishment of emotional life.
'Just a few more tests should clinch the diagnosis.' This defence applies more to doctors than to their patients. Incurable illness and death are inescapable reminders of the limitations of medicine. The feelings of inadequacy and sadness that this creates may be defended against by a preoccupation with diagnostic precision and excessive investigation and treatment.
FURTHER READING ON ANXIETY Holmes J 1993 John Bowlby and attachment theory. Routledge, London Marks I 1987 Fears and phobias. Oxford University Press, Oxford
LOSS, GRIEF AND BEREAVEMENT
Numbness
Searching Part of the 'work' of grief involves a mental combingthrough of the events that led up to the loss of the loved one. This phase is often accompanied by intense anxiety and restlessness. Searching, a form of separation anxiety, may lead to apparently aimless wandering, or visits to familiar spots associated with the lost one. The bereaved person appears to be struggling to negate the reality of the loss, or to rewrite history with a different, happy ending. Acceptance of loss only occurs when this impossible task has been attempted countless times.
Guilt Man is not an island, and human beings are inevitably vulnerable to loss. The mourning response - a patterned sequence of psychophysiological reactions to the loss of a loved one - is as deeply embedded in our psyche as are the phases of inflammation in our pathophysiology. Common to both are the experience of pain, immobility and gradual recovery.
Pangs of guilt or self-blame are a very common feature of bereavement. Survivors blame themselves, often quite irrationally, for the loss of their beloved. 'If only', they say, T had phoned the doctor earlier/not gone on holiday/been kinder...'. This response can be seen as an example of omnipotence, a relic of childish thinking which attempts to deny human vulnerability to fate and fortune.
217
Anger Anger and guilt go together in bereavement. Outbursts of anger towards medical staff or close relatives often occur after a death, and should be met by acknowledgement of the underlying pain rather than with retaliation.
Detachment As mourning proceeds, so the grieving individual begins to separate himself from the loss and develop new interests and attachments. Pangs of grief recur, particularly at times of stress and on special dates such as birthdays, Christmas, and anniversaries of loss.
one. Feelings of guilt (associated perhaps with past fantasy wishes that the person would die) are more intense in such cases. 'Symbiotic' relationships, such as those involving unmarried daughters living with their mothers, are also often difficult to recover from when they are severed. Personality of the survivor. Dependent, insecure or depression-prone individuals are more vulnerable to prolonged grief, as are those with difficulty in expressing feelings. The latter may in part account for the greater vulnerability of men to lasting problems after bereavement. Social circumstances of the survivor. A lack of close family, friends, religious beliefs or employment all make recovery from loss more difficult.
Acceptance When mourning is 'successful' and circumstances favourable, the bereaved individual may come to accept that death and loss are part of life and may sometimes even be enriched by the experience. More usually, scars remain, and many bereaved people continue to struggle with feelings of meaninglessness and diminished vitality for many years.
Physiological changes Psychological reactions to loss are accompanied by physiological changes, including disturbance of corticosteroid metabolism and depression of T-lymphocyte response. Death from 'a broken heart' is a reality: mortality rates, mainly from coronary artery disease, are higher in widowers and widows than in their non-bereaved counterparts.
DELAYED OR PATHOLOGICAL MOURNING Return to near-normality after a major loss generally takes from 1 to 3 years. However, chronic states of depression, numbness, anger, anxiety and hopelessness can continue for much longer following a bereavement. The patient becomes stuck in one of the phases of mourning and is unable to progress towards detachment and acceptance. The likelihood of pathological grief depends on four main factors: • Type of death. A sudden, untimely (of a child, for example) or horrifying death is especially hard to accept (see Recent Advances in Post-traumatic Stress Disorder). • Nature of the relationship. An ambivalent relationship (one in which love and hate coexist) is more likely to lead to pathological mourning than a straightforward
1
218
MCQ 8.1
MANAGEMENT About one-third of bereaved persons may be in need of professional support or intervention. Support groups, such as those for widows (in the UK, CRUSE) or for parents whose children have died (the Compassionate Friends), can be very helpful. Psychotherapy may be necessary in order to recapture and work through buried feelings associated with the loss. Sometimes this is systematized as guided mourning, in which the sufferer is encouraged to think about the lost one, talk about the details of his or her death, look at photographs of him or her, visit the grave, and so face and accept loss with diminished denial.
FURTHER READING ON LOSS, GRIEF AND BEREAVEMENT Garland C (ed) 1999 Understanding trauma: a psychoanalytical approach. Butterworths, London Parkes C M 1988 Bereavement: studies of grief in adult life, 2nd edn. Penguin, London
DEPRESSION The complaint of 'depression' can refer to a number of different feelings and reactions - anger, boredom, frustration,
SUMMARY 11 Features of depressive illness (as opposed to unhappiness) • • • • •
Sustained lowering of mood Severe Definite onset Low self-esteem Physiological changes: disturbance of sleep, appetite, weight, libido • Sometimes atypical features brought to the surface by depressive illness: pain, obsessional thoughts, violence
RECENT ADVANCES IN POST-TRAUMATIC STRESS DISORDER (PTSD) The word trauma comes from the Greek 'to pierce'. It is now known that trauma, whether individual or in mass disasters, pierces not just the body but also the psyche of those affected, either directly, or as witnesses or relatives. Also, the recognition that as many as 60% of psychiatric inpatients, whatever their diagnosis, may have been sexually abused in childhood suggests that many psychiatric disorders have PTSD as at least a component of their aetiology. These people, after diagnosed as 'personality disordered', are sometimes referred to as suffering from 'complex PTSN'. In the USA the lifetime prevalence of traumatic events - accidents, suicide, homicide or sexual assault is estimated to be around 70%. Of those so exposed, 20-40% will develop post-traumatic stress disorder. Diagnostic criteria include feelings of intense fear, horror and hopelessness at the time of the traumatic event; intrusive imagery ('flashbacks') in waking consciousness and dreams; avoidance behaviour, e.g. being unable to pass the spot where an accident occurred, or to read accounts of similar events; hyperarousal phenomena, such as disturbed sleep, increased reactivity to noise, muscular tension, poor concentration; and significant interference with normal coping behaviour; all of these lasting for more than one month after the event.
Risk factors include the nature of the trauma itself: the more horrific and violent, the greater the likelihood of PTSD; denial of emotional difficulty on the part of the sufferer; a previous history of trauma, especially in childhood; and dismissal of the severity of the symptoms by significant others such as family and doctors. Comorbidity (i.e. the coexistence of other diagnoses) is common, especially affective disorder. Neurobiology of PTSD. It is now known that prolonged exposure to high cortisol levels (as occurs in clinical stress) produces shrinkage of the hippocampus and that PTSD is associated with neuro-anatomical changes, especially in the non-dominant hemisphere. Management includes: (a) 'debriefing' - a detailed 'action replay' of the traumatic event and the sufferer's reactions, although there is some evidence to suggest that this may have a reinforcing effect and so should be used judiciously; (b) cognitive-behavioural treatment directed at intervening in the intrusive thought-avoidance cycle: the subject is systematically asked to recall the painful events until they can look squarely at them without undue anxiety; and (c) long-term psychotherapy if the trauma has reawakened previous childhood trauma such as sexual abuse; (d) in some cases antidepressant medication can be helpful.
anxiety, hopelessness and helplessness - as well as the specific psychophysiological state that psychiatry recognizes as 'depressive illness' and which is sometimes colloquially referred to as 'clinical depression'.
table, and takes no pleasure in anything. He feels he has no future and that it is pointless or impossible to make plans. Thoughts of suicide almost invariably present, although the patient may try to resist these by saying I would not have the courage'. • Low self-esteem. The patient feels worthless, inadequate, unwanted and useless. He feels intense guilt and plagues himself with thoughts of past failures and mistakes. He can only see himself in a negative light and emphasizes his weaknesses and faults. • Physiological changes. The most important of these is sleep disturbance. Anorexia, weight loss, loss of libido, constipation, retardation (slowing of thought and movement) or occasional agitation are also all important features, especially in severe or psychotic depression. • 'Atypical' features. Sometimes a depressed patient may present atypically, with physical symptoms such as unexplained pain, obsessional thoughts, agoraphobia, criminal behaviour (such as shoplifting) or episodes of anger and violence. These may have been brought to the surface by a depressive illness. In a so-called 'smiling' or 'masked' depression, the patient conceals severe depressive feelings behind a cheerful facade.
DEPRESSIVE ILLNESS Clinical features Clinical depression can be distinguished from both 'ordinary' depression or sadness (transient depressive moods) and depressive personality by three main features: • Depressive illness is a sustained depression of mood lasting for weeks or months. • The seventy of the depression is great enough to interfere with normal functioning. • The depression has a definite onset, with a distinct change from normal to depressive thinking. Depressive illness involves an alteration of many different aspects of mind, body and behaviour. It is nearly twice as common in women as in men. The features of depression may be summarized under four main headings: • Depressed mood. The patient feels weepy and miserable, 'low in spirits', anxious, lacking in concentration and irri-
Although the presentation of depressive illness can vary greatly, there are two common clinical pictures (Table 8.6). 1
8
219
TABLE 8.6 Clinical features of neurotic and psychotic depression Clinical features
Psychotic
Neurotic
Severity of depression Delusions/hallucinations Sleep disturbance
More severe Yes Early morning wakening Yes, prominent
Less severe No Difficulty in getting off to sleep Yes/No
Worse on wakening and a.m. Yes Yes
No, or worse p.m.
Yes No
Sometimes
No
Yes
Yes
Yes
No
'Vegetative features', e.g. weight loss, constipation Diurnal mood variation 'Reactive', i.e. precipitated by loss Genetic factors, e.g. family history of manic-depressive psychosis Dexamethasone suppression test abnormal Response to tricyclic antidepressants Response to ECT
Neurotic depression Here the patient, despite depressive feelings, remains in contact with reality: 'I know it is stupid, but I feel as though I have let everybody down'. The patient might be a woman in her 30s with several small children, living in poor housing and with a husband who drinks and who is having an affair which she has just discovered. She is tearful, has lost weight and cannot fall asleep at night. She feels she is not coping with her job or housework, and no longer enjoys company or television.
Psychotic depression
220
Depressive psychosis is a part of manic-depressive psychosis, an affective psychosis. The depth of the depression is here much greater than in neurotic depression. The ratio of women to men affected is more equal. The patient becomes immobilized in both thought and action. He wakes very early in the morning and may have diurnal mood variation, feeling at his worst in the morning and improving slightly towards the evening. Depressive delusions develop, the patient becoming convinced that he has, for example, brought ruin on his family, that he is evil or ugly or radioactive. Depressive hallucinations may occur: the patient may hear a voice telling him that he is evil, or he may feel that his insides are rotting and complain that he smells. Endocrine disturbance may occur in psychotic depression, with disruption of the pituitary-adrenal axis. In some cases the normal diurnal variation of cortisol output is abolished, providing the basis of the dexamethasone suppression test, in which dexamethasone is administered but fails to reduce urinary steroid levels.
SUMMARY 12 Factors contributing to depression • Loss • Genetic • Biochemical, e.g. reduced catecholamine levels at postsynaptic nerve endings • Social, e.g. lack of close relationships, unemployment, lack of good childhood experiences to build self-esteem, learned helplessness
DIFFERENTIAL DIAGNOSIS OF DEPRESSION The differential diagnosis of depression includes: • Organic illness, especially hypothyroidism • Drug administration, especially steroids and some antihypertensive drugs • Alcohol-induced depression, where depression is secondary to alcoholism (or drug addiction), and withdrawal of the intoxicant results in lifting of depressive symptoms • Anxiety states, as anxiety is a common feature of depression. When they coexist, treatment of the depression usually (but not always) removes the anxiety • Other psychoses, especially schizophrenia.
THE CAUSES OF DEPRESSION Depression is often divided into: • Reactive depression, whose symptoms correspond with neurotic depression and which is said to be a response to external events; • Endogenous depression, where the symptoms are psychotic in character and where there is no clear environmental precipitant. The distinction is misleading. Psychotic depression is usually also 'reactive' in the sense that it is triggered by a painful event in the patient's life; and neurotic depression can be 'endogenous' in the sense that genetic and personality factors influence the likelihood of an individual developing depression in response to misfortune. Loss Loss plays a central role in the origins of depression and is the link connecting grief with depression. The grieving person is in pain not just because of the loss of an external relationship, but because he has lost a part of himself. His internal world as well as his external world has been impoverished. The similarity between the clinical features of grief and those of depression are striking. In grief, an external loss dominates the picture; in depression, it is an internal feeling of loss. In 70% of depressions there has been a preceding external loss or stress: a bereavement (delayed grief is best seen as a special case of depression),
loss of job, break-up of a relationship, a child leaving home or a theft, for example. It is when this then leads to a feeling of internal loss - of optimism, vitality and (especially) of self-esteem - that a depression occurs. Whether or not a particular individual reacts to loss by developing depression depends on a number of interrelated factors, genetic, social, developmental and psychological.
Genetic/biochemical make-up Twin studies have shown that genetic factors play an important part in manic-depressive psychosis. Changes in neurotransmitter biochemistry in depression are important: current views emphasize a reduction of catecholamine levels at postsynaptic nerve endings. Antidepressant drugs may work by preventing the breakdown of cerebral amines (monoamine oxidase inhibitors), or reducing their reuptake (tricylic drugs) at central nerve endings. Similarly selective serotonin reuptake inhibitors (SSRIs) increase the concentration of serotonergic neurotransmitters in the synaptic cleft.
Current social situation The presence of a close confiding relationship, usually with a spouse, protects individuals from developing depression after the experience of loss. Employment is another protective factor; the unemployed are thus doubly vulnerable to depression, the loss of a job being a precipitant and lack of a job being a vulnerability factor. Women with three or more children under 15 and long-term social and financial difficulties are more vulnerable to depression following loss.
Early childhood experience Women who have lost their mothers before the age of 11 - whether through death, separation (for example, due to illness) or divorce - are especially vulnerable to depression in later life. A reservoir of good experiences in childhood is needed for an individual to develop a lasting sense of self-esteem. This provides a child with a good and secure internal world which can withstand the inevitable separations and losses of later life, and enables them to respond to such situations with appropriate sadness rather than by developing depression.
Psychological factors Recent studies of depression have focused on the vicious circle of depressive thinking and its accompanying negative assumptions about the self and the world. The depressed individual has developed learned helplessness, feeling that nothing he can do will make any difference to the situation. Actions and experiences that might make the individual feel better are avoided, and he continues to view himself in a negative light. His depression thus becomes a self-fulfilling prophecy. Depression produces and may be produced by patterns of dysfunctional thought, such
SUMMARY 13 Management of depression Psychological treatment Exploratory therapy Cognitive-behavioural therapy Family/marital therapy
8
Physical treatment Anti-depressants ECT
as dichotomous thinking (seeing everything as black or white), catastrophization (making a drama out of every crisis - inability to buffer and cope with minor setbacks), and a cascade of negative thoughts about the self that are triggered by everyday events, minor losses or difficulties. These serve to reinforce a basic view of the world characterized by hopelessness about the future, helplessness in the present, and guilt and remorse about the past.
Management Mild depression This is best dealt with by psychotherapy, which may take one of three main forms. Exploratory and psychodynamic psychotherapy Here, the patient is encouraged to express depressive feelings, to vent anger and despair and - through the relationship with the therapist (who may be a GP, social worker, psychotherapist or physician) - to experience the responsive empathy and containment that was lacking in childhood and so to recognize and recapture some of the good experiences the depression has blotted out. As self-esteem improves, so the patient can begin to tackle some of his current difficulties, which in a depressed state seem overwhelming. Cognitive-behavioural therapy (CBT) and interpersonal therapy (IPT) Controlled trials have shown that CBT is as effective as antidepressants in the treatment of mild-to-moderate depression. CBT counteracts learned helplessness and negative depressive thinking by challenging the erroneous assumptions on which they are based (e.g. if I phone my boyfriend and he is out, it does not mean that he does not love me, merely that he is working late), and by considering positive features of the self. The patient is encouraged to set himself small, easily accomplished tasks and to feel pleased if he succeeds. IPT is similarly focused and time limited. It explicitly adopts a medical model, seeing depression as an illness over which the patient has little control. IPT homes in on one of four underlying factors that contribute to depression: 'role transitions', e.g. depression associated with retirement, or becoming a mother, or divorce and so becoming single; grief and bereavement linking depression with unworked-through losses; interpersonal conflict, usually with partners; and social skills deficits: here depression is linked with lack of personal effectiveness and competence, and therapy is specifically designed to improve communication and social flexibility.
221
Family and marital therapy Here the aim is to improve the marital relationship, which can then provide a bulwark against depression in response to loss. Partners often unwittingly contribute to the maintenance of a depressed state, perhaps by being overconcerned and 'helpful' and so reinforcing the sufferer's sense of their own helplessness and loss of role. The safe expression of anger can strengthen a relationship and reverse the inward turning of anger that is so common in depression. Moderate depression A combination of antidepressant drugs and psychotherapy can be more effective than either alone in treating moderate depression. Both depressed mood and biological symptoms improve with drugs; low self-esteem and social difficulties improve with psychotherapy. Antidepressants are always indicated when sleeplessness and guilt are prominent features. Tricyclic antidepressants (TCA) such as amitriptyline (75-200 mg/day) take 10-14 days to produce their full effect. Side-effects include parasympathomimetic symptoms of dry mouth and urinary retention, constipation, blurred vision and 'muzziness'; and cardiac arrhythmias can occur. Dosulepin (dothiepin) and lofepramine have fewer side-effects. Imipramine and clomipramine are less sedative. Tricyclics should be avoided in patients with prostatism or a history of heart disease. Mianserin, a tetracyclic, has fewer side-effects but can produce haematological reactions and is possibly also less effective in its antidepressant action. If mianserin is used, a blood count should be carried out every 4 weeks. Selective serotonin re uptake inhibitors (SSRIs) such asfluoxetine,fluvoxamine, sertraline and citralopine have fewer antimuscarinic side-effects and low cardiotoxicity, and are therefore preferable, especially when the suicide risk is strong. They may, however, cause nausea and vomiting. Venlafaxine has mixed SSRI and TCA properties and is another popular antidepressant. Monoamine oxidase inhibitors (MAOIs) such as phenelzine (15-90 mg daily) are still occasionally useful as second-line drugs, especially when phobic symptoms are present, but dietary restrictions (e.g. no cheese or yeast-extract) are needed because of harmful (hypertensive) interactions with tyramine-containing substances. Moclobemide is a newer MAOI that can be taken without any major dietary restrictions. Severe depression Depressed patients who are severely incapacitated, psychotic or actively suicidal require hospital admission. Antidepressants, which may have to be given in large doses (up to 250mg of amitriptyline or equivalent daily), are the first line of treatment.
222
ECT Despite debate about its mode of action and efficacy, and despite popular prejudice, controlled trials of electroconvulsive therapy (ECT) have shown it to be an effective and rapid treatment for depressive delusions and hallucinations (Fig. 8.4); it is also free from side-effects, apart
FIG. 8.4 Effect of ECT on severity of depression
from the dangers of the anaesthetic and some short-term memory impairment. ECT is a first-line treatment in depressive stupor or where the patient is refusing food and drink. When the patient refuses consent, in the UK it can only be given after Section 3 of the 1983 Mental Health Act has been applied and a second, independent, psychiatric opinion obtained, although in a life-threatening situation one application of ECT may be given pending the second opinion. ECT produces a rapid improvement in severe depression and is especially effective in elderly patients, in whom tricyclics may produce confusion and cardiac arrhythmias. The basis of ECT is the delivery of a convulsion or fit, and its effectiveness depends on an adequate fit of around 25 seconds. A 'course' of ECT, given twice or thrice weekly, should deliver a total of around 250 seconds of fit if relapse is to be avoided. ECT can be given to both hemispheres (bilateral) or to the non-dominant one (unilateral), depending on the position of the electrodes. Unilateral ECT produces less memory impairment but may also be less effective. ECT is very effective in the short run but, unless supported by psychological and pharmacological therapies, relapse is also common. Chronic or recurrent depression Most depressive illness has a tendency to remit, but relapse is common. Prolonged treatment with tricyclics has a prophylactic effect, as does 'maintenance' psychotherapy. Relapse of depressive psychosis may in some cases be prevented by prophylactic lithium carbonate. Chronic depressive states are rare but disabling, and prolonged attendance at a supportive day hospital may be required.
FURTHER READING ON DEPRESSION Brown G, Harris T 1978 The social origins of depression. Tavistock, London
TABLE 8.7 Clinical profiles of suicide and parasiticide Suicide
Parasuicide
Central theme
Despair, depression
Anger, frustration
Epidemiology
Increase in men aged 15-25, 1985-1999
Increase in all groups 1985-1999
8
Commoner in women aged Age, sex, class Commoner in age range 25-34; commoner in men 18-35 and in social than women; no class classes IV and V preference; recent increase in death by suicide in young men Social circumstances
Isolated, e.g. unemployed, retired, divorced, children left home, few friends or religious/social groups
Disturbed but not isolated, e.g. teenager unhappy with parents or boyfriends
Method and build-up
Planned. Usually leaves a note; method often violent, e.g. hanging, shooting, drowning
Impulsive. Commonest method is swallowing pills. Cutting (usually wrists) a more disturbed subgroup
Alcohol
May play a part - 'Dutch courage'
Attempt very commonly associated with alcohol/ drugs, i.e. reduced impulse control
Illness
90% of suicide case are mentally ill, usually with depressive illness. Physical illness also common
Only about 30% are mentally ill. Some have personality disorder. Majority normal or with 'minor affective illness'
Outcome
Not all 'succeed'. Survivors need hospital admission for treatment of mental illness
Not all survive, but most do. About 5% repeat. May benefit from counselling or psychotherapy
FIG. 8.5 Death rates for suicide and undetermined injury in England 1969-91
Lee A 1999 (ed) Affective and non-pychotic disorders. Gaskell, London Scott J 1995 Psychological treatments for depression. Br J Psychiatry 167: 289-292
SUICIDE AND PARASUICIDE Suicide appears to be an integral part of human psychology. There are few individuals lucky and happy enough never to have had even a fleeting thought of suicide at some point in their lives. There has been a worrying increase in suicides in young men (Fig. 8.5). 'Parasuicide', a syndrome of deliberate self-harm, appears to be a relatively recent phenomenon and has reached epidemic proportions over the past 25 years. It is the commonest cause of hospital admission for women under 65, and the second commonest for men. Many cases of deliberate self-harm go unreported; probably only about one-third reach hospital.
Clinical profiles The clinical profiles of suicide and parasuicide are, on the whole, distinct (Table 8.7). A person who commits suicide could be a male with a previous history of depression and alcoholism, recently divorced or made redundant, living alone and with few close friends or relations. He deliberately tells the neighbours and milkman that he is going away for the weekend, and then takes a bottle of aspirin or shoots himself. A parasuicidal person might be a woman in her late teens living with her mother and stepfather, and getting on badly with her boyfriend. After a row with him, in which both have been drinking, she goes home, swallows some of her mother's sleeping tablets, and is then noticed to be drowsy. When challenged about what has happened, she immediately 'confesses' and is rushed to hospital.
The central theme of suicide is despair and depression; in parasuicide it is anger and frustration. Although there are important differences there are also psychological similarities. Both involve a physical attack on self, on the body. In both cases the patient feels a combination of personal inadequacy and anger towards friends and family. This anger is directed inward, but there is often a wish to punish or harm those to whom the patient feels close. This is done indirectly via the suicide or suicide attempt. It is often said that parasuicide cases 'do not really mean it'. This is only partially true, and can sometimes be used by staff as justification for adopting a punitive attitude. It is best to assume that both suicide cases and parasuicide cases want both to die, and not to die. The relative proportion of the two feelings varies greatly, but both feel both. A third point of overlap follows from this. Not all suicide cases succeed and, conversely, it is possible in parasuicide to die by mistake. Patients who have made major suicide attempts may recover and, with the help of drugs, psy-
223
FIG. 8.7 Primary diagnosis of suicides (England and Wales Suicide Inquiry cases), 1996-2000 FIG. 8.6 Age and sex profile of general population suicides (England and Wales), 1996-2000
chotherapy and time, regain the will to live. In the majority of parasuicide cases the attempt resolves the difficult social situation that prompted it, and so is not repeated. In a minority - about 5% - the attempts are repeated, and a proportion of these will eventually 'succeed'. Parasuicide repeaters are more likely to have a personality disorder, to be addicted to drugs or alcohol, or to have been in trouble with the law. (See Figs 8.6 and 8.7.) 1
Management of 'failed suicide' The causes of suicide are essentially the causes of depressive illness, and the management of attempted suicide is that of prevention, and particularly the early detection, of depression. About half of successful suicide cases have contacted a helping agency - a counselling organization, a GP, social worker or priest - in the month before they kill themselves. It is important to ask troubled, unhappy or depressed patients about suicidal feelings. Fleeting suicidal thoughts - 'I would like to sleep' or 'I would like to be dead but would never have the courage to do anything' - are less worrying than a definite suicide plan. Talking about suicidal thoughts may in itself be a relief. Suicidal patients with symptoms of depressive illness should be admitted to a psychiatric unit. Patients who are managed as outpatients need to be seen frequently while they are in a suicidal state.
1
224
MCQ 8.2
Antidepressants can be prescribed, but only in small amounts, as hoarding of tablets can be a danger. Although the prevention of suicide remains the ideal, this is difficult to achieve in practice. Counselling organizations such as the Samaritans seem not to have had a major impact on overall suicide rates, but the incidence of suicide in the UK has fallen slightly over the past 30 years compared with the rest of Europe. Suicide is a reminder of the limitations of psychiatric and social care. When a patient who is receiving treatment commits suicide, it is especially stressful for the doctors and nurses involved, as it always is for the patient's family. Feelings of guilt and anger are inevitable. Suicide, like any death, is a reminder that doctors are not omnipotent. In dealing with suicide or the threat of it, it should be remembered that, ultimately, a person determined or ill enough can always find a way to end his life.
DELIBERATE SELF-HARM Causes The causes of attempted suicide cannot be found solely within the individual. Social factors that need to be considered in understanding the increase in parasuicide rates include: • Complex family structures without clear rules or roles, such as unsupported one-parent families; adolescents who want freedom but lack the emotional or financial resources to leave home; families with step-parents; • Drugs being a socially acceptable means of dealing with distress: the commonest tablets taken in parasuicide are mild analgesics and minor tranquillizers;
8
CASE STUDY 8.1 SUICIDE OF A 20-YEAR-OLD ART STUDENT A 20-year old art student was brought by her friends to the psychiatric ward in a highly aroused state. She had not slept for several days, was dishevelled, could not sit still, and was talking 'nineteen to the dozen'. She was convinced that she was a direct descendant of van Gogh and that her paintings were worth several million pounds. She came from a loving family but one in which there was a very high incidence of mental illness. Her mother suffered from alcoholism, her half-sister had committed suicide, and her father, a very successful businessman, had marked mood swings. A diagnosis of hypomania was made. She was treated with haloperidol and started on lithium carbonate. After 2 weeks in hospital she was well enough to return home, but not to resume her studies. She was followed in outpatients and offered fortnightly supportive psychotherapy in addition to her continuing drug therapy. She found the side-effects of the neuroleptic drugs troublesome, and often 'forgot' to take her haloperidol. Her mood continued to be somewhat elated, and she worried her parents by mixing with what they saw as a 'wrong' crowd, many of whom had also suffered psychiatric illnesses or abused drugs. She suffered an episode of depression when an exboyfriend killed himself while drunk, and had once more to be admitted to hospital for a brief period. Two years after her original admission she felt well enough to resume her studies at art college. Things seemed to be progressing well, and she reduced her contact with psychiatric services to a
3-4-monthly outpatient attendance. She wanted to come off all her drugs, and was only persuaded to continue with lithium with some difficulty. Then one weekend, apparently without warning, she was found dead in her flat having taken an overdose of aspirin. On reconstructing the preceding history it appeared that she had taken no lithium for several weeks prior to her tragic death. Lithium levels were supposedly checked by the student health service every 3 months, but she had failed her most recent appointment.
Questions 1. What was the diagnosis? 2. Could her suicide have been prevented?
Discussion She showed many of the features of manic-depressive psychosis, bipolar type. There was a strong family history of mood disorder. She showed features of hypomania on first admission, which responded to neuroleptics and a mood stabilizer. Later she developed depressive symptoms in response to a painful life event. The mortality rate from suicide in manic-depressive illness is around 10%, and there is some evidence that taking a mood stabilizer such as lithium reduces mortality. There was an administrative and ethical conflict between the patient's reasonable desire to lead as normal a life as possible and the fact that she was
An epidemic factor. Deliberate self-harm is often behaviour learned from friends, fellow patients, relatives or television.
Management The medical management (p. 23) of the parasuicide patient takes initial precedence over the social and psychiatric
suffering from a potentially lethal psychiatric illness. Insisting on regular contact with medical/psychiatric services - her GP, community psychiatric nurse or consultant psychiatrist - might well have meant that her deteriorating mental state and poor drug compliance would have been picked up. Even better would have been attendance at a 'lithium clinic' run as part of a mental health service. Ongoing psychotherapy could also have identified the recurrence of her depressive symptoms and her irrational view of herself as useless and a burden to everybody, which was revealed in her suicide note. But all of this is to be wise after the event. She appeared to be doing well, and there is a limit to the extent to which treatment can be imposed on someone who feels and seems to be functioning well. Her case illustrates one of the most poignant dilemmas of psychiatry. Severe mental illness affects young people and has a mortality comparable to that of diseases such as leukaemia. She survived for nearly 5 years after diagnosis, a result which would be considered quite good in physical medicine but can lead to a very pessimistic appraisal of psychiatric treatments. All this had to be discussed in the case review, which occurs whenever there is a suicide among patients known to psychiatric units - open meetings in which staff can express their feelings without fear of censure, and work through the inevitable emotions of guilt, failure, anger and despair that suicide can evoke.
assessment. Medical staff often feel angry with overdose patients compared to those whose illness is not selfinflicted and, like alcoholics and drug addicts, such patients may become scapegoats. Their irresponsibility affronts the overworked nurses and doctors, who are often similar in age and maturity to the patient. In addition, medical staff work in a stressful and hierarchical situation in which they can at times feel angry or frustrated, and these emotions
225
can be displaced into a punitive attitude towards parasuicide patients. This can be avoided if ward procedures give time for discussion of these patients and the feelings they arouse.
History A careful history must be taken from the overdose patient, who should be kept in hospital until alert and cooperative enough for this to be possible. The presence of depressive illness and suicidal rather than parasuicidal features must be identified. The risk of a repeat attempt has to be assessed (Table 8.8). Social isolation, marked sleep disturbance preceding the attempt, strong feelings of guilt or unworthiness, evidence of preplanning, inability to look to the future and previous psychiatric history - especially if there are drug or alcohol problems - all point to serious disturbance and should lead to referral to a psychiatrist. A detailed account of the attempt itself and of events surrounding it should be taken. It is often unhelpful to ask the patient 'why' he harmed himself. If the patient knew, he might not have had to do so. In attempted suicide one often finds an acting-out of feelings, rather than the capacity to contain or verbalize them. The patient will find it much easier to answer questions about 'what happened,
TABLE 8.8 Deliberate self-harm: assessment of severity of disturbance. Ideally, all eases should be referred for psychiatric assessment, Psychiatric referral is essential if any of the following are present Circumstance of the attempt Evidence of preplanning (e.g. suicide note, use of car exhaust) Violent method used (e.g. attempted hanging) Social circumstances of patient Alone Away from home Personal history of patient Recent loss (e.g. bereavement, divorce/separation, unemployment) Physical illness Previous attempts Alcohol or drug addiction History of depressive illness Family history of patient Suicide Depressive illness Mental state examination Sleep disturbance, low mood before attempt Low self-esteem, hopelessness Psychotic features (e.g. 1 deserve to die')
226
Future No relatives or other support Unresolved crisis Continued determined suicidal intent
and how'. This provides an 'action replay' of the attempt, which will contain the clues to the question of 'why'. Most commonly the patient feels angry but is unable to express this directly, usually for fear of rejection by a partner, spouse or parent on whom he feels dependent. As in depression, he dare not bite the hand that feeds, and so attacks himself instead. It can be useful to ask the patient who he thinks would have been most distressed if he had died. Later, it is often helpful to discuss alternative strategies with the patient, to examine what he could have done in the same situation other than attempt suicide. Followup counselling after discharge, either as an individual or in a family, by a social worker, psychiatrist or psychotherapist, may be offered, although less than half of patients accept such help. However, even without follow-up the prognosis of parasuicide, in the absence of depressive illness or personality disorder, is fairly good.
FURTHER READING ON SUICIDE AND PARASUICIDE Hawton K 1987 Assessment of suicidal risk. Br J Psychiatry 150: 145-153. Hawton K, Catalan J 1987 Attempted suicide: a practical guide to its nature and management. Oxford University Press, Oxford Owens et al 1999 Assessment of deliberate self-harm in adults. In: Lee A., ed. Affective and non-psychotic disorders. Gaskell, London.
MANIA AND HYPOMANIA Clinical features In depression, mood is abnormally lowered. In mania, or its milder form hypomania, it is abnormally elevated. In unipolar manic-depressive psychosis the patient may have recurrent depressive or recurrent manic episodes. If both manic and depressive episodes occur, the patient has bipolar manic-depressive psychosis. There are three main groups of symptoms in mania and hypomania: • Psychological symptoms. The patient feels elated, cheerful and expansive, and his thoughts are speeded up. He may develop grandiose delusions of wealth, potency and fame. He is full of optimistic (and unrealistic) plans for the future. • Physical symptoms. The patient is restless, sleeps little, eats voraciously or not at all, often loses weight, has poor concentration, and tries to do several things at once. • Behavioural symptoms. The patient often spends large amounts of money, dresses flamboyantly and may behave in an outrageous, disinhibited and promiscuous manner. Outbursts of irritability and aggression are common. Speech is rapid, may be incoherent, and flits from subject to subject (known as flight of ideas). The patient is often humorous in an irreverent and infectious way.
CASE STUDY 8.2 A 32-YEAR-OLD WOMAN WHO HAS TAKEN AN OVERDOSE A 30-year-old married woman was sent to A&E by the emergency GP service having been found by her husband in a comatose state with a bottle of Prozac beside her and smelling of alcohol. She was admitted to the medical ward, given a fluid diuresis, and made a full physical recovery within 12 hours. The duty psychiatric team was then called to evaluate her. She said that she had been feeling low for several weeks, with poor sleep and reduced appetite. She had had a difficult year, since her mother had been killed in a car accident, and her 9-year-old son had been diagnosed as suffering from hyperactivity attention deficit disorder and excluded from his school. Her husband, a builder, had been unemployed because of a bad back, and on the day of the overdose they had received a final demand for a gas bill which she could not pay. This felt like the final straw - she felt she could not cope, her husband was out at the pub with his friends, and her son would be better off without her. She and her husband had been getting on badly, with lots of rows, she had no libido and they had not had sex for several months. She had a history of puerperal depression after the birth of her son, and had taken a minor overdose in her teens following a row with her boyfriend. She was an only child. Her parents had separated when she was 13. She had stayed with her mother who soon remarried, but the patient had not got on with her stepfather. She saw her father infrequently and felt awkward with him. On examination she was a bedraggled, miserable-looking person, appearing older than her 30 years. She was overweight. History-taking was difficult and she made little eye
contact. Her speech was normal in form but slightly slowed. She was subjectively and objectively depressed. She felt guilty towards her family, feeling she had let them down and that she was in some way responsible for her son's problems. She had no delusions or hallucinations. Cognition was normal and she was of average intelligence. The interviewer felt a mixture of pity and irritation towards the patient. She said that she no longer felt suicidal, but was unable to visualize how things would be different if she returned home. On being offered admission to a psychiatric ward, she refused.
Questions 1. What is the diagnosis? 2. How serious is the risk of further self-harm or suicide? 3. Should she be compulsorily admitted to hospital?
Discussion The diagnosis of depressive illness is fairly clear in this case. She gives a history of low mood, poor appetite, loss of libido and difficulty in sleeping over several weeks, culminating in an overdose of tablets with suicidal intent. She felt guilty, unattractive and useless. This was not a purely situational episode of deliberate selfharm, although there was an impulsive element to it, and there was no evidence of preplanning and she had not written a suicide note. The depression was of moderate severity, but there were no psychotic features. She claimed that her suicidal feelings had resolved, but was unable to give
8
a convincing account of how things could change in her life. Her home support was problematic. There was a definite, but not extreme, continuing suicide risk. Compulsory admission is a grave step, especially in the absence of psychotic features, but to let her go home might be to court disaster. During these deliberations her husband appeared on the ward. He was interviewed and revealed himself to be a reasonable man, desperately worried about his wife and shocked by her suicide attempt. He admitted that he too had felt depressed and had tended to resort to alcohol and avoid his home problems by going to the pub with his friends. He was strongly opposed to compulsory admission and said that he would guarantee to keep a close eye on his wife. Compulsory admission requires the consent of the nearest relative, unless that power is taken away by applying to a local magistrate - an extreme measure. A further attempt to persuade the patient to stay in hospital was made, and she reluctantly agree to stay voluntarily. While on the ward she was started on a more sedative antidepressant, sertraline, joined a self-esteem and assertiveness group, and she and her husband attended marital therapy sessions, in which her anger about the way in which she felt he had abandoned her was clearly expressed. He accepted the legitimacy of this and apologized. She could link this with her feelings about her father, who had abandoned her after her parents' divorce, and began to see that, despite his faults, her husband was a loyal and loving man. Her suicidal feelings lifted, she began to sleep better and was discharged from hospital, although therapy continued.
227
Hypomania frequently coexists with depressive symptoms: the patient laughs and cries almost simultaneously. This is known as a mixed affective state. Hypomanic episodes may, like depression, be triggered by a painful rejection or loss. This has led to the concept of manic defence, whereby the patient escapes into mania as a way of avoiding unhappy or sad feelings.
Management A hypomanic patient can cause havoc to both himself and his family. Hospital admission is often indicated but may be hard to achieve voluntarily, as the patient denies illness, often claiming to have never felt better, or to have discovered the secret of life. Immediate management is with tranquillizers such as chlorpromazine (100-600 mg daily) or haloperidol (15-60mg daily). Subsequent relapses may be prevented by prophylactic lithium carbonate (800-1600 mg daily). Lithium also has a mild immediate antimanic effect. Blood levels should be monitored regularly and be in the range 0.8-1.5mmol/L. Lithium may produce hypothyroidism and renal damage, leading to nephrogenic diabetes insipidus, and thyroid and renal function should be monitored. Other side-effects include abdominal pain, fine tremor, subjective memory impairment, thirst and lowered zest for life. Patients should be encouraged to keep up fluid intake in hot weather. Anticonvulsants such as carbamazepine (400-1600 mg daily) can be used as second-line antimanic prophylactics if lithium is ineffective or cannot be tolerated.
SCHIZOPHRENIA Just under 1 % of the population develop schizophrenia at some point in their lives, a statistic that appears to hold true for all cultures and countries. Chronic major mental illness in people under 65 is due mainly to schizophrenia. Until the move towards community care began, about half of all hospital beds in the UK were in mental hospitals and the majority of these (for the under-65s) were occupied by patients with a schizophrenic illness. As the number of hospital beds has fallen, a significant proportion of the vagrants living in large inner-city hostels and prison recidivists are found to be suffering from schizophrenia.
Aetiology Schizophrenia is the core disorder in adult psychiatry. Much debate has raged about the nature of schizophrenia, or even whether it is a valid clinical entity. It is probable
1
228
MCQ 8.3
Chances of developing schizophrenia (%) Relationship Parent: one Parents: both Sibs (neither parent schizophrenic) Sibs (one parent schizophrenic) Children Half sibs Uncles and aunts Nephews and nieces Grandchildren First cousins Fraternal twins Identical twins FIG. 8.8 Lifetime expectation of schizophrenia in relatives of schizophrenics
that schizophrenia is not a single disease but a group of related conditions. Both genetic and environmental factors are important in the aetiology of schizophrenia. It is best seen as a developmental disorder of the brain to which genetic and perinatal factors (birth trauma or maternal viral infection) contribute, but manifesting itself in late adolescence when brain maturation is finally completed. Pathogenic environments contribute to relapse in schizophrenia, but their role in aetiology is uncertain. It is possible that abnormal brain development may result from unstimulating or traumatic environments. • Twin and adoption studies have demonstrated the role of heredity in schizophrenia (Fig. 8.8). The concordance rate for identical twins is about 50%, that for nonidentical twins around 15%. • The efficacy of antipsychotic drugs such as chlorpromazine, with its inevitable parkinsonian side-effects, suggests a disturbance of midbrain dopaminergic pathways in schizophrenia (the 'dopamine' hypothesis). There is convincing evidence of increased D2 activity in patients with positive symptoms of schizophrenia. Dopamine abnormality may be the end result of other metabolic aberrations. It seems likely that serotonin (5HT) is also involved, perhaps by increasing D2 levels. Also glutamate, an excitatory neurotransmitter, may behave abnormally, leading to underactivity of Nmethyl-D-aspartate, which in turn may stimulate abnormal dopamine and 5HT activity. • A subgroup of patients show ventricular abnormalities on CT scan. There is slight ventricular enlargement, a reduction in the normal asymmetry between the cerebral hemispheres and, particularly in males, a reduction in cortical grey matter, especially in the temporal lobes. It has been suggested that structural abnormalities are more common in patients who lack a family history of the illness, suggesting that non-genetic organic factors, perhaps associated with perinatal brain injury, may be important in some cases.
SUMMARY 14 Schneider's first-rank symptoms
TABLE 8.9 Relapse rate for schizophrenia
• Delusional perception • Auditory hallucinations Audible thoughts (thought echo) Voices arguing or discussing ('third person') Voices commenting on the patient's actions • Thought disorder Thought withdrawal Thought insertion Thought broadcasting • Passivity experiences: delusions of control 'Made' feelings (includes somatic hallucinations) 'Made' actions Somatic passivity (body invaded from outside)
A. At 9 months
• Family and social factors have also been shown to be important, although not pathognomonic. In established schizophrenia the relapse rate is high when the patient is living in an over-involved family where there is a negatively charged emotional atmosphere (high 'expressed emotion', or 'EE') (Table 8.9). • Schizophrenic patients have a high state of psychophysiological arousal, possibly related to family stress. This may reflect limbic system dysfunction and lead to a difficulty in processing sensory stimuli.
8
Relapse rate 50% 12%
High EE homes Low EE homes B. In high EE homes Face-to-face contact
Maintenance therapy
Relapse rate
High High Low Low
No Yes No Yes
92% 53% 42% 15%
Delusions In schizophrenia these include the feeling that one's thoughts originate from outside ('thought insertion'), that they are being interfered with, removed ('thought block' and 'thought withdrawal') or transmitted to outsiders as though on a loudspeaker ('thought broadcasting'). 'Passivity feelings' are the feeling that one's thoughts or actions are 'made' from outside.
Delusional perception Clinical features Schizophrenia usually starts in young adulthood (the exception being paraphrenia, a form of paranoid schizophrenia affecting the elderly). There is a slight preponderance of men. The features of the illness can be divided into two parts: the effects on mental processes, and the effects on social functioning.
Mental disturbance There is a general disturbance of mental functioning in schizophrenia. The normal progression of logical thought is disrupted ('thought disorder'). The privacy of the self is breached. Certain patterns of disorganization of thinking are characteristic of schizophrenia, and are known as Schneider's first-rank symptoms.
Hallucinations These are usually auditory. Characteristic of schizophrenia are 'third-person' hallucinations, in which more than one person is heard discussing the patient and referring to him as 'he', 'she' or 'it'. Voices commenting on a person's actions like a 'running commentary' are also characteristic, as are voices that echo the patient's thoughts. Tactile or 'kinaesthetic' hallucinations, for example electric-shock feelings in the limbs, are rare but pathognomonic.
In delusional perception, a neutral stimulus (e.g. a car number plate or a traffic light) suddenly acquires special and often frightening significance for the patient. 1
SUMMARY 15 Management of schizophrenia • First attack: admit to hospital or day hospital for assessment, confirm diagnosis, establish contact and initiate treatment. • Treat symptoms with neuroleptics. Chlorpromazine 100mgt.d.s. by mouth Trifluoperazine 5mg t.d.s. by mouth Risperidone 2-4 mg b.d. by mouth Examples of Olanzapine 5-10 mg b.d. by mouth moderate moderatedoses doses Flupentixol ('Depixol') 40 mg 2-weekly Fluphenazine ('Modecate') 25 mg 2-weekly Treat side-effects as necessary with antiparkinsonian agents, e.g. Kemadrin 5 mg t.d.s. • Assign 'community key worker' as part of community care programme who will offer supportive psychotherapy and coordinate care package. • Assess family situation: offer psychoeducational programme to lower 'EE' if indicated. • Rehabilitation: attend day hospital, day centre, sheltered workshop, live-in hostel, sheltered housing. • Where resistant to medication consider newer neuroleptics: clozapine and risperidone.
229
Social deterioration The second main feature of schizophrenia is social deterioration. This is known as a negative feature of the illness, as opposed to the positive features of thought disorder, delusions and hallucinations. The patient may withdraw from social contact, give up his job, shun his friends and family, and spend many hours in isolation.
Differential diagnosis
Antipsychotic drugs These are of two main types: the so-called 'typical' antipsychotics, and the newer 'atypicals', orginally developed in the search for drugs with fewer extrapyrimidal side-effects (EPSs), which are rapidly becoming standard treatments. 'Typicals' can be divided into three main groups. All are potent D2 receptor antagonists.
An important subtype of schizophrenia is paranoid schizophrenia, characterized by paranoid delusions. Here the onset is later (around 30-40 years of age), social deterioration is much less marked, and the personality is relatively well preserved. Schizoaffective disorder has features of both schizophrenia and an affective illness, e.g. first-rank symptoms plus considerable depression. Its diagnosis is intermediate between that of the two 'parent' disorders. Not all madness is schizophrenia. The differential diagnosis includes:
• A group characterized by profound sedative effects and moderate antimuscarinic and extrapyramidal effects, e.g. chlorpromazine (50-1000 mg daily); • Moderate sedative effects, marked antimuscarinic effects, but fewer extrapyramidal effects, e.g. thioridazine (25250 mg daily), often used as a sedative in the elderly; • Fewer sedative and antimuscarinic effects but more pronounced extrapyramidal effects, e.g. trifluoperazine (2-30 mg daily); haloperidol (2-80 mg daily); flupentixol (2-100 mg daily).
• Organic psychosis, such as acute confusional states and drug- and alcohol-related psychosis; • Manic or depressive psychosis (in which auditory hallucinations occur but are more often 'second-person', in which voices speak directly to the patient); • Hysteria; • Stress-induced or 'psychogenic' psychosis; • Severe personality disorder.
Atypical' antipsychotics tend to have strong 5HT2a receptor antagonist activity. They include:
Prognosis The course of schizophrenia is very variable. About 30% of patients have only one episode. A good prognosis is more likely if the psychosis has an acute onset, a clear precipitant, florid symptoms, marked mood change in addition to disturbance of thinking, and good previous social adjustment and personality. At the other end of the scale, about 15% remain severely disabled and will still be in institutional care after a year. In these patients the negative features of schizophrenia (withdrawal and inertia) may predominate. In the middle group, representing the majority of patients, the illness has a fluctuating course but relapse and some residual disability are likely to occur.
Management Acute schizophrenic symptoms respond well to antipsychotic medication. There is some evidence that prompt treatment is associated with a good prognosis. The patient will normally be admitted to a psychiatric unit and treated initially with 100-1000 mg daily of chlorpromazine or its
1 230
equivalent. The longer-term management of schizophrenia is difficult. It involves both prevention of relapse and management of chronic disability.
MCQ 8.4
• Clozapine. This has serotonergic and dopaminergic properties and is effective against positive and negative symptoms of schizophrenia which have failed to respond to typicals. Its main drawback is that it causes agranulocytosis in 3% of subjects, and weekly blood count monitoring is necessary. Excessive salivation and sedation can also be problematic. • Risperidone. Also effective against positive symptoms, but can cause agitation and insomnia. • Olanzapine and quetiapine (an anagram of quiet-apine!, subtly drawing attention to its sedative properties) are also effective drugs and generally well tolerated, although they can cause alarming weight gain. A wide range of side-effects and idiosyncratic reactions may be produced with the antipsychotic drugs (Table 8.10). Perhaps the most serious of these is the rare but potentially fatal neuroleptic malignant syndrome, characterized by hyperthermia, confusion, muscular rigidity and autonomic disequilibrium (tachycardia, labile blood pressure, sweating). The patient should be admitted immediately to a medical unit; all antipsychotics should be discontinued and bromocriptine and dantroline given. Psychosocial interventions Analytical psychotherapy is generally not favoured in schizophrenia, and indeed the emotional arousal it may evoke can cause deterioration. There are, however, a number of 'psychosocial interventions' that significantly improve the wellbeing of patients with this disease. These comprise: • Family intervention. Because high 'EE' is associated with relapse, measures to reduce EE, either in families or in the hostels where some patients with schizophrenia live,
TABLE 8.10 Side-effects and toxic effects of antipsychotic drugs (e.g. chlorpromazine, flupentixol) Type of effect
Examples
Autonomic (antimuscarinic)
Blurred vision Dry mouth Constipation Precipitation of glaucoma Postural hypotension Inhibition of ejaculation Urinary hesitancy Akinesia (Parkinson-like) Acute dystonia Tardive dyskinesia (involuntary repetitive movements) Akathisia (motor restlessness) Weight gain Galactorrhoea and amenorrhoea Gynaecomastia Agranulocytosis Cholestatic jaundice Skin rashes
Extrapyramidal
Endocrine effects
Hypersensitivity reactions
Neuroleptic malignant syndrome Provocation of epileptic fits Hypothermia (especially in the elderly) Skin photosensitivity
will be valuable. A programme of 'psychoeducation' for families teaches them about the nature of the disorder and, via family group therapy or regular therapy sessions with families, works to reduce the emotional tension and foster a more benign atmosphere. Long-term supportive psychotherapy. Therapy in schizophrenia has to be long-term: perceptible change may take 4 years or more. A stable consistent therapeutic relationship with a psychiatrist or community key worker is needed and often bears fruit. Cognitive-behavioural therapy (see Recent Advances box). 1
Management of chronic disability Chronic mentally ill patients are severely handicapped. Their prospects of employment are poor, they may have little or no family support, and their capacity to care for and occupy themselves may be very limited. They are sometimes also shunned or made scapegoats by society, which tends to fear and despise madness. For at least 150 years these problems were dealt with by removing patients from society and locking them away in mental hospitals, thereby reinforcing the helplessness and isolation produced by the illness. Because of this, and also because mental hospitals are expensive to run and often sited on valuable land, government policy in the UK has now shifted away from the mental hospitals and towards community care. Patients are supposed to be cared for within the local community, in a network of hostels, sheltered houses, day hospitals and day centres, and community mental health centres. These are run by a locally based team of professionals, the 'multidisciplinary team' including community psychiatric nurses (CPNs), social workers and general practitioners, as well as psychiatrists. However, although this pattern of care is desirable for many patients, and is already a reality for some, it is not necessarily suitable for all patients, some of whom continue to need highly staffed or secure facilities on an intermittent or continuous basis. The care programme approach aims - through ensuring that every patient has an identified key worker, a definite 'care programme' and regular reviews with all concerned - to prevent patients from drifting away from services and thus to prevent the relapse that is likely to ensue when continuity of care is lost.
8
FURTHER READING ON SCHIZOPHRENIA Drug and Therapeutics Bulletin 1996 Drug treatment of patients with schizophrenia. Drug Ther Bull 33:81-86 Kane J, McGlashan T 1995 Treatment of schizophrenia. Lancet 346:820-825 Lewis S, Buchanan R 1998 Schizophrenia. Health Press, Oxford
PARANOID STATES Long-term maintenance on medication (which in the case of 'typicals' can sometimes be given in the form of a weekly or fortnightly injection because of problems of compliance) prevents relapse in schizophrenia. Phenothiazines can, however, have unpleasant and serious side-effects, especially a feeling of tiredness and extrapyramidal syndromes of stiffness and involuntary movements (Table 8.9). Antiparkinsonian drugs such as orphenadrine (100 mg t.d.s.) or Kemadrin (5 mg t.d.s.) should be given to counteract these. Reducing family tension has also been shown to prevent relapse. This can be achieved by family counselling sessions and by physical separation of the patient from an over-involved family through the provision of hostel accommodation and/or attendance at a day centre.
Paranoia means literally 'to be beside oneself, or 'out of one's mind'. In psychiatry, it refers to a psychosis whose
SUMMARY 16 Conditions resulting in paranoid states • • • • • •
Organic psychosis Manic-depressive psychosis Paranoid schizophrenia Paranoid psychosis Paranoid personality Paranoia in the elderly
231
RECENT ADVANCES IN THE PHYSHOSOCIAL MANAGEMENT OF SCHIZOPHRENIA Schizophrenia remains psychiatry's greatest challenge. Although the essential nature of the schizophrenias remains as elusive as ever, the past few years have seen, for the first time for two decades, significant psychotherapeutic advances. There is evidence that the longer the time between the onset of symptoms and beginning treatment, the worse the prognosis. This has led to much current interest in the notion of 'early intervention' in schizophrenia - trying to pick up the prodromal stages of the illness and initiating treatment, both psychosocial and pharmacological, as early as possible.
Psychosocial treatment of schizophrenia Exciting results have recently been claimed for cognitive-behavioural treatment in schizophrenia. Contrary to earlier views, it seems that patients can develop some control and mastery over their symptoms, especially abnormal beliefs and auditory hallucinations. Patients can, for example, distract themselves from voices by concentrating on external tasks, by playing music on 'Walkman' headphones, or even by 'bargaining' with the voices so that they confine 'their' attentions to particular times of the day. With the help of a therapist, or even a self-help 'voices' group, patients can also be encouraged to test the validity of delusions, e.g. 'if I go into that shop I will be killed', and on the basis of the 'results' of these 'tests', modify their beliefs. Early studies of these approaches are encouraging in producing, for some patients at least, reduced symptoms, improved
central theme is a feeling of persecution and fear of being attacked. Paranoid states are common in general medical and hospital settings. A postoperative patient may suddenly rip out an intravenous cannula and attack one of the nurses. A patient may refuse all drugs, convinced that the staff are torturers dressed up as doctors and nurses. The conditions resulting in paranoid states are as follows: • Organic psychosis. This is by far the commonest cause in hospital settings. Paranoid delusions are frequently found in patients with acute confusional states. Any of the causes of organic psychosis (p. 208) may be responsible, with steroid-induced psychosis, alcohol withdrawal syndrome and amphetamine psychosis being particu-
1
232
Case 8.1
social functioning and compliance, and reduced drug dosages.
Compliance therapy A major problem in schizophrenia is drug noncompliance. Borrowing on the techniques of 'motivational interviewing' developed for addiction, researchers have shown that compliance can be dramatically improved if the clinician provides much greater information about the drugs, and attends closely to patients' feelings about side-effects and the stigma associated with taking long-term antipsychotic medication. A simple useful intervention appears to be to compare the schizophrenia sufferer's need for medication with the diabetic's need for insulin. From this perspective schizophrenia becomes a disability to be lived with, rather than a disease which is either denied or devastating. Assertive outreach programmes aim to tackle non-compliance by treating the patient in his or her home environment and by offering intensive therapeutic nursing, family and practical help at a time of maximum stress.
Early intervention The prognosis in schizophrenia is worse the longer the gap between the onset of symptoms and starting therapy. Early intervention programmes aim to identify and treat young schizophrenia sufferers using a combination of destigmatization, drug therapy, combating concomitant substance misuse ('dual diagnosis') and psychosocial intervention.
larly common. Alcoholism may also produce a chronic paranoid state in which auditory hallucinations predominate (p. 251). Manic-depressive psychosis. Feelings of being disliked and shunned are common in depression, and may assume psychotic proportions if the patient feels he is so wicked that he is deservedly in danger of attack. Paranoid ideas can occur in mania, but elation and overactivity are usually more prominent features. Paranoid schizophrenia (see p. 229). Paranoid psychosis. Sometimes the patient develops paranoid delusions and hallucinations without the full range of features of schizophrenia. There is often a sexual content to the psychosis. The patient may, for example, become convinced that his spouse is having an affair (morbid jealousy, or Othello syndrome). The feeling that workmates or strangers are accusing the patient of homosexuality is often a prominent feature of paranoid psychosis. Paranoid personality. People with paranoid personalities have a tendency to mistrust and blame others, and so
frequently become involved in complaints and battles with authority. The patient is often sensitive, isolated, insecure and quick to take offence, and misinterprets the behaviour of others as hostile. When his fragile self-esteem is threatened by illness or rejection, he may develop a paranoid psychosis. • Paranoia in the elderly. Elderly patients may develop a paranoid psychosis (paraphrenid) with schizophrenic features. Deafness, social isolation and previous paranoid personality are important predisposing factors. Common to all the different forms of paranoia are isolation, insecurity, mistrust and misperception. In some cases the defence of projection seems to be operating. Here an inner state of persecution is transferred on to the external world, presumably as a defensive manoeuvre designed to reduce inner mental tension. Thus a cancer patient may develop a paranoid state in which he denies there is anything physically wrong, but refuses to leave hospital on the grounds that he is in danger of being attacked. Here the 'hostility' felt from the cancer within is attributed to the outside world instead. Paranoid states can be treated symptomatically with phenothiazines (see p. 230), but the underlying cause itself should be treated whenever possible.
SOMATOFORM DISORDERS Somatoform disorders are conditions in which (a) physical symptoms are present for which no organic or physiological basis can be found, and (b) where there are demonstrable underlying psychological factors or conflicts, i.e. the physical symptoms are manifestations of underlying psychological distress or disease.
Terminology and definitions There are several terms commonly used to describe physical disorder in which psychological mechanisms may be important. The outmoded but still widely used term psychosomatic illness refers to conditions in which there is definite structural physical illness (e.g. bowel inflammation in ulcerative colitis) but whose precipitant or maintaining factors are thought to be in part psychological. The term functional is sometimes used to describe symptoms produced by changes in organ function in the absence of structural change. Functional illness may or may not be psychological in origin. Functional bowel disease (irritable bowel syndrome, see p. 817), for example, may result from faulty diet or disturbance of the autonomic system (potentially stress related) or both. Controlled trials suggest that chronic intractable irritable bowel syndrome responds well to psychotherapy. The term psycho genie usually implies that the symptoms are entirely psychological in origin. Many of the ill-defined
conditions seen in general practice and medical outpatient clinics could be labelled psychogenic, although this term may obscure the fact that physical factors (e.g. muscular tension) are also important. The concept of hysteria (p. 235) has a long history and has become differentiated from the more non-specific psychogenic symptoms. Hysteria is divided into two types:
8
• Conversion disorders. These are psychogenic illnesses often simulating neurological disorders - based on unconscious mechanisms, in which mental conflict is avoided both by 'converting' anxiety into physical symptoms (hence conversion hysteria) and by dissociation (i.e. a split between the mental self and the physical self). • Somatization disorders. These are polysymptomatic disorders in which the patient experiences multiple unexplained symptoms without physical disease and in the context of a disturbed personality. 1 In psychosomatic illness psychological factors aggravate, prolong or cause relapses in an illness whose basis is physical (just as a poor ward atmosphere has been shown to delay postoperative wound healing). Psychogenic symptoms are often based on circular patterns in which, for example, emotional conflict produces muscular tension, which results in pain, which leads to greater emotional stress, or anxiety (e.g. fear that the pain may be due to cancer), which results in more muscular tension and so on. Chronic fatigue syndrome (CFS, see p. 236) can be thought of as a somatoform disorder; some however would classify it as a psychosomatic illness, in which psychological factors exacerbate an organic illness, albeit one whose pathology is currently unknown.
MIND-BODY MODELS There are two extreme but widely held views on the nature of psychosomatic illness. The first, corresponding to the philosophical position of materialism, holds that all phenomena are physical in origin and denies the existence of the mind. For the materialist there are no psychogenic conditions, only illness whose physical cause has yet to be determined. The second, idealist, view holds that psychosomatic illness is mental in origin. There are problems with both these models. The materialist might point to the numbers of patients labelled as hysterical who have subsequently died of carcinoma or multiple sclerosis; but the existence of mind is undeniable. The idealist, on the other hand, tends to confuse the symbolic meaning of an illness with its cause, claiming, for example, that a man who developed oesophageal cancer did so because he could not swallow his wife's infidelity. A classic error of this type was the pre-1956 theory of Down's syndrome. This held that Down's syndrome was caused by physical or mental trauma in pregnancy, as mothers of Down's syndrome babies regularly reported such traumatic incidents. Only when the chromosomal abnormality
233
234
responsible was found was it realized that the trauma theory was a retrospective rationalization rather than a causal explanation. In reality, the relationship between mind and body is far more complicated than either the pure materialist or the idealist model allows. The interesting questions concern the interactions between the mental and the physical, just as many important problems in genetics involve interactions between heredity and environment. For example, there is good evidence that psychological adversity in childhood - neglect or abuse - is associated with poor physical health in adult life. The mechanisms by which this is mediated remain to be elucidated. To some extent they may result from excessive alcohol and drug abuse, and smoking, which are associated with both psychological stress and poor physical health. The effects of stress via the hormonal system on immune mechanisms may also play a part. Thus the 'Descartian' split between mind and body is beginning to be seriously challenged. It has been cogently argued that we 'think with our bodies': that the body is more than just a metaphor for much emotional experience (we speak of 'gut feelings' and 'emotional pain'), but that we use bodily sensations to help us choose between different equally rational courses of action. Body and mind, reason and emotion are ultimately inseparable.
more likely to develop coronary artery disease than those with more placid temperaments. This is particularly true where aggression plays a large part in the 'type A' makeup. Similarly, the prognosis of breast cancer may depend in part on personality: women who are emotionally inhibited appear to have, on average, a less good prognosis than those more able to express anger and sadness. The intervening variables that link the psychological to the physical are largely unknown. Autonomic and corticosteroid responses to stress play their part, as do changes in the immune system (especially T lymphocytes), but the precise pathways and links remain to be elucidated. Current evidence does not support the view that psychosomatic diseases are primarily psychological in origin, nor that any specific relationship exists between personality type and a particular disease or target organ.
Experimental evidence
Development of the body image
There is evidence that painful events in a person's life can precipitate physical illness. The link between stress and myocardial infarction, for example, is well documented (Fig. 8.9). Bowel disease, such as ulcerative colitis or even appendicitis, may also be triggered by a preceding painful or stressful life event. Personality plays an important part in determining the impact of such events. Individuals with 'type A personality' (competitive, driving) are, other factors being equal,
In adult life mind and body are separate realms. The body is experienced as an object among other objects in the world, but is also, for its 'owner', the source of knowledge and sensation and the means by which contact and communication with others is possible. The mind, though experienced as a separate domain, is indissolubly connected to the body. As Freud pointed out, it only takes a toothache to feel that 'the molar hole contains my soul'. The adult state in which the self comfortably inhabits both mind and body, experiencing each as separate and yet connected, is a complex product of health, maturation and culture. The infant is born in a state of psychosomatic unity: pain for a young child is both mental and physical. In adult life physical illness may produce regression to a childlike state. Childhood experiences may play a crucial part in determining later relationships between mind and body. In early childhood, the parents' love and care for the child and his body sow the seed of healthy self-love in later life. A girl who was 'meant' to be a boy may have to struggle with the effects of her parents' disappointment for years to come. Later, the adolescent has to learn to accept his or her body and sexuality. Self-acceptance is an essential precondition of loving others. When this process is disturbed, some individuals may, when anxious, ask their doctor for an examination, complaining that there is something wrong with their body or even asking for it to be changed by plastic surgery. The patient is looking for the acceptance and care he feels he missed from his parents. If external relationships fail, the patient may turn for interest and gratification to his
FIG. 8.9 Experience of potentially stressful life events by myocardial infarction patients in the 12 weeks before Ml occurred
PSYCHOLOGICAL APPROACHES TO SOMATOFORM DISORDERS Psychiatric understanding of psychosomatic and psychogenie illness can be considered under two headings: the development of the body image, and repression and the unconscious.
own body, and this too can lead to development of, and preoccupation with, psychogenic physical symptoms.
Repression and the unconscious Repression is the active removal from consciousness of painful or disturbing thoughts, feelings or memories. The mind's eye is blinded to problems and conflicts. The difficulties and the feelings they evoke remain, however, even though the patient is unconscious of them. They may then manifest themselves in physical symptoms, by the process of displacement. Thus a 20-year-old student presented with a hysterical hemiplegia and unexplained fits. She described her family life as happy and uneventful. In the course of therapy it emerged that her father had had a disabling stroke when she was 10, and that a fellow student had attempted to rape her a few weeks before her hemiplegia presented. She had 'forgotten' both of these painful events, but the neurological aspect of her presenting symptoms were reminiscent of her father's disability, suggesting that at some level they were still active in her mind, albeit at an unconscious level. The trauma of the rape re-evoked the shock, terror and vulnerability she had experienced when her father became ill.
'MINOR' PSYCHIATRIC ILLNESS Minor psychiatric illnesses are hard to classify and often go undetected, hiding behind and contributing to physical symptoms (Tables 8.11 and 8.12). In these illnesses a somatic 'facade' conceals difficulty in adjustment to social stress ('adjustment disorders'), symptoms of anxiety and/ or depression, or personality difficulties. Once these are explored and the patient reassured, the physical symptoms may be relieved. In considering patients with somatization disorders, a number of psychosocial factors should be explored: • Stress factors, especially recent losses, such as bereavement, unemployment, children leaving home, financial difficulties, divorce and termination of pregnancy; • Social support, relationship with partner (including sexual relationship), parents, children and friends, housing conditions; • Personality: how the person has reacted to stress in the past, previous stressful or painful experiences, especially in childhood, and whether the patient is able to respond with appropriate anger or sadness; • Alcoholism, drug abuse and eating disorders, which frequently present indirectly via physical symptoms.
FURTHER READING ON SOMATOFORM DISORDERS Goldberg D, Huxley P 1980 Mental illness in the community - the pathway to psychiatric care. Tavistock, London Lloyd G 1991 Textbook of general hospital psychiatry. Churchill Livingstone, Edinburgh
TABLE 8.11 Characteristics typical of doctors who frequently detect psychological problems • • • • • • •
8
Show empathy Sensitive to emotional cues Use appropriate psychiatric questions and probes Tend to ask for clarification of the patient's complaints Make early eye-contact with the patient Do not bury themselves in notes Good at dealing with interruptions and garrulous patients
TABLE 8.12 Psychiatric illness in general practice: how much goes undetected? Category
All patients
Probability of detection by GP
Physical illness without psychiatric disorder Physical illness and unrelated psychiatric disorder Physical illness with secondary psychiatric disorder
67%
not available
8%
19%
1%
74%
19% 13.5%
47% 33%
5.5%
85%
5%
95%
Somatization Physical illness with symptoms exacerbated or caused by psychiatric disorder Somatized psychiatric illness (no diagnosable physical illness) Psychiatric disorders presenting with psychological symptoms
Smith G 1999 Managing somatoform disorders. In: Lee A (ed) Affective and non-psychotic disorders. Gaskell, London Wilson A, Hickie I, Lloyd P 1994 A treatment of chronic fatigue syndrome: science and speculation. Am J Med 96:544-550
HYSTERIA The essential features of hysteria are: (a) physical symptoms, (b) absence of organic pathology, and (c) psychological conflict.
Classification and clinical features There are three main patterns of hysteria: monosymptomatic, polysymptomatic and epidemic. Monosymptomatic hysteria (conversion disorder) Typically there is gross loss of neurological function. This may involve: • the limbs, e.g. paralysis, anaesthesia or dystonia
235
RECENT ADVANCES IN CHRONIC FATIGUE SYNDROME (CFS) Patients suffering from feelings of chronic physical exhaustion frequently present to physicians and sometimes to psychiatrists. Although there may be nothing new in this - such patients were formerly seen as suffering from 'neurasthenia' - much recent effort has been devoted to the clarification of diagnostic criteria, the search for possible causes, and developing structured treatment approaches. The criteria for CFS include disabling physical fatigue which is unexplained by primary physical or psychiatric diagnoses, myalgia, depression and poor concentration, all lasting for more than 6 months. CFS subsumes other diagnostic labels such as Royal Free disease, postviral syndrome and, where there is or has been definite evidence of infection, postinfectious fatigue syndrome. There is no generally accepted theory about causation. Enteroviruses have been implicated, and increased litres of anti-Coxsackie B IgM are reported; muscle fibre damage is found in some cases; some have claimed deficiency of intracellular magnesium. In contrast to the metabolic explanations, psychiatric intervention shows much promise. Fifty per cent of CFS sufferers meet the criteria for major depression. Whether this is cause or
consequence is unclear: one study found that 100% of patients who lacked evidence of infection were depressed, suggesting that 'CFS' represents a number of disorders of differing aetiology. Management includes:
• the higher functions, e.g. hysterical fits, hysterical blindness, fugue states (in which the patient has complete memory loss), or even hysterical psychosis (where the patient develops a short-lived and dramatic psychosis in response to external stress).
with monosymptomatic hysteria, their prognosis is poor and is related to general personality difficulties rather than a specific conflict.
The pattern of dysfunction follows the patient's 'idea' of how the body works, rather than anatomy. Similarly, in hysterical psychosis the patient behaves in the way he thinks a madman ought to behave, rather than demonstrating the specific symptoms of schizophrenia. A neurologist can usually determine the integrity of the nervous system, either by subtle physical examination (extensor activity in apparently paralysed limbs) or by investigation (intact visual evoked potentials in hysterical blindness). The patient may also exhibit the belle indifference described by Janet, i.e. an apparent lack of anxiety in the face of a crippling disorder. Psychophysiological measures of arousal show that hysterical patients are in fact often highly aroused, despite the absence of manifest anxiety.
236
Polysymptomatic hysteria (Briquet's syndrome, somatizotion disorder) Patients suffering from polysymptomatic hysteria (usually women in their 30s) develop a wide variety of physical complaints with no organic basis over a number of years. These often involve pain in the abdomen, back and pelvis. Such patients have often been extensively investigated by physicians and frequently admitted to hospital. Their medical notes are thick but inconclusive. Unlike patients
• A sensitive and tactful approach in which the patient is engaged and supported via the adoption of a psychosomatic approach (see main text) which does not attempt to deny the reality of the symptoms or to undermine directly the patient's belief system about his illness; • Psychotherapy directed to helping the patient to adjust to the losses (e.g. of job, mobility, social life) that result from CFS; • Cognitive-behavioural therapy aimed at reattribution of symptoms (e.g. 'I am tired because I am unused to exercise, rather than because my muscles are irremediably damaged'); • Anxiety management to reduce tension and panic; a programme of graded exercise • if depression is a prominent feature; prescription of antidepressants.
Epidemic hysteria This rare and self-limiting condition occurs in schools and other situations where young people are in close proximity. Fainting, nausea and paraesthesia brought on by overbreathing are common presentations. The condition is sometimes wrongly assumed to have an infective cause.
Diagnosis Hysteria is not an easy diagnosis to make. A proportion of patients diagnosed as hysterical turn out to have genuine organic disease: multiple sclerosis or occult cancer, for example. Others may develop another psychiatric condi-
SUMMARY 17 Psychological mechanisms in hysteria • • • • • • •
Dissociation Denial Primary gain - elimination of mental pain Secondary gain - attention, care Identification Illness behaviour Unconscious avoidance of conflict
tion, such as a depressive illness or even schizophrenia. However, it is important to recognize and diagnose hysteria when it does occur, so as to spare the patient unnecessary investigation. Hysteria and organic illness can also, and often do, coexist; establishing one diagnosis should not prevent the search for another.
SUMMARY 18 Management in hysteria • • • • • •
8
'Psychosomatic' attitude on part of doctor Exploration of conflict Behavioural approaches (Antidepressants) Abreaction Long-term psychotherapy
Meaning and aetiology The manifestations of hysteria are often dramatic, and therein lies a clue to its nature. Most people, especially as children, have the capacity to act a role. This involves an internal splitting, or dissociation, between the actor and his part. The actor is not really Hamlet, yet becomes Hamlet as he acts the role. The hysteric is not paralysed and yet, psychologically, can become so. According to Freud, the symptoms in hysteria have a meaning which can be understood in terms of the patient's life. Psychological theories of hysteria also highlight several other important aspects of the illness: • Defence. Hysteria is a defence against the anxiety created by conflict. A young man from an academically minded family was facing exams which he feared he would fail; he became paralysed. • Unconscious behaviour. Although a conflict is often obvious to others, the patient is unconscious of it. • Personal gain. There are two kinds of gain for patients in being ill. The primary gain is the fact that they are unaware of their conflict and thus do not experience anxiety. The secondary gain is the care and attention they get from family, friends and relatives. This is only possible if the family to some extent go along with it, or allow the patient to manipulate them. Here they may be meeting their own needs, e.g. the husband who only feels potent when he has a sick wife to look after. 'Manipulation' is a normal process in childhood, and hysteria always has childlike aspects. The child who does not want to go to school develops a tummy-ache; his mother lets him stay at home with her. A similar process is at work in hysteria. The child is not consciously making himself ill or malingering (as, for example, is the soldier who deliberately shoots himself in the foot to avoid going to battle): there really is a pain, even if it clears up quickly once the danger of having to go to school has passed. • Identification. A common finding in the histories of hysterical patients is that there has been a close relative who has suffered illness, often serious. The young man who became paralysed because he feared his exams had had a younger brother who had died with cerebral palsy, and on whom his parents had lavished all their care and attention. The patient often has such a model of illness and its accompanying behaviour which influences him. Sociologists speak of 'illness behaviour' to describe the socially sanctioned behaviour that accompanies illness and which is not strictly related to the pathophysiology of the disease. Sick people are allowed to retire tem-
porarily from work and spend time in bed; they receive flowers, cards and gifts from relatives and are treated with special consideration; they are allowed to be childish and demanding. Their medical attendants also adopt a particular role, usually one of reassurance, benevolence and quasi-omniscience. One of the rules of illness behaviour, however, seems to be that the patient should recover, or at least attempt to recover. When this does not happen there may be a sudden switch: the previously privileged patient may be seen as manipulative, attention-seeking and deviant, and be shunned or covertly punished by irate relatives and medical attendants. In hysteria this often results in a worsening of the symptoms.
Management It is tempting to try to argue a hysterical patient out of his illness. Occasionally this can be helpful, but more often it entrenches the patient more deeply in his symptoms and an escalating battle between doctor and patient may then ensue. There is, moreover, a sense in which the patient is right: he is ill, but psychologically, not physically. There is something wrong, namely a psychological conflict, albeit one of which the patient is unconscious. A more helpful approach is therefore to adopt a psychosomatic attitude. This involves explaining to the patient that stress can cause illness, that he may have a psychological conflict, and that there may be a connection between this and the physical problem, both of which are real. The patient who has committed himself to a physical illness should be offered appropriate physical treatments (e.g. physiotherapy, massage) and should not be deprived of it out of spite. When recovery does take place the temptation to say T told you so' should be resisted. Instead, the patient needs a face-saving formula: the paralysed person must be allowed to put his crutch down gradually, inadvertently even, not have it knocked from under him. The psychological principles of treatment are: • Exploration of conflict. With allowance for face-saving, this is perhaps the most helpful strategy. If the conflict is removed (e.g. the time for exams past) the symptoms will usually remit. • Cognitive-behavioural approaches. These are often useful. They (a) aim to avoid reinforcement of the symp-
237
toms, e.g. by suggesting to ward staff or relatives that they respond positively to any signs of movement in the paralysed patient, but as far as possible ignore (nonpunitively) helpless behaviour; (b) are directed towards helping the patient overcome his cognitive responses (e.g. of panic and catastrophe) towards the imagined illness. The latter is sometimes known as 'reattribution therapy' - the patient learns how he wrongly attributes normal bodily sensations to illness, and that this may be influenced by emotion, especially anxiety. Drugs. Where hysteria is secondary to a depressive illness antidepressants should be prescribed. In general, however, drug treatment should be avoided in hysteria, as the patient is often very suggestible and tends to develop dramatic reactions and side-effects. Hysterical amnesia can sometimes be approached by abreaction, in which painful experiences are 'relived' with the help of an intravenous injection of a sedative drug such as diazepam. Psychotherapy. Some patients will benefit from longterm psychotherapy.
HISTRIONIC PERSONALITY AND RELATED CONDITIONS There are a number of conditions that are related to hysteria but which take the form of a lifelong personality disorder rather than an illness. These conditions share with hysteria the capacity for dissociation and the use of illness for manipulation of those around them.
HISTRIONIC PERSONALITY A patient with histrionic personality (usually female) finds it difficult to form close attachments, and when she does they are highly dependent. Her emotions are often superficial and rarely satisfying. She may be very alluring and attractive to men, but finds it difficult to enjoy sex herself. She carries with her an atmosphere of drama: her life is often a series of emotional or practical crises. Her feelings
SUMMARY 19 Conditions related to histrionic personality
238
Multiple personality
Aspects of the self entirely dissociated from one another, with lives of their own
Factitious illness
Self-inflicted illness
Fictitious illness Patient travels from hospital to hospital (Munchausen's syndrome) with fictitious illnesses. Pseudologia phantastica.
are dramatized and exaggerated; her headaches are always 'migraines', her diarrhoea 'dysentery' and her pains invariably 'excruciating'. She uses her crises to coerce those around her (including doctors and nurses), and sometimes has a husband whom she abuses and yet clings to, and who appears to submit willingly to all her demands. As a child she may have felt emotionally neglected and insignificant, helpless and dependent. The anger and manipulation that manifest themselves in adult life can be seen as a continuation of this, an attempt, through the coercive power of illness, to keep attached to her those whom she feels may otherwise ignore or abandon her. Patients with histrionic personality sometimes develop the physical symptoms of hysteria.
MULTIPLE PERSONALITY The adult personality is made up of a number of elements: • Some come from identifications based on parents ('he has his father's temper and his mother's charm'). • Some represent different aspects of the self: the caring self, the aggressive self, the childish part of the self, and so on. • Some can be defined in terms of relationships: in a marriage a partner may be expected to be a spouse, lover, parent, colleague and friend. Eric Berne has summarized the different aspects of the self as 'parent', 'adult' and 'child', all of whom coexist within one person. In the mature personality there is a blending together of the different aspects into a coherent whole, so that a person is all of a piece, although minor discontinuities and splits in the personality are common. The fascinating but rare clinical condition of multiple personality, in which several quite separate personalities appear to inhabit the same individual (fictionalized in such works as DrJekyll and Mr Hyde and The Three Faces of Eve), is an extreme example of this everyday splitting. In multiple personality the different personalities have lives of their own which are entirely dissociated from one another; the good self is totally unaware of the bad self and would be horrified by its activities. This enables, say, a prudish aspect of the self to live alongside the sexual side without being aware of it, thereby avoiding anxiety or guilt. Patients with multiple personality can occasionally be helped towards integration with psychotherapy.
FACTITIOUS ILLNESS Patients with unexplained symptoms are sometimes found - often after lengthy investigation - to have caused their own illness. A patient with unexplained and extensively investigated 'haemoptysis' was found to be venepuncturing herself, swallowing blood and then spitting into a sputum pot; a person with unexplained intestinal bleeding
may be inserting foreign bodies into the rectum; hypoglycaemic attack can be produced by insulin injections in non-diabetics; dermatitis artefacta (p. 436) is yet another example of such factitious illness. Occasionally such behaviour is due to psychosis, but more often it is a manifestation of a personality disorder. These patients are often very 'nice'; they may be nurses or members of the other caring professions. They are often on good, even intimate, terms with medical staff. They may induce incomprehension, abhorrence and anger once they are discovered. Factitious illness is best seen as an extreme example of histrionic personality disorder. The patient has split off an angry, destructive, defiant part of herself which acts semiautonomously and of which the 'good' self may be partially unaware. The principles of management of hysteria may be applied in these cases. A full history will reveal underlying conflicts, and the patient can then be told, in as gentle and unconfrontational a way as possible, that these conflicts may be responsible for her symptoms and that she may thus be playing a part in causing her own illness. Although the patient may become angry, the results of such an approach are rarely disastrous. The patient will often be relieved and even begin to accept psychological help.
FICTITIOUS ILLNESS: MUNCHAUSEN'S SYNDROME Baron von Munchausen was an 18th-century fictional character who travelled extensively and told fantastic stories. His name is now used to describe a group of patients with characteristic features: • Patients often experience recurrent unexplained symptoms, especially abdominal or chest pain, which are often thought to be due to renal colic, myocardial infarction or intestinal obstruction. The patient may be given opiates and have had several inconclusive laparotomies, which reveal themselves as multiple abdominal scars. • These patients travel from hospital to hospital, usually discharging themselves after a brief admission, and using a variety of assumed names. • They give dramatic accounts of their lives, for example stories of heroic wartime feats or tragic losses, none of which can be corroborated and none of which quite add up. These stories are sometimes labelled pseudologia phantastica, Munchausen patients may be seen as the male counterparts of factitious illness patients. They are hard if not impossible to manage or help, but awareness of the diagnosis will avoid unnecessary or dangerous investigations. Most doctors have had at least one experience of being hoodwinked in this way, and this may be a necessary learning experience. The doctor must be friendly but firm in refusing to treat these patients as though they are ill. The patient usually disappears, but may occasionally accept social help and often become highly dependent on medical services.
SUMMARY 20 Factors contributing to anorexia nervosa • • • •
8
Contradictory social attitudes towards eating and thinness Enmeshed, i.e. mutually overdependent, families Fear of loss of control of eating and of sexuality Fear of separation
EATING DISORDERS Eating is not just about physiology: food has great psychological and sociological significance. Morality starts with the child's discovery of what is good and bad to eat, and a mother's self-evaluation may continue to depend on how well she feels she feeds her family. Birth, the reaching of adulthood, marriage and death are all marked by a meal. In addition, there are two factors, specific to many highly industrialized western societies, that are of especial relevance to eating disorders: the role of the food industry, with its large marketing system; and the emphasis on a slim body image as a mark of vitality and attractiveness. Eating disorders are increasingly common, especially among women (Fig. 8.10). Although the overall incidence of anorexia nervosa is only 1 per 100000 population, 1% of 16-18-year-olds are affected; 2% of women attending a family planning clinic suffer from bulimia nervosa; and the prevalence among dance students is 20%.
ANOREXIA NERVOSA Aetiology and pathogenesis No single cause of anorexia nervosa has been found. A number of factors appear to be involved: • Social pressures towards both eating and thinness, though contradictory, are important.
FIG. 8.10 Epidemiology of anorexia nervosa Social class distribution of anorexic patients (father's occupation) compared with that for general population.
239
CASE STUDY 8.3 A 30-YEAR-OLD WOMAN WITH AN EATING DISORDER AND A WEIGHT OF 30 KG A 30-year-old woman was admitted to a psychiatric unit weighing 30 kg. Her body mass index (weight in kilogrammes divided by height in metres, squared) was, at 13, near the lower limit considered to be compatible with life. She was brought in by her husband, who had been increasingly worried about her but up to this point had been unable to persuade her to accept help. She had had eating disorder symptoms since at least the age of 15, when she had left home to live with her boyfriend, who eventually become her husband. She was terrified of excess weight and weighed herself several times a day. She ate little more than a crispbread and a slice of cucumber daily. She had never had regular periods, although, unusually for someone with anorexia nervosa, had managed to get pregnant with the help of ovulationassisted fertility treatment. She was closely involved with her mother, to whom she presented an 'everything is normal' front, while seeing her almost every day. She was very worried about her parents' marriage, which she saw as in great jeopardy. She was treated with a refeeding schedule, with which she was surprisingly compliant, until she weighted 45 kg, and then was discharged from hospital. Her outpatient care consisted of a combination of individual psychotherapy and family therapy. Her individual therapy concentrated on looking at all the ways in which she pretended to herself and others that she was eating when in fact she was avoiding food. It used an 'addiction' model and suggested that she was addicted to not eating in the way that an alcoholic is addicted to alcohol - using it as a refuge whenever she felt stressed or confused. Therapy also looked at her
240
image of herself as a woman, and at how frightened she was about becoming 'like' her mother, whom she saw as being trapped in a loveless marriage, constantly at her father's beck and call. The family therapy sessions tried to help extricate her from the parent-child relationship she had established with her husband and to foster a more equal partnership, in which she took charge of her own eating, rather than either deceiving him or relying on him to prompt her to eat. There were no further admissions, but her weight hovered just under 7 stone for many years, and she said that the idea of being 7 stone terrified her. Over the years she made many life changes. She left her husband and formed a new partnership, which was more emotionally open and caring, although not without its problems. Her new partner was more able to help her to eat at times when she was in the grip of her anorexic symptoms. Her parents' marriage also broke up, and she become much less involved with her mother.
Questions
1. Could intervention have started earlier? 2. What is the long-term prognosis of anorexia nervosa?
Discussion It is notoriously difficult to engage people suffering from anorexia nervosa in treatment. Teenage sufferers are often taken unwillingly to the doctor by worried parents. It is always important for the doctor usually a family doctor in the first instance - to interview the patient on her own and to make determined
attempts to establish rapport, a process which may take several interviews. There is a danger that the doctor will be pulled into identification either with the worried and exasperated parents, in which case he may become heavy handed and insensitive, or with the patient, when he may minimize the seriousness of the situation and fail to be appropriately firm and challenging. Anorexia is 'delusional' in the sense that such patients are convinced that they are fat, despite every rational argument to the contrary. There has been much debate about the ethics of admitting people with anorexia compulsorily to hospital. The current consensus is that the thinner the patient the less rational they are, and that in lifethreatening situations the use of the Mental Health Act is justified. On the other hand, it is essential to help the patient move towards taking responsibility for her own illness, and a Section may militate against that. Many patients put on weight while in hospital but immediately revert to dangerous weight loss once they are back home. Anorexia nervosa is a very varied illness, with many different trajectories, making it difficult to generalize about prognosis. In general, the shorter the interval between onset of illness and treatment, the better the prognosis. Most studies suggest a 60-70% recovery rate within 5 years. The longer the period of illness the greater the mortality. Different studies have shown lifetime mortality of between 5 and 10%. Partial recovery is probably the best that can be hoped for in a chronic form of the illness such as that suffered by the patient described, whose symptoms had lasted for more than 15 years.
• The fear of losing control, both of eating and of sexuality, and a feeling of inadequacy and of not being a separate person are characteristic of the anorexic's inner world. Anorexia is an attempt by the individual to remain in complete control by regulating her food intake and her weight, and thereby putting her sexuality into reverse. • Family function in anorexia is often abnormal. The families (where food is frequently a central theme) tend to be 'enmeshed', i.e. mutually overdependent. This causes little difficulty in early childhood, but with the advent of adolescence the family may be threatened by the possibility of autonomy and separation. • Endocrine abnormalities occur in anorexia nervosa. Hypothalamic function is disturbed, with reduced luteinizing hormone (LH) and gonadotrophic hormone output, but this is more probably a consequence rather than a cause of weight loss. Low levels of plasma thyroxine and plasma TSH are also common. There may be alkalosis if there is surreptitious vomiting.
Clinical features
overweight, which may appal the girl, who then begins to pursue thinness. Her thoughts are dominated by food and how to avoid it. She absents herself from family meals, although she may pride herself on providing food for others, while secretly despising and envying those who eat normally or, as she sees it, gluttonously. As long as she is thin she will be happy. To be thin is to be good; to be fat, bad. She may augment her efforts at dieting by taking laxatives, amphetamines or diuretics, and by self-induced vomiting. Battles about food may develop with her parents. Denial of weight loss (p. 216) is an important feature: she may conceal her emaciation within voluminous and floppy clothes. She is physically overactive as part of her secret plan for weight loss. Sometimes, deliberately excessive exercise may be a major factor in the weight loss. She complains of a feeling of 'fullness' in her stomach which prevents her from eating. She will be emotionally and socially, but not intellectually, less mature than her peer-group. Physical examination will reveal thinness, scanty secondary sex characteristics, possibly peripheral cyanosis, a soft downy covering of the face and body (lanugo hair), hypotension and bradycardia.
8
Four features are characteristic of anorexia nervosa.
Differential diagnosis • The most important is phobic avoidance of normal weight. The patient is terrified by the idea of her normal weight. • With this goes a distortion of body image, known as overperception. By asking women to choose a silhouette that they feel represents their shape, it can be shown that it is normal for women aged 15-30 to perceive themselves as up to 50% fatter than they really are. Patients with anorexia nervosa see themselves as at least 100% bigger than they are: an emaciated girl of 35kg may be disgusted by what she perceives as her gross obesity. • The consequence of phobic avoidance and overperception is relentless dieting, especially the renunciation of carbohydrates. • Amenorrhoea is an essential diagnostic feature. In males (10% of all anorexics) there is disturbance of sexual function, usually with loss of libido. Anorexia nervosa usually starts in early or midadolescence. There is frequently an initial period of mild
SUMMARY 21 Features of anorexia nervosa • • • • • • • • • •
Phobic avoidance of normal weight Lanugo hair Hypotension Relentless dieting Denial, concealment Self-induced vomiting, laxatives Overperception of body image Excessive exercise Enmeshed families Amenorrhoea
The clinical picture may be one of two types: • In typical anorexia the only obvious psychological abnormality is the difficulty in eating. Here, the main differential diagnoses are organic causes of weight loss in a young woman, for example malabsorption syndrome, thyrotoxicosis or occult neoplasm. • An atypical picture also occurs. Here the woman is often older (in her 20s) and her anorexic symptoms coexist with other psychiatric features, such as depressive symptoms of misery and withdrawal; obsessional symptoms centring, for example, on cleanliness; and personality difficulties.
Management A patient weighing less than 35 kg should be admitted to hospital. A behavioural regimen in which the patient agrees on a target weight and is rewarded with privileges (watching television, being allowed visitors) in return for weight gain is usually effective in the short term. Occasionally a small dose of a phenothiazine (e.g. chlorpromazine 50 mg b.d.) is helpful. However, the patient will often lose weight again once she is discharged, unless psychotherapy is also started. Psychotherapy is the treatment of choice for outpatients. Mild anorexia can respond to simple counselling. In more severe cases family therapy is the best treatment for those under 17, whereas for older patients (especially if they have left home) individual psychotherapy is the preferred treatment. In each case, the aims of therapy are: • to maintain normal weight (body mass index 18-25) and a regular eating pattern. Some patients use therapy as a diversion from this central task;
241
to help both patient and family to move away from the area of food as a focus for all conflicts and difficulties; to help the patient accept herself as she is, in both her body and her feelings, i.e. to cope with the problems in living from which the eating disorder may have been a diversion as well as a cause.
SUMMARY 22 Treatment of bulimia nervosa • Keep a diary of everything eaten and all episodes of vomiting • Re-establish dietary control; eat three meals per day even if bingeing • Identify triggers to bingeing (anger, loneliness) • Challenge erroneous assumptions, e.g. 'If I eat a chocolate bar will become grossly obese and no-one will love me'
Prognosis Twenty-five per cent of anorexic patients recover spontaneously; 25% make a full recovery with medical intervention; about 25% continue to experience some difficulties with eating but can lead a normal life; and 25% remain quite severely handicapped. About 5-10% die of the condition. Poor prognosis is associated with later onset, 'atypical features' (see above), marked body image disturbance and self-induced vomiting. Recovery is accompanied by a reversal of the hormonal abnormalities and the onset of normal menstruation. 1
BULIMIA NERVOSA Bulimia nervosa is a syndrome of 'binge eating' (bulimia: to stuff oneself with food) and self-induced vomiting in the presence of normal weight. There is an overlap here with anorexia nervosa, where binge-vomit cycles can also occur, but in anorexia the patient is always abnormally thin and also amenorrhoeic. The usual age of presentation in bulimia also tends to be older, with patients (usually women) in the 20-30 age range, rather than the teens. The bulimic is frightened of becoming fat, but can accept her normal weight. She is terrified by her greed and tries to avoid its consequences by making herself sick. She normally feels deeply ashamed about this. She lives in a state of dietary chaos, in which she is determined to fast, succeeds for a while, then succumbs to hunger and starts eating. She binges, then feels guilty, makes herself sick and then starves; and so the cycle starts again. The physical consequences of bingeing and vomiting include erosion of dental enamel from exposure to gastric acid, Mallory-Weiss oesophageal tears, and even oesophageal rupture. Repeated vomiting causes hypokalaemia, which may in turn produce tetany, paraesthesiae, ileus, cardiac arrhythmias and epileptic fits. Bulimia is more common than anorexia: the prevalence rate in Europe and North America is 1-2%, compared to 0.5-1% for anorexia; 20% of women attending a family planning clinic admitted to bingeing, and 2% had the full syndrome. Like anorexia, bulimia may exist either on
1
242
MCQ 8.5
2
MCQ 8.6
its own, or as part of a general disturbance of personality, and be associated with alcoholism, deliberate self-harm or shoplifting, all of which make the prognosis less good. Treatment of bulimia nervosa is usually successful and involves helping the woman to re-establish a regular eating pattern, and to feel less guilty. The bulimic often feels a great relief when dietary control is re-established, unlike the anorexic, who feels threatened at the idea of giving up her own control. In addition to a cognitive-behavioural approach, exploration of the conflicts underlying the bulimia (such as marital difficulties or feelings of anger which the patient is unable to express) is also necessary. A proportion of bulimics have experienced sexual abuse in childhood, and this too needs psychotherapeutic exploration.
OBESITY Obesity in itself is not a psychiatric problem, but morbid obesity can be experienced as a severe handicap, comparable to amputation or disfigurement. Respiratory, endocrine and cardiovascular complications are common and serious, and gross obesity should, like anorexia nervosa, be considered a life-threatening condition. Obese people feel ostracized and experience self-disgust. They long to be 'normal' and may become depressed by unsuccessful efforts at dieting. There are often marital and family difficulties which are both a cause and a consequence of their obesity. The prognosis for weight loss, either by dieting or surgery (e.g. intestinal bypass) is not good. Psychotherapy can be a precursor to weight reduction if it helps the patient to accept himself as he is. The patient may then find it easier to diet, being less inclined to resort to the comfort of food whenever an emotional upset occurs.
FURTHER READING ON EATING DISORDERS Fairburn G C, Wilson G (eds) 1992 Binge eating. Guilford, New York. Schmidt U, Treasure J 1992 Getting better bit(e) by bit(e). Laurence Erlbaum, Hove Tiller J, Schmidt U, Treasure J 1993 Treatment of bulimia nervosa. Int Rev Psychiatry 5:75-86.
by doctors) and 'bad' ones (self-administered by addicts). This distinction does not take account of the fact that almost all drugs, even when medically prescribed, have harmful effects and can be misused: analgesics and tranquillizers are the best examples of this. Conversely, opiates can be of great benefit in the treatment of severe pain. Current definitions of drug dependence are based on the interaction between the individual and the drug, leading to a compulsion to take it:
8
• In order to experience its psychic effects, and/or • To avoid the unpleasant effects of its withdrawal (abstinence syndrome). There is no single cause of drug addiction. The prevalence of addiction is determined by:
FIG. 8.11 New and former addicts notified to the Home Office
• The availability of the drug. The greater the availability, the greater prevalence of addiction. In Hong Kong, where heroin is widely available, 8-10% of the adult male population is addicted. • The accessibility of the drug. This explains the relative commonness of drug addiction among doctors and nurses, and in inner-city and coastal areas. • The susceptibility of individuals to addiction or misuse. Management of drug addiction is equally multifaceted and involves a combination of physical, psychological and social rehabilitation.
DRUG DEPENDENCE Addiction to illicit drugs, especially opiates, is a source of widespread medical and social concern (Table 8.13) 2. There are several reasons for this. First, there has been an epidemic increase in opiate abuse over the past 50 years. In 1936 there were about 500 known addicts in the UK (of whom one-quarter were doctors); by the mid-1970s this figure had risen to 6000; and in 1988, following the introduction to the UK of cheap heroin, the number of known addicts was estimated to be at least 50000 (Fig. 8.11), of whom 9000 were registered with the Home Office. By the year 2000 this figure had reached 20000. Secondly, the impact of opiate addiction has profound medical and social consequences. Within 5 years of diagnosis 10% of addicts will have died from drug-related causes, including AIDS, hepatitis B and overdose. Thirdly, 'drug addiction' is a microcosm of a much wider social problem. Finally, there is increasing concern about the way that substance abuse complicates and worsens the prognosis of many psychiatric illnesses. For example, schizophrenia may be accompanied by, and sometimes be difficult to distinguish from, cannabis, heroin and/or amfetamine abuse, leading to a so-called 'dual diagnosis'.
Nature and causes of drug dependence In the past, definitions of drug abuse have concentrated on a contrast between the harmful and the beneficial effects of drugs, thus dividing drugs into 'good' ones (prescribed
OPIATE ADDICTION Causes The most important cause of opiate addiction is availability. Susceptible individuals expose themselves to the drug, either because they inhabit a subculture in which drug taking is prevalent, or because they are psychologically vulnerable owing to family difficulties, depression or boredom. The pharmacological features of opiates - tolerance and withdrawal syndrome - ensure the establishment of a habit, and social as well as physiological factors then maintain the addiction and make rehabilitation difficult.
Biochemical factors The discovery in 1977 of the encephalin neurotransmitters was a major advance in the understanding of opiate addiction. Endorphins are naturally occurring, opiate-like substances which mediate pain and other sensations in the midbrain. It is possible that individuals susceptible to addiction may genetically be deficient in endorphins and so 'opiate hungry'. Both opiates and endorphins reduce the amount and effects of other cerebral neurotransmitters, such as acetylcholine. This has led to the 'supersensitivity' theory of withdrawal syndrome, which postulates that addicted individuals have reduced amounts of transmitter reaching postsynaptic receptors. Stopping the drug then
243
TABLE 8.13 Addictions: Prevalence data Substance use is one of the major social and health problems facing society Illicit drugs • 23% of those aged 14-15 have taken an illegal drug in last year, 13% in last month, 29% of those aged 16-24 in last year, 14% in last month. • Known heroin addicts have increased from about 5000 in 1980 to about 50000 now, with growth continuing at about 20% per year. • The number of seriously problematic drug misusers in UK is estimated to be between 100000 and 200 000. • Amfetamine seizures have increased from about 3000 in 1987 to about 18000 in 1997. Cocaine use is also increasing rapidly. Alcohol • 41% of men aged 18-24 drink above recommended levels, but recent increase highest among young women (currently 25%). • Alcohol use increasing rapidly among schoolchildren - currently 5-10% 14-15-year-olds drinking more than recommended adult levels. • 51% of rough sleepers are alcohol dependent. • More elderly people are drinking above recommended limits - from 1984 to 1996 increase from 12% to 18% of men, and 3%-7% of women. Smoking • By 13 years, 19% smoking cigarettes daily. 29% of 16-19-year-olds are current smokers, 39% of 20-24-year-olds and 28% of all adults. Mortality • Between 1000 and 3000 drug misusers died as a result of overdose in 1998 in England and Wales (uncertainty relates to problems with current databases). Compared to the general population, mortality rates are higher among addicts (SMR = 7) • Injecting drug users have a mortality 12-22 times greater than their peers. Compared to the general population, suicide rates are high among addicts (SMR for males = 4.4; SMR for females = 11.3). • 25% of road accident fatalities have blood alcohol above 80mg%, 30% of pedestrians sustaining injuries. Illicit drugs are found in blood of 15-20% of drivers involved in fatal road accidents. • 40000 alcohol-related deaths per annum. • 120000 smoking related deaths per year in England and Wales. This accounts for 20% of deaths at all ages, and 25% of deaths between 25 and 35. Psychological and physical morbidity • 62% long-term injectors are positive for hepatitis C, and 52% for hepatitis B. About 80% of those positive for HCV will develop long-term infection, and 5% of those positive for HBV. About 20% of those with chronic infection will develop cirrhosis or liver cancer. Between 152000 and 228000 drug users in the UK are currently infected with HCV. • 10000 individuals seek help for their own or someone else's drinking problems each day. • 30-40% of hospital in-patients drink alcohol excessively. Alcohol is associated with heart disease, liver cirrhosis, cancer, neurological and gastro-intestinal problems. • 30-40% of substance misusers also have a psychiatric diagnosis. 60% of parasuicides are alcohol related. In a health district of 250000, 3000 problem drinkers will also have severe mental health problems. • Alcohol is strongly related to high-risk sexual practice, unwanted pregnancy and sexually transmitted disease. • Domestic violence, accidents and social disharmony: 30% of divorces, 40% of domestic violence, 20% of child abuse cases and 30% of domestic accidents are associated with alcohol misuse. Crime • 32% of proceeds of acquisitive crime is spent on heroin or cocaine. • The costs of drug-related crimes to the criminal justice system is at least £1 billion per year. Approximately 30% of prisoners are problem drinkers. 30-60% prisoners claim to have offended under influence of alcohol. 60% of those arrested test positive for drugs, 20% for opiates. Costs • The costs to industry of excessive alcohol consumption are estimated at £2330 million per year, as a result of unemployment, premature death and sickness absence. • Smoking costs the NHS approximately £1500 million per year. For a typical health authority this means £14 million per year, broken down as GP visits £2.5 m, prescriptions £1.5m, in-patient stays £3.2m, day-care £1.9m and outpatient visits £4.9m. Cost-effective treatments require proper training and specialist support • Many studies have shown that the treatment of opiate users saves much more money than it costs. • In North American studies it is estimated that for every $10000 invested in alcohol treatment, $30000 is saved by the managed care provider. • Smoking cessation interventions cost between $212 and $873 per life year gained, compared with £17000 as the median cost per life year gained of 310 common medical interventions.
244
results in a sudden increase in transmitter and stimulation of the already supersensitive receptor.
Psychological factors Drugs can be administered ('dropped') by injection ('fixing'), either subcutaneously ('skin-pop') or intravenously ('mainline'); or by smoking ('chasing the dragon'). All these methods are powerful reinforcers in the pavlovian sense:
TABLE 8.14 History and examination of suspected opiate abuser History Previous contact with a prescribing doctor or clinic History of recent use (doses, frequency, legal, illegal) Assessment of demands or requests Assessment of withdrawal symptoms Current legal problems
• Primary reinforcement from both the pleasure ('buzz') and the removal of withdrawal symptoms; • Secondary reinforcement from the associated rituals of administration, e.g. filling the needle; • Social reinforcement from fellow addicts.
Examination Injection sites: needle marks, tracks, bruises, thrombosed veins, abscesses, skin ulcers Arterial spasm or gangrene (caused by, e.g. dipipanone, cyclizine) Jaundice from hepatitis Emaciation
Psychiatric factors
Investigation Urine for drug assays Liver function tests Hepatitis serology HIV test (with consent)
Opiate addiction is more likely to be a cause than a consequence of psychiatric illness. 'Loners' may well be suffering from anxiety and depressive symptoms which they are trying vainly to treat with opiate drugs. Hospitalized addicts (as opposed to the generality of addicts) tend to be suffering from personality disorder and to have difficulty in forming close relationships. Addicts are caught in a vicious circle in which their primary relationship comes to be with the drug, which is felt to be more accessible, reliable and instantly gratifying than a person. There is some evidence that family discord and alcoholism are more common in the childhood histories of addicts than in controls. The anxiety associated with the early stages of opiate withdrawal may mirror early childhood experiences of separation from desired, but inaccessible, parents.
Social factors There is no particular social class preponderance for opiate addiction.
Presentation Addiction to opium and its derivatives, morphine and heroin (diacetyl morphine), can be considered as a model of drug addiction in general. The physical signs that should arouse suspicion of opiate abuse are listed in Table 8.14. Addicts present to doctors in one of four ways: • With infective complications of self-administered injections, e.g. septic abscess at injection site or septicaemia, infectious hepatitis or manifestations of HIV; • With confusion or unconsciousness due to drug overdose, either deliberate or accidental; • Wanting, or apparently wanting, help with their habit; • With a withdrawal syndrome. This consists of a craving for the drug together with physiological features, which include rhinorrhoea, lacrimation, yawning, perspiration, irritability, gooseflesh, nausea, diarrhoea, cramps,
8
muscle pains, tachycardia, flushing and involuntary movements. It is not life-threatening and the symptoms begin to recede about 72 hours after last taking the drug.
Management Legal requirements In the UK, any doctor attending a patient who is known or suspected to be addicted to opiates is required to inform the Home Office Drug Branch. Only specially licensed doctors are permitted to prescribe morphine and diamorphine (heroin) for the maintenance of addiction. Other opiates, such as methadone, may be prescribed by any doctor for the management of withdrawal syndrome, but this should be done only with great constraint and in an emergency. General management Drug abusers may not be open about their habit, which should be suspected in unexplained cases of psychosis, sepsis, serum hepatitis or HIV infection. Scapegoating should be avoided, and drug users should be treated with the same concern and courtesy as any other patient. At the same time, caution should be exercised: addicts may steal prescription pads and syringes, and exaggerate their drug needs in order to obtain drugs, which are then sold. In an initial interview a urine screen should be carried out to confirm that the patient is a user, and blood should also be tested for hepatitis serology and HIV (the latter normally with the patient's consent). Whenever possible, the patient should then be referred for specialist help. Occasionally
245
TABLE 8.15 A typical detoxification schedule for opiate addiction 10-day detoxification (volume kept at 25 ml)
28-day detoxification (volume kept at 25 ml)
Methadone 25 mg/day - 2 days 15mg/day-2days 8 mg/day - 2 days 4 mg/day - 2 days 2 mg/day - 2 days
Methadone 30 mg/day - 4 days 25 mg/day - 3 days 20 mg/day - 4 days 13 mg/day-3 days 10 mg/day-4 days 6 mg/day - 3 days 3 mg/day - 7 days
TABLE 8.16 Characteristics of methadone linctus which justify its use as a treatment • • • • •
Non-injectable Not attractive to users looking for buzz Low street retail value Controlled drug - able to be prescribed on daily collection Long half-life for established users, hence reliable urine testing and stabilizes drug-taking experience • If it does 'leak' from the drug service to the streets it is likely only to be used by established users for whom it is a safer preparation. Some of these will use purchased methadone for detoxification • As a linctus', consumption can be supervised if necessary
(e.g. in a casualty department at a weekend) withdrawal symptoms have to be treated and a dose of methadone given equivalent to the average daily intake which the doctor calculates is being used. The usual dose is between 20 and 70 mg of methadone. Typical detoxification schedules are given in Table 8.15. Where heroin intake is low, diphenoxylate and clomethiazole (chlormethiazole) can be used. Prescriptions should be on a daily basis for not more than 2 days. A clear management policy should be instituted and explained to the patient. Treatment of medical complications of addiction The main medical complications of addiction are septicaemia (p. 273), hepatitis (p. 846), endocarditis (p. 574) and HIV infection (Ch. 11).
Rehabilitation In the UK, all regions have drug clinics to which the addict should be referred. Here, the patient may be offered an oral methadone maintenance programme (Table 8.16) in the hope - not always realized - of reducing the use of illicit drugs. An attempt is made to form a rapport with the user. After establishing a baseline habit, some addicts will be gradually withdrawn from the drug over a 10-week period, either as an outpatient or, more rapidly, as an inpatient. Others will be stabilized on a maintenance methadone programme as a way of facilitating a period of stability in their life which reduces the need for crime and enables them to form a relationship with the drug clinic team. Withdrawal is an essential, but by no means sufficient, aspect of treatment. Addicts exposed to enforced abstinence, e.g. in prison, almost always relapse when released. Psychotherapeutic and social help is also needed if the addict is to remain drug-free.
FIG. 8.12 Changing patterns of consumption of non-opiate drugs in the UK A Prescriptions for sedatives/tranquillizers and hypnotics, 1974-1985. B Current benzodiazepine use and dependence in the UK. In one year, (A) 9-10 million people use benzodiazepines. (B) Of these, 3.2-3.5 million use them for more than 4 months and are at risk of dependence. (C) Of these, 0.64-1 million are likely to suffer withdrawal problems.
Benzodiazepines ADDICTION TO NON-OPIATES
246
Dependence on non-opiate drugs has become a major health problem in recent years. The changing pattern of dependence is shown in Figure 8.12.
Benzodiazepines have now replaced barbiturates both in popularity and as a cause for widespread addiction. Although the three million annual prescriptions cause less mortality than barbiturates (as they do not produce respiratory depression), they are an important source of mor-
TABLE 8.1? Symptoms of benzodiazepine withdrawal • • • • • • • •
Insomnia Anxiety Depression Outbursts of anger Muscular pains Tremor Headache Nausea, weight loss, anorexia
• Sweating • Tiredness • Perceptual abnormalities Visual disturbance Depersonalization Vertigo • Fits • Psychosis
bidity (see p. 216). There is an increased incidence of road traffic accidents in benzodiazepine takers. A withdrawal syndrome occurs in patients who have taken more than 20 mg daily over 6 weeks (Table 8.17). The symptoms of minor affective disorder (often self-limited), for which benzodiazepines are initially prescribed, may also then become part of a withdrawal syndrome, which can be mistaken for the original illness and lead to further prescriptions. Like barbiturates, benzodiazepines are best withdrawn in a slowly reducing dosage over several weeks. Antidepressants or even ECT (see earlier) may be needed to treat the depression associated with withdrawal.
Barbiturates Barbiturate addicts now comprise a small number of older patients (mostly women) who are relics of the barbiturate era, and a number of young multiple-drug users for whom barbiturates are one of a number of drugs in their repertoire. The effects of barbiturates are similar to those of alcohol, i.e. intoxication, ataxia and depression of consciousness. Respiratory depression due to overdose is a frequent cause of death. A withdrawal syndrome occurs in which convulsions are common. This should be controlled by pentobarbital (short-acting) 4-6-hourly. Withdrawal should be carried out slowly over several weeks.
Stimulants Amfetamines do not appear to cause physiological dependence, but produce a psychosis which is clinically very similar to paranoid schizophrenia. Symptoms abate within 2 weeks of withdrawal. Diagnosis is by urine screening. Treatment is by neuroleptics such as phenothiazines. Withdrawal from amphetamines often leads to a severe state of depression. Ecstasy, a synthetic amfetamine derivative, is widely used, especially at 'rave parties'. Fits, hyperpyrexia, renal failure and death may follow. Tactile hallucinations ('formication') are a feature of cocaine intoxication, which otherwise produces effects similar to amfetamines.
Removing the hydrochloride molecule from cocaine produces 'crack', which can be smoked rather than snorted. Crack is said to be the most powerful stimulant of all and produces profound depression and anxiety, and concomitant craving, following withdrawal.
8
Hallucinogens Hallucinogenic drugs such as LSD (lysergic acid diethylamide) and 'magic mushrooms' produce a toxic psychosis characterized by vivid hallucinations and delusions. Prolonged psychosis may be precipitated by LSD in susceptible individuals. 'Flashbacks' may occur for several months after an LSD 'trip'.
Cannabis Cannabis, like alcohol, appears to have few harmful effects if taken in moderation. Ten per cent of all young people have tried cannabis at some time, and 25% of students use it at least once a week. In some cultures and subcultures (e.g. Rastafarians) regular cannabis use, especially among males, is the rule. The active principle is tetrahydrocannabinol (THC), which is sometimes used as an antiemetic in terminal care. As with LSD, excessive use (or occasional use in susceptible subjects) produces a psychosis, and a withdrawal syndrome may occur. It has been suggested that regular use of cannabis may produce a state of apathy or amotivational syndrome.
Solvent abuse Inhalation of solvents such as toluene and acetone (used as vehicles for glue and other agents) produces a temporary state of euphoria. Glue-sniffing is common in certain youth subcultures. It is dangerous: an appreciable mortality has been recorded from direct cerebral damage, as well as asphyxia from the use of polythene bags to concentrate the vapour. Morbidity includes hepatitis, renal damage, cardiac arrhythmias, polyneuropathy and aplastic anaemia.
Drug screening Urine can be analysed for benzodiazepines, cannabis, amfetamines and opiates (but not LSD), and this is a useful test in cases of psychosis where drug abuse may be a possible cause.
ALCOHOLISM Alcohol is a major cause of medical and psychiatric morbidity in the UK (Table 8.18; see Table 8.13) and worldwide. In the UK, a 200% increase in alcohol consumption since 1950 (Fig. 8.13) has been accompanied by a 25-fold increase in admissions for alcoholism to psychi-
247
TABLE 8.18 Alcohol consumption and alcoholism in the United Kingdom (population 55 million) Alcohol consumption
Estimated numbers
Regular drinkers Heavy drinkers Problem drinkers Addicted drinkers
36m 2m 700000 200000
TABLE 8.19 Criteria of alcohol dependence • • • • •
More than 80 g of alcohol consumed daily Tolerance: blood alcohol levels greater than 150mg/100mL Withdrawal symptoms Continued drinking in spite of psychological, social, and physical problems Abnormal blood tests, e.g. macrocytic anaemia and raised y-GT
Definitions Some criteria for alcohol dependence are given in Table 8.19. Two important patterns of alcoholism require definition: problem drinking and alcohol dependence. Problem drinking The WHO defines alcoholism as drinking that causes emotional, social or physical damage to the individual. Problem drinkers may suffer from all three, e.g. anxiety or depression related to alcohol; divorce, unemployment or financial difficulties; and gastritis or physical trauma associated with drinking. Alcohol dependence The essential feature of alcohol dependence is the development of a withdrawal syndrome when the drug is removed. The dependent alcoholic will drink, usually early in the day, in order to stave off withdrawal symptoms such as nausea, tremor, sweating or agitation. Other features of alcohol dependence include: • Narrowing of the drinking repertoire. The ordinary drinker's consumption varies from day to day. The dependent alcoholic has a daily drinking routine that must be followed. • Predominance of drinking over other activities. For the alcoholic, drink, even if it is clearly damaging their life, comes first. • Tolerance. The capacity of the dependent individual to drink large quantities of alcohol is an expression of physiological tolerance.
FIG. 8.13 Trends in alcohol consumption and expenditure in the United Kingdom A Alcohol consumption 1910-1990. 00 Consumer expenditure on alcohol, 1965-1990.
248
atric hospitals. About 20% of admissions to medical wards are due to alcohol or alcohol-related diseases. Forty per cent of male attenders at hospital casualty departments have drink-related problems (p. 861). In 2000 40% of UK students drank above safe limits and 25% of the general population drank above safe limits.
Presentation: the hidden alcoholic Alcoholics have to be very ill or very brave to complain of their condition directly. Only about 10% of alcoholics in the community are in contact with psychiatric services, and about half are known to other agencies such as GPs, social services or parish priests. The remainder are unknown and untreated. Doctors need a high index of suspicion if they are to diagnose these hidden alcoholics correctly. The following factors should alert the examining doctor: • Unexplained gastrointestinal complaints • Complaints of anxiety and depression or panic attacks without obvious external precipitants
SUMMARY 23 Some presentations of undeclared alcohol abuse (should raise Index of suspicion') Psychological Memory lapses Depression Anxiety Outbursts of unprovoked anger Suicide attempts Morbid jealousy Paranoia Acute confusional state (DTs) Unpredictability
Physical Gastrointestinal symptoms Dyspepsia Pain Nausea Haematemesis Neurological symptoms Tremor Paraesthesia Muscular weakness Unexplained fits
Social Marital difficulties Problems at work Accidents at home or on the roads Delinquency, crime Violence
TABLE 8.20 The CAGE questions* • • • •
Have you ever felt you ought to Cut down on your drinking? Have people Annoyed you by criticizing your drinking? Have you ever felt bad or Guilty about your drinking? Have you ever had a drink first thing in the morning to steady your nerves or get rid of a hangover (Eye-opener)?
'Positive answers to two or more of these suggests a drinking problem.
Table 8.21 Factors associated with risk of alcoholism Factor
Examples of occupations affected
Availability of alcohol
Workers in the drink trade, caterers, business executives Coal miners, seamen, medical students, journalists Company directors, lawyers, GPs Commercial travellers, seamen, oil-rig workers, service personnel Coal miners, doctors, military personnel, actors Doctors, the unemployed Doctors, workers in the drink trade
Social pressure to drink
• • • • • •
Social difficulties, e.g. marital disruption, absenteeism Unexplained accidents Smelling of alcohol at unexpected times Single males over 40, socially isolated females Certain occupations, e.g. publicans, journalists, doctors Unexplained macrocytosis, or elevated liver enzyme values.
Where alcoholism is suspected, a detailed alcohol history should be taken. Vague questions such as 'How much do you drink?' are unlikely to be informative, but positive answers to two or more of the CAGE questions (Table 8.20) suggest a drinking problem. A detailed account of a typical 'drinking day' is required. Alcohol intake is measured in units. One unit equals half-a-pint of beer, a quarter-of-a-pint of strong lager, one 'short' or one glass of wine. Regular intake of six units or more per day puts men at risk of alcohol dependence. Women need half as much (i.e. three units per day) for half as long (e.g. as little as 2 years) for dependency to occur. The patient should be asked when he last had a day without a drink; about the longest period without a drink in the preceding 5 years; about withdrawal symptoms; and about blackouts. A 'drink diary', in which the patient records his drinking behaviour for a week, can be a useful aid to history taking. Raised serum y-glutamyl transpeptidase (y-GT) and increased mean corpuscular volume (MCV) are useful supportive evidence of abnormal drinking and are also helpful in monitoring progress. A blood alcohol concentration may confirm suspicions of recent excessive intake.
Aetiology Mutually interacting genetic, psychological and cultural factors underlie alcoholism. Adoption studies show that adopted children of alcoholics are four times as likely to develop alcoholism as are adopted children of nonalcoholics. The biochemical mediator of an inherited
8
Freedom from supervision Separation from normal social or sexual relationships Strains, stresses, and hazards High or low income Collusion by colleagues
tendency to alcoholism is unknown; however, active alcohol dehydrogenase leading to higher (and unpleasant) acetaldehyde levels has been postulated as protective against alcoholism. Psychological factors operate in two ways in alcoholism: • Imitation learning. An individual's tendency to drink follows that of his subculture, parents and peer group (Table 8.21). • Alleviation of unpleasant feelings. Alcohol reduces unpleasant feelings such as social anxiety and guilt. Each time an individual drinks, the experience of reduction of unpleasant mood ('drowning your sorrows') is reinforced. Family disruption is a common experience in the history of alcoholics. The true aetiology should be distinguished from the reasons for drinking offered by the patient, as the alcoholic's explanation of why he drinks is often a rationalization. The alcohol addict drinks because of his physiological state of addiction.
Physical complications The physical complications of alcoholism (see Chs 12,16, 24) include liver disease (Ch. 16), neurological syndromes (Ch. 24) (including peripheral neuropathy, cerebellar
249
CASE STUDY 8.4 A 50-YEAR-OLD FARMER WITH CONFUSION A 50-year-old separated farmer was brought to A&E by his neighbour because he had been acting strangely for 2 days and was saying things that did not make sense. He was unable to give a clear history, but it seemed that he had separated from his wife 6 months previously and had been living on the farm on his own, although she continued to visit by day to help with the farm work. He had a new girlfriend but she lived in a different part of the county and he felt he could not afford the petrol to visit her. He had no previous psychiatric history and denied illicit drug taking, but was a smoker and admitted to heavy drinking over the past few months. He had been eating poorly. His farm had been in the family since the 14th century, but times had been hard recently and he had had to diversify into holiday letting, and had sold his milk quota. On examination he was a well-built man with obvious signs of weight loss. He was dishevelled and confused. His speech was normal in form but rambling. He did not appear depressed. He believed that he was being spied on by some unknown power, and that his thoughts could be extracted from his brain. His level of attention and orientation seemed to fluctuate, but on systematic examination he was generally orientated although he got the date wrong. Physical examination was essentially normal, apart from the evidence of weight loss and slight generalized tremor and sweatiness. He was admitted to the psychiatric ward for further observation but almost at once appeared to fall and injured the back of his head, with extensive bleeding. He remained unconscious for several minutes. The emergency crash team was called, but his vital signs were normal and consciousness returned. He was very confused, complained of headache,
250
and on examination, although his pupils reacted equally to light there was weakness of elevation of the eyes, which was hard to evaluate as his cooperation with examination was poor. He became more lucid as the day went on, and was able to explain that he had been drinking a bottle or more of vodka a day for several months, but that he had decided to stop drinking some 5 days before admission, and confirmed that he had eaten little for several weeks. Later he had a grand mat fit.
Questions 1. What is differential diagnosis in this man's case? 2. What further investigations are needed? 3. What treatment, if any, should be instituted?
Discussion There are several diagnostic possibilities here. 1. The combination of delusional ideas with fluctuating consciousness makes this likely to be a confusional state ('acute brain syndrome') rather than a functional psychosis such as late-onset schizophrenia ('paraphrenia'), although at this stage no possibilities should be ruled out. 2. A first presentation of a psychotic illness in a 50-yearold man, accompanied by weight loss with a history of smoking, who then develops fits, should arouse the suspicion of organic pathology, such as a cerebral secondary tumour from a bronchial primary, or possibly cerebral non-metastatic manifestations of lung cancer.
3. The head injury was confusing: was his confusional state the result of the head injury and a possible subdural haematoma, or was some intracerebral pathology causing fits? 4. The history of heavy drinking, poor diet, sudden cessation of alcohol intake and possible eye muscle dysfunction makes alcohol withdrawal syndrome ('DTs') or even Wernicke's encephalopathy a distinct possibility - alcohol problems are common and 'common things commonly occur'. An emergency CT scan could help decide whether there was any intracerebral pathology - a haematoma or a tumour - although this investigation is difficult in such a restless and confused subject. Chest X-ray would eliminate the possibility of a lung primary. Liver function tests and haematology would help clarify whether there was any evidence of alcohol-related damage. Interviewing informants such as his ex-wife or girlfriend would help confirm and clarify the history - a good history is worth a thousand investigations in psychiatry. In the absence of any positive evidence of intracerebral pathology a presumptive diagnosis of DTs with possible Wernicke's encephalopathy was made. His confusional state coming on 5 days after stopping drinking, 'rum fits', and eye movement disorder were consistent with this diagnosis. He was given injections of parenterovite and started on a 'detox regimen' of reducing doses of carbamazepine, starting with 400 mg q.d.s. and reducing to 200 mg daily over a 5-day period. He made a good recovery and returned to his farm, determined to decide between his wife and girlfriend, to employ a neighbour to provide him with regular meals, and to abstain from alcohol.
degeneration, myopathy and convulsions), cardiomyopathy, pulmonary tuberculosis, anaemia, hypoglycaemia and pancreatitis. Children of alcoholic mothers may be born with a syndrome of low birthweight and developmental retardation known as the fetal alcohol syndrome.
Psychiatric complications There are three levels of severity at which psychiatric complications of alcoholism occur. In the initial stages the patient may present with minor psychiatric symptoms of panic attacks, anxiety, depressions or sexual difficulties. If withdrawn suddenly from the drug, the alcoholic addict is at risk for delirium tremens and sometimes alcoholic hallucinosis. Prolonged and severe alcohol addiction leads to alcohol-related dementia, including Korsakoff's psychosis (Ch. 24). Delirium tremens (DTs) is discussed on page 1438. Alcoholic hallucinosis Alcoholics may experience auditory hallucinations, usually derogatory or persecutory, in the presence of clear consciousness (consciousness is always clouded in DTs). These usually stop when drinking ceases but occasionally persist, suggesting coexisting schizophrenia. Morbid jealousy Alcohol is a frequent cause of a syndrome of morbid jealousy, in which an individual (usually male) becomes convinced that his spouse is unfaithful. Wernicke-Korsakoff syndrome (q.v.) and alcoholic brain damage are discussed in Chapter 24.
Management The outcome of treatment for alcoholism (Table 8.22) depends less on the nature of the treatment than on the social situation and personality of the patient. Addicts with a stable family and employment and a good personality do best. The impulsive or psychopathic drinker lacking home, family or job has a very poor prognosis for sobriety. The aim of treatment should almost always be abstinence. Any doctor who attempts to help alcoholics must be prepared for disappointment, as relapses ('slips') are common. A combination of limit-setting and acceptance is needed in all of the following treatment approaches.
TABLE 8.22 Outcome of treatment for alcoholism Outcome
1 year (%)
2 year (%)
Improved Still drinking Dead Lost to follow-up
35 45 1
25
19
21
51 3
Psychotherapy A supportive relationship, with either a spouse, a peer (e.g. through Alcoholics Anonymous) or a professional helper, is probably essential. Formal psychotherapy or social help should be conditional on sobriety, on the principle that whatever an alcoholic's problems (and they will be many), drink makes them worse. Wherever possible, the spouse and family should be included in any psychotherapy programme.
8
Inpatient treatment Brief admission for 'drying-out', or longer admission to a therapeutic community with group therapy, can help maintenance of sobriety. Patients who need admission are by definition more disturbed, and the long-term prognosis is therefore often poor. Drug treatment Disulfiram (Antabuse) reacts with alcohol to produce acetaldehyde, producing unpleasant feelings of flushing and nausea. Some patients find it helpful to have this internal 'chemical fence' to discourage drinking. Alcoholics anonymous Alcoholics Anonymous (AA), started in the 1930s by an alcoholic doctor ('Bob'), is a worldwide self-help organization for alcoholics run by ex-alcoholics. It offers a structured personal and group psychotherapy programme aimed at sobriety. An important feature of AA is that it provides a social life that is not based on pubs or drinking. A parallel organization, Al-Anon, offers support to the families of alcoholics. 'Shop-front'/'dry house' programmes The 'skid-row' alcoholic has usually lost everything - job, home, family, possessions, friends - through drinking, and special facilities are needed for this group of patients (about 10% of alcoholics). These include non-threatening 'drop-in' day centres, after-care hostels and long-term medical and social support.
Prevention There is a direct relationship between per capita consumption and the price and availability of alcohol. As the real cost of alcohol has fallen steadily in the UK over the past decade, so per capita consumption and hence alcoholism rates have risen accordingly (Fig. 8.11). Internationally, there is a direct correlation between the price of alcohol and the incidence of cirrhosis and other indices of severe alcoholism. Governments, through pricing policies and licensing laws, can have a direct effect on alcoholism rates. Well-funded education programmes are also needed to alert the public to the dangers of alcohol.
251
FURTHER READING ON ALCOHOLISM AND DRUG ABUSE Chick J 2000 Treatment of alcohol dependence. In: Gelder M, Lopez-Ibor J, Andreason N (eds) New Oxford textbook of psychiatry. Oxford University Press, Oxford Ghodse A 1997 Drugs and addictive behaviour. Blackwell, Oxford Heather N, Robertson I 1997 Problem drinking. Oxford University Press, Oxford Royal College of Psychiatrists and Royal College of Physicians 2000 Drugs: dilemmas and choices. Gaskell, London
MENTAL HANDICAP OR LEARNING DIFFICULTIES Mental handicap can be defined as the arrested or incomplete development of the cognitive (i.e. intellectual) part of the mind. Such a broad definition covers a wide range of individuals: • Severely mentally handicapped, who lack speech, are unable to learn, cannot dress or feed themselves, may be incontinent, and may have stereotyped movements such as rocking or thumb-sucking. The majority are looked after in institutions. • Moderately mentally handicapped, who have a considerable handicap (e.g. very restricted speech) but are able to live in sheltered accommodation in the community. • Mildly mentally handicapped, who have the capacity to learn and to live normal, if somewhat restricted, lives. Their primary problems are social and educational rather than medical. Most can live independently in the community.
MENTAL ILLNESS AND MENTAL HANDICAP It is only recently that mental illness and mental handicap have been properly distinguished. It is now understood that the majority of mentally handicapped people are not psychiatrically ill, and that they should be cared for by the social, rather than medical, services. Nevertheless, the mentally handicapped are particularly vulnerable to mental illness because of both their physical handicap and their emotional and social immaturity. They can develop the full range of mental illnesses, including schizophrenia, manic depression, anxiety states and hysteria. Distress is likely to be expressed behaviourally, for example through withdrawal, temper tantrums, compulsive masturbation or lawbreaking (e.g. shoplifting or self-exposure), rather than verbally.
• A single gene disorder, e.g. untreated phenylketonuria, tuberous sclerosis, mucopolysaccharidoses, untreated galactosaemia and Tay-Sachs disease; • Chromosomal, e.g. Down's syndrome, fragile-X mental retardation, deletion and duplication syndromes; • Traumatic, e.g. birth injury or anoxia. Here, the mental handicap is usually associated with spasticity; • Infective, e.g. maternal toxoplasmosis, cytomegalovirus and rubella; bacterial and viral meningitis. All may cause severe mental handicap; • Other causes include rhesus incompatibility, lead poisoning, and maternal drugs such as anticonvulsants or alcohol. Mild mental handicap usually lacks a specific inherited or environmental cause. It is thought to be a result of polygenie inheritance, often coupled with an impoverished environment.
AUTISM AND ASPERGER'S SYNDROME Autism is one of the most serious of the development disorders. It is characterized by 'autistic aloneness', in which the child is unable to make warm relationships; speech and language disorder, in which conversation as opposed to monologue may be deficient; an obsessive desire for sameness; and bizarre mannerisms. IQ is usually impaired, although the child often has artistic or musical abilities. The aetiology is unknown but is thought to be genetic, and possibly also due to perinatal minor brain injury. There is no known treatment that alters the condition, although individual psychotherapy has been claimed to have achieved remarkable results in some cases. The management usually consists of support for the family and special educational arrangements for the child. As in autism, in Asperger's syndrome there are marked impairments in social interaction, but the development of language and curiosity about the environment is normal. Sufferers usually show intense circumscribed interests or restricted repetitive stereotyped patterns of behaviour. The abnormalities persist into adult life, and most Asperger sufferers are 'loners', who are able to work but rarely able to sustain intimate relationships.
Management The principles of management of adult mental handicap are shown in Table 8.23.
Prevention CAUSES OF MENTAL HANDICAP 252
Moderate and severe mental handicap usually has a distinct cause. This may be:
Primary prevention is exemplified by rubella inoculation and the provision of lead-free paint. Secondary prevention is made possible by genetic counselling and by prenatal diagnosis and screening (see Ch. 3, p. 74).
TABLE 8.23 Principles of management of adult mental handicap • Accurate diagnosis • Treatment of coexisting mental and physical illness • Provision of training facilities, day centres, sheltered workshops and social clubs • Residential provision, e.g. hostels for those whose relatives cannot cope or are not available • Provision of emotional support for carers who, for example, worry about what will happen when they are no longer able to care for their mentally handicapped dependant
FURTHER READING ON MENTAL HANDICAP OR LEARNING DIFFICULTIES Bouras N 1994 Mental health in mental retardation. Cambridge University Press, Cambridge Matson J, Mulick J (eds) 1991 Handbook of retardation. Pergamon, Oxford
PSYCHIATRY AND THE LAW Mental illness may be associated with crime in one of three ways: • Psychosis. The most famous example of a crime being the result of a psychosis is the 19th century McNaughten case, in which a man who had tried to shoot the American President was acquitted 'by reason of insanity'. • Neurotic disorder. Depression, for example, may make a criminal act such as shoplifting more likely ('diminished responsibility'). • Psychopathic personality.
ANTISOCIAL PERSONALITY DISORDER People with an antisocial personality disorder may be described as those with persistent social difficulties (often, but not always, involving law-breaking) in the absence of a psychosis or neurosis. Their crimes, if they do occur, may be as trivial as repeatedly breaking shop windows, or they may be serious, such as murder. In the 19th century these individuals were classified as 'morally insane'; they were not deluded or hallucinated, but they appeared not to know right from wrong, or to be aware of the consequences of their actions. The term antisocial personality disorder is now used in order to avoid the derogatory connotations of 'psychopath'. The concept implies: • A persistent abnormality of interpersonal functioning, extending backwards to a childhood which was often disrupted and poor ('depraved because deprived');
• A major problem of social adjustment; • The absence of another psychiatric disorder.
8
An antisocial individual has trouble not just in relation to himself or to immediate family (although this usually does happen), but also to institutions such as the law, school, the armed services, employment and marriage. He is both dependent on institutions and unable to coexist peaceably with them. There is often associated alcohol and/or drug abuse. The dividing line between normal and abnormal is harder to draw in this than any other psychiatric category and it is not a diagnosis that should be applied lightly. It is also important not to make such patients scapegoats. Antisocial individuals sometimes benefit from psychotherapy (providing firm limits are set), and from help with the social consequences of their disorder, such as homelessness and unemployment.
Dangerousness and risk assessment Psychiatrists are often called upon to assess the dangerousness of an individual so that decisions can be made about whether he should be allowed to live freely in the community. Assessment of dangerousness, which cannot be an exact science and will always to some extent be dependent on clinical judgement, rests on two main criteria: • Past behaviour. Violent or law-breaking behaviour in the past is the most reliable predictor of future trouble. A very careful history, taken in an atmosphere of trust, is essential if this is to be reliably assessed. • Psychological understanding of the causes of specific episodes of violence. Unless caused by organic factors such as epilepsy, violence rarely, if ever, emerges out of the blue. There are always antecedents and triggers that can be identified and which constitute a psychological explanation for the violent episode. These can best be elucidated by reconstructing a detailed 'action replay' of the events leading up to the episode. Thus many people resort to violence when they feel cornered, threatened, or are made to feel inadequate. Substance abuse often plays a major part in lowering thresholds to violence. Risk can be reduced if these factors are known, and steps can be taken to avoid them; conversely, situations likely to increase the likelihood of violence can be identified.
MENTAL HEALTH LEGISLATION Psychotic patients lack insight and may occasionally be dangerous, either to themselves or to others. In the UK, until the 1930s nearly all psychiatric inpatients were legally detained in hospital. Today, less than 10% of patients are detained on a 'Section'. Although compulsory admission is sometimes necessary for the protection of the patient and the public, this power is open to misuse or even abuse. The
253
CASE STUDY 8.5 APPLICATION OF THE MENTAL HEALTH ACT TO A 45-YEAR-OLD MAN WITH HYPOMANIA A 45-year-old man was brought by his son to the accident and emergency department at 11.30 at night. The history was that since losing his job recently he had not slept for several days, had run up huge debts on his credit cards, and had become irritable and aggressive, so much so that his wife had temporarily moved out of the family home. He was complaining of a headache and his son, who was at his wits' end, had persuaded him to come to the hospital to have it investigated. On assessment there was no previous history of formal psychiatric disorder, although he had been prone to mild episodes of depression and withdrawal. Physical examination revealed no abnormality. He was restless, spoke rapidly without sticking to the subject, and was hard to interrupt. He appeared to have no insight into his situation and repeatedly demanded to leave. The provisional diagnosis was hypomania. The junior psychiatrist was worried about him, and felt that he needed further psychiatric assessment. Not surprisingly, he refused the offer of informal admission to hospital. Arrangements were therefore made for him to have a formal mental health assessment. This involved assembling a consultant psychiatrist (who was approved under Section 12 of the 1983 Mental Health Act), a mental health-approved social worker and his GP. During this time the patient was insisting on leaving, but with the help of psychiatric nurses he was distracted enough to stay. Eventually the assessment team arrived, he was duly put on a Section
254
for assessment and admitted, with much protest, to the psychiatric ward, with a diagnosis of hypomanic disorder.
Questions 1. Under what powers can patients be held in hospital against their will? 2. What safeguards are there for both patient and doctor in this situation? The law requires that a strict procedure be followed if someone is to be deprived of their liberty under the Mental Health Act. There is often a period prior to bringing that procedure into play in which the patient may need to be restrained. The legal safeguard here is 'common law', i.e. the right (and duty) of a citizen to protect an individual from causing harm either to others or to himself. In this instance the patient was clearly in danger of harming others or himself. His aggression had resulted in his wife having been physically hurt; equally, he was likely to provoke others to hurt him; his financial profligacy (a typical symptom in hypomania) was also self-injurious. His headache was unexplained, and he needed investigation and overall assessment as well as restraint. Following the mental health assessment he could be given appropriate treatment - in this case tranquillizing drugs such as haloperidol - and if he refused to take them forcible administration was
United Kingdom Mental Health Act of 1983 (currently under review) aimed to provide safeguards against such abuse, and the Sections of the Act of particular relevance to general physicians are described below. In all cases it is a duty of the hospital administration to inform the patient of his Section, and a statutory right of the patient to appeal against compulsory detention.
permissible (although this is rarely necessary). The assessment procedure could begin in a safe environment. The 'Sectioning' procedure involves a clear reading to the patient of his 'rights' including the right of appeal against the Section, to be heard by independent experts in as short a time as possible. In this case the full mental health assessment team had to be brought together. However, had the patient already been formally admitted to hospital the junior psychiatrist would have had the right to impose a 'Section 5.2' on the patient, giving the staff the powers to hold him against his will for up to 72 hours, until a formal assessment could be mounted. Thus the combination of the 'common law' provision, with rights of appeal, gives both doctor and patient some safeguards. The Section 2 imposed on the patient was in fact lifted some 2 weeks later as his clinical condition improved, his insight returned, and he could begin to see that he needed help. Had this not happened, the Section 2 would have expired by the end of 28 days, and were he to have needed further restraint a 'Section 3' treatment order would have been needed. The rules of appeal apply equally to this procedure. The Mental Health Act is currently under review in the UK. It is likely that any decisions about detention for longer than 28 days will be taken out of the immediate hands of clinicians altogether, and referred to a mental health panel comprising an independent psychiatrist, a lawyer and a lay member.
Admission for assessment (Section 2) The patient may be detained for up to 28 days if (a) he is suffering from mental disorder which warrants assessment; or (b) he is a danger to himself or others. The application for such assessment must be made by a social worker or the patient's nearest relative. There has also to be a medical
recommendation from two medical practitioners. One of these must be a doctor officially approved as having special psychiatric experience ('Section 12' doctor, often a consultant psychiatrist); the other should, if possible, have known the patient previously (and is thus usually the patient's GP). In an emergency the patient may be detained for up to 72 hours (Section 4) on the basis of only one medical recommendation, which need not necessarily be by a psychiatrist.
detained patients can still be treated without their consent (e.g. given ECT or phenothiazine drugs), but a second opinion must first be obtained from a doctor appointed by the Mental Health Commission. Patients may not undergo psychosurgery (a brain operation occasionally undertaken in cases of depression or phobic anxiety) if they do not consent to it. Even if they do, a doctor and two nonmedical appointees of the Mental Health Commission must scrutinize the case to ensure that consent has been validly given.
8
Admission for treatment (Section 3) The patient may be detained for up to 6 months. The conditions of the application and recommendation are therefore more stringent, and the rights of appeal greater than under Section 2. The patient must have a defined mental disorder, be thought likely to improve, and be unable to be cared for within the community. Section 3 can be extended for a further 6 months, with the approval of an independent tribunal.
Emergency detention of patients already in hospital (Section 5) An informal patient may be held in hospital for up to 72 hours on the recommendation of the doctor in charge of his treatment without a Section 2 or 3 being instituted. Under Section 5(4), a psychiatric nurse can detain an informal patient already being treated for mental illness for up to 6 hours. Under Section 5(2) a patient in a general hospital who is being treated by a non-psychiatrist can be detained, under the report of the doctor in charge of the case (the 'responsible medical officer' RMO), for up to 72 hours. A psychiatrist should see the patient as soon as possible to decide whether further detention is needed. Section 5(2) cannot be renewed.
Powers of the courts (Sections 36, 37, 38) Under these Sections, mentally ill offenders can be compulsorily admitted to psychiatric units for assessment and treatment, rather than going to prison.
Place of Safety Order (Section 136) Police officers have the power to remove to a place of safety any person whom they find in a public place who appears to be suffering from mental disorder and who is in immediate need of care and control for his own sake or that of others. Once removed, the patient must be medically examined and assessed. The place of safety is often a police station, but may also be a hospital A&E department.
Consent to treatment (Sections 57, 58) An important feature of the Act is a tightening of the procedure surrounding consent to treatment. Compulsorily
FURTHER READING ON MENTAL HEALTH LEGISLATION Faulk M 1994 Basic forensic psychiatry, 2nd edn. Blackwell, Oxford Gunn J, Taylor P 1993 Forensic psychiatry: clinical, ethical and legal issues. Butterworth-Heinemann, Oxford
MEDICINE AND THE EMOTIONS There are two basic types of mental activity. One is pictorial, non-rational and emotional, and concerns the biological fundamentals of birth, attachment, sex, separation and death, as well as art and creativity; the second is rational, verbal and logical and concerns the achievement of specific goals and the solving of particular problems. Freud called these the primary and secondary processes. Non-rational thinking is primary because it precedes rational thinking developmentally: infants and young children think in feelings and pictures. The secondary processes are only gradually acquired. In healthy adult life both coexist. Much of waking life is dominated by secondary processes, but in dreams, daydreams and instinctual activity the primary processes take over. In mental illness the balance of primary and secondary processes may be disturbed: the psychotic, for example, is dominated by primary processes, whereas the patient with obsessional neurosis is trying to apply the false logic of secondary processes to his emotions. Modern medicine is based on scientific rationality. This means that at times doctors may find it difficult to comprehend the emotional reactions of the patient to illness, death or sexuality. For the doctor, the patient who needs a routine hernia operation presents a technical problem to be solved; the patient, however, may at some level be wondering whether he will survive the operation and, if so, whether his sex life will continue. Medical training is predominantly a training in rationality, in learning to set feelings aside. In order to understand the 'irrational' anxieties that trouble patients the doctor has to remain in touch with and respect the primary processes. The following sections on sex, and on death and dying, highlight some of these issues.
255
SEX AND MEDICINE Sex matters for three main reasons: identity, attachment and continuity. Sexual abuse in childhood threatens all three and is an important underlying cause of psychiatric disturbance.
Identity Gender is fundamental. When a baby is born the mother asks 'Is it alright?', then 'Is it a girl or a boy?'. Gender is integral to a sense of identity, and this can be threatened by illness at any of the stages of development. Hypospadism, hirsutism, hernia, delayed puberty, amenorrhoea, infertility, hysterectomy, prostatectomy, diabetes-related impotence are just a few of the many medical conditions that may threaten the sense of identity that is rooted in gender and sexual functioning.
Attachment Human attachment occurs through the body. Even when communication is at a distance, hands are, needed to write a letter, a voice to speak on the telephone. Sexual bonding is a powerful and rewarding form of attachment. The adolescent worries whether his or her body is 'good', 'big' or attractive enough to find a partner. Where sexuality is threatened by illness and disability, the patient fears that the basis of his or her attachment may be undermined: 'Who will want me i f . . . I have a colostomy ... a mastectomy ... am impotent... ?' Psychogenic symptoms such as lower abdominal discomfort, pruritus or back pain may both arise from and lead to sexual difficulties. Such symptoms may draw attention to an underlying sexual anxiety, and at the same time provide the patient with the care and attention that he fears may be lost through sexual failure. Occasionally, guilt about masturbation may be based on the misconception that it is 'wrong' or harmful, and this too may lead to psychogenic symptoms.
Continuity Psychologically, sex and reproduction may serve as an insurance against the fear of extinction. The idea of personal death is more acceptable if there is family continuity, or if an individual feels he has contributed something: that children, memories, ideas or objects will live on in the next generation. Threat to this sense of continuity can lead to feelings of anxiety or depression.
1
256
MCQ 8.7
TABLE 8.24 Common anxieties about sex Adolescence Masturbation Homosexuality Genital inadequacy Young adults Impotence Anorgasmia Infertility Lack of libido
Middle-aged Extramarital affairs Sex and illness Any age Incest Fetishism Non-consummation of marriage
Taking a sexual history Sex, at least in theory, is no longer a taboo subject, but in practice both doctor and patient are likely to feel anxious about some aspects of their sexuality. It is important that the doctor feels reasonably comfortable when asking about a patient's sexual life. All human beings have a sexual life - in the sense of thoughts, fantasies and feelings about sex - regardless of whether or not they are celibate. The doctor needs to be sensitive to the common anxieties about sex and to be aware of those that may apply to a particular patient's age and situation (Table 8.24).
SEXUAL AND MARITAL DIFFICULTIES Divorce and family disruption are becoming increasingly common. More than one in three marriages in the UK now ends in divorce; in the USA the figure is one in two. There is good evidence that in general marital disharmony and divorce are psychologically damaging for children, who are more likely to have emotional disorders in adult life and to underachieve academically than their counterparts from stable families. Nevertheless, single mothers and even same-sex parents are capable of providing a loving and nurturing environment for their children. Partly in response to this, there is now great interest in marital and family therapy. The commonly encountered sexual difficulties are impotence, premature ejaculation and delayed ejaculation for men, and vaginismus and lack of sexual enjoyment (including anorgasmia) for women. Both sexes may suffer diminished libido. Transient difficulties are common; it is only when they are persistent and cause distress that they constitute a problem. Sexual problems may be primary, i.e. present from the onset of sexual life, or secondary, i.e. developing after a period of satisfactory sexual functioning.
Erectile dysfunction This can be defined as the inability to achieve an erection sufficient for satisfactory sexual intercourse.
Aetiology Contrary to popular belief, as many as 50% of cases of impotence are organic in origin. Where impotence is psychologically based, it arises out of anxiety. This may be in the context of an episode of anxiety/depression, or as a manifestation of personality disorder. Organic causes include: • Endocrine causes, such as hypopituitarism and hypogonadism • Diabetes. At least 30% of diabetic men experience impotence by the age of 50 • Vascular disease, such as Buerger's disease • Alcoholism • Drug induced, e.g. diuretics, p-blockers and neuroleptics.
•
•
•
Treatment • If psychogenic, the Masters and Johnson approach outlined below is normally effective. • The underlying cause should be treated whenever possible. • Symptomatic treatment: - Intracavernosal injections of papaverine, papaverine plus an a-blocker such as phentolamine, or alprostadil (prostaglandin E2) can be self-administered and are effective in up to 70% of cases. The main danger is priapism, and erections lasting more than 4 hours should be treated as an emergency, with venous aspiration together with a vasoconstrictor. The drug Viagra is a significant advance over these cumbersome measures. In the presence of sexual desire and stimulation it produces good erections that have a more 'natural' quality. - Mechanical aids such as a vacuum condom are also useful in some cases. The Masters and Johnson approach Current thinking about sexual dysfunction has been greatly influenced by the work of Masters and Johnson, who studied the physiology of sexual response and introduced a new classification and treatment for sexual difficulties. General principles of the Masters and Johnson approach include the following: • Treatment is in couples. Sexual difficulties are often complementary (e.g. premature ejaculation and an-
SUMMARY 24 The Masters and Johnson approach • • • • • •
Treatment in couples Physical examination/history-taking (to reassure they are 'normal') Instruction in sexual arousal Instruction initially not to make love (to dispel anxiety) Graded exercises based on 'sensate focus' Psychotherapy if necessary
•
•
orgasmia), even though one member may present as the person with the problem. The non-presenting partner is given the role of co-therapist. Physical examination and careful history-taking of both partners are required both to rule out organic causes of sexual dysfunction and to reassure the patients that they are 'normal'. There is more to sex than penetration. Sexual arousal, especially in women, depends on a series of steps, arid a man may need to learn that foreplay cannot usually be omitted if his partner is to be fully aroused. Anxiety is seen as a central element in sexual dysfunction. Anxiety is antagonistic to sexual arousal, and a vicious circle can arise in which the patient fears they will fail (for example to maintain erection, not to ejaculate prematurely, or to have an orgasm), which makes them 'try' harder, which makes them less able to relax and respond to sexual stimuli and thus more, rather than less, likely to 'fail'. The aim of treatment is to break this circle. Paradoxically, the couple are initially instructed not to make love, in order to prevent performance anxiety. They are given a series of graded exercises based on sensate focus or stroking, in which they learn to give and receive pleasure. Initially this is non-genital, but later moves on to 'genital sensate focus', i.e. mutual masturbation. It is ironic that whereas masturbation was viewed (wrongly) by 19th century psychiatry as a major cause of insanity, it is now considered important that both sexes are able to masturbate without guilt. Psychological factors in sexual dysfunction may also need treatment, through either individual or marital therapy. Unexpressed anger is a common cause of sexual disharmony: a couple who cannot row may also not be able to make love. Fear of loss of control, ignorance or guilt may also affect sexual pleasure.
8
The results of the Masters and Johnson approach are generally good, with 60-70% improvement rates reported in well-motivated couples. 1
FURTHER READING ON SEX AND MEDICINE Hawton K 1985 Sex therapy: a practical guide. Oxford University Press, Oxford Hawton K 1995 Treatment of sexual dysfunction by sex therapy and other approaches. Br J Psychiatry 167:307-314
DEATH AND DYING Death is an integral part of medicine, but doctors and other medical staff often feel confused by the psychological and ethical questions it poses. Should a terminally ill patient be kept alive as long as possible, or allowed to die in peace? Should every patient with a fatal illness be told of his diagnosis, and if so how should they be told? Can a dying
257
patient be helped to come to terms with death, and how can this happen? What are the psychological reactions in the relatives of dying patients, and what support do they need? These questions are problematic not only because of a lack of training and technique, but also because death is an intrinsically difficult subject which all but the exceptionally compassionate find hard to face. Patients and doctors alike deny the reality of death in order to carry on with life.
REACTIONS IN THE PATIENT The response of the patient to the knowledge that he has a terminal illness can be compared to a bereavement reaction. The patient enters a state of grief for the loss of his own life. The initial reaction is usually one of numbness and shock, a struggle between denial and acceptance. The patient attempts to fight off what is happening and cannot believe it is true, that it is happening to him. This is often followed by a period of severe anxiety, in which the patient becomes dependent on visitors, family and medical staff, and finds it very hard to be alone. A period of sadness and weeping is inevitable. Anger is also a normal feature of this phase, and the patient may become difficult, complaining, ungrateful and demanding. With time, however, the patient gradually becomes calmer, and during this phase the opportunity to talk may be very helpful. This series of reactions may be compressed into a few hours or spread over months, and, as with bereavement, does not follow a neat, orderly course.
TALKING TO DYING PATIENTS Breaking bad news and talking to dying patients is an art that can be learned through watching others, and through discussion of the feelings and difficulties it arouses. The patient can often be helped if staff and family recognize the subsequent reactions for what they are and then let the patient talk about his anger, panic and sadness. When this has happened the patient may feel better.
258
SUMMARY 25 Emotional reactions in terminally
ill patients • • • • • •
Numbness and shock Struggle between denial and acceptance Severe anxiety Sadness and weeping Anger Eventual calmness
The issue of 'to tell or not' is a false alternative. Some patients want to know their diagnosis in great detail; others would rather not know. It is unnecessary and inappropriate to confront all patients with the stark reality of their illness. On the other hand, far more patients than are officially 'told' want to know their diagnosis or know it already. The patient needs space and time in which to discuss his feelings and ask questions. Gentle probing may be needed to help the patient make use of this opportunity.
REACTIONS IN THE FAMILY Like the patient, families also go through an anticipatory grief reaction when a loved one is dying. The death of a child or adolescent is especially painful and unsupportable. Spouses of dying patients are particularly vulnerable. They may, for example, feel angry with their husband or wife for being ill, and feel very guilty about having such unvoiced thoughts. The stress of death may lead to tense and angry outbursts, either within the family or outside it at medical staff. Doctors and nurses should be prepared for this. Family counselling can help with these grief reactions and help to make death and bereavement, when they come, more bearable.
FURTHER READING ON DEATH AND DYING Holland J, Rowland J (eds) 1990 Handbook of psycho-oncology. Oxford University Press, Oxford
9 Infectious, Tropical
and
Parasitic Disease Mark H Wansbrough-Jones and Stephen G Wright
The relationship between humans and microorganisms 259 Principles of diagnosis and management 261 Antimicrobial agents 262 Infection in the immunocompromised patient 269
Rickettsia 305 BACTERIAL INFECTIONS 307 Gram-positive cocci 308 Gram-negative cocci 310 Gram-positive bacilli 311 Gram-negative bacilli 315
Control of infection 271
Mycobacteria 325
Syndromes of infection 273
Spirochaetes 329
VIRUS INFECTIONS 283
Actinomycoses 330
Enveloped double-stranded DNA viruses 283
Madura foot 331
Enveloped single-stranded DNA viruses 289 Non-enveloped double-stranded DNA viruses 290 Enveloped single-stranded RNA viruses 290 Non-enveloped single-stranded RNA viruses 302 Non-enveloped double-stranded RNA viruses 303 CHLAMYDIAL, MYCOPLASMA AND RICKETTSIAL INFECTIONS 303
Nocardioses 331 SYSTEMIC MYCOSES 332 PROTOZOAL INFECTIONS 335 Protozoal infection of the gut 335 Genital tract protozoa 342 Free-living protozoa causing human disease 342 Non-pathogenic gut protozoa 343
the upper hand, particularly over children. Worldwide, infectious gastroenteritis is the most common cause of death in children under the age of 1 year. The causative organisms are similar in underdeveloped and western countries, but in the former there is more frequent exposure from water supplies, methods of food preparation and poor standards of hygiene, including sewage disposal. The outcome is worse because of the severity of dehydration. Table 9.1 shows how the frequency of some infections varies in different areas of the world. The figures illustrate differences attributable to climate (malaria), standards of hygiene (typhoid) and immunization (poliomyelitis, measles and diphtheria). The mortality associated with these diseases is also higher in underdeveloped countries because of a poor nutritional state at the onset of illness and limited access to medical facilities. The pattern of infections is constantly changing. Infectious diseases become less important as a cause of death as the standard of living improves. England in 1860 was much the same as parts of Africa and southeast Asia today with respect to some infectious diseases (Table 9.2). Improvements in standard of living and immunization account for the change in many of these diseases, but sometimes the pathogen itself changes in virulence. Scarlet fever (scarlatina) is no longer the feared disease it was 50 years ago because erythrogenic toxin-producing streptococci have become less virulent. Changes in microorganisms may produce little change in the clinical disease but are of no less significance. The type of meningococcus most commonly incriminated in bacterial meningitis in the UK has for many years been group B, but recently there has been a resurgence of group C infections. Meningococcal vaccine will protect against group A or C infection, but group B meningococci are poor immunogens. Similar antigenic variation occurs repeatedly in influenza virus. Most of the changes in the pattern of infections are gradual. New infections are extremely rare but can have an enormous impact; an example is human immunodeficiency virus (HIV), the cause of the acquired immune deficiency syndrome (AIDS). All of the infections encountered in temperate and developed areas of the world will be found in tropical regions. Certain infections are exclusive to the tropics because of climate, and the presence of animal reservoirs and insect vectors.
Tissue and blood protozoa 343 HELMINTH INFECTIONS 358 Nematodes 359
Chlamydia 303
Trematodes 370
Mycoplasmas 305
Cestodes 375
The relationship between humans and microorganisms is usually one of balanced conflict. In the first months of life encounters with microorganisms are both a threat and a stimulus to the development of complex immune responses. In many parts of the world microorganisms appear to have
THE RELATIONSHIP BETWEEN HUMANS AND MICROORGANISMS Microorganisms that can cause disease in humans are widely distributed in nature, and humans are colonized by vast numbers of organisms. Whether a particular organism causes disease is determined by its natural distribution, its pathogenicity, and the state of the host defence systems. With common pathogens it is likely that immunity will develop early. The age at which this occurs can influence the outcome of infection. At extremes of age the immune
259
TABLE 9.1 Cases of infection reported to WHO from different geographical regions and countries Region or country Americas (all) USA* Europe
Malaria (1993) 984000 1217
50000
Poliomyelitis (1995)
Measles (1994/5)
Typhoid (1980/1)
Diphtheria (1994/5)
0
22988
42160
0 202
286
324
73729 23594
75203
245379
28418
1420 3791
7810
708
0 49483
312
Africa
2590000
643 411
S.E. Asia
3077000
2269
106773
329980
674000
226
110776
145
614
0
7763
265
13
E. Mediterranean
W. Pacific England and Wales
292000
1992
(Data supplied by Communicable Diseases Surveillance Centre, Colindale.) All figures are to nearest 100. *AII figures for USA are for 1995. AII figures for England and Wales are 1995 (except malaria - 1993)
TABLE 9.2 Deaths from infection in England in 1800 fall age groups) Cause
Number
Measles Scarlatina (scarlet fever) Smallpox Diphtheria Typhus Whooping cough Cholera Tuberculosis
9557 9 681 2749 5212 13012 8553 327 58564
system is either immature or in decline, and the patient is highly vulnerable. Paradoxically, during childhood many viral infections are silent or mild, but the same infection in an adult may be severe and complicated. This may reflect a difference in the vigour with which inflammatory responses are generated.
PATHOGENICITY
260
Microbial pathogenicity - that is, the potential of a microorganism to cause disease - is determined by its ability to enter the host and colonise, to penetrate tissues, to evade host defences and to damage tissues. The virulence of an organism is its degree of pathogenicity. An organism is described as highly virulent if a small number of microbes can cause severe disease. Skin is an effective barrier to most organisms and they usually enter either through a breach or via more delicate mucosal surfaces, such as those of the oropharynx and respiratory tract. Attachment to the cell membrane is essential for viruses, and bacterial colonization is also often facilitated by a specific attachment mechanism. Examples are Vibrio cholerae or Escherichia coll in the intestine, and
E. coli in the urinary tract. In each case a determinant on the bacterial surface interacts with a specific receptor on epithelial cells. Some pathogenic organisms cause disease at the site of colonization by producing toxins (V. cholerae),but most traverse the epithelium and their further success depends on their ability to avoid host defences. In the first encounter between human and organism innate immunity is the only defence. In the case of bacteria this centres on phagocytosis, and some bacteria are equipped with capsules that confer resistance to phagocytosis. Interferons play a major part in first-line resistance to viruses, but viruses differ both in their ability to stimulate interferon production and in their susceptibility to its effects. The mechanisms of disease provoked by bacteria are complex, but a distinction can be made between effects caused by exotoxins (tetanus or diphtheria toxins, for example) and those resulting from release of bacterial components such as endotoxins.
SUSCEPTIBILITY TO INFECTION
The effects of even virulent microbes are curtailed by an immune response. Infections therefore typically result from a small number of identifiable situations: • First encounter with a virulent organism, in sufficient numbers, entering by an appropriate route; • Breach of normal anatomical barriers, e.g. by surgery, injury or indwelling lines; • Impairment of innate immune responses; • Impairment of adaptive immune responses. When anatomical barriers are breached by surgery, tissues that are usually sterile are exposed to normal microbial flora at the adjacent site. Similarly, accidental injury often results in exposure to environmental organisms, such as Clostridium tetani present in the soil. Impairment of immune responses leads to susceptibility to infection by organisms of low pathogenicity as well as
9
FIG. 9.1 Incubation periods and periods of communicability of common infectious diseases
to virulent organisms. Infection by organisms of low pathogenicity is called opportunistic. Patients with impaired immunity may therefore present with frequent infections, infection caused by opportunist microorganisms, unusually severe disease caused by infection, or repeated infection by the same organism.
• Incubation period: time from contact with microorganisms to onset of symptoms (Fig. 9.1) • Prodromal illness: minor symptoms preceding the definitive illness • Overt disease • Resolution (convalescence).
This approach will often lead to a simple management plan. It may also be necessary to establish the source in the community. In some cases the doctor has a legal obligation to notify the disease (see Control of infection, p. 271).
This pattern is often influenced by the immune state of the patient and may be altered by drug therapy. Some symptoms, such as sore throat and fever, are more commonly associated with infection than with other disease processes. The pattern of fever may be helpful, but patients may say that they have had a fever when they have not measured their temperature. They may mean aching in the limbs, sweatiness feeling hot or cold, shivery, or true rigors. Of these, a rigor is a good indicator. This is a sensation of coldness accompanied by shivering (associated with a rise in temperature) followed by a hot sensation and marked sweating. Although no one symptom is specifically associated with infection there are many symptom complexes that are highly suggestive of an infective aetiology. For example, although headache has many causes, the combination of headaches with fever, photophobia and vomiting strongly suggests infection of the meninges (meningitis).
Is the disease caused by infection and, if so, where is the site of infection?
Examination The findings on examination may be helpful in three ways:
A careful history and examination will provide important indicators that the patient is suffering from infection.
• Some infections are associated with signs that are specific or which suggest only a short list of differential diagnoses. Examples are the rash of chickenpox or measles, neck stiffness caused by acute meningitis, or the characteristic cough of whooping cough. • More commonly a combination of signs is highly suggestive of an infection. For example, exudative tonsillitis, generalized lymphadenopathy and splenomegaly together suggest infectious mononucleosis; fever, relative bradycardia, splenomegaly and rose spots suggest typhoid. • Physical signs may indicate the site of infection. Consolidation in the lungs suggests pneumonia; loin tenderness is associated with pyelonephritis; inflammation,
PRINCIPLES OF DIAGNOSIS AND MANAGEMENT The principles guiding the clinician in the diagnosis and treatment of an infective illness can be considered by asking some simple questions: • Is the disease caused by infection and, if so, where is the site of infection? • What is the microorganism responsible? • Which drugs can eliminate the organism, and will treatment benefit the patient?
History Three aspects of the history are likely to be helpful: • Pattern of the illness • History of contact with patients with a similar illness, or types of behaviour that confer a risk of infection • History of travel to places where particular infections are known to be common. Illnesses caused by infection tend to have a form that is reproduced in most individuals and which is characterized by the following features:
261
volume of fluid permits. The yield will be higher and a Gram stain can be performed. • Think of culture before allowing a tissue specimen to be immersed in fixative such as formalin. • Ensure that specimens for culture are transported to the laboratory without delay. Microorganisms must be nurtured, and all too often they die waiting for transport, or are overgrown by contaminant organisms. Specimens for viral or fungal culture often require special collection techniques and the laboratory should be consulted before obtaining the specimen.
Which drugs can eliminate the organism from the infected site, and wifl treatment benefit the patient?
FIG. 9.2 111ln white cell scan in a paracolic abscess At 24 hours after the intravenous injection the activity is localised, indicating the accumulation represents an enclosed abscess rather than inflamed bowel. (Reproduced by kind permission of Dr Seth Saverymuttu.)
swelling and fluctuance beneath the skin suggest an abscess.
What is the microorganism responsible? A careful history and examination may point to a diagnosis of infection and can be specific for a particular infection. More frequently, infection is strongly suspected but the site and the organism responsible are unknown. Imaging techniques are often helpful in finding the site of infection, e.g. ultrasound or CT scanning can demonstrate an abscess in soft tissues. Gallium or technetium (99mTc) leukocyte scans frequently demonstrate a soft tissue abscess. In the latter technique the patient's leukocytes are labelled with 99mTc and reinjected (Fig. 9.2). Labelled leukocytes enter sites of acute inflammation, such as an abscess, surgical wounds and the bowel wall of patients with inflammatory bowel disease. Before appropriate treatment can be started the right samples must be collected and sent to the laboratory. The laboratory can give most help if the correct samples are taken and are accompanied by a brief summary of the patient's illness. The drug history is particularly important, as antibiotic in the sample may inhibit the growth of bacteria in vitro. There are simple rules for the collection of samples:
262
• Avoid contamination of the sample with irrelevant organisms by careful cleansing, e.g. cleanse skin with antiseptic before taking blood for culture, and wear gloves during venepuncture. • When infected fluid is to be cultured (e.g. pus) send a fluid sample in a sterile bottle rather than a swab, if the
Some guidelines for the choice of antimicrobial drugs are given on page 263. Whether treatment is to be started immediately or after the results of laboratory tests are available depends on the severity of the disease and the likely consequences of delay. There is virtue in waiting until the precise diagnosis is known if the clinical situation permits, and this applies particularly when antibiotics have been given before admission to hospital. Acute meningitis and septicaemia are obvious exceptions because the patient may die before a final result is available, but even then it is desirable that the correct specimens are obtained before treatment is started. Valuable preliminary information can be obtained by Gram staining and microscopy of specimens such as sputum or pus. Direct testing for microbial antigens may increase in importance for disease caused by a limited range of organisms, such as acute meningitis. Treatment is not always beneficial to the patient, even when an antimicrobial drug with appropriate activity can be delivered to the site of infection in adequate concentration. Faecal excretion of salmonellae may be prolonged by treatment with some antibiotics.
ANTIMICROBIAL AGENTS The choice of antimicrobial drugs is central to the management of infection. General measures should not be neglected: these include use of analgesics, attention to nutrition and hydration, and cleaning, debridement or drainage of infected areas. The term 'antimicrobial agent' can be applied to any substance that is active against microorganisms. Strictly, an antibiotic is a substance produced by a microorganism which inhibits the growth of another. In this chapter 'antibiotic' will be used (inaccurately) to refer to antibacterial drugs, whether synthetic or naturally produced. In this section the dose of antimicrobial is not normally given, as this often depends on the nature of the particular infection being treated, and the reader should refer to sections on the management of specific diseases. Only the more severe side-effects are noted here.
edge of antibiotics, including the known sensitivity of particular organisms to them. The latter are not constant, and so treatment is often started on the basis of an intelligent guess and modified later according to laboratory results. Bacterial sensitivity is tested using discs impregnated with antibiotic and measuring the size of the ring of inhibition on culture plates. Other factors are also important in the choice of antibiotic, such as absorption and penetration to the site of infection. Whenever possible the antibiotic chosen should have a spectrum of antibacterial activity limited to a few organisms, as the broader the spectrum the greater the chance of side-effects owing to disturbance of the normal microbial flora. The choice between a bactericidal and a bacteriostatic drug is not usually critical but it may be important when the organisms are fairly inaccessible, as in infective endocarditis, or when host defences are impaired (see Table 9.6). Combinations of antibiotics are used for one of three purposes:
Choice of appropriate drugs The selection of a suitable antimicrobial agent is fairly straightforward when the microorganism responsible is known (Table 9.3), but often this is not the case and a sensible guess has to be made as to the organisms responsible. In the case of a urinary tract infection in a previously healthy young woman, for example, faecal organisms such as E. coli would be the most likely pathogens, and this would guide initial therapy. The information required to make an appropriate choice can be summarized as follows: • • • • •
Probable organism(s) Probable antimicrobial sensitivities of the organisms Ability of the chosen drugs to reach the site of infection History of allergy to drugs Interaction of these drugs with any other drugs the patient is taking • Side-effects of the chosen drug • Cost of the drug.
• To obtain a spectrum of antibacterial activity that could not be achieved with a single agent (e.g. treatment of septicaemia when the causative organism is not known); • To take advantage of synergy between drugs (e.g. during the initial treatment of infective endocarditis); • To prevent the emergence of resistant organisms (e.g. treatment of tuberculosis).
An example of the process of decision is shown in Figure 9.3. This logical sequence assumes a considerable knowl-
TABLE 9.3 Common sensitivities of some bacteria to antibiotics Bacteria
1st choice
2nd choice
Streptococci (except anaerobic) Staphylococci Neisseria meningitidis Neisseria gonorrhoeae Gram-positive bacilli Escherichia coli (urinary tract) Pseudomonas aeruginosa
Penicillin
Erythromycin
Flucloxacillin Penicillin Azithromycin Penicillin Trimethoprim
Erythromycin Cefotaxime Penicillin
H. influenzae (respiratory infection) Gram-negative (septicaemia)
Route of administration The ideal drug would give adequate serum levels after oral administration, whatever the state of the patient. However, an ill patient often cannot swallow tablets and absorption from the gut may be unreliable. The choice between intravenous (i.v.) and intramuscular (i.m.) administration is determined by the form in which the drug is available and its pharmacokinetics, the discomfort of intramuscular administration, and practical issues such as accessibility of veins and other drugs being administered. Topical antibiotic treatment is sometimes useful in the eye (p. 304), on the skin (Ch. 10) or in the respiratory tract (e.g. in cystic fibrosis, see p. 651), but the development of resistance is a problem.
Amoxicillin
Piperacillin and gentamicin (usually requires a combination) Co-amoxiclav
Ceftazidime and gentamicin
Cefotaxime
Ciprofloxacin Piperacillin and gentamicin
Erythromycin
Duration of treatment The aim of treatment with antibiotics is to eliminate infec-
Antibiotic
Probability of sensitivity
Penicillin
>95%
+ +When meninges inflamed (iv administration)
Allergy
Low
Cefotaxime
>95%
+ + (iv administration only)
Allergy in 10% of penicillin-allergic subjects
High
1st choice in Western world if penicillin allergy
Chloramphenicol
>95%
+ + +(Oral or iv administration)
Very rare marrow aplasia
Low
1st choice in Third World country
Penetration
9
Toxic effects
FIG. 9.3 Choice of antibiotic in a patient with acute pneumococcal meningitis
Cost
Decision 1st choice if no allergy
263
tion, when this is achievable, or to reduce the number of organisms to a point at which host immunity can do the rest. Surprisingly little is known about the duration of treatment needed to achieve these aims in most infections, and there is considerable unsupported dogma regarding the importance of completing a prescribed course of antibiotics. The usual argument for finishing a course of treatment is that early discontinuation encourages the emergence of resistance. However, resistance rarely arises during treatment except when the bacterial population already contains resistant mutants, as in streptomycin therapy for tuberculosis. It is most likely to occur in chronic and heavy infections (e.g. Pseudomonas aeruginosa infection in cystic fibrosis), and with particular antibioticbacterial groupings, such as quinolones or fucidic acid in staphylococcal infections, cephalosporins in some Gram-negative infections, and rifampicin in infections by many bacterial species. There is good evidence about the duration necessary for treatment of tuberculosis, urinary tract infection, gonorrhoea and infective endocarditis, but virtually none about upper and lower respiratory tract infections, which account for 75% of community prescriptions. Opinions vary considerably about the appropriate time to treat in most other infections, and often the only advice available is to be guided by the clinical response.
MECHANISM OF ACTION OF ANTIBIOTICS
TABLE 9.4 Examples of major pathogens which have developed new resistance patterns
Antibiotics act in one of the following ways:
Organism
Resistance to
• Inhibition of bacterial cell wall synthesis (penicillins and cephalosporins); • Inhibition of particular aspects of bacterial cell function: protein synthesis (aminoglycosides, chloramphenicol, tetracyclines, macrolides, clindamycin); DNA replication (rifampicin, quinalones); microbial enzymes (sulphonamides, trimethoprim, isoniazid).
Enterococcus Strep, pneumonias N. gonorrhoeas Staph. aureus
Ampicillin/gentamicin Penicillin Penicillin Methicillin (flucloxacillin)
Resistance to antibiotics There are two major ways in which resistance occurs: • The bacterium produces an enzyme which inactivates the antibiotic. The best-known example is B-lactamase, which alters the B-lactam ring of penicillins and cephalosporins (Fig. 9.4). Aminoglycosides and chloramphenicol are other drugs broken down by bacterial enzymes. • The bacterium may alter such that the antibiotic is rendered ineffective. This occurs either by a change in the permeability of the bacterial cell wall or by an alteration at the target site of the antibiotic.
264
FIG. 9.4 Structure of B-lactam ring
Resistance tends to emerge by natural selection in a population of bacteria exposed to antibiotic. This may be acquired by mutation (leading to a single base alteration), but more often it is the result of incorporation of new
genetic material into the bacterial nucleus or the transfer of genetic material from other organisms in the form of extrachromosomal DNA as plasmids (episomes) and transposons. There is an increasing problem with emergence of resistance among bacteria (Table 9.4) which is largely related to the use of antibiotics acting as a selection pressure. In hospitals methicillin-resistant Staphylococcus aureus (MRSA) colonize the skin of patients admitted with other problems and can be difficult to clear. For the majority of patients these organisms are harmless, but they can cause deep infection in certain, groups, such as orthopaedic and cardiac surgery patients, and there is controversy about whether hospitals should isolate all colonized patients and attempt to clear their skin of infection, or just take steps to protect high-risk groups. On a wider scale, antibiotics introduced in poor communities for the treatment of common conditions become useless after a few years because resistance develops.
This has happened when trimethoprim was given for the treatment of dysentery in the past, and it is an emerging problem with antibiotics used to treat gonorrhoea and Strep. pneumoniae infections. It is most likely to happen when antibiotics are given in inadequate doses in a random manner, which happens when they are available over the counter. Antibiotic policies have been devised to avoid the problem but they are most easily applied in hospitals, and even there they are not wholly successful. So far pharmaceutical companies have been able to produce new compounds to keep ahead of the problem, but it is important that we learn more about the ways in which resistance emerges if it is to be controlled.
ANTIBIOTICS IN COMMON USE B-Lactams
These are the most commonly used antibiotics and have in common the B-lactam ring (Fig. 9.4). There are two major groups, the penicillins and cephalosporins. Penicillins Benzyl penicillin or penicillin G is a highly potent bactericidal natural penicillin which was the forerunner of all the other penicillins. Long-acting forms, procaine and benzathine penicillins, allow longer intervals between doses. Its disadvantages are that it can only be given parenterally, it has little activity against Gram-negative organisms, and many staphylococci are resistant to it. Semisynthetic and synthetic penicillins have been developed to circumvent these problems. Doses are now usually expressed in mg (600mg = 106 units = 1 megaunit). Standard adult dose: 300 mg 6-hourly; high dose 600 mg 4-hourly. Phenoxymethyl penicillin is a natural penicillin which is acid resistant and can therefore be taken by mouth for the treatment of minor infections with streptococci which are highly sensitive. Absorption is variable, and so it should not be used for more serious infections. Standard adult dose: 500 mg qds. Broad-spectrum penicillins, such as ampicillin and amoxicillin, have useful activity against Gram-negative organisms, excluding Pseudomonas species. They are well absorbed from the intestine. Standard adult doses: amoxicillin 250 mg tds; ampicillin 0.25-lgqds. B-Lactamase-resistant penicillins, such as flucloxacillin and methicillin, are used mainly to treat penicillinaseproducing staphylococci. Standard adult dose: flucloxacillin 250 mg qds. Co-amoxiclav is a combination of amoxicillin and the B-lactamase inhibitor clavulanic acid, which makes the amoxicillin active against resistant strains of Staph. aureus, H. influenzae, E. coli and many Bacteroides and Klebsiella species. Standard adult dose: 375 mg (containing amoxicillin 250 mg) tds. Antipseudomonal penicillins: the ureidopenicillins (azlocillin and piperacillin) are distinguished by their activity against Pseudomonas species and have a broader
spectrum of activity against Gram-negative organisms. Standard adult doses: azlocillin 2 g 8-hourly; piperacillin 150mg/kg/day in divided doses, up to 16g daily in severe infections. Toxicity. The most common problem is hypersensitivity causing rash and anaphylaxis (see p. 96). This is an allergic reaction which develops 10-14 days after first exposure, but much sooner on re-exposure. Its severity varies from mild to fatal according to the reactivity of the patient, the dose of drug and the route of administration. There is crossreactivity between penicillins, and to some extent with cephalosporins. Ampicillin is particularly likely to cause rash in patients with infectious mononucleosis.
9
Cephalosporins Cephalosporins have a similar structure and mode of action to penicillins but modifications to their structure have produced a range of drugs with a broader spectrum of activity. Examples are cefaclor, which has a broad spectrum of activity, including some against staphylococci, and can be taken orally (standard adult dose: 250 mg tds); cefotaxime, a parenteral drug with a very broad spectrum excluding Pseudomonas (standard adult dose: 1g 12hourly, or up to 4 g 8-hourly); and ceftazidime, similar to cefotaxime but including Pseudomonas activity (standard adult dose: 1 g 8-hourly, or up to 2g 8-hourly). Ceftriaxone has a similar spectrum of activity to cefotaxime but is unusual in that it is given only once a day (standard adult dose: 1 g daily, or up to 4g daily; doses above 1 g given in several sites). These drugs are expensive and their use should be part of a defined antibiotic policy. Their sideeffects are similar to those of penicillins. Other B-lactams Imipenem is a carbapenem which differs from other (3lactams in its remarkable spectrum of antibacterial activity and resistance to hydrolysis by most B-lactamases and other enzymes. It is administered in combination with cilastatin, which inhibits its renal metabolism by inhibiting a kidney enzyme (standard adult dose: 500mg 12-hourly, up to 750mg 12-hourly). CNS side-effects such as convulsions and confusion limit its usefulness, and meropenem is less likely to cause such toxicity (standard adult dose: 500mg 8-hourly, up to 1 g 8-hourly). These are reserve drugs, only prescribed when conventional drugs have failed. Aztreonam is a monolactam with a spectrum of activity limited to some aerobic Gram-negative bacteria (standard adult dose: 2g 12-hourly). Macrolides Erythromycin is an extremely useful drug with a macrolide structure. It can often be used as an alternative to penicillin when the patient is allergic. In addition it is active against Haemophilus influenzae, Mycoplasma, Legionella, Bordetella pertussis and Campylobacter (standard adult dose: 250mgqds). Newer macrolides such as clarithro-
265
mycin and azithromycin are less likely to cause gastrointestinal side-effects and can be given in shorter courses than erythromycin (standard adult doses: clarithromycin 250 mg bd; azithromycin 500 mg daily for 3 days, or as a single 1g dose treatment for genital chlamydial infection). Chloramphenicol Chloramphenicol is a cheap drug, well absorbed and distributed, with useful activity against Gram-positive and negative cocci and H. influenzae. Its major drawback is the very rare but usually fatal induction of marrow aplasia. It is also difficult to use safely in babies. Standard adult dose 50mg/kg/day in four doses. Tetracyclines Tetracyclines were widely used to treat exacerbations of chronic bronchitis until resistance became common. Now their main use is for the treatment of chlamydial infection, but they are also active against Mycoplasma, Brucella, rickettsiae, Coxiella and Borrelia. They should not be used in pregnant women and children under 9 years old because they cause staining of teeth and sometimes dental hypoplasia. Doxycycline is less prone to cause diarrhoea than other tetracyclines but occasionally causes oesophageal ulceration. Standard adult dose: 200mg on day 1, then l00mg daily. Aminoglycosides Aminoglycosides such as gentamicin, amikacin and tobramycin are used in serious Gram-negative infections. They are ototoxic and nephrotoxic. Blood levels have to be monitored carefully, especially when there is renal impairment, as they are excreted purely by the kidneys. Peak blood levels are measured 15 minutes after intravenous or 1 hour after intramuscular administration, and trough levels immediately before the next dose. Standard adult doses: gentamicin 2-5mg/kg/day in two doses; amikacin 15mg/kg/day in two doses; tobramycin 3 mg/kg/day in three doses. Sulphonamides and trimethoprim Sulphonamides were the first synthetic antimicrobial drugs, but their use is now limited by the development of resistance and by the frequency of troublesome sideeffects such as nausea, rash (Stevens-Johnson syndrome at worst) and bone marrow toxicity. Sulfamethoxazole is still widely used in combination with trimethoprim (cotrimoxazole; standard adult dose 960mg bd, but see p. 344 for treatment of Pneumocystis carinii infection) because they were thought to be synergistic, but it now seems that trimethoprim alone is just as effective in the treatment of
1
266
MCQ 9.1
Gram-negative urinary infection. Trimethoprim can cause thrombocytopenia and megaloblastic anaemia. Standard adult dose 200mgbd. Clindamycin Clindamycin is a lincosamide with activity against Grampositive organisms, including resistant staphylococci, but also against anaerobic organisms. It achieves good penetration into bone and can be used to treat osteomyelitis. Common side-effects include rash and diarrhoea, rarely with pseudomembranous colitis. Standard adult dose 300mgqds. Metroindazole Metronidazole is an excellent drug for the treatment of anaerobic infection. It is cheap when administered orally or rectally, and the more expensive intravenous preparation is rarely indicated. It is also the first choice in treatment of Giardia lamblia, amoebic disease and Trichomonas vaginalis. Serious side-effects are rare, but nausea and abdominal pain are common. Standard adult dose 400mgtds. Sodium fusidate Sodium fusidate is highly bactericidal against staphylococci, including penicillin-resistant ones, but resistance develops during treatment unless another drug is given concurrently. It is reserved for treatment of serious infections such as septicaemia and osteomyelitis. It is necessary to monitor for hepatotoxicity. Standard adult dose 500 mg tds. Vancomycin Vancomycin is reserved for serious penicillin-resistant staphylococcal infection or for the treatment of pseudomembranous colitis. Serum levels must be monitored, as it is ototoxic and nephrotoxic. Standard adult dose 1g infused over 100 minutes 12-hourly, or 125mgqds orally for pseudomembranous colitis. Teicoplanin is a similar drug which is slightly less toxic. Standard adult dose 400 mg 12-hourly for three doses, then reduce to 200400 mg daily. Quinolones Nalidixic acid has been used exclusively in the treatment of urinary infection by Gram-negative organisms, as adequate levels are only found in the urine. Standard adult dose 1 g qds. Resistance to this group of drugs is rare, as they are not susceptible to plasmid-mediated resistance. The newer generation. of 4-fluoroquinolones includes ciprofloxacin, which is well absorbed from the intestine and widely distributed. Standard adult dose 500 mg bd. This group contains the only orally administered drugs active against Pseudomonas, and they have become increasingly important in the management of gut infections and severe systemic infections, including typhoid. Major toxicity is uncommon.
Rifampicin Rifampicin, a synthetic derivative of rifamycin, is central to the treatment of tuberculosis but is also very active against staphylococci, streptococci and E. coli. Its major toxicity is to the liver. Standard adult dose 300 mg bd, but see p. 645 for the treatment of tuberculosis. Quinuprastin/dalfoprastin Quinuprastin/dalfoprastin is a new streptogramin recently licensed in the UK and the USA which is active only against Gram-positive bacteria, including methicillinresistant Staphylococcus aureus, vancomycin-resistant Enterococcus faecium (but not E. faecalis) and penicillin/ macrolide-resistant pneumococci, and its use should be restricted to treatment of such infections. Administration is recommended through a central venous catheter, as peripheral lines tend to develop complications. Linezolid Linezolid, a new oxazolidinone antibiotic is active against Gram-positive bacteria which are resistant to other antibiotics. It can be given orally or intravenously (600 mg every 12 hours by either route). 1
ANTIFUNGAL DRUGS Most fungal infections of the skin are treated with topical preparations, but cuticular infection requires prolonged systemic therapy. Visceral infections also require systemic therapy. Amphotericin B and nystatin Amphotericin B and nystatin are polyene antibiotics produced by Streptomyces species. They exert a fungistatic effect by binding to sterols in the fungal cell membrane, causing leakage of cell components. Amphotericin B acts synergistically with the unrelated compound flucytosine, probably by increasing permeability to flucytosine. Amphotericin B can be administered intravenously, after which there is wide tissue distribution but poor penetration to brain and meninges. The plasma half-life is 24 hours and it is excreted very slowly in the urine, 40% of the infused dose appearing in the urine during the following week. Amphotericin B has a broad spectrum of activity and is used against the agents of candidiasis, aspergillosis, histoplasmosis, blastomycosis, coccidioidomycosis, cryptococcosis and some organisms causing mucormycosis. Minor symptoms following infusion are common, and a wide variety of symptoms may be unpleasant enough to require suppression with analgesics, antiemetics etc. More serious side-effects occur when there is impairment of renal function, which is exacerbated by the resultant rise in plasma drug levels. Renal and haematopoietic toxicity are the main problems. Therapy has to be interrupted to allow a fall in plasma level. It is given in a dose of 0.25 mg/kg body weight
intravenously over 6 hours, increasing to 0.8 mg/kg according to tolerance. Treatment is withdrawn intermittently as required to maintain the plasma level at l-1.5mg/L. A less toxic liposomal form of amphotericin B is expensive and its use is limited to febrile neutropenic patients and to those unable to tolerate the native form. Standard adult dose of liposomal amphotericin: Img over 10 minutes test dose, then 3 mg/kg/day in one dose. Neither amphotericin B nor nystatin is absorbed from the intestine but they are useful as topical or mucosal preparations, particularly for treatment of Candida infections. Nystatin is available as a suspension or pastilles for oral infection, cream and pessaries for vaginal infection, and cream or ointment for skin infections.
9
Flucytosine Flucytosine is a synthetic fluorinated pyrimidine which enters fungal cells and inhibits metabolism by interfering with DNA and RNA synthesis. It can be given in combination with amphotericin B for treatment of systemic fungal infections, but is rarely used now. Standard adult dose 200 mg/kg/day in four doses, each infusion over 20-40 minutes. Imidazoles Ketoconazole, miconazole and clotrimazole are imidazole drugs. Most are available only topically and have activity against dermatophytes and Candida. Imidazoles have no place in the treatment of systemic fungal infections. The mode of action is not fully understood, but imidazoles interfere with synthesis of sterols and other fungal membrane lipids, resulting in defective cell wall synthesis. In vitro they enhance killing of Candida by leukocytes. Ketoconazole is an oral preparation which is useful for treatment of severe mucosal infections, such as oesophageal candidiasis which is not responsive to topical treatment. The major toxicity is drug-induced hepatitis, which can progress to irreversible hepatic failure. Standard adult dose 200 mg daily. Triazoles Triazoles are a new group of antifungal agents, including fluconazole and itraconazole, which are useful as oral agents for treating systemic mycoses. Both are effective in treating oesophageal candidiasis using very short courses, e.g. a single dose of fluconazole 150 mg. Prolonged treatment in patients with immunodeficiency often results in emergence of resistant strains of Candida, but at present cross-resistance between itraconazole and fluconazole is uncommon. Fluconazole (but not itraconazole) penetrates into the CSF and is useful for treatment of cryptococcal meningitis (dose 400mg, then 200mg i.v. daily). Sideeffects are rare but there is a small risk of hepatotoxicity. Standard adult dose of itraconazole: 100 mg daily. Griseofulvin and terbinafine Griseofulvin, produced by Penicillium griseofulvum, is
267
absorbed from the gastrointestinal tract and deposited in keratin, where it inhibits the growth of dermatophytes. It is relatively non-toxic and can be used in extensive dermatophyte infections which are unresponsive to topical treatment. It is particularly useful for nail and scalp infections (p. 389), but has to be given for weeks or months. Serious side-effects, such as bone marrow and neurological disorders, have been reported occasionally after griseofulvin use. Standard adult dose: 500mg daily. Terbinafine, an allylamine, can also be used for these infections and may be effective after shorter courses. Standard adult dose: 250 mg daily. 1
ANTIVIRAL TREATMENT Considerable progress has been made in synthesizing agents which specifically inhibit an essential step in virus replication without causing host toxicity. This has been achieved: • By using an agent which is activated by the virus, thus localizing its action within infected cells; • By using an agent which inhibits virus metabolism specifically. Usually this is achieved when the agent inhibits a viral enzyme. Drugs have been developed which are active against herpes viruses, human immunodeficiency virus, hepatitis B and C, influenza viruses, enteroviruses, respiratory syncytial virus, and some viruses which cause viral haemorrhagic fever.
Drugs active against herpes group viruses Aciclovir, the most widely used agent currently available, produces its specific effects using both of these mechanisms. It is inactive until phosphorylated to a triphosphate by viral thymidine kinase in infected cells. In this form it produces its main antiviral action by inhibiting viral DNA polymerase, essential for synthesis of viral DNA. Aciclovir triphosphate is a more powerful inhibitor of viral than of host DNA polymerases. Aciclovir seems to be a safe drug but is expensive. Its use is restricted to situations in which it is clearly beneficial (Table 9.5). Newer drugs such as famciclovir and valaciclovir are similar in their spectrum of activity and toxicity but differ in absorption, so that famciclovir can be given less often than aciclovir, and valaciclovir achieves a higher serum concentration than aciclovir after oral administration. During acute viral infections much of the inflammation is caused by the host response in the later part of the illness, 1
268
MCQ 9.2
TABLE 9.5 Treatment of herpes virus infections with aciclovir Virus
Infection
Route
Herpes simplex virus
Encephalitis Neonatal infection Primary genital infection Keratoconjunctivitis Prophylaxis: bone marrow transplantation Shingles in immuncompromised patients Chickenpox in immunocompromised children Chickenpox in neonates Chickenpox in adults Possible Chickenpox pneumonia
IV IV 0 T 0 IV IV IV IV 10
Varicella zoster
IV = intravenous; 0 = oral; T = topical
and antiviral treatment must be started early to be effective. Antiviral treatment does not affect virus integrated into the host genome, and treatment of the primary herpes simplex infection does not influence subsequent viral reactivation. Ganciclovir, an antiviral drug licensed for treatment of cytomegalovirus (CMV) infection, is activated by phosphorylation in a similar way to aciclovir, but depends on human cellular enzymes for this process (Fig. 9.5). Because phosphorylation occurs in infected and normal cells, toxicity is greater than that of aciclovir and it causes bone marrow suppression. Foscarnet, a phosphonate, also inhibits CMV DNA polymerase and has a different toxicity from ganciclovir.
Antiretroviral drugs There are three main classes of antiretroviral drugs: nucleoside and non-nucleoside inhibitors of HIV reverse transcriptase, and a third class that inhibit HIV protease. At least three drugs are used in combination to limit the development of resistance and, once started, treatment is normally maintained for life (see Ch. 11).
Ribavirin (tribavirin) Ribavirin is another nucleoside analogue that is active against a wide spectrum of DNA and RNA viruses, but its clinical use is confined to treatment of severe respiratory syncytial virus infection causing bronchiolitis, some of the viral haemorrhagic fevers such as Lassa fever, and hepatitis C virus infection in combination with interferon-a. For RSV infection it is given by inhalation.
Interferons Interferon-a, which is produced by T lymphocytes, has been shown to inhibit replication of hepatitis B and hepatitis C viruses, possibly by inhibiting virus assembly. It has many side-effects, including flu-like syndrome early in
9
FIG. 9.5 Mechanisms of action of ganciclovir Virus replication in host cells induces the enzymes (guanosine kinase and phosphorylase). Because the same enzymes are involved in phosphorylation of ganciclovir, infected cells have higher concentrations of ganciclovir triphosphate. This is the activated form, which blocks viral replication,
therapy, lethargy throughout treatment, bone marrow toxicity and depression, and is only effective in a small proportion of patients, but it is the only substance known to have any influence on these infections at present.
FURTHER READING ON ANTIMICROBIAL AGENTS
TABLE 9.6 Some microorganisms causing infection in immunocompromised patients Type
Microorganism
Remarks
Deficiency
Bacteria
Gram-positive, e.g. Pneumococcus Gram-negative, e.g. H. influenzae Mycobacteria, e.g. avium intracellulare
Encapsulated
Ab/Neut/S
Encapsulated
CMI
Both tuberculous and non-tuberculous Reactivation
CMI
Encephalitis Virulent Septicaemia/ pneumonia Mucosal Systemic Meningitis Pneumonia Cerebral Gut Gut Systemic Systemic
Ab Ab/CMI Ab/Neut
Lambert H P, O'Grady F, Finch R, Greenwood D 1996 Antibiotic and chemotherapy, 7th edn. Edinburgh: Churchill Livingstone.
INFECTION IN THE IMMUNOCOMPROMISED PATIENT An immunocompromised patient is defined as one in whom any part of the innate or adaptive immune response is defective. Defects of the immune system are physiological (neonates and the aged), and either primary or secondary. Primary immune deficiency diseases are rare and an account is given in Chapter 4. Secondary immune deficiency is more common and of increasing importance. Causes of secondary immune deficiency are: • Malignant disease and its treatment; • Drug-induced chronic immune suppression, e.g. in organ transplantation or chronic inflammatory diseases, such as systemic lupus erythematosus (SLE); • Infection: the most severe infection is HIV (Ch. 11), but many other viruses cause a milder deficiency of cellmediated immunity (CMI); • Splenectomy; • Chronic diseases, e.g. chronic renal failure, malnutrition, protein deficiency, diabetes mellitus. These conditions cause varying combinations of neutropenia and impairment of humoral and cellular immunity. Deficiencies of antibody or neutrophils are associated with infection by encapsulated bacteria, yeasts and fungi. Defi-
Viruses
Yeasts Fungi Protozoa
Helminths
Herpes, e.g. herpes simplex virus, varicella zoster virus, cytomegalovirus Echo Live vaccines, e.g. measles Candida Aspergilius Cryptococcus Pneumocystis Toxoplasma Cryptosporidium Giardia lamblia Malaria Strongyloides
CMI
CMI CMI CMI CMI/Ab CMI CMI CMI/Ab Ab/S CMI
Ab = antibody; Neut = neutrophil; CMI = cell-mediated immunity; S = post-splenectomy
cient CMI causes infection by a wider range of pathogens, including Gram-positive and -negative bacteria, viruses, yeasts, fungi, protozoans and helminths (Table 9.6). In all these situations immunization with live viral vaccines is dangerous, as the attenuated organism may behave as a pathogen. The pattern of infection in immunocompromised
269
SUMMARY 1 Management of the neutropenic patient with fever
TABLE 9.7 Organisms causing pneumonia in immunocompromised patients
• Take samples for culture: blood, urine, stool, i.v. line tip, etc. as appropriate • Start treatment after taking samples, guided by any previous culture results • Examples of empirical treatment regimens: - gentamicin plus piperacillin or ceftazidime - If no response within 48 hours, switch to - vancomycin If no response, or recurrence, particularly if previous antibiotic courses given - amphotericin B or fluconazole for Candida septicaemia • If chest X-ray shows pulmonary infiltrates, add erythromycin initially for atypical pneumonia. Consider a wide range of organisms (including M. tuberculosis) and viruses (e.g. CMV) if there is no response to antibiotics
Bacteria Gram-positive, e.g. Strep. pneumoniae Gram-negative, e.g. H. influenzae, Klebsiella pneumoniae Viruses Cytomegalovirus, herpes simplex, varicella zoster Measles (giant cell pneumonia) Protozoa Pneumocystis carinii Fungi/yeasts Candida Aspergillus
NOSOCOMIAL INFECTION patients is unusual in several respects. Bacterial infections in splenectomized patients are sudden in onset and rapidly progressive, fulminant pneumococcal septicaemia being the most common. Cellular immune deficiency causes viral infection to be more severe, prolonged and widely disseminated than is usual. Fever in the neutropenic patient (see Summary 1) During periods of neutropenia the onset of fever should be taken to indicate serious infection unless there is an obvious alternative explanation. 'Blind' treatment with antibiotics is started immediately after the collection of specimens, including blood cultures. Blood cultures are negative in over half of such fever episodes, but the choice of antibiotics is guided by positive results in which Gram-negative bacteria, including Pseudomonas species, predominate, and a combination of a broad-spectrum penicillin with activity against Pseudomonas (e.g. piperacillin) and gentamicin is often used (p. 265). New pulmonary infiltrates on chest radiograph New pulmonary infiltrates may be due to infection with a wide range of possible pathogens (Table 9.7). Sputum induction, bronchoscopy and lavage, and transbronchial biopsy may provide diagnostic information. Invasive procedures have a risk in neutropenic and thrombocytopenic patients.
270
Reactivation of herpes viruses Patients with impaired CMI may suffer severe herpes virus infection. Shingles (varicella zoster) in patients with Hodgkin's disease tends to involve more than one dermatome, and there may be dissemination of virus causing widespread chickenpox lesions on the skin and occasionally in viscera. Within affected dermatomes lesions are dense and heal slowly. Reactivation of herpes simplex virus (HSV) may cause extensive perioral ulceration and occasionally visceral dissemination. CMV reactivation causes pneumonia in renal transplant recipients.
Hospital patients may be particularly susceptible to infection and hospital bacteria are often resistant to common antibiotics. Susceptibility is increased in postoperative patients, patients with bums, patients on ventilators, in malnourished patients, and in disease states that compromise immunity specifically. Hospital-acquired infections are known as nosocomial and are a particular problem on intensive treatment units. Nosocomial infection is an increasing problem and the resistance pattern of bacteria is constantly changing. The most important factors influencing the likelihood of cross-infection are the use of handwashing, the ratio of nurses to patients, the number of visits from doctors and the space between patients. The bacteria associated with particular situations can sometimes be predicted, e.g. staphylococci and streptococci are common causes of surgical wound infections, and Pseudomonas frequently infects burns. In ventilated patients difficulties arise in deciding whether bacteria such as Pseudomonas are merely colonizing the respiratory mucosa or whether they are pathogenic. Antibiotic treatment of colonising organisms is undesirable since the local flora then change to more resistant organisms. With increasing use of antibiotics there has been a resurgence of outbreaks of nosocomial infection with methicillin (and flucloxacillin)-resistant Staphylococcus aureus (MRSA). MRSA colonize the skin and nose of normal or diseased subjects, but they are particularly persistent in patients with any form of skin lesion. In most cases MRSA do not cause disease, but occasionally vulnerable patients can develop septicaemia or local suppuration which necessitates the use of vancomycin. Because MRSA spreads rapidly from person to person it is important to isolate infected patients from other vulnerable patients, and to screen staff for carriage. Colonized subjects are treated with topical antiseptic preparations and, in the case of staff, removed from work until repeated swabs are clear. Vancomycin-resistant staphylococci have been isolated and the increasing use of this antibiotic has led to a problem with resistant enterococci. There is some evidence
that antibiotic cycling in intensive care units - that is, changing the first-choice antibiotics every few months limits the rate of increase in resistance among common nosocomial bacteria. For example, resistance to gentamicin in enterobacteriaceae such as Klebsiella pneumoniae and Serratia marcescens increases when gentamicin is used, but decreases when amikacin is substituted. However, there is no consensus on the best policy at present. The use of antibiotics must be controlled both in hospitals and in the community. Most hospitals have antibiotic control policies which recommend the antibiotic to be used in a particular situation and restrict the administration of some drugs to special situations. Policies for antibiotic prophylaxis before surgery need to be reviewed regularly to keep ahead of the development of bacterial resistance.
CONTROL OF INFECTION Containment of outbreaks of infection is required when susceptible subjects may develop a serious illness if they become infected. It is not always desirable to contain infection. Chickenpox, a mild disease in normal children, is usually severe in adults and so outbreaks among schoolchildren should not be controlled. In a hospital where non-immune patients are liable to develop severe manifestations, however, it is important to prevent crossinfection to non-immune individuals (about 10% of the adult population). Isolation of patients in single rooms greatly facilitates control of infection. Other measures are determined by the mode of transmission and the degree of infectivity of the organism. Transmission is by: • Respiratory secretions (e.g. measles, pulmonary tuberculosis) • Excretions and secretions (e.g. gastroenteritis, hepatitis A, typhoid) • Skin contact and fomites (e.g. MRSA). Respiratory transmission can be prevented by having the patient and/or the attendants wear appropriate masks. Organisms transmitted in respiratory secretions usually infect others through the upper or lower respiratory tract, and gowning and handwashing are of minor importance. When excretions and secretions are infectious the most important containment measure is handwashing. When close contact is necessary with a highly infectious patient, such as a patient excreting Shigella in the faeces, gowns and gloves are worn. Special arrangements are needed for the disposal of excreta, contaminated dressings and contaminated clothing and bedding. When microorganisms are found in significant number on the skin, in fomites and in dust around the patient, as when MRSA colonize patients in hospital, additional precautions must be taken, including the use of overshoes together with gowns and gloves.
TABLE 9.8 Notifiable diseases under the Public Health (Infectious Disease) Regulations 1988 (UK, October 1988) Acute encephalitis Acute poliomyelitis Anthrax Cholera Diphtheria Dysentery (amoebic or bacillary) Food poisoning Leptospirosis Malaria Measles Meningitis meningococcal pneumococcal Haemophilus influenzae viral other specified unspecified Meningococcal septicaemia (without meningitis) Mumps
9
Ophthalmia neonatorum Paratyphoid fever Plague Rabies Relapsing fever Rubella Scarlet fever Smallpox Tetanus Tuberculosis Typhoid fever Typhus fever Viral haemorrhagic fever Viral hepatitis Hepatitis A Hepatitis B Hepatitis C other Whooping cough Yellow fever
AIDS is not a statutorily notifiable disease but doctors are urged to participate in a voluntary confidential reporting scheme Source: PHS Communicable Disease Surveillance Centre
In many countries some infections are notifiable (Table 9.8), that is, the medical attendant is obliged by law to report the case to the authority that controls the area in which the patient lives so that steps can be taken to trace contacts. Notification also allows surveillance of the incidence of these infections. Most patients have ceased to be an infectious risk by the time they are discharged from hospital, but intestinal pathogens often remain in the stools for several weeks. Carriers of such pathogens are advised to avoid handling food for others, to wash hands regularly and to avoid towel sharing. Following notification, stool samples will be checked by the local authority until they are pathogen free.
IMMUNIZATION Active immunization Active immunization is the administration of antigen to induce a protective immune response in the host. Antigens used include crude preparations of killed organisms, extracellular products of organisms, and live attenuated organisms. The aim is to induce an optimal response at the site where infection normally occurs, but it has proved difficult to achieve this at mucosal surfaces. Currently, oral poliomyelitis vaccine is the most successful intestinal vaccine because the attenuated virus induces a prolonged and renewable response in the gut. Oral vaccines have been developed against typhoid and shigel-
271
Contraindications to immunization
TABLE 9.9 UK immunization schedule (2001) Age
Immunization
Type of vaccine
Route
2 months
Diphtheria Tetanus Pertussis Polio H. influenzae type b Meningococcus type C As above Measles, mumps, Rubella (MMR)* Diphtheria Tetanus Polio MMR BCG Tetanus Polio Diphtheria Rubella
Toxoid Toxoid Killed Live attenuated Capsular antigens Conjugate vaccine As above Live attenuated
IM or SC IM or SC IM or SC 0 IM or SC IM As above IM
As above
As above
Live attenuated
ID
As above
As above
3 and 4 months 12-18 months 5 years
10-14 years School-leaving Adults
Diphtheria Polio Tetanus Hepatitis B Influenza
For seronegative women For non-immunized " Selected groups
IM
*MMR introduced into UK in October 1988 Detained in UK until MMR established IM = intramuscular; SC - subcutaneous; 0 = oral; ID = intradermal
losis but they are less effective. Oral cholera vaccine has been developed using the adjuvant properties of cholera toxin B subunit, and tests in Bangladesh have yielded promising results. In contrast, the cholera vaccines available using heat-killed organisms are ineffective. A similar local immune system operates in the respiratory tract and further studies may help to develop local vaccines against respiratory pathogens. The immunization schedule in the UK in 2001 is shown in Table 9.9. Mumps vaccine was introduced as part of the routine childhood immunization schedule in 1988. The policy of immunizing only females against rubella has also been changed, as there is still a notable incidence of congenital rubella. BCG (bacille Calmette-Guerin) immunization for protection against tuberculosis is more important in children of racial groups with a high incidence of the disease, and it may be given to neonates who are at risk of developing meningitis. In North America the incidence of tuberculosis was not high enough to justify its routine use. In contrast, BCG vaccination of neonates is a common practice in the tropics.
1
272
MCQ 9.3
• Live vaccines should not be given to anyone with untreated malignant disease or with any form of immunodeficiency, including those receiving immunosuppressive therapy, or to pregnant women. • Live vaccines should not be given within 3 weeks of another injected live vaccine. • Coincidental severe febrile illness may limit the response to immunization. Immunization should therefore be postponed, but not forgotten. • Significant documented allergy to any component of the vaccine may be a contraindication to its use. • Rubella vaccine should not be given in pregnancy, and pregnancy should be avoided for 1 month after immunization against rubella. 1
Passive immunization Passive immunization is the administration of antibody preparations to prevent or ameliorate infection. Pooled human immunoglobulin is the crudest form, and was commonly used to protect travellers against hepatitis A virus infection. More defined preparations of hyperimmune globulin contain high levels of antibodies to particular organisms, usually viruses, which are not present in sufficient concentration in pooled human immunoglobulin to provide protection. Examples are hepatitis B immunoglobulin given following needle-stick injuries, varicella zoster immunoglobulin used in neonates born to mothers who have recently developed chickenpox (p. 284), and tetanus immunoglobulin used for patients at risk of developing tetanus. Most current antibody preparations are derived from human serum. Passively administered antibody has a short half-life, giving protection for only a few weeks. Treatment has to be given soon after exposure to be effective.
PREVENTIVE MEASURES FOR OVERSEAS TRAVEL OR RESIDENCE The question that is most commonly asked prior to overseas travel to or residence in the tropics or subtropics is 'what vaccines are needed?' In fact, the main disease threats do not come from vaccine-preventable conditions, but from trauma, alcohol-related illness, sun exposure, unprotected sexual contacts and infectious diarrhoeal disease. Malaria is the main threat that is amenable to preventive measures.
Protection of skin The skin must be protected against biting insects. This is important not only for the prevention of malaria, but also for protection against viral, rickettsial, protozoal and filarial diseases transmitted by insect vectors. Exposure to ticks occurs mainly in rural bush areas and
so appropriate clothing and footwear is needed to prevent ticks getting on to the skin. Evening and night hours are times for maximum frequency of biting by many insects, and at these times the skin should be covered as much as possible wearing shirts with long sleeves and long trousers or skirts. Insect repellent (diethyltoluamide (DEET)containing compounds with formulations designed to have a long retention time on the skin) is applied to exposed areas, including the forearms, lower legs, ankles and feet, and face and neck. Elasticated wrist and ankle bands can be impregnated with DEET and worn for the same purpose. Mosquito nets should be used in malarial areas if doors and windows are not screened. Impregnation of bed nets and curtains with permethrin enhances protection through its residual insecticidal action. It is also useful to spray bedrooms with insecticide last thing at night. Schistosomiasis is acquired by contact between skin and slow-flowing or still water containing cercariae. Swimming and paddling in fresh water are best avoided in endemic areas.
Protection against malaria Measures to prevent mosquito bites (see above) and chemoprophylaxis against malaria are the sole means of preventing malaria in the traveller. The traveller must be told that there is no vaccine against malaria and that none of the vaccines received prior to travel is of any benefit in this regard. Details of chemoprophylaxis against malaria are given in Table 9.36, p. 352.
Immunization for travellers or overseas residents A range of vaccines is available and the commonly used ones are listed in Table 9.10. Poliomyelitis is still common in many areas of the world, and so adequate vaccination should be assured in all travellers. Meningococcal vaccine is most often recommended for backpackers in subSaharan Africa. It is occasionally a requirement for travel to specified countries, e.g. Saudi Arabia for the Hajj pilgrimage. Yellow fever vaccination is essential for those visiting tropical Africa, the Caribbean and South America. Oral poliomyelitis and yellow fever vaccines should be given either together or separated by an interval of 3 weeks. Active hepatitis A vaccination is available and is usually used in preference to passive immunization, although it is more expensive. Hepatitis B vaccination is particularly recommended for those at particular risk, i.e. healthcare and hospital laboratory workers, although increasingly backpacking travellers are having this vaccine. Pre-exposure rabies vaccination is needed by those who may have any contact with animals, but again increasing numbers of tourists undertaking overland travels are having pre-exposure vaccination. The intradermal route allows more economical use of the vaccine. Tetanus vaccination is needed for any who may be at particular risk of trauma, e.g. military personnel, construction workers etc.
TABLE 9.10 Immunization for travellers to the tropics
9
Isolated visit to main tourist areas Typhoid Polio Hepatitis A Yellow fever (for some locations) Extensive travel (backpacking, trekking, gap-year students) Typhoid
Polio Hepatitis A & B Rabies Meningococcal disease A & C (sub-Saharan Africa) Yellow fever (West Africa, Central & South America, Trinidad) Frequent visitor (business or holiday) or resident Typhoid Hepatitis A & B Rabies Yellow fever (West Africa, Central & South America, Trinidad) Meningococcal disease A & C Note: these groupings of vaccines are guidelines only and need modification for individuals in relation to their potential exposure during proposed travels. Although on a risk/cost analysis some of these recommendations may seem excessive, they give the traveller coverage for vaccine-preventable conditions endemic in many areas. All travellers should be up to date with childhood vaccines.
Typhoid vaccination is a sensible precaution for many areas, but those vaccinated should be told that having the vaccine does not mean that they are 100% protected and can be careless about sources of water and food. Although the whole-cell killed vaccine has the greatest efficacy it also has the greatest incidence of side-effects and is not now obtainable. The choice lies between two vaccines: (a) the Ty21a oral vaccine containing the epimerase-deficient strain of S. typhi, which has the appeal of stimulating an immune response at the site of entry of the natural pathogen, and (b) the vaccine based on the Vi antigen of S. typhi. Cholera vaccination is not effective.
Protection of the gut Gastrointestinal infection is the most common affliction faced by the traveller. Boiled water used to make tea and coffee or left to cool in a covered, clean container is safe to drink. Bottled drinks are safe. Water from the tap or water used to make ice cubes may not be safe. Tincture of iodine (2%) can be used to sterilize water, adding 0.5mL per litre and allowing it to stand for 30 minutes. Iodine is more potent than chlorine-based sterilizing tablets.
SYNDROMES OF INFECTION SEPTICAEMIA Septicaemia is uncontrolled bacterial infection in the blood. Unlike septicaemia, transient bacteraemia is fairly common
273
in normal subjects. Septicaemia is a much more serious condition which is likely to lead to death if untreated.
Aetiology A wide range of bacteria can cause septicaemia, but they can be divided into those that do so as part of a primary infection by a single organism acquired in the community, and those that cause septicaemia as a complication of another process, such as abdominal sepsis following surgery, when there is often a mixed infection. Community-acquired infections are usually recognized as part of a specific illness, as when Strep, pneumoniae septicaemia complicates pneumonia, meningococcaemia with meningitis, or E. coli septicaemia with pyelonephritis. The other kind of septicaemia is usually seen in hospitals, often in a debilitated patient, and the likely bacteria can often be predicted from the clinical situation.
Pathogenesis Whole bacteria and substances released by bacterial lysis trigger a complex series of events. A major component is endotoxin, the lipopolysaccharide component of Gramnegative bacterial cell walls, of which lipid A is thought to be responsible for most of the toxic effects. Lipid A can activate complement and Hageman factor and can cause the release of cytokines, including tumour necrosis factor. Important pathological consequences ensuing from activation of the potent inflammatory pathways are hypotension, increased vascular permeability and consumptive coagulopathy. Less attention has been paid to the effects of Grampositive organisms, but activation of inflammatory processes can certainly be triggered by cell membrane components of these organisms. An example is alternate pathway complement activation (Fig. 4.1, p. 80) by teichoic acid found in Staph. aureus membranes.
negative septicaemia, but also occurs with Gram-positive septicaemia. For this reason the general term septicaemic shock is usually used. Prolonged hypotension leads to acute renal failure, and disseminated intravascular coagulation causes bleeding. Acute respiratory distress syndrome (p. 697) frequently complicates hospital-acquired septicaemia. The diagnosis is based on clinical assessment, but blood cultures, urine cultures, wound swab and any aspirate from an infected site should be obtained at the time the patient is seen, so that antibiotic treatment can be started without undue delay. The antibiotic regimen can be changed if necessary when culture results are available and the response to treatment has been assessed. Blood cultures should be taken whether the patient is febrile or not.
Management Treatment is urgent because of the high mortality. Antibiotics and circulatory support are the mainstays of management. The use of plasma expanders and selective vasoactive drugs is discussed on page 731.
Antibiotics The initial choice of antibiotics is based on a logical guess at the bacteria responsible (p. 263). As few antibiotics as possible are given to achieve the necessary cover. At present a common choice is a combination of a broadspectrum penicillin, such as ampicillin, with an aminoglycoside such as gentamicin. One problem is that many patients are in incipient renal failure, which enhances the toxicity of gentamicin. Newer drugs, such as cefotaxime and piperacillin, are active against Gram-positive and Gramnegative bacteria and lack the toxicity of gentamicin, but they are more expensive. If anaerobic septicaemia is suspected metronidazole is often used, and for hospitalacquired staphylococcal infection a B-lactamase-resistant penicillin, such as flucloxacillin, is added. Pseudomonas infections are treated with a combination of drugs, e.g. azlocillin and gentamicin. 1
Clinical features and diagnosis The manifestations depend on the age of the patient, the illness being more featureless and more lethal at extremes of age. Signs are usually non-specific, but there are signs in the skin suggestive of the diagnosis, such as purpuric lesions associated with meningococcaemia and pustular lesions in staphylococcal septicaemia. Usually there is a rapid deterioration in the patient's condition, including a change in mental state. Fever is often present, with tachycardia and a bounding pulse, but as the condition progresses the patient becomes hypothermic with a rapid thready pulse and peripheral vasoconstriction. The latter situation is often considered to be typical of Gram1 274
MCQ 9.4
PYREXIA OF UNKNOWN ORIGIN When a patient has an elevated body temperature for a period of longer than 3 weeks without a cause being found the diagnostic problem is called pyrexia (or fever) of unknown origin (PUO). A febrile patient may lose the normal diurnal variation in body temperature or may sometimes have an exaggerated diurnal pattern, with a rise during the night causing drenching night sweats (common in tuberculosis and lymphoma) followed by a rapid fall. Many patterns of fever are described but they are rarely helpful in diagnosis.
Causes of PUO The most common causes of PUO vary according to the
age of the patient, and published incidences vary with the type of institution at which the problem is studied. Infection is usually the most common cause in children, whereas infection and neoplastic disease are equally important in adults. Connective tissue disease can present with fever at any age: Still's disease and SLE are commoner causes in children and young adults, and polymyalgia and giant cell arteritis more frequent in the elderly. Infection Most bacterial infections cause an illness which is clinically manifest within 3 weeks, but there are some exceptions. Bacterial endocarditis can cause low-grade illness, particularly in the elderly. Most cases can be diagnosed by blood culture, but occasionally blood cultures are repeatedly negative. Infection in the biliary tract may be associated with only minor clinical signs and little abnormality of liver function tests. Intracellular bacteria, such as Brucella and some Salmonella species, can cause recurrent septicaemia, but this can usually be diagnosed by blood culture. Deep-seated abscess is a possible cause of PUO, and modern imaging techniques are helpful in locating the collection (p. 262). Tuberculosis is still a major cause of PUO in developing countries and in some temperate countries such as the UK. Often the granulomatous lesions of tuberculosis are too small to cause pulmonary radiological abnormalities, and the site of infection is often outside the lungs. In recent years tuberculosis has become a common feature of HIV infection. Viral infections rarely cause PUO (within the definition), with the important exception of HIV. The history should therefore enquire into sexual practices, intravenous drug abuse and transfusions. Fungal infections rarely cause PUO without a predisposing cause, but they may do so as a complication of immunosuppressive disease or therapy. An exception is histoplasmosis.
Neoplasia Lymphomas frequently produce a prolonged period of fever before any other manifestation emerges. Leukaemias can also cause PUO, but this is sometimes caused by a complicating infection. Many occult solid tumours can present as PUO, among them hypernephroma, pancreatic carcinoma, intestinal tumours, bronchial carcinoma, ovarian tumours and sarcomas. Fever is particularly likely when there are hepatic metastases. Atrial myxoma is a rare benign tumour (p. 582) which occasionally produces an illness similar to bacterial endocarditis. Connective tissue (autoimmune) disease Most diseases in the category of connective tissue disease can present with PUO before the characteristic disease pattern emerges. SLE, rheumatoid arthritis and Still's disease (including the adult form), polyarteritis nodosa, temporal arteritis and polymyalgia rheumatica should be considered depending on the clinical setting.
Miscellaneous Granulomatous conditions. Granulomatous conditions include sarcoidosis, granulomatous hepatitis and Wegener's granulomatosis. Sarcoidosis often lacks overt signs in the early phase of the disease and should be considered, particularly in ethnic groups with a high prevalence, such as West Indians. Factitious. One of the most odd forms of human behaviour is the habitual feigning, or the deliberate inducement, of illness. Factitious fever is caused in two ways:
9
• In the first the fever disappears when the temperature is measured by someone other than the patient, with the patient under continuous observation. The patient is either saying that fever exists when it does not, or is manipulating the thermometer. • In the other, more serious form the patient induces true fever by self-injury or self-infection. The methods used are diverse, but faeces are the usual source of organisms and infection is induced by rubbing or injecting organisms into the skin or blood. Suspicion is aroused when mixed and varying organisms which could be faecal are found in an unexpected site, or when infection persists despite treatment that would normally be effective. The condition is more common in young females than in males, and the deceit may be helped by some medical knowledge. There are sometimes personal problems, which suggest that this behaviour is a plea for attention or help. When suspicion grows that fever is factitious it is wise to avoid directly confronting the patient with the possibility. Usually it will be denied, and sometimes confrontation can precipitate a psychiatric crisis, even resulting in suicide. It is preferable to attempt to solve the associated problems if they can be identified and to create a situation in which it is difficult for the patient to continue to provoke sepsis, e.g. by removing intravenous catheters or covering inflamed sites. The patient should be made to realize that the manoeuvres are understood, if possible without a direct accusation. The best efforts to resolve factitious fever often fail, and patients either return intermittently or present themselves to another medical team. Bowel disease. Inflammatory bowel disease is usually associated with incriminating symptoms such as weight loss and diarrhoea, but these may be slow to emerge. Whipple's disease, caused by the periodic acid-Schiff-positive Grampositive bacterium now known as Tropheryma whippelii, usually presents with polyarthralgia and diarrhoea in middle-aged men, but initially there may be only PUO and abdominal pain (see p. 792). Intestinal lymphoma may also present with the latter symptoms. Drug reaction. Once thought of, drug reaction is a straightforward cause of PUO. The possibility that the fever is caused by a drug is tested by withdrawal. Multiple pulmonary emboli. When frequent small embolic events occur, pyrexia may be the sole manifestion before the pulmonary circulation is greatly compromised.
275
SUMMARY 2 Causes of pyrexia of unknown origin in UK Frequency is given in parentheses • • • • •
Infection (30%) Neoplasia (25%) Connective tissue (autoimmune) disease (20%) Miscellaneous (12%) Undiagnosed (13%)
Other causes. Other occasional causes of PUO are alcoholic hepatitis, familial Mediterranean fever and occult haematoma. There are some young women whose normal evening temperature runs above the normal range by up to 0.5°C. This usually comes to light after an infection with slow recovery. Once it is established that there is no underlying pathology the patient can be reassured. Tropical causes are discussed below.
Diagnosis A careful history and examination of the patient is essential, and it is important to return to the patient repeatedly to go over parts of the history and to look for emergent physical signs. Simple screening tests which may need to be repeated at intervals include full blood count, ESR and CRP, routine biochemistry of blood and urine, cultures of blood, urine and other relevant samples, and chest radiograph. Additional investigations are guided by the clinical findings. There are two approaches. One is to perform tests which are more or less specific for particular diseases, e.g. exclude autoantibodies in autoimmunity or antibodies to particular pathogens. The other is to investigate a particular site which seems to be generating symptoms or signs. The latter is more often helpful, and it is in this area that advances in imaging techniques change the methods for diagnosing PUO. Ultrasound is particularly useful for abdominal examination, both in the detection of solid tissue abnormalities, such as tumours of the kidney or pancreas, lymph node enlargement or infiltration of the liver, and in locating collections of pus (subphrenic, perinephric, intrahepatic etc.). CT scanning supplements, and is in some situations superior to, ultrasound, for example when intestinal gas limits the views on abdominal ultrasound. MR scanning is often more sensitive than CT and is clearly superior for detecting lesions in soft tissue and bone. CT scanning and ultrasound are used to guide the needle during tissue biopsy. The use of 99mTc-labelled leukocytes is described on page 262.
MCQ 9.5
276
Even if no localized lesion has been found by imaging techniques, certain biopsy procedures are sometimes rewarding. If the liver enzyme tests are abnormal percutaneous liver biopsy should be considered, as diffuse granulomatous or infiltrative diseases such as sarcoidosis or lymphoma may be detected. Marrow aspiration and biopsy may reveal cryptic tuberculosis, or lymphomatous or carcinomatous infiltration. The marrow and liver biopsy should be cultured for Mycobacterium tuberculosis, bacteria including Brucella fungi and, where relevant, leishmania. Patience and persistence are essential in managing PUO. Neoplasia is the major cause of death among PUO patients, and so the exclusion of treatable neoplastic disease such as lymphoma is a priority. In some cases there is evidence to support a diagnosis of bacterial infection although the infection cannot be defined, and it may be justified to give blind antibiotic treatment. This should be aimed at the type of infection suspected. For example, a Staph. aureus osteomyelitis would require two antibiotics, such as flucloxacillin and fucidic acid, whereas an appendix abscess could be treated with ampicillin, gentamicin and metronidazole to cover E. coli, enterocci and anaerobic bacteria. In other circumstances a therapeutic trial of treatment for M. tuberculosis may be required. In most studies about one-fifth of cases remain unsolved despite the best efforts. 1
The approach to the patient with fever from or in the tropics Febrile illness is common in the tropics, or after travel to the tropics. The causes encompass infectious and noninfectious causes. Infections include those peculiar to tropical regions and those common worldwide (such as urinary tract infection, pneumonia) (Table 9.11). Clinical features A detailed history is essential. This should include accurate recording of the dates of travel, duration of stay and countries visited, with information on the places involved (cities, rural areas, beach resorts etc.) and the reasons for travel. Information about sexual contact during travel is also important. The history should also include details of vaccination prior to travel and malaria prophylaxis,
TABLE 9.11 Leading causes of imported fever (Hospital for Tropical Diseases) Malaria P. fdlciparum P. vivax P. ovale Viral (presumed) Dengue (proven) Bacterial gut infections
42% 57% 9% 4% 25% 6% 5%
9
TABLE 9.12 Incubation periods for some tropical diseases Type of organism
Short (less than 2 weeks)
Intermediate (2-6 weeks)
Long (more than 6 weeks)
Viruses
Arbovirus infections (e.g. Dengue) Marburg virus disease
Poliomyelitis Hepatitis A virus Arenavirus infection Ebola virus infection Lassa fever virus infection Haemorrhagic fever with renal syndrome
Hepatitis B Non-A, non-B hepalitis Rabies HIV
Q fever
Rickettsia Bacteria
Typhoid
Typhoid Brucellosis Leptospirosis Relapsing fever Lymphogranuloma venereum
Protozoa
Trypanosoma cruzi infection
Malaria Toxoplasmosis Trypanosoma rhodesiense infection
Helminths
with some assessment of the regularity of taking prophylaxis. The chronology of events should be recorded, particularly noting the interval between the end of the patient's travels and the onset of illness where this has occurred after leaving the tropics. This gives an idea of the incubation period of the disease (Table 9.12). Physical examination should pay attention to the presence of skin lesions, oral lesions, jaundice, adenopathy, hepatosplenomegaly, and involvement of the nervous system. After initial assessment it is vital to reassess the patient at frequent intervals, looking for the appearance of diagnostic symptoms and signs. Antimalarial chemoprophylaxis should be discontinued while investigation is proceeding as it may suppress parasitaemia and prevent diagnosis of malaria.
Visceral leishmaniasis Trypanosoma gambiense infection
Schistosomiasis (Katayama syndrome)
SUMMARY 3 Causes of imported fever Malaria Dengue Other arboviral infections Tuberculosis AIDS related infections Typhoid Rickettsial infections Amoebic liver abscess Visceral leishmaniasis Viral haemorrhagic fevers* * While numbers of cases of VHF are very low it is essential to consider this group of conditions in any patient who has visited an endemic area, is febrile and has a low platelet count. See risk assessment, p. 298.
Investigations The investigations performed will depend on the clinical diagnosis or the differential diagnosis. • Blood films should be examined daily for malaria parasites in any febrile patient who has been to a malarial area until either a diagnosis is made or the fever resolves. Blood films may also be examined for trypanosomes in a patient who has been in rural east or west Africa. A full blood count is useful for looking for leukocytosis (suggesting bacterial infections), leukopenia (typhoid, viral infections), pancytopenia (visceral leishmaniasis) or eosinophilia (helminthiasis: schistosomiasis, fascioliasis, visceral larva migrans, clonorchiasis, Bancroftian filariasis). • A Mantoux test should be done early on. • Blood cultures should be taken and, if brucellosis is a possibility, kept under observation for up to 6 weeks, as the organism grows slowly.
• Serological tests that may be useful include those for syphilis, leptospirosis, rickettsial diseases, brucellosis, amoebiasis, leishmaniasis, trypanosomiasis, toxoplasmosis, filariasis and schistosomiasis. They should be used selectively in relation to the clinical presentation and the exposure. A serum sample should be taken on admission and saved, and a second sample taken 10 days later. This pair of sera can then be used to look for a change (usually a rise) in titre. • Imaging procedures should include a chest X-ray and the scanning procedures mentioned under PUO are used as clinically indicated. • Liver and marrow biopsy (see PUO above) are also performed where there is a clinical indication, with samples cultured for routine organisms, brucella, fungi and parasites, in addition to histological examination of sections and microscopy of smears for tubercle bacilli and leish-
277
mania. Bone marrow culture may yield S. typhi in a patient who has previously taken antibiotics.
Management Ideally treatment will follow from the specific microbiological diagnosis of the cause of fever. Occasionally it is necessary to treat the patient for a disease suspected clinically but not proven by available laboratory tests. This may be treatment for malaria, or typhoid or rickettsial infection, or tuberculosis in fevers of longer duration. 1 12
GASTROENTERITIS Gastroenteritis is defined as an acute disease with diarrhoea and/or vomiting and a variable degree of systemic illness. 'Food poisoning' is a term used to describe a selflimiting form of gastroenteritis caused by eating contaminated food.
Aetiology A large variety of microorganisms can cause gastroenteritis (Table 9.13) but in over half of all cases the causative organism cannot be identified. Salmonellae and Campylobacter species are among the most frequent causes. In children the spectrum of organisms is slightly different and rotavirus is the most frequently recognized agent.
Epidemiology Gastroenteritis is a common infection in all parts of the world, occurring sporadically or in epidemics. Epidemics occur when a common source of food or drink is contaminated with micro-organisms and when infection spreads from person to person by the faecal-oral route. For example, Salmonella enteritidis frequently colonize the gut of chickens bred in battery conditions and may infect the oviduct and eggs of hens in batteries. During evisceration in the factory the meat is contaminated and the salmonellae survive freezing and thawing. If such chickens are not thoroughly cooked, salmonellae are ingested and colonize the intestine. During the last few years there have been outbreaks of diarrhoea due to E. coli O:157, which in patients of all ages can go on to cause a haemolytic uraemic syndrome with a significant mortality. This has occurred in retail food outlets where both cooked and uncooked meats are on sale, with the opportunity to contaminate cooked meats with E. coli O:157 from uncooked meat. Some forms of gastroenteritis show striking seasonal variations in frequency but these are usually significant only in temperate areas. Rotavirus is the most common
1
278
Case 9.1
2
MCQ 9.6
TABLE 9.13 Common causes of gastroenteritis Cause
Clinical presentation
Invasive bacteria Shigella species Salmonella species Campylobacter jejuni
Dysentery Diarrhoea, vomiting Diarrhoea predominantly
Toxin-producing bacteria Enteroxin E.coli(ETEC) Vibrio cholerae
Secretory diarrhoea Secretory diarrhoea
Neurotoxin Staphylococcus Bacillus cereus Clostridium botulinum
Vomiting (short incubation) Vomiting (short incubation) Vomiting, diarrhoea, neurological
Cytotoxin Clostridium difficile
Bloody diarrhoea, haemolytic uraemic syndrome Watery diarrhoea
Tissue-damaging viruses Rotavirus Norwalk virus Adenovirus Enterovirus
Infantile diarrhoea Winter vomiting Diarrhoea, vomiting Diarrhoea, vomiting
Protozoa Cryptosporidium Entamoeba histolytica Giardia lamblia Cyclospora cayetanensis
Diarrhoea Dysentery Chronic diarrhoea Diarrhoea
E. coli 0:157
cause of infantile diarrhoea worldwide. In Britain and the USA its peak incidence is in 2 or 3 months during the winter, but in tropical climates there is little seasonal variation. Outbreaks of food poisoning caused by Salmonella, Campylobacter or toxin-producing Staph. aureus are more common in summer.
Pathogenesis Organisms must evade the host defences and colonize the intestine before they can cause disease. Gastric acid is an important defence, and patients with a partial gastrectomy are susceptible to intestinal infection. Some bacteria have on their surface determinants that bind to epithelial receptors. Examples are Vibrio cholerae and some strains of E. coli. The known mechanisms by which microorganisms cause diarrhoea can be divided into two groups: toxin secretion and mucosal damage. These are not mutually exclusive, and for many organisms the precise mechanism is unknown. Toxin secretion Three different mechanisms are recognized by which toxins can cause intestinal pathology. Cholera is a good example of small intestinal toxin-mediated secretory diarrhoea (see
9
CASE STUDY 9.1 ACUTE INFECTIVE DIARRHOEA A 21-year-old female student was travelling in rural Nepal staying in guest houses. Overnight she developed fever, chills and generalized body aches and pains. The next day she was anorexic and developed acute watery diarrhoea, but after 12 hours started to get severe griping abdominal pains which were particularly severe in the left lower quadrant. The character of the diarrhoea changed to the passage of frequent small volume stools, with exacerbation of pain. After 12 hours the stools became uniformly bloodstained. She also described the sensation of wanting to empty the rectum with extreme pain in the anus and relatively little blood-stained material coming out (tenesmus). She was wakened from sleep numerous times in the first 24 hours of the illness and sought medical attention at a local hospital. On examination she looked unwell. Pulse 110 regular, BP 90/60, temperature 38.4°C. There
Questions 1. What is the differential diagnosis? 2. What investigations should be performed? 3. What are the main points of management?
was tenderness over the left lower quadrant of the abdomen. She passed a small amount of blood stained watery stool shortly after admission. Comment This history is suggestive of acute invasive bacterial infection of the gut. It is typical of shigellosis, with the initial fever, followed by acute watery diarrhoea and then dysenteric diarrhoea, passing small volumes of stool with pain and tenesmus. However, the distinction between shigellosis, Campylobacter infection and salmonellosis is clinically unreliable. The marked systemic upset initially would be against giardiasis, cyclospora (first described as a cause of diarrhoea in Asia among western travellers in Nepal), cryptosporidium, toxigenic E. coli and cholera. Amoebic dysentery begins more insidiously and is gradually progressive. Investigations must include examination of the stool for amoebic trophozoites, and culture for Shigella and Salmonella. The finding of amoebic cysts in her stool is irrelevant, as motile trophozoites with ingested red cells would be evident in faecal smears in invasive amoebiasis. Microscopy of the stool would have shown large number of pus cells, which do support a diagnosis of invasive bacterial infection.
p. 322), and enterotoxigenic strains of E. coli secrete a heatlabile enterotoxin which acts in a similar way. In staphylococcal food poisoning neurotoxin-secreting staphylococci multiply in food, and the toxin causes vomiting and diarrhoea within hours of ingestion. Staphylococci are not detected in the stools of patients with this type of food poisoning. Bacillus cereus, which contaminates reheated rice, causes vomiting by a similar mechanism. Cytotoxins, such as verotoxin produced by E. coli O:157 and toxin B of Clostridium difficile, cause tissue damage. Mucosal damage Shigellae invade the colonic mucosa and cause local inflammation, and so the faeces contain blood and inflammatory cells. Impairment of water absorption from the colon and exudation of protein-rich fluid through the
Since amoebic cysts were seen in a faecal smear, she was treated with metronidazole as well as norfloxacin for shigellosis. She was also given intravenous fluids as she could not initially tolerate ORS, but within 36 hours of starting treatment the fever regressed and the diarrhoea started to improve, though after finishing 7 days' treatment with both drugs bowel actions remained abnormal both in frequency and the consistency of the stools. No more blood was seen for the remainder of her stay in Nepal or after her return to the UK. The management was appropriate, though one could argue that there were sufficient clues to suggest that norfloxacin alone would have been enough. With marked systemic upset and dysenteric stools there are clear indications to give antibiotics. Rehydration by the oral route was first attempted, with recourse to intravenous fluids when that failed. The persisting abnormalities of bowel habit after effective treatment are an indication of postinfective intestinal irritability, but it is essential to ensure that there is no persisting infection, such as giardiasis, and that there is no possibility of non-specific inflammatory bowel disease which, some reports indicate, may be precipitated by acute gastrointestinal infection.
inflamed and ulcerated mucosa are the cause of fluid stools. Salmonellae, Campylobacter and rotavirus are also invasive and cause tissue damage, but the precise mechanisms are not understood. Damage to the brush border of the enterocytes causes temporary disaccharidase deficiency, which may prolong the diarrhoea even after the pathogen has been eliminated.
Clinical features Most episodes of gastroenteritis are mild and self-limiting. The incubation period is usually short, ranging from a few hours with staphylococcal food poisoning up to 5 days with Campylobacter infection. Vomiting, diarrhoea and cramping abdominal pains are typical features. Large volume stools suggest a small bowel diarrhoea. The stools are fluid
279
without blood or pus in toxin-mediated disease (e.g. cholera), but when invasion and mucosal damage occur in Salmonella, Shigella and Campylobacter infections blood and mucus may be seen in the stool. The appearance of the stools is an unreliable guide to the type of organism. The major consequence of gastroenteritis is dehydration with electrolyte imbalance. Babies are more vulnerable and can rapidly become severely dehydrated. It is essential that the clinician can make a reasonably accurate assessment of the degree of dehydration and Table 9.14 gives some guidelines. Fever and signs of systemic illness suggest invasive pathogens. Some invasive organisms can cause septicaemia (e.g. Salmonella typhimurium), and some shigellae produce neurotoxins which enter the circulation in the absence of septicaemia and, on reaching the central nervous system (CNS), cause headache and meningism. The illness is usually over within 7 days, but symptoms are liable to persist for longer with shigellae and Campylobacter. Persistent diarrhoea suggests Giardia infection, especially if steatorrhoea is present. Although amoebiasis is commonly thought of as a cause of acute watery diarrhoea in the tropics it is in fact relatively uncommon, causing only 6% of cases in a large study from Bangladesh. Usually the diarrhoea has an insidious onset and gets worse gradually, though all ranges of severity are possible, from the passage of a little bloodstained mucus with stools to a severe illness every bit as bad as ulcerative colitis.
Diagnosis The diagnosis is usually clear, but problems arise when there is vomiting in the absence of diarrhoea; when abdominal pains are accompanied by localized tenderness, suggesting pelvic inflammatory disease or appendicitis; and when blood in the stools is taken to indicate inflammatory bowel disease. A positive diagnosis is established by identification of the organism in stools by microscopy, antigen assay (for rotavirus) or culture.
Management The management of diarrhoea is concerned mainly with the management of dehydration. After an assessment of the degree of dehydration using the criteria set out in Table 9.14, a plan of management is determined. Where there is no dehydration (<5% body weight lost) oral fluids are given freely and normal feeding is encouraged. When there is some dehydration (5-10% body weight lost) the deficit should be replaced using oral dehydration solution (ORS; Table 9.15) 80ml/kg over 4 hours. In addition to ORS, water and other non-electrolyte fluids should be 1
280
MCQ 9.7
TABLE 9.14 Assessment of dehydration A No dehydration
B Some dehydration
C Severe dehydration
Condition
Alert
Eyes
Normal
Restless*/ irritable* Sunken
Tears Mouth and tongue Thirst Drinks Skin turgor
Present Moist
Absent Dry
Lethargic*, unconscious* Very sunken and dry Absent Very dry
None Normally Normal
Thirsty* Eagerly* Reduced*
Drinks poorly* Not able to drink* Markedly reduced*
Features in bold with * are key signs. If 2 signs from column C including 1 key sign are present then severe dehydration is present; if 2 signs from column B including 1 key sign are present, there is some dehydration. (After A Manual for the Treatment of Diarrhoea, World Health Organisation 1990.)
TABLE 9.15 Composition of oral rehydration solution (WHO formulation) Sodium chloride Trisodium citrate, dihydrate Potassium chloride Sucrose Made up to 1 litre with clean water
3.5 g/L 2.9 g/L 1.5 g/L 40 g/L
given to provide water for insensible losses. After each bowel action an additional 400 mL of ORS should be given to replace continuing losses. Oral rehydration solution very effectively replaces lost fluid despite the presence of an enterotoxin-mediated secretory process in the gut, but it does nothing to reduce the volume of diarrhoeal stools produced. The use of rice flour as the source of glucose in cereal-based ORS solutions not only replaces lost fluid but also reduces the volume of faecal effluent. It has the further advantage of being widely available in areas of the world where infectious diarrhoeal diseases are common, but preparing cereal-based ORS requires heating the solution to make a palatable gruel. When there is severe dehydration (>10% body weight lost) intravenous access should be established immediately and Ringer's lactate (or normal saline if that is not available) infused at 30mL/kg over 30 minutes, and then 70mL/kg over 2 hours. Thereafter, continuing losses should be replaced orally if the patient is able to drink, or intravenously if not. In all patients with diarrhoea it is essential that their progress is assessed every hour, so that if symptoms and signs are deteriorating on an ORS regimen they can be
switched to intravenous fluids. Vomiting may prevent successful ORS therapy, but first the administration of frequent small volumes of fluid by mouth should be tried. When initial rehydration has been achieved, continuing faecal losses should be replaced by ORS, 400 mL after each bowel action, and feeding begun as soon as the patient wants to eat. Bowel sedatives have little place in the management of intestinal infections and they may be harmful, precipitating toxic dilatation in elderly and young patients in infections with the invasive bacterial pathogens. Antibiotics are normally not required, but they are needed when there is profuse watery diarrhoea, marked systemic upset and obviously dysenteric (bloodstained) diarrhoea. Empirical treatment with ciprofloxacin 500 mg twice daily for 5 days is usually given. In addition, the following situations merit antibiotic treatment: • • • • • • • •
Septicaemic Salmonella infection (ciprofloxacin) Severe shigellosis (ciprofloxacin) Severe Campylobacter infection (erythromycin) Yersinia (doxycycline) V. cholerae (doxycycline) Entamoeba histolytica (tinidazole, metronidazole) Giardia lamblia (tinidazole, metronidazole) Cyclospora cayetanensis (co-trimoxazole).
Problems associated with use of antibiotics are exacerbation of diarrhoea, prolonged carriage of some organisms (e.g. salmonellae) and development of resistance to multiple antibiotics (e.g. shigellae). There is evidence to suggest that antibiotic treatment in E.coli O:157 infection may increase the risk of renal complications by promoting toxin release. 1
FURTHER READING ON GASTROENTERITIS A manual for the treatment of diarrhoea 1990. Geneva: World Health Organization Programme for the Control of Diarrhoeal Diseases.
ACUTE UPPER RESPIRATORY INFECTION
TABLE 9.16 Causes of upper respiratory infection Disease
Causative organism
Common cold and pharyngitis
Rhinovirus Coronavirus Influenza virus Parainfluenza virus Respiratory syncytial virus Adenovirus Unknown
Pharyngitis/tonsillitis
As above, plus: Epstein-Barr virus B-haemolytic streptococcus group A Mycoplasma pneumoniae Mixed anaerobes and spirochaetes* Corynebacterium diphtheriae* Neisseria gonorrhoeae*
Stomatitis
Candida albicans Herpes simplex virus Coxsackie A and other enteroviruses Mixed anaerobic bacteria
9
*Less common
treatment of choice for streptococcal pharyngitis, with erythromycin for penicillin-allergic subjects. Ampicillin and related drugs should be avoided, as they often cause a rash in patients with infectious mononucleosis. Upper respiratory infections are frequently complicated by otitis media in children and, less often, by sinusitis in adults or children. These are usually caused by secondary bacterial infection, and it is therefore important to recognize them and treat with antibiotics. Common bacterial causes of otitis media include Strep. pneumoniae, H. influenzae (mainly untypable), group A B-haemolytic streptococci and Branhamella catarrhalis. Many H. influenzae are now resistant to amoxicillin, and co-amoxyclav can be used instead. The bacteria that cause acute sinusitis are similar to those incriminated in otitis media, but anaerobes, Gramnegatives and Staph. aureus should also be considered. Upper respiratory anaerobic bacteria are usually penicillin sensitive, in contrast to those found in the large bowel.
Common cold and pharyngitis The common cold has an incidence of 1-4 episodes per person per year. Large gaps remain in our knowledge of pathogenesis, although it is clear that many viruses can cause the same clinical entity. There is considerable overlap between organisms causing colds and those causing pharyngitis (Table 9.16). Pharyngitis is more important, as it is often part of a more systemic illness. The majority of episodes of pharyngitis are caused by viruses. Antibiotic treatment should be reserved for culture-proven cases of streptococcal pharyngitis. In the developed world, group A streptococcal pharyngitis is now rarely complicated by rheumatic fever or glomerulonephritis. Penicillin, as a single i.m. dose or orally for a minimum of 10 days, is the
Acute stomatitis In contrast to pharyngitis, the microbial cause of acute stomatitis can often be diagnosed from the appearance of lesions in and around the mouth. Candida is a common pathogen, particularly in debilitated patients, patients receiving broad-spectrum antibiotics and patients with HIV infection. White plaques occur on an erythematous background. The distribution is wide, including the buccal mucosa. Ulcers are usually superficial and not easily confused with primary herpes simplex infection. The latter is often associated with perioral clusters of vesicles. Severely painful ulceration of the mouth and lips in a young immunocompetent patient is usually due either to
281
Stevens-Johnson syndrome or to primary herpes simplex infection. Coxsackie virus infection may cause small, scattered vesicles and ulcers, but they are more sparse than those of herpes simplex and less painful. Noninfective causes of ulcers must also be considered, such as aphthous ulcers and, rarely, Behget's disease (p. 1153). Infections in the subcutaneous tissue spaces of the
CASE STUDY 9.2
CHRONIC FATIGUE
A 34-year-old female nursery school teacher in a stable relationship complained of recurrent episodes of sore throat, the most recent of which was 2 months ago. She had had difficulty throwing off 'flu and other infections for 3 years and felt tired all the time. She had pains in the neck and the 'glands' in her neck were going up and down. Her muscles ached during and after exertion and she became fatigued sooner than she would have expected. She denied depression and had no problems at work. There were no abnormalities on examination and, in particular, no lymphadenopathy but minimal tenderness in the anterior cervical region. Muscle power was normal and there was no convincing muscle tenderness. Her affect was normal but she was clearly tired of her symptoms, sometimes sighing while describing them, and she was anxious about an underlying persistent disease of a 'weak immune system'. Questions
1. What is the differential diagnosis? 2. What further investigations would you perform? 3. What would be your approach to management? Discussion
The GP had checked her full blood count repeatedly so we know that she did not have neutropenia or lymphopenia. Examination of the pharynx showed normal tonsils but it would be helpful to see her during an episode of sore throat to exclude 282
face and neck often originate from periodontal infection. Ludwig's angina is an anaerobic bacterial infection of the submandibular and sublingual spaces which causes firm swelling of the tissues below the chin. These may press inwards and compromise the airway. There is accompanying fever and tachycardia and the patient requires urgent antibiotic treatment, usually with penicillin and metronidazole.
recurrent tonsillitis. Persistent pharyngeal infection with group A Phaemolytic streptococcus may cause recurrent sore throat but it does not cause tiredness between episodes. One of her episodes of sore throat could have been infectious mononucleosis caused by EBV infection (or, less commonly, CMV or toxoplasma infection); this usually causes one continuous episode of illness and recurrence is rare beyond 12 months after the initial episode but it can cause tiredness persisting for up to 6 months. Many patients are anxious that recurrent upper respiratory infections indicate a disorder of the immune system. This is not so in the absence of recurrent candidiasis and it is not necessary to undertake immunological investigations to prove it but reassurance is often helpful. Simple causes of tiredness such as anaemia and hyper- or hypothyroidism can be excluded by examination and confirmed by appropriate tests. Rather than requesting a wide range of investigations, it is advisable to target them at excluding diseases which have been a particular cause of anxiety to the patient if the anxiety can not be allayed by reasonable discussion. Assessment by a sympathetic psychiatrist can be helpful and should be regarded as a part of the overall investigation of patients with very prolonged symptoms. Chronic fatigue syndrome is diagnosed when the combination of symptoms illustrated by the above patient is present with negative investigations for organic disease. Many patients have the
somatic symptoms of depression but deny the state of depression or attribute it to the presence of physical symptoms. Sometimes anxiety seems to be a more important factor. The term myalgic encephalomyelitis (ME) should be avoided since none of these patients has encephalomyelitis. The patient was reassured by a wide range of normal investigations (including FBC, ESR, CRP, U&E, LFTs, thyroid function, auto-antibody screen, CXR, negative IgM antibodies to EBV, CMV and toxoplasma and negative throat swab). She was seen by a psychiatrist who found no evidence of depression but she discussed some family stress at Christmas and uncertainty about her career; when she was on holiday at Christmas, there was a family row in which she acted as mediator between her brothers and her mother which she found very stressful. Later she was able to resolve this but she missed her holiday because of the stress and her illness (flu). At work she had been considering whether she should go part-time because of her symptoms or aim for promotion to a deputy school headship. Her symptoms had been improving slowly and she now felt optimistic with the summer holidays looming. She was offered counselling which she attended and found useful. She also undertook a graded exercise programme and at review sessions she was encouraged to work through her fatigue. By end of the year, she was working full-time in the same job and coping despite some persistent tiredness.
SEXUALLY TRANSMITTED DISEASES Sexually transmitted diseases (STDs) are infections commonly transferred through sexual contact. They are discussed in detail in Chapter 11.
CHRONIC FATIGUE SYNDROME (POSTVIRAL SYNDROME, MYALGIC ENCEPHALOMYELITIS) This syndrome is seen most often in young adults. There is a prolonged period of lethargy, often with muscle pains and fatiguability, usually after an episode reminiscent of a viral illness but sometimes in the absence of an evident acute illness. The problem causes great distress to patient and relatives because an explanation is lacking and there is prolonged inability to work or play at expected levels, often coupled with an unreasonable need for sleep. Doctors are frustrated by their inability to establish a positive diagnosis or to give any specific treatment, and the patient often turns to alternative medicine.
Aetiology The syndrome is heterogeneous and no single explanation will fit all patients. The term 'myalgic encephalomyelitis' is misleading as there is no evidence of encephalomyelitis and myalgia may not be present. A number of infections have been associated with this syndrome and they are not all viral. Infectious mononucleosis is the best known and studied, but CMV infection and toxoplasmosis have been suspected, and it is likely that many other organisms can act as triggers in susceptible individuals. Enteroviruses, particularly of the Coxsackie group, have also been suspected but
evidence is inconclusive. Often the only evidence for infection at the onset is a history of febrile illness, perhaps with pharyngitis or lymphadenopathy, and a full blood count may have revealed some atypical mononuclear cells. The relationship of postviral syndrome to depression is complex. There is no doubt that some patients develop the symptoms and signs of depression and benefit from antidepressant treatment. More commonly the patient becomes depressed as a result of the illness but lacks many of the features of primary depression. In this situation antidepressant therapy is unlikely to be beneficial.
9
Clinical features The central symptoms are profound lethargy and easy fatiguability. Often these are accompanied by muscular pains, headaches and symptoms suggestive of fever, such as sweating. This is usually mild, and when the temperature is recorded it is normal or only minimally elevated in the evenings. Exertion exacerbates tiredness, and the patient often goes to bed early and wakes late still feeling tired.
Management Patients benefit greatly from having their illness taken seriously, and if a precipitating infection can be positively identified this also helps. Sometimes the greatest problem is anxiety about the outcome or about whether there is an underlying disease that has not been diagnosed, so reassurance is important. When patients have restricted their activity it is worth trying to rehabilitate them by a programme of daily exercise, starting with something light such as walking or swimming, and gradually increasing it in a documented way. The patient is assured that exercise is not harmful and advised to sleep as required. Most patients recover spontaneously within weeks rather than months, but a few continue to suffer for over a year.
VIRUS INFECTIONS Viruses are usually classified according to their nucleic acid content and morphology. The classification of viruses used in this section is shown in Tables 9.17A and B. Arboviruses (arthropod-borne) are viruses transmitted by the bite of an insect vector. Most arboviruses are togaviruses, but bunyaviruses and orbiviruses (RNA viruses in the reovirus family) are also included.
ENVELOPED DOUBLE-STRANDED DNA VIRUSES HERPES VIRUSES Six herpes viruses cause disease in humans: • Varicella zoster virus (VZV)
• • • • •
Two herpes simplex viruses (HSV 1 and 2) Epstein-Barr virus (EBV) Cytomegalovirus (CMV) Human herpes virus 6 Herpes virus associated with Kaposi's sarcoma (HHV8).
Morphologically, herpes viruses are very similar and indistinguishable by electron microscopy. They are similar in some aspects of their behaviour, notably their ability to establish latent infection with the potential for reactivation. During latency in dorsal root ganglia VZV shows no demonstrable evidence of viral replication for many years. With HSV there is evidence of a low level of replication, and reactivation is more frequent. EBV infects B lymphocytes, and EBV and CMV replicate at a low level continuously. CMV can often be detected in the urine of asymptomatic carriers, and herpes simplex in saliva. The mechanisms by which virus replication is suppressed are
283
TABLE 9.17A Classification of viruses:DNA
TABLE S.176 Classification of viruses: RNA
Morphology
Virus
Morphology
Virus and disease
Enveloped double-stranded
Herpesviridae Varicella zoster (VZV) Herpes simplex (HSV I, II) Epstein-Barr (EBV) Cytomegalovirus (CMV) Human herpes virus 6 (HHV6) Human herpes virus 8 (HHV8) Poxviridae Vaccinia Variola (smallpox) Orf Parvoviridae Hepadnaviridae
Enveloped single-stranded
Orthomyxoviridae Influenza Paramyxoviridae Parainfluenza Respiratory syncytial disease Mumps Measles Togaviridae Rubella Alpha (equine encephalitis) Flaviviridae Dengue Yellow fever Encephalitis Hepatitis C Bunyaviridae Arenaviridae Lymphocytic choriomeningitis Lassa Filoviridae Marburg Ebola Retmviridae Lentiviruses (HIV 1 and 2) Oncoviruses - type C (HTLV1 and 2) Rhabdoviridae Rabies Vesiculostomatitis Coronaviridae Coronavirus Reoviridae Rotavirus Reovirus Picornaviridae Rhinovirus Enteroviruses Coxsackie A, B Echo Polio Enterovirus 70, 71 Hepatitis A Caliciviridae Norwalk Hepatitis E virus Astroviridae Astroviruses
Enveloped single-stranded
Hepatitis B Hepatitis D
Non-enveloped double-stranded
Adenoviridae Papovaviridae Papilloma Polyoma
incompletely understood, but T cell-mediated immune mechanisms probably have an important role, as all the herpes viruses are liable to reactivate in patients with depression of cell-mediated immunity, such as those with lymphoma or leukaemia.
Varicella zoster virus infection Chicken pox (varicella) This illness is easy to recognize, common and highly infectious. It is a febrile illness with a vesicular rash (Fig. 9.6). During the primary infection there is a viraemic phase when VZV becomes widely disseminated in white cells. In normal subjects it only produces significant lesions in the skin and mucous membranes, but infection of cutaneous sensory nerves leads to infection of dorsal root ganglia, and here the virus enters a latent state. Reactivation later causes herpes zoster (shingles). During primary infection VZV is present in nasopharyngeal secretions and is transmitted readily by coughing and sneezing. It is also in vesicle fluid in chickenpox and shingles, and this can be a source of transmission. The incubation period of chickenpox is 15-18 days and the patient is infectious from a few days before the rash erupts until new lesions cease to appear. The severity of chickenpox is determined by the age and immunological state of the patient. It is most severe in neonates if they have no maternal antibody to VZV, and in patients immunocompromised by disease such as leukaemia or by immunosuppressive therapy. It is usually a mild disease in children, but it becomes increasingly severe after puberty. 284
Clinical features In children chickenpox starts with the appearance of the
Non-enveloped double-stranded Non-enveloped single-stranded
rash, which is often sparse and not accompanied by constitutional symptoms. The most troublesome feature of the illness is itching. In adults there is a notable prodromal illness lasting 2-3 days, during which headache, backache, shivering and fever occur, sometimes with a sore throat and cough. The more severe the prodromal illness, the more profuse is the rash that follows. The rash starts on the trunk and spreads to the face and limbs (Fig. 9.6). Lesions appear in crops which progress rapidly through the sequence macule, papule, vesicle, pustule, scab. Often the first visible lesions are vesicles containing clear fluid with little surrounding erythema, but the pustular stage is reached within 24 hours. Vesicles on the
9
FIG. 9.6 Vesicles and pustules in a patient with chickenpox
palate, tonsils and pharynx rapidly burst, leaving superficial ulcers. Crops of skin lesions erupt over 2 or 3 days, but it takes several more days for them all to heal. Constitutional symptoms, if present, lessen with the onset of the rash and disappear within 2 days. Complications Secondary infection of the skin lesions, including the scalp, occurs because of scratching, but it usually responds to cleaning and bathing and rarely requires antibiotics. Chickenpox pneumonia occurs in one-fifth of adults, and more frequently in immunocompromised patients. It varies in severity from transient dyspnoea to a fulminant pneumonia. Postinfectious encephalitis is extremely rare and has a variable course, but it is often severe or fatal. Its onset is within a week of the rash and cerebellar involvement is characteristic. Bleeding into the skin, nose or intestine, also rare, is due either to steroid-responsive thrombocytopenia or to consumptive coagulopathy, when the prognosis is much worse. Neonatal chickenpox Most women are immune by the time they reach childbearing age, but if a mother develops chickenpox within a few days of having a baby the child is born without the protection of maternal IgG antibodies transferred across the placenta, and it is immediately exposed to the virus. If the child becomes infected during the first 5 days of life disease is severe, with multi-organ involvement. Disease can be prevented or made milder by the administration of varicella immune globulin 250 mgi.m. at birth. Aciclovir l0mg/kg is given intravenously 8-hourly for 7 days if any signs of infection (e.g. fever) appear. This does not seem to prevent the virus becoming latent. Congenital chickenpox Rarely, VZV can cross the placenta during the first 20 weeks of pregnancy, causing fetal damage or death. Diagnosis and management A clinical diagnosis of chickenpox suffices in most cases.
FIG. 9.7 Dermatomal distribution of varicella zoster lesions
Electron microscopy is the quickest way to establish that a herpes virus is present in vesicle fluid, but does not establish its type. The virus can be identified by tissue culture inoculation, and antibodies are detected by a complement fixation test. Treatment with aciclovir (p. 268) is required only in severe cases susceptible to complications such as chickenpox pneumonia, in immunocompromised patients (such as children with malignant disease), and in neonates (Table 9.5, p. 268). Intravenous treatment (l0mg/kgt.d.s in adults; 500mg/m2 for children aged 3 months to 12 years; l0mg/kg for children less than 3 months) is needed in order to achieve adequate serum concentrations. Many patients with chickenpox pneumonia need ventilation (see Ch. 14) and antibiotic treatment for secondary bacterial infection, the most common organism being Staphylococcus aureus. Shingles (zoster) When VZV reactivates within a dorsal root ganglion it migrates down the nerve into the skin and causes a crop of lesions identical to those of chickenpox but confined to the dermatome (Fig. 9.7). Pain within the dermatome may precede the eruption by a few days and is often severe. One or two adjacent dermatomes on the trunk are most commonly affected, but involvement of the ophthalmic division of the fifth cranial nerve is important because the eye can be damaged by the virus or by secondary bacterial infection.
285
In the elderly it is common for a mild viraemia to occur, causing a few scattered lesions to appear outside the involved dermatome. More serious dissemination with visceral involvement is seen in immunocompromised patients. Patients with Hodgkin's disease are particularly susceptible to shingles, especially during chemotherapy. The skin heals over 2-3 weeks and there is often some residual pain for a few weeks. Rarely, intractable pain continues for years (post-herpetic neuralgia). This is more common following ophthalmic zoster, and after severe infections in immunocompromised patients. 1 Management Most patients do not require admission to hospital and treatment of pain is the main concern. Continuous treatment with simple analgesics such as paracetamol is often effective and should be tried before drugs that have more side-effects. Oral treatment. A small increase in the rate of healing has been demonstrated when oral aciclovir is used in high dose, 800 mg five times daily for 7 days. This benefit may be enhanced with the use of newer alternatives such as valaciclovir, as higher serum levels of aciclovir are achieved. Less frequent administration is needed with famciclovir 250 mg thrice daily. Intravenous treatment. Intravenous aciclovir (l0mg/kg t.d.s for adults) should be given to immunocompromised patients for 1 week. It reduces pain, shortens the healing time and limits dissemination of the virus. Evidence for the benefit of prednisolone in reducing post-herpetic neuralgia is controversial and it is not recommended. Topical treatment • In ophthalmic zoster it is important to combine an antibiotic (e.g. chloramphenicol drops) with aciclovir ointment. • Pruritus treatment, e.g. calamine, is soothing for a few minutes. • Antivirals, e.g. idoxuridine and aciclovir, are impractical and of limited value. 0
Herpes simplex virus infection HSV 1 and 2 cause patterns of disease that differ clinically and epidemiologically but share some characteristics. Both establish permanent, latent infection within sensory nerve ganglia following primary infection, with reactivation causing episodes of disease in the area supplied by the nerve. These viruses are indistinguishable morphologically but can be separated by differences in antigen expression. Infection with HSV 1 is more common. Antibodies are detectable in 80-100% of adults in lower socioeconomic groups, and in 30-50% in higher socioeconomic groups. Both viruses are readily transmitted, mainly in vesicle fluid. HSV 1 is usually acquired during childhood, but HSV 2 infection is mainly transmitted sexually and is most common in sexually promiscuous adults. Clinical expression of infection with these viruses is strongly influenced by age, nutrition and the immunological state of the patient. An immunologically immature neonate is overwhelmed by disseminated HSV infection acquired during parturition. Infection in older children is often asymptomatic or causes localized disease which is most severe in the presence of malnutrition. 0 Primary infection with HSV 1 Acute herpetic gingivostomatitis in children 2-4 years old presents with fever, sore throat, and submental and anterior cervical lymphadenopathy. Clusters of vesicles appear around the lips and in the mouth from gums to pharynx (Fig. 9.8). Inside the mouth lesions rapidly ulcerate, causing pain and dysphagia with consequent drooling of saliva. The child is miserable and may become dehydrated if not encouraged to drink through a straw. The lesions heal over 1-2 weeks. Primary infection can occur anywhere on the skin and, on the finger, a herpetic whitlow can closely mimic a bacterial paronychia. Widespread involvement of the skin can occur in individuals with atopic dermatitis (eczema herpeticum, p. 399) and, particularly in infants, this can be associated
SUMMARY 4 Varicella zoster and herpes simplex infection
286
Primary
Reactivation
VZV HSV 1
Chickenpox Acute or asymptomatic gingivostomatitis Keratoconjunctivitis Encephalitis
Shingles Cold sores Keratoconjunctivitis
HSV 2
Genital
Genital
1
Fig. 9.1
2
MCQ 9.8
4
Fig. 9.3
5
Fig. 9.4
3
Fig. 9.2
FIG. 9.8 Gingivostomatitis caused by primary herpes simplex 1
with systemic symptoms. In the eye keratoconjunctivitis can cause scarring of the cornea and loss of vision. Herpetic encephalitis in adults presents a characteristic clinical picture owing to necrotic lesions in the temporal lobe. This rare manifestation of primary HSV infection is described on page 1422. Primary infection with HSV 2 Although HSV 1 and 2 can cause identical disease, HSV 2 is largely associated with genital infection (see p. 456). 4 Infection of neonates can occur during parturition when the mother has genital herpes, particularly if her infection is primary rather than recurrent. The infant develops scattered clusters of vesicles which recur in the same sites subsequently. Alternatively there may be rapid deterioration as the virus disseminates to all the viscera, causing encephalitis, pneumonia and hepatitis, with a high mortality. Usually this severe illness starts in the first few days after birth, but occasionally onset is delayed several weeks. Reactivation of HSV The mechanisms involved in maintaining latency are not fully understood. Reactivation may occur after exposure to ultraviolet light, an episode of infection or trauma to the sensory nerve. Many episodes have no identifiable precipitant. Reactivation is more common in irnmunocompromised patients, particularly those with leukaemia undergoing treatment. The characteristic lesion of reactivated HSV 1 is a cold sore. Patients often experience minor discomfort in the form of tingling or itching up to 24 hours before a lesion appears. Lesions can occur anywhere on the skin or mucous membranes, but are commonly adjacent to the lips. 5 A macule rapidly progresses to a papule and then to a cluster of vesicles which involute, ulcerate and scab. The whole process takes 1-2 weeks. See Chapter 11 for symptoms of reactivation of genital herpes (p. 456).
underdeveloped countries and in crowded living conditions, but infection is delayed in more prosperous environments. Infection in adolescents and adults usually causes infectious mononucleosis (glandular fever). Other diseases related to EBV infection are nasopharyngeal carcinoma, Burkitt's lymphoma, the very rare syndrome of X-linked recessive progressive combined variable immunodeficiency, and lymphoid interstitial pneumonitis in children with AIDS.
9
Infectious mononucleosis Infectious mononucleosis is an acute febrile illness caused by EBV and characterized by a severe sore throat and generalized lymphadenopathy. Pathology and pathogenesis EBV enters through the pharyngeal epithelium and replicates in B lymphocytes, causing them to proliferate. Fifteen per cent or more of blood mononuclear cells appear 'atypical' during acute infection: these are T lymphocytes reacting to the presence of infected B lymphocytes. EBV does not establish a true latent state but maintains a low level of replication throughout life. During infectious mononucleosis, the spleen and lymph nodes are intensely infiltrated with mononuclear cells and the spleen is unusually friable. Haemorrhage may occur into the subcapsular area, and rarely this leads to intraperitoneal haemorrhage. Clinical features Infectious mononucleosis is most common in adolescents and young adults, but children as young as 5 years old may be affected. The illness is more severe in older patients. The incubation period is uncertain but is probably 1-2 weeks. There is a gradual onset of malaise, general aching and fever. The throat becomes painful and engorged with enlarging lymphoid tissue, so that speech is nasal and swallowing is inhibited by pain. The tonsils are large and coated with thick, white exudate (Fig. 9.9). Petechiae may be seen on the soft palate. There is generalized lymphadenopathy
Management of herpes simplex HSVs are highly sensitive to aciclovir and other DNA polymerase-inhibiting drugs. Only serious primary infections with HSV 1, such as encephalitis in adults, severe eczema herpeticum or disseminated neonatal infection, warrant treatment with systemic antiviral drugs. The usual dose of aciclovir for intravenous treatment of herpes simplex is 5mg/kgt.d.s., but for encephalitis l0mg/kg is needed. Initial attacks of genital herpes are treated with 5 days of aciclovir, with an antibiotic if secondary infection has occurred. For recurrences attention to local hygiene is all that is required and 5% aciclovir ointment may be helpful for local lesions.
Epstein-Barr virus infection Epstein-Barr virus (EBV) is a herpes virus which is transmitted by close oral contact. Infection is frequently acquired asymptomatically during early childhood in
FIG. 9.9 Acute tonsillopharyngitis caused by primary Epstein-Barr virus infection
287
in most patients and splenomegaly is common. Uncommon features (occurring in less than 15% of patients) are rash, jaundice and tender hepatomegaly. Thrombocytopenia or autoimmune haemolytic anaemia occur rarely. The acute stage of the illness lasts 2-3 weeks and most patients are entirely well within a month. A small proportion of patients, particularly when older, make a slower recovery, continuing to feel lethargic for a variable period (see Chronic fatigue syndrome, p. 283). Differential diagnosis Other viral causes of sore throat and lymphadenopathy, such as adenovirus, influenza virus and rhinovirus, must be considered (see Table 9.16). Streptococcal infections can cause an identical appearance in the throat, but the lymphadenopathy is mainly in the anterior cervical region. Streptococci are found on throat swabs in 10% of patients with infectious mononucleosis and their role is unclear. Many virus infections are associated with atypical lymphocytes on the blood film, but these can be distinguished from glandular fever cells by an experienced observer. Atypical lymphocytes are also seen in acute CMV infection and occasionally in toxoplasmosis. Both of these conditions can cause lymphadenopathy but they rarely produce sore throat. Laboratory features Atypical mononuclear cells are usually present in the blood film at some stage of the disease. Tests for heterophil antibodies, i.e. antibodies to heterologous erythrocytes, are the Paul-Bunnell and Monospot tests. Heterophil antibodies are present in 90% of patients by the third week of illness, but in only 30% during the first week. Specific IgM antibody measurements are not reliable. Liver function tests are often abnormal. Management No specific treatment is available. Simple analgesic therapy is used to relieve discomfort in the throat, and frequently the patient can only take fluids in the early stages. Occasionally the degree of congestion is such as to threaten the airways; a short course of prednisolone, starting at 30 mg daily and tailing off over 2 weeks, can produce a rapid reduction in the size of the tonsils. If penicillin therapy is indicated for treatment of concurrent Streptococcal infection, ampicillin and amoxicillin should be avoided as they cause a severe maculopapular rash. X-linked recessive progressive combined variable immunodeficiency (Duncan's disease) This rare inherited disease is now recognized as an abnormal response to EBV infection. Patients either die of overwhelming EBV infection in the acute stage or develop
288
1
MCQ 9.9
4
MCQ 9.10
2
Fig. 9.5
3
Fig. 9.6
a progressive immunodeficiency following infection. Lymphoma may complicate the late stages. 1
Cytomegalovirus (CMV) infection CMV is a herpes virus which rarely causes significant disease in immunologically competent subjects. Infection is usually asymptomatic, but it may be associated with a mild febrile illness during which atypical mononuclear cells appear in the blood; these cells are similar to those seen in infectious mononucleosis. Primary infection in the neonate causes serious disease, and primary infection of pregnant women can cause congenital defects in the fetus. As with other herpes viruses, infection is lifelong. CMV replicates at a low level throughout life, but when immunity is suppressed the rate of replication increases. Patients with kidney or heart transplants are particularly at risk, and CMV sometimes causes severe disease in patients with AIDS (pp. 446-448). Transmission The virus is present in blood during primary infection and can cross the placenta. It can also be transmitted in blood used for transfusion. Infected organs transplanted from seropositive donors can cause primary infection in the recipient, but most CMV disease in renal transplant patients is caused by reactivation. The virus is shed from the cervix during active infection and is also present in semen and urine. Acute infection in normal adults There may be a mild febrile illness which is recognized as viral infection when atypical mononuclear cells are seen in a blood film. Sore throat, generalized lymphadenopathy and splenomegaly occur in less than one-third of patients. Abnormal liver function tests show that there is usually a mild hepatitis, but jaundice is rare. The average age for symptomatic infection is 30 years, about 10 years older than for infectious mononucleosis. Complications are rare in immunocompetent patients, and when they occur they are mild. Pneumonitis, myocarditis, meningoencephalitis, Guillain-Barre syndrome, thrombocytopenia and haemolytic anaemia have all been described. Infection in immunosuppressed patients Both primary infection and reactivation can cause disease in immunosuppressed patients, but in renal transplant recipients the more severe disease is seen during primary infection. Asymptomatic reactivation is common and is shown by culture of virus from urine. Fever, sometimes with atypical mononucleosis, is the most common presentation of disease, followed by interstitial pneumonitis. Interstitial pneumonitis presents with insidious onset of fever, a non-productive cough and dyspnoea. Chest radiography shows bilateral diffuse interstitial changes indistinguishable from those of many other opportunistic
infections. Diagnosis is usually made by transbronchial biopsy. Hepatitis is usually mild, but occasionally causes hepatic failure. CMV may be a harmless passenger in the gastrointestinal tract of patients. Its association with enteritis is strongly suggested by the coincidence of seroconversion and haemorrhagic lesions anywhere from the stomach to the rectum, causing a severe diarrhoeal disease and blood loss. A response to treatment with antiviral drugs supports the existence of this clinical entity. In the mouth and oesophagus of AIDS patients, CMV can cause large punched-out ulcers. 2 Severe choroidoretinitis causes progressive loss of sight, starting in one eye and then affecting the other. Large white exudates containing haemorrhagic areas occur. 3 Diagnosis Virus can be cultured from urine, throat washings or buffy coat during active replication, and IgM antibodies are detectable in serum by an immunofluorescence test. In histological sections 'owl's eye' cells are strongly suggestive of CMV infection. Management Intravenous ganciclovir, 5mg/kgb.d. for 14-21 days, is the treatment of choice for immunocompromised patients with CMV disease. AIDS patients with retinitis have a high risk of relapse with loss of vision, and maintenance treatment can be given with oral ganciclovir 1gt.d.s. Bone marrow toxicity is common and an alternative treatment is foscarnet 200mg/kg for 14-21 days, with monitoring of renal function and serum calcium. 4
Human herpes virus 6 infection Human herpes virus 6 (HHV6) has recently been identified in patients with AIDS and has subsequently been found to be widely distributed. It is the cause of roseola, a common febrile illness of young children characterized by the appearance of a rash when the fever and illness are resolving. The temperature is high but the child is relatively well. There is often cervical and postauricular lymphadenopathy. When the temperature starts to fall, or within 2 days, a maculopapular erythematous eruption appears on the trunk: this lasts for a few days. Blood count reveals neutropenia initially, which may be followed by mild leukocytosis. The illness resolves without complications.
Human herpes virus 8 (HHV8) or Kaposi's sarcoma (KS)-associated herpes virus HHV8 has been identified consistently in KS lesions of AIDS patients and it is now thought to be the cause of this spindle cell tumour. Epidemiological studies show that asymptomatic infection is common in Mediterranean and African countries where KS occurred independently of
HIV infection. It is likely that cofactors are required for the development of KS, but these have not yet been identified. Despite the relationship between KS and AIDS in homosexual men, transmission of HHV8 between individuals is likely to be similar to that of EBV, as infectious virions have been found in saliva. It is rarely detected in semen even though viral DNA is detectable in the prostate. Treatment of AIDS patients with antiretroviral drugs, particularly protease inhibitors, results in regression of KS lesions (see Chapter 11).
9
POX VIRUSES Variola and vaccinia Variola virus is the cause of smallpox, an infection of low infectivity transmitted between humans by close contact. Immunization introduced globally using the refined vaccine containing vaccinia virus led to the eradication of smallpox in 1979, and only accidental laboratory infections have occurred since then. Vaccination against smallpox is no longer justified.
Orf virus infection Orf virus causes a single nodular lesion at the site of an abrasion which has been in contact with an infected lamb.
ENVELOPED SINGLE-STRANDED DNA VIRUSES PARVOVIRUS The association between infection with human parvovirus and disease has only been recognized since the 1980s. The virus was first noticed in sera from normal subjects during screening by electron microscopy (1975), but in 1983 it was reported to be the cause of erythema infectiosum ('slapped cheek disease' or 'fifth disease'). A more serious consequence is that the virus can cause aplastic crises in patients with sickle cell disease.
Clinical features of erythema infectiosum Parvovirus infection is probably transmitted between humans by nasopharyngeal secretions and causes a range of illness ranging from asymptomatic to a febrile systemic illness with a rash. After a mild prodromal illness consisting of fever, headache, upper respiratory symptoms and myalgia lasting 2-A days, a rash appears on the arms and chest, spreading peripherally, even to the palms and soles. The classic 'slapped cheek' appearance of erythema infectiosum is seen in less than half of infected patients. Elsewhere the rash is maculopapular and fluctuates in intensity. It often develops a lacy reticular pattern on the limbs
289
and leaves a short-lived pale brown pigmentation as it fades over a week. The rash is frequently pruritic. Other features during the rash are generally mild, but include fever, malaise, headache and sometimes arthralgia, lymphadenopathy and splenomegaly.
Complications Complications are rare. Adult women may develop symmetrical peripheral polyarthritis, which can be the sole manifestation of infection. Although it usually resolves within 3 months it may continue for several years. Aplastic crises are not a feature of infection in patients who are otherwise normal haematologically, but when the red cell life is reduced, as in sickle cell disease or hereditary spherocytosis, arrest of erythropoiesis for 5-10 days causes a significant fall in haemoglobin level. The same effect has been observed in patients with advanced AIDS.
Diagnosis and management IgM serum antibodies detected by enzyme-linked immunosorbent assay (ELISA) or radioimmunoassay (RIA) are diagnostic of recent infection and persist for about 2 months. A change in litre of IgG antibodies also indicates recent infection. Virus isolation is not feasible and detection of viral protein is reserved for research purposes. There is no specific treatment at present.
NON-ENVELOPED DOUBLE-STRANDED DNA VIRUSES
affects adults and often follows minor trauma to the eye. Type 8 is the usual pathogen. Haemorrhagic cystitis. Caused by types 11 and 21, haemorrhagic cystitis is a childhood infection. Adenoviruses are also uncommonly associated with diarrhoeal disease, intussusception, and meningitis or encephalitis. Diagnosis of adenovirus infection is usually made on clinical grounds. It can be confirmed by virus isolation or by identification of viral antigen by immunofluorescence where these techniques are available, or by detecting a rise in serum antibody titre. There is no effective antiviral treatment, but most disease is mild and self-limited.
PAPOVAVIRUSES The important members of the papovavirus group are papilloma or wart viruses and polyoma viruses. Palmar and plantar warts are benign infections, common in childhood, which often regress spontaneously with increasing age. They are caused by viruses which are distinct from the anogenital warts viruses; the latter are sexually transmitted (see Ch. 11, p. 456, and Ch. 10, p. 393).
Genital warts See Chapter 11 (p. 456).
ENVELOPED SINGLE-STRANDED RNA VIRUSES ORTHOMYXOVIRUSES
290
ADENOVIRUSES
Influenza virus infection
Adenoviruses are a common cause of upper respiratory infection in children and cause a variety of other illnesses, depending on the serotype of virus and the age of the patient. Over 40 serotypes have been isolated from humans, and many of these are known to have pathogenic potential. Virus can frequently be isolated from the posterior pharyngeal lymphoid tissue of asymptomatic subjects, suggesting that it can remain latent for long periods. Upper respiratory infection. Common cold and pharyngitis occur in all age groups, and serotypes 1-6 are the usual cause. Lower respiratory infection. Tracheobronchitis and pneumonia are rare in children but young adults may be affected. This is one of the differential diagnoses of atypical pneumonia. Types 4 and 7 are the most common causes. Pharyngoconjunctival fever. An acute infection spreads among young children in close contact, often caused by adenovirus type 3. Epidemic keratoconjunctivitis. Epidemic keratoconjunctivitis is a more severe form of eye infection which
Influenza types A and B are the main viruses in this family, but there is also a type C virus. Influenza is an ancient disease characterized by regular winter epidemics, with occasional much larger outbreaks (pandemics) when there is a major shift in antigenic type against which there is little immunity in the population. Although the disease is normally mild and self-limiting, the elderly and those with chronic chest disease are susceptible to complications, resulting in a considerable mortality. Epidemiology Epidemics of influenza start with cases in children and spread to the adult population. As the epidemic progresses, vulnerable adults start to present in hospitals and the size of the epidemic becomes apparent when absenteeism causes problems at work and in schools. Epidemics usually peak within 3 weeks and last about 6 weeks. They occur in winter - December to April in the northern hemisphere and May to September in the southern hemisphere. In tropical countries virus isolates can be obtained year
round, but epidemics tend to occur after changes in weather, whereas in temperate climates it is rare to find the virus in the community between epidemics. Surprisingly, several variants of the virus are found to be circulating during an epidemic, but they are sufficiently similar to previously recognized viruses for some crossimmunity to exist. Variants that appear late in the course of an epidemic are sometimes the ones responsible for an outbreak during the following winter. Pandemics have occurred infrequently over the last century, in 1889, 1918, 1957, 1968 and 1977. They result from the emergence of new viruses in which there are major changes in the surface proteins, mainly neuraminidase and haemagglutinin, against which the populations of the world have no immunity. The mechanism for these changes is likely to be genetic reassortment and some evidence suggests that this occurs in animal reservoirs, such as birds and lower mammals. Two neuraminidases and three haemagglutinins have been detected at various times in the last century and these are recognized in the name given to a subtype of virus. For example, the virus responsible for the 1918 epidemic was H1N1, and another severe epidemic in 1957 was caused by H2N2. The severity of an outbreak is determined by the extent of change in antigenicity of the virus, so that if the neuraminidase and the haemagglutinin both undergo a major change, the severity of disease and the size of the epidemic are greater than if only one determinant changes. After a major antigenic shift causing a pandemic, smaller variations in antigenicity known as antigenic drift occur over a variable period (9-30 years in the past century) and the population gradually builds up immunity to the possible variants of the new virus subtype. The scene for the next major antigenic shift may be set by the level of herd immunity to the subtype variants, but other factors probably make a contribution also. Clinical features Influenza is transmitted by droplets of respiratory secretions and the incubation period is 1-3 days. Influenza A and B cause a similar illness, but influenza C only gives rise to sore throat. The onset of influenza is rapid, with symptoms of fever, including chills, sweats and sometimes rigors accompanied by malaise, anorexia, headache and marked myalgia. The severity of general symptoms varies greatly between individuals, from mild to prostrating. They are worst in the first 3 days and usually disappear within a week. Cough and sore throat are variable features which tend to increase as other symptoms subside and resolve over 2-3 weeks. On examination the patient is initially febrile, flushed and tachycardic, with minor nasal discharge. The pharynx may be inflamed and cervical lymph nodes palpable and tender. Complications The elderly are more vulnerable to all complications. The
most common is exacerbation of chronic bronchitis, and this is responsible for most adult admissions to hospital in influenza epidemics. Asthma is also exacerbated. Bacterial pneumonia, often caused by Strep, pneumoniae, Staph. aureus or H. influenzae, can occur in chronic bronchitics or patients with no previous history of chest disease, but it is more common in smokers. Viral pneumonia caused by influenza virus itself is a severe complication which usually occurs in patients with underlying disease of the chest or cardiovascular system, alth
