Paediatric Gastroenterology (Atlas of Investigation and Management)

An Atlas of Investigation and Management

PAEDIATRIC GASTROENTEROLOGY José M Moreno-Villares • Isabel Polanco

CLINICAL PUBLISHING medwedi.ru

An Atlas of Investigation and Management

PAEDIATRIC GASTROENTEROLOGY José M Moreno-Villares, MD Nutrition Unit Department of Paediatrics Hospital Universitario 12 de Octubre Madrid, Spain

Isabel Polanco, MD, PhD Professor of Paediatrics Head of Department of Paediatric Gastroenterology and Nutrition Hospital Infantil Univeritario La Paz Facultad de Medicina, Universidad Autónoma Madrid, Spain

CLINICAL PUBLISHING OXFORD

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Clinical Publishing an imprint of Atlas Medical Publishing Ltd Oxford Centre for Innovation Mill Street, Oxford OX2 0JX, UK Tel: +44 1865 811116 Fax: +44 1865 251550 Email: [email protected] Web: www.clinicalpublishing.co.uk Distributed in USA and Canada by: Clinical Publishing 30 Amberwood Parkway Ashland OH 44805 USA Tel: 800-247-6553 (toll free within U.S. and Canada) Fax: 419-281-6883 Email: [email protected] Distributed in UK and Rest of World by: Marston Book Services Ltd PO Box 269 Abingdon Oxon OX14 4YN UK Tel: +44 1235 465500 Fax: +44 1235 465555 Email: [email protected]

© Atlas Medical Publishing Ltd 2009 First published 2009 All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, without the prior permission in writing of Clinical Publishing or Atlas Medical Publishing Ltd. Although every effort has been made to ensure that all owners of copyright material have been acknowledged in this publication, we would be glad to acknowledge in subsequent reprints or editions any omissions brought to our attention. A catalogue record of this book is available from the British Library ISBN-13 978 1 84692 009 7 ISBN e-book 978 1 84692 604 4 The publisher makes no representation, express or implied, that the dosages in this book are correct. Readers must therefore always check the product information and clinical procedures with the most up-to-date published product information and data sheets provided by the manufacturers and the most recent codes of conduct and safety regulations. The authors and the publisher do not accept any liability for any errors in the text or for the misuse or misapplication of material in this work. Printed by Henry Ling Ltd, Dorchester, Dorset, UK

Contents Preface

vi

Contributors

vi viii

Abbreviations 1 Failure to thrive in infants and children JOSÉ M MORENO-VILLARES, MD, AND ANTONIO MONICA GUERRA, MD

1

2 Vomiting JOSÉ M MORENO-VILLARES, MD, AND MARÍA JOSÉ GALIANO SEGOVIA, MD

11

3 Diarrhoea Acute diarrhoea ENRIQUETA ROMÁN RIECHMANN, MD

19 19

Chronic diarrhoea ANGELES CALZADO AGRASOT, MD, BEGOÑA POLO MIQUEL, MD, AND CARMEN RIBES-KONINCKX, MD, PHD

25

4 Constipation CAROLINA GUTIÉRREZ, MD, JERÓNIMO GONZÁLVEZ, MD

34

72

9 Liver disease Cholestasis PIOTR SOCHA, MD, JOANNA PAWŁOWSKA, MD, AND ANIL DHAWAN, MD, FRCPCH

84 84

Hypertransaminasaemia in childhood LUÍS PEÑA-QUINTANA, MD, AND DANIEL GONZÁLEZ-SANTANA, MD

92

10 Coeliac disease ISABEL POLANCO, MD, PHD

99

11 Ulcerative colitis CARLOS SIERRA SALINAS, MD, JAVIER BLASCO ALONSO, MD 12 Crohn’s disease DAVID ZIRING, MD, JORGE VARGAS, MD

104 AND

110 AND

13 Short bowel syndrome JAVIER BUENO, MD

AND

5 Abdominal pain in childhood 46 IÑAKI X. IRASTORZA TERRADILLOS, MD, AND JUAN C. VITORIA CORMENZANA, MD, PHD 6 Gastrointestinal bleeding GEORGE GERSHMAN, MD, PHD

56

7 Cow’s milk allergy ANTONIO NIETO, MD, PHD, ANGEL MAZÓN, MD

65 AND

8 Abdominal masses JUAN A. TOVAR, MD, PhD

14 Congenital gastrointestinal malformations IÑAKI EIZAGUIRRE, MD, AND AGUSTÍN NOGUÉS, MD

117

124

15 Paediatric appendicitis ADOLFO BAUTISTA CASASNOVAS, MD

134

16 Paediatric clinical dietetics AMAYA PEÑALVA ARIGITA, RD

144

Index

155

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Preface Paediatric gastroenterology emerged as a speciality in the 1960s. Since then it has become an essential component of major academic paediatric programmes throughout the world. The introduction of new diagnostic techniques that required special skills, as well as the development of complex new therapies for children with gastrointestinal disorders, were cornerstones in the development of the speciality. The recognition that appropriate nurition during infancy and childhood is vital for health and the profound impact that many gastrointestinal diseases may have upon growth also contributed to the discipline’s development. Many excellent paediatric gastroenterology texts have been published since the first textbook on the subject was published in the early 1970s, but there are not so many based on excellent figures and comprehensive tables. Paediatric Gastroenterology, An Atlas of Investigation and Management,

provides concise and practical information for readers. Topics on the three main areas of the speciality – gastroenterology, hepatology, and nutrition – constitute the body of this book. The authors were carefully selected to provide a comprehensive and clear account of their assigned topics. All of them have been willing to dedicate their time, knowledge, and effort in preparing their chapters. Our most sincere thanks to them. It has been a pleasure to work with Clinical Publishing’s production team who have helped to produce a book of outstanding quality. We hope and expect that this Atlas will be of benefit to all physicians dealing with gastrointestinal problems in children. José M Moreno-Villares, MD Isabel Polanco MD, PhD

Contributors Adolfo Bautista Casasnovas, MD, PhD Head of Paediatric Surgery Section University Hospital of Santiago de Compostela Santiago de Compostela, Spain Javier Blasco Alonso, MD Gastroenterology, Hepatology and Nutrition Division Hospital Materno-Infantil Málaga, Spain. Javier Bueno, MD Paediatric Liver Transplantation Unit Paediatric Surgery Department Hospital Valle de Hebrón Barcelona, Spain

Mª Ángeles Calzado Agrasot, MD Paediatric Gastroenterology and Hepatology Unit Hospital La Fe Valencia, Spain Anil Dhawan, MD, FRCPCH Paediatric Liver Centre Institute of Liver Studies Variety Club Children’s Hospital King’s College Hospital London, UK Iñaki Eizaguirre, MD, PhD Paediatric Surgery Department Donostia Hospital San Sebastian, Spain

María José Galiano Segovia, MD Centro de Salud Maria Montessori Leganés Madrid, Spain George Gershman, MD, PhD Associate Professor of Pediatrics David Geffen School of Medicine Chief, Division of Pediatric Gastroenterology and Nutrition Harbor-UCLA Medical Center Torrance California, USA Jerónimo Gonzálvez Piñera, MD, PhD Associated Professor of Paediatric Surgery Department of Paediatric Surgery University General Hospital Albacete, Spain

Contributors vii

Daniel González-Santana, MD Paediatric Gastroenterology Division Las Palmas de Gran Canaria University Hospital Universitario Materno-Infantil de Canarias Spain Antonio Monica Guerra, MD, PhD Nutrition Unit University of Porto Porto, Portugal Carolina Gutiérrez Junquera, MD, PhD Associated Professor of Paediatrics Department of Pediatric Gastroenterology University General Hospital Albacete, Spain Iñaki X. Irastorza Terradillos, MD Paediatric Gastroenterology Division Hospital de Cruces Bilbao, Spain Angel Mazón, MD Paediatric Allergy Division Hospital Infantil La Fe Valencia, Spain José M. Moreno-Villares, MD Nutrition Unit Department of Paediatrics University Hospital 12 de Octubre Madrid, Spain Antonio Nieto, MD, PhD Paediatric Allergy Division Hospital Infantil La Fe Valencia, Spain Agustín Nogués, MD Paediatric Radiology Department Donostia Hospital San Sebastian, Spain

Joanna Pawłowska, MD Department of Gastroenterology, Hepatology and Immunology The Children’s Memorial Health Institute Warsaw, Poland Luis Peña-Quintana, MD Paediatric Gastroenterology, Hepatology and Nutrition Division University Hospital Universidad de Las Palmas de Gran Canaria Spain Amaya Peñalva Arigita, RD University Hospital Valle de Hebrón Barcelona, Spain Isabel Polanco, MD, PhD Professor of Paediatrics Head of Department of Paediatric Gastroenterology and Nutrition University Hospital La Paz Universidad Autónoma Madrid, Spain Begoña Polo Miquel, MD Paediatric Gastroenterology and Hepatology Division Hospital La Fe Valencia, Spain Carmen Ribes-Koninckx, MD, PhD Paediatric Gastroenterology and Hepatology Division Hospital La Fe Valencia, Spain Enriqueta Román Riechmann, MD Department of Paediatrics Hospital de Fuenlabrada Madrid, Spain

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Carlos Sierra Salinas, MD Gastroenterology, Hepatology and Nutrition Division Hospital Materno-Infantil Málaga, Spain Piotr Socha, MD Department of Gastroenterology, Hepatology and Immunology The Children’s Memorial Health Institute Warsaw, Poland Juan A. Tovar, MD, PhD Professor and Chief, Department of Paediatric Surgery University Hospital La Paz Madrid, Spain Jorge Vargas, MD Division of Gastroenterology and Nutrition Department of Paediatrics Mattel Children’s Hospital at UCLA Los Angeles, USA Juan C. Vitoria Cormenzana, MD, PhD Professor of Paediatrics Basque Country University Chief, Paediatric Gastroenterology Division Hospital de Cruces Bilbao, Spain David Ziring, MD Division of Gastroenterology and Nutrition Department of Paediatrics Mattel Children’s Hospital at UCLA Los Angeles, USA

viii

Abbreviations α1-ATD alpha-1-antitrypsin deficiency AAP American Academy of Pediatrics AFP alpha-fetoprotein AIH autoimmune hepatitis ALT alanine aminotransferase AMA antimitocondrial antibodies ANA antinuclear antibodies APC antigen-presenting cell ASCA anti-Saccharomyces cerevisiae antibodies ASMA antismooth muscle antibody AST aspartate aminotransferase BA biliary atresia BMI body mass index BRIC benign recurrent intrahepatic cholestasis Btl. bottle BUN blood urea nitrogen CD coeliac disease CFU colony-forming units CK creatine kinase CM cow’s milk CMA cow’s milk allergy CMV cytomegalovirus CNS central nervous system CPM caloric–protein malnutrition CrD Crohn’s disease CT computed tomography CTT colonic transit time Da Dalton DH dermatitis herpetiformis DNA HBV hepatitis B virus DNA EBV Epstein–Barr virus EC endoscopic capsule EF elemental formulas EH extensively hydrolyzed (formula) EIA enzyme immunoassay ERCP endoscopic retrograde cholangiopancreatography ESPGHAN European Society of Pediatric Gastroenterology, Hepatology, and Nutrition

FGID functional gastrointestinal disorders FTT failure to thrive GER gastro-oesophageal reflux GERD gastro-oesophageal reflux disease GFD gluten-free diet GGT gamma glutamyl transpeptidase GI gastrointestinal GIST gastrointestinal stromal tumour GN ganglioneuroma Hb haemoglobin HB hepatoblastoma HC head circumference Hct haematocrit HD Hirschsprung’s disease HIV human immunodeficiency virus HP Helicobacter pylori HPN home parenteral nutrition HSP Henoch–Schönlein purpura HUS haemolytic uraemic syndrome IBD inflammatory bowel disease IBS irritable bowel syndrome IF infant formula IDI intractable diarrhoea of infancy IGF-1 intestinal growth factor IL interleukin INSS International Neuroblastoma Staging System IQ intelligence quotient LA laparoscopic appendectomy LDH lactate dehydrogenase LF lactose-free (formula) LKM liver/kidney microsomal antibodies MAC middle arm circumference MCV mean cell volume MIBG meta-iodine-benzyl-guanidine MRI magnetic resonance imaging NAFLD nonalcoholic fatty liver disease NASH nonalcoholic steatohepatitis NB neuroblastoma NEC necrotizing enterocolitis NK natural killer cells

NKT natural killer T cells NPD negative predictive value NSAID nonsteroidal anti-inflammatory drug OA open appendectomy OCTN organic cation transporter gene ORS oral rehydration solution ORT oral rehydration therapy pANCA anti-neutrophil cytoplasmic antibody with perinuclear staining pattern PFIC progressive familial intrahepatic cholestasis PH partially hydrolyzed (formula) Pi protease inhibitor PN parenteral nutrition PPV positive predictive value RAST radioallergosorbent test RDA recommended dietary allowances RDW red blood cell differentiation width RNA HCV hepatitis C virus RNA SBS short bowel syndrome Sc scoop SE semi-elemental (formula) SGOT serum glutamic oxalacetic transaminase SGPT serum glutamic pyruvic transaminase SIOP Societé Internationale d´Oncologie Pédiatrique STEP serial transverse enteroplasty TPN total parenteral nutrition TNF tumour necrosis factor TS tricipital skinfold TSH thyroid stimulating hormone UC ulcerative colitis UPDG galactose-1-phosphate-uridyl transferase US ultrasonography WBC white blood count WD Wilson´s disease WI Waterloo index WHO World Health Organization

Chapter 1

1

Failure to thrive in infants and children José M Moreno-Villares, MD, and Antonio Monica Guerra, MD Introduction

Estudio Longitudinal de Crecimiento, Curvas de 0 a 18 años Instituto de Investigación sobre Crecimiento y Desarrollo FUNDACIÓN ORBEGOZO. (Bilbao-España)

Evaluation of growth and development in the primary care setting is a cornerstone of paediatric care. Usually head circumference, weight, and length are measured at birth, and then on an intermittent basis throughout the rest of childhood. When a divergence from the standard growth curve occurs, in either direction, a careful assessment is required to determine the aetiology. Undernutrition or ‘failure to thrive’ (FTT) is a common nutritional problem in the infant and toddler paediatric population. The identification of patients with FTT is a routine part of residency training in paediatrics.

Inappropriate nutrient intake and growth parameters FTT is a clinical label frequently used to describe infants and young children, generally under 3 years, who fail to grow as expected using established growth standards for age and gender along a period of time (usually longer than 3 months) (1.1). Weight is a measure of the varying combination of height, body fat, and muscle bulk, which makes it a less straightforward measure of growth than height. Nevertheless, because of its widespread availability and ease of measurement, it is the most usual tool when growth measure is considered. What constitutes a normal rate of weight gain (Table 1.1)? It is often assumed that normal growth constitutes tracking along the birth centile. However, weight at birth is a reflection of the intrauterine environment and is of limited prognostic value. Many children deviate from their earlier centile position, and this divergence may

1.1 Eleven-month-old male, with growth faltering in the last 4–5 months, more severe in the last 2 weeks. Reduction in >2 major percentiles for weight.

not become pathological. Although the most commonly used definition of abnormality is that falling below a predetermined centile, usually the third (1.2), this would include a number of constitutionally small children. An alternative definition applies when a child has a weight curve that has fallen more than two standard deviations or

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Failure to thrive in infants and children

Table 1.1 Normal weight gain and frequency of monitoring

Normal weight gain Birth to 5 months

15–30 g/day

6 to 12 months

15 g/day

12 months to 2 years

6–8 g/day

2 years to 6 years

38 g/month

Frequency of monitoring Monthly for the first two months, every other month from 2 to 6 months; every 3rd month from 6 to 24 months, and yearly from 2 to 6 years old

1.2 An 18-week-old female, with irritability and poor weight gain since birth. Weight below 3rd percentile.

Definition of FTT FTT describes an infant or child whose current weight or rate of weight gain is significantly below that expected of similar children of the same age and sex. Most paediatricians diagnose FTT when a child’s weight for age falls below the fifth percentile of the standard growth charts or it crosses two major percentile lines (1.3). One problem arises from the use of different growth charts; misinterpretation may occur if different genetic backgrounds are not considered. This problem may be overcome if universal growth references could be used. The World Health Organization (WHO) has recently published charts resulting from the Multicenter Growth Reference Study, and are intended to substitute for the National Center for Health Statistics/WHO (NCHS/WHO) growth reference, which has been recommended for international use since the late 1970s (www.who.int/childgrowth/standards/curvas_por_indicador es/en/index.html) (1.4, 1.5). FTT is not a final diagnosis but a description of a physical state; therefore, a cause must always be sought. Because the description itself is vague it has been proposed to use growth failure or undernutrition as a diagnostic replacement for FTT.

Estudio Longitudinal de Crecimiento, Curvas de 0 a 18 años Instituto de Investigación sobre Crecimiento y Desarrollo FUNDACIÓN ORBEGOZO. (Bilbao-España)

percentiles below a previously established rate of growth. However, up to 30% of healthy term infants cross one percentile line and 23% cross two percentile lines (in either direction) by the age of 2 years.

Estudio Longitudinal de Crecimiento, Curvas de 0 a 18 años Instituto de Investigación sobre Crecimiento y Desarrollo FUNDACIÓN ORBEGOZO. (Bilbao-España)

2

1.3 Four-month-old male. Loss of >2 major percentiles since birth.

Failure to thrive in infants and children 3

A

A

B

B

1.4 WHO growth curves. Height/length for age (boys).

1.5 WHO growth charts. Length/height for age (girls).

Until recently, the evaluation of a child with FTT focused on factors related to external environment or to medical causes. Currently, the child’s feeding behaviour and the interaction between the caregiver and the child has taken on greater importance. Feeding is an interactive process that depends upon abilities and characteristics of both the parents and the child.

Organic causes

Nonorganic causes

False failure to thrive

Aetiology FTT has been historically dichotomized as organic versus nonorganic (1.6). Organic FTT results from a major organ system illness or dysfunction, while nonorganic FTT is generally a diagnosis of exclusion. A third category has been added, mixed FTT, to recognize the fact that many organic FTT often have a psychological component. This approach is quite simplistic and inadequate for patient management. There is growing evidence that feeding difficulties are

1.6 Aetiology of FTT.

central to the development of the disorder. Family stressors, psychiatric disorders of parents, and disturbances in the infant–parent relationship may interfere with the development of an adequate feeding relationship.

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4

Failure to thrive in infants and children

It is important to note that an infant presenting with presumed FTT may have a normal variant of growth1. Specific infant populations with growth variations also need

to be considered when making the diagnosis of FTT, for instance, infants with intrauterine growth retardation or premature infants.

Table 1.2 Normal variants of growth presenting as FTT Genetic short stature

Ex-premature infant

Constitutional delay

Catch down growth

Birth weight

Low to normal

Normal if corrected for gestation

Low to normal

Above expected for genetic background

Parental percentiles

Low

Normal

Normal

Normal

Progress along percentiles

Low percentile but do not cross percentiles

Low if corrected but follow percentile curves

May be an initial fall in first 6 months and then follow percentiles

Initial fall in 6–12 months and then follow percentiles

Table 1. 3. Classification of FTT by pathological causes

Inadequate caloric intake • Food not available – Type or volume of food not appropriate (e.g. too diluted formula) – Poverty and food shortages – Neglect – Feeding technique, parent–infant interaction problems • Lack of appetite – Chronic illness – Psychosocial disorder • Mechanical feeding difficulties, e.g. oral-motor dysfunction or malformation Reduced absorption or digestion of nutrients • Pancreatic insufficiency: cystic fibrosis • Loss or damage to villous surface – Coeliac disease – Cow’s milk protein allergy – Vitamin or mineral deficiencies • Cholestasis

Excessive loss of nutrients • Vomiting – Gastro-oesophageal reflux – Other causes of vomiting: central nervous system disorders, metabolic disease • Malabsorption/diarrhoea – Inflammatory bowel disease – Short bowel syndrome • Renal losses – Renal failure or tubular acidosis – Diabetes mellitus or diabetes insipidus Defective utilization • Chromosomal or genetic abnormality • Metabolic disorder • Endocrine disorder • Congenital infections Increased metabolism • Chronic infection or inflammation • Hypoxaemia (congenital heart disease, chronic lung disease) • Hyperthyroidism • Malignancy

Failure to thrive in infants and children 5

Within the group of normal variants of growth presenting as FTT, four main patterns occur (Table 1.2)2. There are also growth curves available for syndromes with abnormal growth (e.g. Down syndrome, Noonan syndrome, Prader–Willi syndrome) (1.7, 1.8). There are many reasons why an infant does not take on adequate nutrition. A more useful classification of FTT is then based on pathophysiology, as shown in Table 1.3.

Evaluation

1.7 Patients with special conditions, e.g. Down syndrome, chromosomopathies and other genetic conditions, have their own growth rate and deserve specific growth curves.

1.8 Patient with a Silver–Russell syndrome.

1.9 Algorithm of management of FTT in primary care.

History and examination The history is essential in defining the underlying cause of growth failure in children (1.9). The evaluation should include an assessment of the diet and eating behaviours, past and current medical, social, and family history, and should include a complete physical examination (Table 1.4)3. A

FFT is suspected

Most likely normal variant of growth

Clinical history Physical examination Assessment of intake

Red flag signs

Basic laboratory investigations

Yes

Organic failure to thrive

Treatment – primary care

Anomalous results?

Hospital

No

Nonorganic failure to thrive

Success

Further work up/treatment – hospital

Follow up Nutritional advice Psychological support Lack of success

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Failure to thrive in infants and children

Table 1.4 Evaluation of medical history in FTT

Dietary history

• Are they recurrent?

• Amount of food and/or formula

• Chronic medical conditions

• Is the formula prepared correctly?

• Past hospitalizations, injuries, accidents

• Food patterns: types of foods, especially beverage consumption (milk, juices, sodas)

• Vomiting? Social history

Feeding history

• Who lives in the home?

• When does the child eat? Where? With whom?

• Who are the caregivers?

• Breastfed?

• Who helps to support the family?

• Positioning of the child

• What is the child’s temperament?

• Feeding battles

• Any family problems?

• Snacking Family history Past and current medical history

• Medical conditions or FTT in siblings

• Obstetric history • Birth history, including weight and height

• Growth pattern in other members of the family, especially parents and siblings

• Neonatal period

• Mental illness

• Recent acute illness especially upper airway infections, otitis, gastroenteritis

Table 1.5 Classification of undernutrition in children15, 16

Normal

Mild risk

Moderate risk

High risk

Weight for age (%)

>90

75–89

60–74

<60%

Weight for height (%)

>90

80–90

70–79

70%

Height for age (%)

>95

95–90

89–85

<85%

thorough psychosocial history is mandatory. An accurate assessment of growth requires the evaluation of current and past parameters including height or length, weight, and head circumference. Occasionally further assessments are performed such as mid-upper arm circumference, various skin fold thicknesses, body proportions and, if indicated, puberal assessment.

The severity of a child’s undernutrition can be classified most easily using the Waterlow and Gomez criteria (Table 1.5), as a percentage of the median for age. Further examination beyond growth should include physical examination (1.10), including inspection of any physical sign of neglect or abuse, stigmas of underlying syndromes, dysmorphic features, skin rashes, and observation of feeding if possible.

Failure to thrive in infants and children 7

Observing or videotaping the interaction between a parent and a child, especially during a feeding session in the office, may provide valuable information about the aetiology of FTT4.

Investigations Laboratory evaluation should be guided by history and physical examination findings only. A well-targeted battery of investigations may provide guidance. There are no routine laboratory tests that should be performed on every child, because the majority of children with FTT have no laboratory abnormalities. In those requiring investigation, a simple initial sequence can be performed (Table 1.6).

1.10 Clinical signs of malnutrition in a patient with FTT who was found to have coeliac disease.

Table 1.6 Investigations in failure to thrive

Initial evaluation

• Coeliac screen

• Full blood examination/erythrocyte sedimentation rate or C-reactive protein

• Thyroid function test

• Chemistry panel: urea, creatinine, lytes

• Stool microscopy and culture

• Bone age

• Iron status: iron, ferritin, transferrin, % saturation • Blood glucose • Liver function tests: GGT, SGPT, SGOT, alkaline phospatase, bilirubin • Urinalysis • Urine culture

Third step (if clinically indicated or abnormal data from the initial investigations) • Metabolic screen (blood and urine for organic acids and amino acids, ammonia, lactic/pyruvic acids, ketone bodies in urine) • Karyotype

Second step

• Allergy investigations

• Acid–base balance

• Sweat test

• Immunoglobulins

• pHmetry/endoscopy

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Failure to thrive in infants and children

Treatment

Dietary recommendations

Medical intervention is dictated by the disease diagnosed. Addressing identified issues of attachment and other psychosocial issues is crucial and often requires input from a multidisciplinary team. Most cases can be managed by nutrition intervention or feeding behaviour modification. Evaluation and treatment is generally accomplished in outpatient settings rather than in the hospital. Nutritional rehabilitation by means of increased caloric intake is often best supervised with the advice of an experienced dietician, allowing exact caloric requirements to be calculated. Asking the parent to write down the type of food and amounts a child eats over a 3-day period is one way of quantifying caloric intake.

Concentrate formula (powder)

Children with FTT will need 150% of the recommended daily caloric intake, based on their expected, not actual, weight for height if tolerated5. As most of these children lack the normal responses to internal hunger/satiation cues, high energy snacks may improve their nutritional status6. In infants this increased caloric intake may be accomplished by concentrating the infant formula or adding carbohydrates or lipids to the formula or the puréed foods (1.11). Toddlers can receive more calories by adding cheese, butter, and so on to common toddler foods. In toddlers and older children we can also use high-calorie milk drinks, that provide 1.0–1.5 kcal/ml. Vitamin and mineral supplementation is also sometimes required. If all these attempts fail it may be necessary to consider nasogastric tube feedings as a last resort (1.12)7. The advantages are ensuring adequate caloric intake and decreasing or eliminating some of the emotional stress and frustrations with feeding times. However, there are also disadvantages, including the suppression of appetite and sometimes the modification of feeding behaviour.

Add modules Infant formula 13% (68 kcal/100 ml)

1 measure in 26 ml

Concentrate formula to 15% (78 kcal/100 ml)

Add maltodextrin 5 g/100 ml (20 kcal)

88 kcal/100 ml

1 measure in 23 ml

Concentrate formula to 17% (89 kcal/100 ml)

Add MCT oil 2 ml/100 ml (16 kcal)

104 kcal/100 ml

1 measure in 20 ml

Concentrate formula to 20% (105 kcal/100 ml)

Add maltodextrin 5 g/100 ml (20 kcal)

124 kcal/100 ml

1.11 There are two ways to increase the caloric intake in an infant: to increase the strength of the regular formula or to add caloric modules (carbohydrates or lipids or both) to the regular formula.

Failure to thrive in infants and children 9

Feeding or eating behaviours Parental anxiety about a child’s FTT can be helped by reassurance. Paediatricians can intervene effectively in many feeding problems, providing useful guidance for parents (Table 1.7). Hospitalization is rarely required and may be counterproductive8. It may be necessary when the safety of a child is a concern, outpatient management has failed, or if the FTT is severe.

Outcomes It is ascertained that children with FTT are at risk of adverse outcomes such as short stature, behaviour problems, and developmental delay9–12. However, there are only a limited number of outcome studies on children with FTT, with different definitions and designs, so it is difficult to make an

assessment on long-term results of FTT. Rudolph and Logan found only a small difference in intelligence quotient (IQ) (equivalent to 3 IQ points) in children with FTT compared to their peers13. This small difference is of questionable clinical significance. The height and weight differences in their analysis were larger, but few children were below the 3rd percentile at follow-up. In the light of these results, the aggressive approach to the identification and management of FTT needs reassessing13. In addition, it is often difficult to disentangle the effects of FTT from those of the high-risk environments in which FTT often occurs (poverty, family stress, and poor parental coping skills). Nevertheless, to decrease the risk of adverse effects, it is important to recognize and treat FTT promptly. Sometimes this necessitates the intervention of communitybased resources14.

Table 1.7 Useful guidance for parents. Tips for preventing food hassles

1 Make mealtimes pleasant 2 Avoid battles over eating. Encourage your child. Food should be used as nourishment, not as a reward or punishment 3 You are responsible for deciding what food your child is offered; your child decides how much to eat 4 Offer a variety of healthy and tasty foods 1.12 In some severe FTT cases, especially if an organic condition is underlying, it is necessary to provide enteral nutrition through a nasogastric tube. This patient has biliary atresia and FTT.

5 Establish a routine of meals and snacks and set times 6 Recognize your child’s cues indicating hunger, satiety, and food preferences 7 Accept your child’s wish to feed him- or herself 8 Try to eat together as a family 9 Establish a maximum time to finish a meal (for instance 30 minutes) 10 Limit possible distractions during meals

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Failure to thrive in infants and children

Conclusion It is common to confuse the description of poor growth with a diagnosis. The term ‘failure to thrive’, although firmly entrenched in the medical lexicon, adds little to our understanding of this condition and does not guide our approach. Many have suggested it should be abandoned. It represents a nonspecific description of symptoms rather than a specific condition. Paediatricians and other healthcare workers must come to a better understanding of the complex dynamics of feeding normal children. When feeding and caloric issues have been ruled out, other considerations should be taken into account. It is not a question of referring a child who is not growing well to the feeding expert, the gastroenterologist, or the endocrinologist, but rather the recognition that a rational, sequential approach needs to be followed, to allow for investigation of all the possible explanations of why a child is not growing.

References 1 Krugman SD, Dubowitz H. Failure to thrive. Am Fam Phys 2003;68:879–84, 886. 2 Bergman P, Graham J. An approach to ‘failure to thrive’. Aus Fam Phys 2005;34:725–9. 3 McCann JB, Stein A, Fairburn CG, Dunger DB. Eating habits and attitudes of mothers of children with nonorganic failure to thrive. Arch Dis Child 1994;70: 34–6. 4 Satter E. The feeding relationship: problems and interventions. J Pediatr 1990;117:S181–9. 5 Maggioni A, Lifshitz F. Nonorganic failure to thrive: an outpatient approach. Pediatr Clin North Am 1998;45:169–87. 6 Kasese-Hara M, Wright C, Drewett R. Energy compensation in young children who fail to thrive. J Child Psychol Psychiatr 2002;43:449–56. 7 Tolia V. Very early onset nonorganic failure to thrive in infants. J Pediatr Gastroenterol Nutr 1995;20:73–80. 8 Marcovitch H. Failure to thrive. BMJ 1994;308:35–8. 9 Dahl M, Kristiansson B. Early feeding problems in an affluent society. IV. Impact of growth up to two years of age. Acta Paediatr Scand 1987;76:881–8.

10 Corbett SS, Drewett RF. To what extent is failure to thrive in infancy associated with poorer cognitive development? A review and meta-analysis. J Child Psychol Psychiatr 2004;45:641–54. 11 Zenel JA. Failure to thrive: a general pediatrician’s perspective. Pediatr Rev 1997;18: 371–8. 12 Drewett RF, Corbett SS. Cognitive and educational attainments at school age of children who failked to thrive in infancy: a population-based study. J Child Psychol Psychiatr 1999;4:551–61. 13 Rudolf MCJ, Logan S. What is the long-term outcome for children who fail to thrive? A systematic review. Arch Dis Child 2005;90:925–31. 14 Wright CM, Callum J, Birks E, Jarvis S. Effect of community based management in failure to thrive: randomized controlled trial. BMJ 1998;317:571–4. 15 Waterlow JC. Classification and definition of proteincalorie malnutrition. BMJ 1972;3:566–9. 16 Gomez F, Ramos-Galvan R, Frenk S, Cravioto JM, Chavez R, Vazquez J. Mortality in second and third degree malnutrition. J Trop Paediatr 1956;2:77–83.

General reading Frank DA, Zeisel SH. Failure to thrive. Pediatr Clin North Am 1988;35:1187–1206. Gahagan S, Holmes R. A Stepwise approach to evaluation of undernutrition and failure to thrive. Pediatr Clin North Am 1998;45:169–87. Jolley CD. Failure to thrive. Curr Probl Pediatr Adolesc Health Care 2003;33:183–205. Kessler DB, Baker SS, Silverman LA. Growth assessment and growth failure. Consensus in Paediatr 2004;1:1–28.

Chapter 2

11

Vomiting José M Moreno-Villares, MD, and María José Galiano Segovia, MD

Introduction Vomiting is a complex behaviour composed of three linked activities: nausea, retching, and expulsion of stomach contents. The vomiting act is characterized by cycles of retching followed by forceful expulsion of gastric contents through the mouth. Although it was previously thought one or two anatomical vomiting centres existed in the central nervous system (CNS), it is now assumed that the central

vomiting centres represent the integrated activity of the paraventricular nuclei arrayed along the central neuraxis controlling a myriad of autonomic functions1. Vomiting may result from a variety of disorders affecting paediatric patients (Table 2.1). History and physical examination may help us to distinguish nonbilious from bilious causes, i.e. proximal or distal to the ampulla of Vater.

Table 2.1 Causes of vomiting and regurgitation

A. Gastrointestinal tract disorders Oesophagus • Achalasia • Gastro-oesophageal reflux (GER) • Hiatal hernia • Congenital vascular or mucosal rings • Stenosis • Foreign body Stomach • Pyloric stenosis • Diaphragmatic hernia • Peptic disease • Antral web Duodenum • Annular pancreas • Duodenitis and ulcer • Malrotation

• Superior mesenteric artery syndrome Intestine and colon • Atresia and stenosis • Meconium ileus • Malrotation, volvulus • Duplication • Intussusception • Soy or cow’s milk protein intolerance • Coeliac disease • Food allergy • Hirschsprung’s disease • Chronic intestinal pseudoobstruction • Appendicitis • Inflammatory bowel disease • Gastroenteritis

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Other abdominal organs • Hepatitis • Gallstones • Pancreatitis B. Extragastrointestinal tract disorders • Infections: sepsis, pneumonia, otitis, urinary tract infection, meningitis • Intracranial hypertension: subdural effusion, hydrocephalus, brain tumour • Intoxications or drugs • Inborn errors of metabolism • Eating disorders • Cyclic vomiting syndrome

Vomiting

Evaluation

Gastro-oesophageal reflux and regurgitation

Vomiting is a common symptom of many disease states. The differential diagnosis of the child with vomiting varies with the age of the patient. Assessment of the child with vomiting should start with a complete history, physical examination, and description of the vomitus. Emesis of gastric contents is characteristic of gastric outlet obstruction, CNS masses or infection, peptic disease, urinary tract infection, otitis, inborn error of metabolism, or psychogenic vomiting. The child who vomits bile-stained material may have an intestinal obstruction and should be investigated urgently. The history and physical examination are essential starting points and should include duration of vomiting, presence of blood, abdominal pain, or fever. Pain located in the right lower quadrant suggests appendicitis. Midline or diffuse abdominal pain suggests pancreatitis or peritonitis. Abdominal distension suggests intestinal obstruction. Viral or bacterial gastroenteritis are usually accompanied by diarrhoea and fever. The presence of mucus and blood in the stool may raise the suspicion of intussusception or bacterial or toxic colitis. The evaluation of bloody vomitus start with the confirmation that the material vomited is blood. Imaging may help to rule out anatomical causes or intestinal obstruction. Further evaluation may include blood count, serum electrolytes, calcium, magnesium, blood urea nitrogen, urinalysis, and culture, and stool examination for occult blood, leukocytes, and parasites. Specific indications from history and physical examination may result in obtaining other tests including abdominal ultrasonography, imaging of the head, test of liver function, serum amylase, toxicology screen, serum ammonia, urinary organic acids, and so on. If there is a bloody vomitus, the most productive test is upper intestinal endoscopy.

70

>1 time/day >4 times/day Is a problem

60 % positive

12

50 40 30 20 10 0

0–3

4–6 7–9 Age (months)

10–12

2.1 Reported regurgitation according to age.

This is defined as effortless expulsion of gastric contents by the mouth and can be asymptomatic or symptomatic. Gastro-oesophageal reflux disease (GERD) is defined as gastro-oesophageal reflux (GER) that occurs too frequently and damages the oesophageal mucosa leading to clinical symptoms. Spontaneous relaxation of the lower oesophageal sphincter is the major mechanism by which GER occurs, with or without regurgitation2. GER is a physiological event that can be seen in a large number of infants: >50% of 2month-old infants regurgitate twice a day. The highest prevalence is at 4 months, when two-thirds of infants regurgitate. By 1 year, <10% still present vomiting daily. GERD affects a much smaller proportion of infants (2.1).

Symptoms/examination The most common symptom is postprandial regurgitation of effortless spit-up. Severe GERD may present with failure to thrive, oesophagitis with haematemesis, dysphagia, heartburn or chest pain, anaemia, aspiration, chronic cough, and wheezing. Rumination is sometimes a symptom as well as neck contortions (Sandifer’s syndrome). Apnoeic episodes in neonates and very young infants can be caused by reflux. GERD is common in neurologically impaired children. If not treated, GERD can lead to Barrett’s oesophagus. This is a metaplasia of the oesophageal squamous epithelium that transforms to specialized columnar epithelium; it is a premalignant condition associated with dysplasia and adenocarcinoma. Peptic strictures can present in cases of severe but asymptomatic oesophagitis.

Diagnosis GER is usually diagnosed by a thorough history and physical examination in infants under 6 months of age. It can be diagnosed on barium swallow by observing regurgitation of barium from stomach to oesophagus. Nevertheless, false-positive and false-negative tests are common. Nowadays, upper gastrointestinal (GI) series only serve to rule out anatomical problems. Ultrasonography is now used as a diagnostic tool to confirm GER. A pH probe (prolonged monitoring of oesophageal pH) is the best test for GERD, but it will miss cases of nonacid GER (2.2). Oesophageal and gastric scintigraphy is sometimes helpful in identifying pulmonary aspiration. Endoscopy is not diagnostic, but evidence of oesophagitis supports the diagnosis (2.3). Impedance studies measure fluid movements rather than luminal pH changes3.

Vomiting 13

2.2 A pH probe (prolonged monitoring of oesophageal pH) is the best test for GER, but it will miss cases of nonacid GER. Top: normal pH probe; bottom: pathological pH probe. pH <4 is considered pathological. (C: chest pain; H: heartburn; M: meal; S: supine.)

M H

8 7 6 5 pH 4 3 2 1 0 11 am

3 pm M

pH

8 7 6 5 4 3 2 1 9 am

1 pm

S

M HH

7 pm M H H

5 pm

11 pm

3 am S

7 am

11 am

M

C

C

9 pm

2.3 Endoscopy is not diagnostic, but evidence of oesophagitis supports the diagnosis. A: oesophagitis; B: severe oesophagitis; C: oesophageal stenosis secondary to oesophagitis; D: Barrett’s oesophagus (arrows).

A

B

C

D

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M

1 am

5 am

9 am

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Vomiting

Treatment In 85–90% of patients, GER will disappear between 6 and 12 months with no treatment (2.4). Regurgitation is reduced by conservative measures such as small, frequent thickened feedings. H2 receptor antagonists (e.g. ranitidine, 5.0 mg/kg/d) and proton pump inhibitors (omeprazol 1 mg/kg/d) are effective in controlling oesophagitis. Prokinetic agents such as metoclopramide (0.1 mg/kg/dose) or domperidone (0.2 mg/kg/dose) may be used to hasten gastric emptying. Low doses of erythromycin may also act as a promotility agent4. Antireflux surgery (Nissen fundoplication) is indicated in selected cases (Table 2.2) but is associated with morbidity. Neurologically impaired children respond less well to medical therapy. Laparoscopic surgery has been associated with increased repeat operations, if compared with open surgery5.

Table 2.2 Indications for antireflux surgery

1 Persistent vomiting with failure to thrive 2 Severe oesophagitis or oesophageal stricture 3 Apnoeic spells or chronic pulmonary disease unresponsive to medical therapy 4 Large hiatal hernias, if symptomatic

Recurrent vomiting

History and physical examination

Are there warning signals?

Yes

Further evaluation

No Are there signs of GERD?

Yes

Further evaluation

No Uncomplicated infantile GER ‘Happy spitter’

• No test • Education

Well child

Yes

• Consider – Thickened formula – Hypoallergenic formula

Resolves by 18–24 months?

2.4 Management of a vomiting infant.

No

• Consultation paediatric GI • Review previous management • Consider: – Endoscopy – Upper GI series – Oesophageal pH probe – Acid suppression ± prokinetic

Vomiting 15

Hiatal hernia Hiatal hernia is the protrusion of a portion of the stomach into the chest through an opening in the diaphragm (2.5). Hiatal hernias are classified as: • Para-oesophageal, if the oesophagus and the gastrooesophageal junction are normally placed but the gastric cardia is herniated beside the oesophagus through the oesophageal hiatus (2.6).

• Sliding, in which the gastro-oesophageal junction and a portion of the proximal stomach are herniated through the oesophageal hiatus. Sliding hiatal hernia is common in childhood. It may present accompanying GER, but many cause no symptoms. Hernias are treated surgically if medical treatment fails6.

B

C

2.5 Hiatal hernia. A: barium study; B: gastro-oesophageal junction placed into the thorax; C: endoscopic retroview from the stomach.

A 2.6 A: The oesophagus and the gastrooesophageal junction are normally placed but the gastric cardia is herniated beside the oesophagus through the oesophageal hiatus (arrows). B: barium study.

A

B

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Infantile hypertrophic pyloric stenosis Infantile hypertrophic pyloric stenosis is a condition resulting from hypertrophy of the pylorus muscle in which the lumen becomes obstructed by mucosa (2.7). It affects 1.5–4.0 per 1,000 live births, and is more common in males (4:1). There is a positive family history in 13%. The underlying mechanism is not understood.

Symptoms/examination Vomiting usually begins between 2 and 4 weeks of age and rapidly becomes projectile after every feeding. The vomitus is rarely bilious. Coffee-ground emesis may be seen as a result of oesophagitis or gastritis. The infant is hungry and nurses avidly. Infants do not generally appear ill unless undiagnosed for an extended period of time: constipation, dehydration, weight loss, fretfulness, and finally apathy can occur. On examination, prominent gastric peristaltic waves may be seen after feeding. The pylorus may be palpable as a small, hard mass or as an ‘olive’ in the right upper abdomen.

Diagnosis Laboratory tests demonstrate hypochloraemic, hypokalaemic metabolic alkalosis. Haemoconcentration is reflected by elevated haemoglobin and haematocrit values. Ultrasound is the gold standard investigation and can reveal a thick pyloric muscle with a long pyloric channel and large pyloric diameter7. It shows a hypoechoic ring with a hyperdense centre, and thickness of circular muscle >4 mm in pyloric stenosis (2.8)8. A barium upper GI study reveals delay in gastric emptying and an elongated narrowed pyloric channel with a double tract of barium (2.9).

Treatment and prognosis Pyloromyotomy is the treatment of choice and consists of incision down to the mucosa along the pyloric length (Ramstedt procedure) (2.10). Laparoscopic pyloromyotomy is gaining acceptance9. Prior to surgery, it is imperative to

A

B 2.7 Infantile hypertrophic pyloric stenosis is a condition resulting from hypertrophy of the pylorus muscle in which the lumen becomes obstructed by mucosa. Laparoscopic view.

2.8 Ultrasound images in infantile hypertrophic pyloric stenosis. A: Longitudinal view of the pylorus showing oval-shaped, enlarged pyloric muscle (dotted line). Pyloric muscle length >14 mm and thickness >3–4 mm are considered to be pyloric stenosis. B: Sagittal view of the pyloric olive.

Vomiting 17

repair dehydration and electrolyte disturbances. The outlook is excellent following surgery. Sometimes vomiting may persist postoperatively for a few days if there is a long preoperative history. Mortality rates are low and usually associated with perforation or infection.

of the duodenum. Treatment consists of decompression by a nasogastric tube and intravenous fluids. With improved nutrition symptoms usually resolve. Occasionally, it is necessary to perform surgery, such as realigning the duodenum or performing a duodenojejunostomy.

Superior mesenteric artery syndrome

Cyclic vomiting syndrome

This syndrome is an unusual cause of recurrent vomiting. The third part of the duodenum is obstructed as it passes between the superior mesenteric artery anteriorly and the vertebral column posteriorly (2.11). Rapid linear growth without weight gain, weight loss, scoliosis, spinal surgery, confinement to bed, and use of a body cast may predispose to the condition10. It may present with unspecific symptoms such as anorexia, nausea, and bilious vomiting. Diagnosis is based on history and plain abdominal X-ray that shows a dilated stomach and proximal duodenum. Upper GI series show a partial obstruction in the third part

The disorder is characterized by recurrent episodes of nausea and vomiting without an identifiable organic cause. The episodes are of rapid onset, often starting during sleep or early morning. It may persist for hours and days. The episodes are separated by completely symptom-free intervals, lasting from several weeks to more than 1 year. They may end spontaneously, may cease after a period of sleep, or may progress to severe dehydration and electrolyte imbalance. The pattern of inciting events and the characteristics of the attack are usually similar in each individual. As the clinical picture mimics migraine attack and headaches may be present in up to 50% of patients, some authors consider cyclic vomiting as abdominal migraine. The diagnosis is based on the history, the normal physical examination, and a meticulous evaluation of other organic disease causing recurrent episodes of vomiting. Diagnostic evaluations should be focused on conditions suggested by the history. Symptomatic treatment should be started as early as possible after the onset of symptoms11, 12.

A 2.9 Barium upper GI study. Narrowing of the pyloric channel with a double tract of barium (‘string sign’) (arrows).

B

2.10 A: Surgical view of hypertrophic pyloric stenosis; B: pyloromyotomy.

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2.11 Superior mesenteric artery syndrome. A: Compression of the third portion of the duodenum between the aorta and superior mesenteric artery; B: upper gastrointestinal tract series shows dilatation of the second portion of the duodenum; C: CT scan shows narrowing between the superior mesenteric artery (arrowhead) and aorta (arrow), with dilatation of the second portion of the duodenum.

50°

A

16°

B

C

References 1 Lawes IN. The origin of the vomiting response: a neuroanatomical hypothesis. Can J Physiol Pharmacol 1990;68:254–9. 2 Kumar Y, Sarvananthan R. Gastro-oesophageal reflux in children. Clin Evid 2005;14:349–55. 3 Vandenplas Y, Salvatore S, Devrecker T, Hauser B. Gastro-oesophageal reflux disease: oesophageal impedance versus pH monitoring. Acta Paediatr 2007;96:956–62. 4 Keady S. Update of drugs for gastro-oesophageal reflux disease. Arch Dis Child Educ Pract Ed 2007;92:ep 114–8. 5 Hassal E. Outcomes of fundoplication: causes of concern, newer options. Arch Dis Child 2005;90:1047–52. 6 Gottrand F. Gastro-oesophageal reflux in infants, children and adults. Hiatal hernia. Rev Pract 2007;57:95–8.

7 Stunden RJ, LeQuense GW, Little KET. The improved ultrasound diagnosis of pyloric stenosis. Pediatr Radiol 1986;16:200–5. 8 Hernanz-Schulman M. Infantile hypertrophic pyloric stenosis. Radiology 2003;227:319–31. 9 Aldrigde RD, Mac Kinley GA, Aldridge RB. Choice of incision: the experience and evolution of surgical management of infantile hypertrophic pyloric stenosis. J Laparoendosc Adv Surg Tech A 2007;17:131–6. 10 Lock G, Scholmerich J. Non-occlusive mesenteric ischemia. Hepatogastroenterology 1995;42:234–9. 11 Chow S, Golldman RD. Treating children’s cyclic vomiting. Can Fam Phys 2007;53:467–9. 12 Chepyala P, Svoboda RP, Orden KW. Treatment of cyclic vomiting syndrome. Curr Treat Options Gastroenterol 2007;10:273–82.

Further reading Hassall E. Step-up and step-down approaches to treatment of gastroesophageal reflux disease in children. Curr Gastroenterol Rep 2008;10(3):324–31. Li BU, Lefevre F, Chelimsky GG, et al. North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition consensus statement on the diagnosis and management of cyclic vomiting syndrome. J Pediatr Gastroenterol Nutr 2008;47(3):379–93.

Chapter 3

19

Diarrhoea ACUTE DIARRHOEA Enriqueta Román Riechmann, MD Definition Diarrhoea is a change in the individual bowel habit resulting in more frequent and/or looser stools. It expresses an acute gastrointestinal inflammation (acute gastroenteritis). In childhood, gastrointestinal infection is the most common cause of acute diarrhoea worldwide1, 2.

enteric adenovirus (types 40 and 41), with some common features (Table 3.2)3. Most common bacteria are Campylobacter spp. and Salmonella spp., followed by Shigella, Yersinia and Escherichia coli. The major parasitic infections are Giardia and Cryptosporidium2.

Aetiology Epidemiology In industrialized countries the most clinically significant agents in infant acute diarrhoea are viruses (Table 3.1), mainly group A rotavirus (3.1A, B). Other viruses involved are human calicivirus (norovirus and sapovirus, formerly known as Norwalk and Sapporo virus), astrovirus and

Viral gastroenteritis is the second most common disease in developed countries. The sporadic form affects all children in the first 5 years of life. Viruses are transmitted fundamentally by the faecal–oral route. There is faecal

Outer capsid: VP 4 Outer capsid:VP 7 Middle capsid: VP 6

Segmented genome A

B

3.1 A: Electron microscopy of rotavirus particles from an infant with acute diarrhoea (courtesy Centers for Disease Prevention and Control, Atlanta, GA, USA); B: schematic of the complete rotavirus particle with structural proteins in the different shells.

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Diarrhoea

Table 3.1 Main agents of infectious acute diarrhoea

Table 3.2 Main features of viral agents

Viruses • Group A rotavirus • Enteric adenovirus • Astrovirus • Human calicivirus – Norovirus – Sapovirus

• RNA viruses (except adenovirus)

Parasites Giardia lamblia Cryptosporidium parvum

Bacteria • Salmonella – S. typhi and paratyphi – Nontyphoidal Salmonella S. enteritidis S. typhimurium • Shigella – Shigella sonnei • Campylobacter – C. jejuni • Yersinia – Y. enterocolítica • Escherichia coli – Enteropathogenic E. coli – Enterotoxigenic E. coli – Enteroinvasive E. coli – Enterohaemorrhagic E. coli – Diffusely adherent E. coli – Enteroaggregative E. coli • Aeromonas

excretion of viral particles in the days prior to clinical symptoms and continuing through to its resolution. Rotavirus is a seasonal infection and in temperate climates infections peak during the winter months3. In bacterial enteric infection transmission can be through contaminated water or foodstuffs.

• Nonlipoproteic envelope • Seasonal distribution • Asymptomatic infection ⇔ severe disease • Frequent coinfections • Endemic, sporadic cases/epidemic, outbreaks • Faecal–oral transmission

Pathophysiology Diarrhoea occurs when the volume of water and electrolytes present in the colon exceeds its capacity for absorption. This can be mainly due to an increase in the secretion and/or a decrease in the absorption level of the small intestine. Decreased intestinal absorption occurs as a result of intestinal damage or inflammation (3.2). Viruses causing diarrhoea infect selectively mature enterocytes, causing cell lysis and producing a decrease in disaccharidase activity and in mechanisms for active sodium and water absorption. The consequence is a malabsorptive or osmotic diarrhoea. Diarrhoea caused by bacterial infection is most frequently secretory. Bacteria can activate one of the intracellular pathways leading to intestinal secretion through enterotoxins.

3.2 Pathogenesis of viral diarrhoea: rotavirus infects selectively mature enterocytes on the tips of small intestine villi, leading to their destruction and villi atrophy. (Courtesy Faculty of Biological Sciences, University of Barcelona, Barcelona, Spain.)

A

B

Diarrhoea 21

Clinical features

Assessment

Acute diarrhoea is a self-limiting process. Viral diarrhoea is typically acute in onset, watery-like, and the faeces do not contain mucus, blood, or white cells. Diarrhoea can lead to dehydration, acidosis, and electrolyte imbalance. Vomiting appears at the beginning of the process. The most common age is 6–24 months and rotavirus infection is associated with a more severe disease3. In the secretory and osmotic diarrhoeas, faeces are watery and profuse. The invasive diarrhoea is frequently characterized by mucus and macroscopic blood. Nevertheless, viral gastroenteritis cannot be distinguished from that caused by bacteria through clinical history or physical examination, although some characteristics may suggest bacterial diarrhoea (Table 3.3).

In most cases, a complete clinical history and a careful physical examination is all that is necessary4–6. These should rule out any life-threatening cause such as intussusception, surgical abdomen, and haemolityc–uraemic syndrome7. The severity of dehydration is assessed in terms of weight loss as a percentage of total body weight. An assessment of dehydration degree can be made by diverse scales of clinical signs and symptoms (Table 3.4, 3.3). Supplementary laboratory studies are usually unnecessary. There are some recommendations on which patients should have blood tests (serum electrolytes, urea/creatinine, bicarbonate) (Table 3.5) and on which patients should have faecal laboratory study (Table 3.6), as aetiology is irrelevant for clinical management. Tests for specific pathogens

Table 3.3 Clinical features suggestive of bacterial diarrhoea • Children older than 3 years • Acute onset • No vomiting

• Hyperthermia • Bloody diarrhoea

• Increase in CRP • Faecal white cells

Table 3.4 Assessment of dehydration degree (adapted from ESPGHAN 2001and CDC report 2003)6, 7 Symptom Body weight loss General condition

Minimal or no dehydration <3% Well, alert

Mild to moderate dehydration 3–9% Restless, irritable

Eyes Tears Mouth and tongue Thirst

Normal Present Moist Drinks normally, not thirsty

Slightly sunken Absent Dry Thirsty, eager to drink

Skin fold Fontanelle Heart rate

Instant recoil Normal Normal

Recoil in <2 seconds Sunken Normal to increased

Quality of pulses

Normal

Extremities Urine output

Normal capillary refill Slightly decreased

Normal or slightly decreased Delayed capillary refill <1 ml/kg/h

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Severe dehydration >9% Lethargic or unconscious: floppy Deeply sunken Absent Very dry Drinks poorly, unable to drink Recoil in >2 seconds Sunken Tachycardia, bradycardia in most severe cases Moderately decreased Cool, mottled <1 ml/kg/h

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Diarrhoea

Sunken fontanelle

Intestinal lumen Crying and irritablility

Sunken eyes

Substrate Na+

Dry mouth

Substrate

Decreased skin turgor 3.3 Signs of dehydration.

Table 3.5 Recommendations on blood tests (adapted from AAP 1996)5, 8

Intestinal villous cell

D-hexoses D-glucose D-galactose L-amino acids

H2O

Substrate Na+ H2O + Na+

3.4 Diagram to show the processes involved in cotransport of organic solutes and sodium and secondary water absorption.

include stool cultures for bacteria and detection of faecal viral antigen by enzyme immunoassay (EIA), agglutination with latex particles, or immunochromatography.

• Severe dehydration • Moderate dehydration where clinical signs might indicate hypernatraemia

Treatment

• Moderate dehydrated patients whose histories or physical findings are inconsistent with straightforward diarrhoeal episodes

There is no specific treatment for acute gastroenteritis. The main objective is to treat the dehydration and to lead to nutritional recovery. Treatment includes two phases, rehydration with quick replacement of fluid deficit, followed by maintenance in which rapid realimentation and maintenance fluids are indicated.

• History of excessive hypertonic or hypotonic fluid ingestion

Rehydration Table 3.6 Recommendations for faecal laboratory study

• Immunocompromised • Blood in the stool • Uncertain diagnosis • Severe or prolonged diarrhoea • Hospitalization • Recent travel abroad

The molecular process for cotransport of glucose and sodium was the basis for oral rehydration therapy (ORT) development (3.4). ORT is recommended globally for the management of acute diarrhoea2, 6–8. The World Health Organization (WHO), the American Academy of Pediatrics (AAP), and the European Society of Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) recommend the use of ORT in the treatment of gastroenteritis with mild to moderate dehydration (Table 3.7). Oral rehydration solution (ORS) is more physiological, cost-effective and has fewer adverse effects that intravenous therapy. Intravenous fluids should be reserved for patients with severe dehydration.

Diarrhoea 23

Table 3.7 Oral rehydration solution composition

WHO (1975) ESPGHAN (1992)

Bicarbonate;

Potassium (mmol/l)

Chloride (mmol/l)

Base (mmol/l)

Glucose (mmol/l)

Osmolarity (mOsm/l)

90

20

80

30Bic

110

310

60

10Cit

74–111

200–250

65

10Cit

75

245

60

WHO (2002) Bic

Sodium (mmol/l)

75 Cit

20 20

Citrate

Table 3.8 Contraindications for oral rehydration therapy

• Severe dehydration

• Persistent vomiting

• Potential surgical pathology

– Shock

• High ongoing faecal losses (>10 ml/kg/h)

• ORT previous failure

– Diminished consciousness

A single hypo-osmolar ORS would be used for all diarrhoeal episodes (cholera and noncholera). These solutions should not be replaced by any other drinks such as clear fluids like water alone or homemade solutions, colas, sports drinks, or fruit juices. There are a few situations in which ORT is contraindicated (Table 3.8). The schedule of ORT should be to give small aliquots frequently (3.5).

Feeding Early feeding may decrease the intestinal permeability changes induced by infection, reduce illness duration, and improve nutritional recovery. The recommendations after the period of rehydration are: • Continuation of breastfeeding in all cases. • In formula-fed infants continuation of a nondiluted formula, without restriction of lactose intake. • Resumption of full normal diet in older children, except for avoiding foods rich in simple sugars, due to its osmotic load.

Micronutrients Zinc has been the main micronutrient implied in the diarrhoeal process. Studies performed in developing countries have shown its effectiveness in the treatment of acute and persistent diarrhoea in children younger than 5 years9. This

• Significant psychosocial situation

has led the WHO and UNICEF to recommend treatment with zinc in all children with diarrhoea in developing countries10.

Probiotics The addition of probiotics to milk or infant formulas or to the rehydration solutions have shown a shortening in the duration of the diarrhoea. A moderate clinical benefit of some probiotics has been shown in the treatment of acute watery diarrhoea, mainly by rotavirus in infants and young children11. This effect seems to be: moderate in reducing diarrhoea by 17–30 hours; strain dependent with Lactobacillus GG most effective; not effective in bacterial invasive diarrhoea; effective in a dose >1010 CFUs and when it is administered early in the disease to children in developed countries.

Drugs Antidiarrhoeal drugs, such as inhibitors of intestinal motility (loperamide and other opiates and anticholinergics), modifiers of the intestinal secretion (bismuth salts), and adsorbent substances (cholesteramine, aluminum salts), are not used in childhood as they have their effectiveness has not been demonstrated and/or they have important adverse effects.

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Acute diarrhoea/gastroenteritis Other causes of diarrhoea and/or vomiting excluded Dehydration assessment

No dehydration

Mild to moderate

Severe

Risk factors? Infants <6 months High frequency of watery stools or vomits

ORS (30–80 ml/kg) over 4 hours and reassessment

IV rehydration

No

Yes Rehydrated?

Discharge

Observation at least 24 hours

Yes

No Consider nasogastric tube or IV rehydration

Normal feeds + maintenance fluids (ORS 10 ml/kg/watery stool)

3.5 Management of acute diarrhoea.

Effectiveness and good oral tolerance of racecadotrile (an antihypersecretor with no effect on intestinal motility) has recently been described. Antiemetic drugs are unnecessary in the treatment of acute diarrhoea, although ondansetron can sometimes be effective in diminishing vomiting and the necessity for hospitalization. The use of antibiotics would only be justified in: • Immunocompromised patients. • All cases of acute diarrhoea by Shigella, Vibrio cholerae, and the majority of those produced by enteroinvasive and enteropathogenic E. coli and by Clostridium difficile. • Some cases of infection by Campylobacter, by Yersinia in cases of serious disease, by Salmonella in infants with bacteraemia, and in all patients younger than 3 months.

Prevention Since the main infectious route is faecal–oral, fundamental to prevention is to reinforce environmental hygiene, with appropriate hand cleaning and cleaning of the objects used in the manipulation of children with diarrhoea. At present there are already two safe and effective vaccines against severe disease by the most prevalent serotypes of rotavirus in human pathology. Both are of oral administration in two (monovalent human, Rotarix®) or three doses (pentavalent bovine–human, Rotateq®). These vaccines can be administered with other regular childhood vaccines. In summary, the management of acute diarrhoea in children younger than 5 years should be: oral rehydration for 3–4 hours, followed by a fast reintroduction of usual feeding plus ORS for maintained losses (3.5, Table 3.9).

Diarrhoea 25

CHRONIC DIARRHOEA Angeles Calzado Agrasot, MD, Begoña Polo Miquel, MD, and Carmen Ribes-Koninckx, MD, PhD Definition and pathophysiology

Aetiology

Chronic diarrhoea is defined as a decrease of consistency or increase in frequency or volume of stools lasting longer than 2 weeks12. Different mechanisms can be involved in chronic diarrhoea and usually a combination of more than one are responsible for this alteration13: • Osmotic diarrhoea: nonabsorbed substances in the distal bowel increases osmotic charge, pulling water along the intestinal lumen. • Secretory diarrhoea: increased secretion of water and electrolytes into the intestinal lumen, surpassing the absorption capability. • Motility alterations: – Hypermotility: unspecific chronic diarrhoea. – Hypomotility: intestinal bacterial overgrowth. • Inflammatory: enterocyte injury with inflammatory response: humoral, cellular, and phagocytic, and with permeability alteration and decrease in disacaridases and transporters. – Infectious: bacteria, parasites. – Chronic inflammatory bowel disease (IBD) (Crohn’s disease and ulcerative colitis). • Digestion disorders (decreased enzymes, deconjugated bile salts).

A wide variety of disorders including organ dysfunction, autoimmune diseases, and congenital alterations14 can account for chronic diarrhoea in infancy as shown in Table 3.10.

Diagnosis A complete clinical history is mandatory. Some clinical signs and symptoms are relevant for a diagnostic approach14, including: • Nutritional repercussion. • Associated symptoms: fever, vomiting, abdominal pain, anorexia. • Stool characteristics: blood, mucous, nondigested substances, steatorrhoea. • Physical examination: failure to thrive, abdominal distension, visceromegaly, tenderness, presence of abdominal masses. • Other organs affected, e.g. skin, respiratory system. • Age of onset: according to the age of presentation, certain disorders are more likely to occur (Table 3.11).

Table 3.9 Practical guidelines for the management of gastroenteritis in children. ‘Six pillars of good practice’ (ESPGHAN 2001)6

l

Use of oral rehydration solution (ORS) to correct estimated dehydration in 3–4 hours (fast rehydration)

ll Use of hypo-osmolar solution (60 mmol/l sodium, 74–111 mmol/l glucose) lll Continuation of breast-feeding throughout lV Early refeeding: resumption of normal diet (without restriction of lactose intake) after 4 hours rehydration V Prevention of further dehydration by supplementing maintenance fluids with ORS (10 ml/kg/watery stool) Vl No unnecessary medication

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Table 3.10 Aetiology of chronic diarrhoea

Pancreatic insufficiency • Cystic fibrosis • Schwachman syndrome Hepatobiliary dysfunction • Deconjugated bile salts due to bacterial overgrowth • Biliary atresia • Cholestasis Congenital alterations in electrolyte transport • Congenital chlorated diarrhoea Carbohydrate intolerance • Congenital alactasia • Secondary lactose intolerance • Primary congenital racial intolerance • Glucose – galactose malabsorption

Infectious • Prolonged viral enteritis • Salmonella • Campylobacter • Yersinia • Giardia lamblia • Cryptosporidium • Bowel bacterial overgrowth • Pseudomembranous colitis Anatomical or surgical disorder • Necrotizing enterocolitis • Short bowel syndrome • Blind loop syndrome • Hirschprung’s disease • Intestinal lymphangiectasia Inflammatory • Crohn’s disease • Ulcerative colitis

Changes in mucosa • Coeliac disease • Cow´s milk intolerance • Soy intolerance • Other food protein intolerance • Congenital microvilli atrophy • Autoimmune enteropathy

Other causes • Abetalipoproteinaemia • Anderson disease • Enteropathic acrodermatitis • Immunodeficiency (congenital or acquired – HIV) • Postenteritis diarrhoea • Protein-losing enteropathy • Bile acid malabsorption

Motility disorders • Toddler´s diarrhoea • Hyperthyroidism • Idiopathic bowel pseudo-obstruction • Irritable bowel syndrome

Table 3.11 Aetiology according to the age at presentation

<1 year

1–3 years

>3 years

Lactose intolerance

Unspecific chronic diarrhoea

Giardia lamblia

Postenteritis diarrhoea

Giardia lamblia

Coeliac disease

Food intolerance

Coeliac disease

Inflammatory bowel disease

Cystic fibrosis

Infectious diarrhoea

Lactose intolerance

Dietetic mistakes

Postenteritis diarrhoea

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Laboratory studies • Stool analysis: faecal characteristics or faecal losses can point to specific syndromes (3.6). • Blood studies (3.7). • Other studies:

Macroscopic stool aspect: consistence, mucous or blood

Presence of fat • Quantitative: different methods can be used such as Van de Kamer, steatocrit • Qualitative: Sudan

• Fat malabsorption • Pancreatic insufficiency

Proteins • Alpha-1-antitrypsin clearance • Quimiotrypsine • Calprotectine • Elastase

• Protein-losing enteropathy • Pancreatic insufficiency • IBD

pH <5.5 Reducing substances

• Carbohydrate malabsorption (glucose-galactose malabsorption)

– Exhaled hydrogen concentration test, mono/disaccharides tolerance test: carbohydrate malabsorption or bacterial overgrowth. – Pancreatic enzymes in duodenal fluid, immunoreactive trypsin, sweat chloride test: pancreatic insufficiency. • Enterocyte, smooth muscle, thyroid and islet cell serum antibodies: autoimmune enteropathy.

Imaging procedures Plain abdominal radiography may rule out anatomical disorders or surgical causes. An abdominal ultrasound may be useful in anatomical or surgical disorders, in infectious diarrhoea, or if IBD is suspected. The use of a barium upper gastrointestinal (GI) study or a barium enema helps in the diagnosis of anatomical or surgical disorders. When IBD is suspected an upper endoscopy or a colonoscopy should be performed and multiple biopsies taken.

Haematology, biochemistry (including proteins, albumin), iron metabolism, vitamin levels, immunoglobulin levels

Nutritional status

Total proteins, albumin

Protein-losing enteropathy

Osmolarity

• >280 mOsm/l – osmotic diarrhoea • <280 mOsm/l – secretory diarrhoea

Coeliac autoantibodies (IgA antigliadin, specific tissue transglutaminase antibodies)

Coeliac disease

Stool culture

• Infectious diarrhoea

IgE, prick test, food antigen RAST Elimination and provocation tests

Food allergy/food intolerance

Erythrocyte sedimentation rate, C-reactive protein level, alpha-1glycoprotein, protein electrophoresis

IBD

Fresh view

Occult blood

Parasites

• IBD • Infectious diarrhoea • Protein sensitivity syndrome

3.6 Characteristics of stools may help to diagnose chronic diarrhoea.

3.7 Biochemical analysis of blood that may help to diagnose the aetiology of chronic diarrhoea.

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3.8 The small bowel is an area of the intestine not A accessible to routine endoscopic techniques. The recent development of the wireless B endoscopic capsule (A) has allowed the possibility of reaching these blind areas of the small bowel. Similar to a large antibiotic capsule, after being swallowed by the patient, the capsule C is propelled by peristalsis. Video images are transmitted (two images per second) from inside the body during 6–8 hours, to a sensor array secured to the patient’s abdomen (B, C). This is then connected to the recorder which stores the data. (Courtesy of Given Imaging Ltd.)

3 1

2

4

5

5

6

7

3

3.9 Schematic diagram of a video-capsule: 1, clear optical dome; 2, lens; 3, illuminating LEDs; 4, CMOS imager; 5, battery; 6, ASIC transmitter; 7, antenna. Weight, 3.7 g.

The wireless endoscopic capsule The small bowel is an area of the intestine not accessible to routine endoscopic techniques. However, the recent development of the wireless endoscopic capsule (EC) (3.8) has revolutionized endoscopy15. Advances in miniaturization of electronic components have allowed the development of a new type of capsule endoscope (3.9, 3.10), enabling endoscopy of the whole GI tract15 with low invasivity. Similar to a large antibiotic capsule, after being swallowed by the patient, the video-capsule is propelled by peristalsis and will transmit video images, 2 images per second, from inside the body over 6–8 hours to a sensor array fixed to the patient’s abdomen and to a recorder. After the stored images are processed by a special software (RAPID™ [Reporting And Processing of Images and Data] Application Software), these can be stored as a high quality video. Individual frames and short videos can be also filed; moreover, digital data allow integration into reports which can be stored, printed, or sent by email. This device is therefore very useful for the diagnosis of occult digestive bleeding and for the diagnosis, follow-up, and extension study of IBD16–18. Wireless EC shows great potential for the study of other

A Video section Thumbnail section Comment Timebar

Video controls B 3.10 Video-capsule processor (A: workstation; B: main screen). (Courtesy of Given Imaging Ltd.)

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Table 3.12 Advantages and drawbacks of the wireless EC system Advantages

Disadvantage

• Noninvasive

• Patient refusal or impossibility to swallow the capsule – the capsule can be introduced into the stomach with a gastroscope

• High-quality images of the entire small bowel • Ambulatory examination • Imaging is possible even in the very frail patient

• The capsule is retained in the stomach, i.e. no images of the small bowel are registered • Small bowel strictures can contraindicate the procedure

3.11 Characteristic Crohn’s disease ulcers obtained by a wireless endoscopic capsule. A: jejunum; B: distal ileum.

A

B

A

B

3.12 Patchy lesions in a young patient with coeliac disease obtained by a wireless endoscopic capsule. A: villi are clearly visible in normal jejunum; B: absence of villi in a patient with coeliac disease.

disorders such as intestinal polyps, graft versus host disease, tumours, and so on (Table 3.12). Its optimal use in paediatric patients has not yet been established. The only actual complication of the procedure is related to the presence of strictures that may cause the capsule to be retained, necessitating removal by interventional or surgical procedures. In chronic diarrhoea, this procedure may be useful to rule

out a specific disorder or when other methods have failed to confirm a diagnosis, for instance Crohn’s disease restricted to areas of the small intestine not accessible by conventional endoscopy (3.11)19. Small villous atrophy, characteristic of coeliac disease, may be patchy or present in distal jejunum making diagnosis extremely challenging by conventional methods (3.12). Although video-capsule endoscopy is not

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currently a first step diagnostic procedure in chronic diarrhoea, further technological improvements, such as a smaller size, new capsule for large bowel, and the possibility of taking biopsies, will surely widen the indications for this procedure.

Toddler’s diarrhoea Toddler’s diarrhoea usually occurs between 6 months and 3 years of age, and is the most frequent cause of chronic diarrhoea in this age group. It usually occurs after an acute beginning (infections, stress, antibiotic treatment). It usually disappears at 2–4 years old, and evolves to recovery spontaneously. The main symptoms are 3–6 depositions/day, not formed, with more or less mucous and undigested food particles. Depositions do not occur nightly. Symptoms are intermittent and self-limited20. There is no pain or abdominal distention and it does not affect weight or height. The physiopathology is not clear although it has been suggested that accelerated intestinal motility or an increase in bile salt elimination are responsible. Sometimes toddler’s diarrhoea has been related to dietary mistakes: low fat and high carbohydrate diet, increased fruit juice intake, or increased water intake.

overgrowth, and even genetic polymorphisms (interleukin-10) have all been implicated. Treatment consists of reassuring parents and giving some dietary advice: some patients may improve if they eliminate or restrict particular constituents of food such as lactose, fructose, sorbitol, flatulent vegetables, or fruits16. Dietetic restrictions are applicable only if there is an improvement following removal of the foodstuffs. In IBS with constipation, fibre intake can improve symptoms. Pharmacological treatment depends on the putative physiopathologic mechanisms. Different approaches can be used, but the efficacy of these treatments has not been established and an individual approach has to be considered (3.13)22.

Intractable diarrhoea of infancy (IDI) IDI is a severe life-threatening diarrhoea within the first 24 months of life, requiring parenteral nutrition. Persistent villous atrophy can be demonstrated in consecutive biopsies and is resistant to the usual therapies (3.14).

Intestinal motility alteration

Anticholinergics

Visceral hypersensitivity

5-HT4 agonists Antidepressants

Irritable bowel syndrome (IBS) According to Roma III21 IBS is recurrent abdominal pain or discomfort for at least 3 days/month in the last 3 months, associated with two or more of the following criteria: • It improves with defecation. • The onset of pain starts with a change in the frequency of the stools. • The onset of pain starts with a change in the characteristics of the stools. Usual symptoms are: deposition frequency range from fewer than three depositions in a week to more than three depositions a day; stools can be hard, pasty, or watery; stool evacuation with effort or urgency, with an incomplete evacuation feeling; mucous stools; abdominal distension impression; and nightly depositions. There is no clear physiopathology: intestinal motility alteration, visceral hypersensitivity, deregulation of the central nervous system and digestive tract interaction, low-grade chronic intestinal inflammation, bacterial

Deregulation central nervous system and digestive tract interaction

5HT agonists

Low grade chronic intestinal inflammation

Probiotics

Bacterial overgrowth

Antibiotics Probiotics Diet

3.13 The pharmacological treatment of irritable bowel syndrome should be individually tailored to the most likely physiopathological cause.

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Mucous stools

Microvillous inclusion disease

Choanal atresia Keratitis

Epithelial dysplasia

Small for gestational age Facial dysmorphy Abnormal hair

Syndromatic diarrhoea (tufting)

Extradigestive disease Autoimmune, autoantibodies

Autoimmune enteropathy

Neonatal

1–3 months

3–12 months Occasionally bloody stool

Cow’s milk allergy and other immune-mediated disorders

3.14 Intractable diarrhoea of infancy. Most usual causes and diagnostic entities according to age of presentation.

Bacterial overgrowth syndrome

Postenteritis syndrome

Bacterial overgrowth syndrome is due to malabsorption resulting from poor enterocyte function and bacterial transformation of nutrients into nonabsorbable and toxic metabolites23. It most commonly present in infants younger than 2 years. It may be associated with anatomical damage, abnormal small bowel motility, and immunological alterations. If bacterial overgrowth is present, there is an alteration of the intraluminal metabolism of carbohydrates. Carbohydrates are fermented into smaller osmotically active molecules and organic acids by bacteria. Increased osmolarity results in osmotic diarrhoea. Alteration of intraluminal metabolism of bile acids occurs, causing deconjugation of the bile acids. These stimulate the colon to secrete fluid (secretory diarrhoea) and inhibit the carbohydrate transporters and reduce intraluminal pH levels. Symptoms depend on the degree of mucosal damage, from abdominal pain or flatulence to severe diarrhoea with malabsorption. The diagnosis can be established by duodenojejunal culture (≥106 UFC/ml) or exhaled hydrogen concentration with an oral carbohydrate load. Treatment consists of nonintestinal absorbable antibiotics.

This presents as a protracted course of acute diarrhoea or early relapse after improvement. It usually appears in infants and toddlers (6 months–3 years). Clinically, it presents as watery stools with or without vomit, anorexia, and failure to thrive. There are conditioning factors such as genetics, medical conditions, the aetiology of infectious acute diarrhoea, nutritional status, and inadequate management of acute diarrhoea (indiscriminate use of antibiotics, hypocaloric diet and excessive carbohydrate intake). When diarrhoea is prolonged, the mucosa is damaged. Enteropathy alters secretory and absorption function and intestinal motility. The treatment consists of transient elimination of cow’s milk and lactose from the diet. If there is a concomitant infectious cause of diarrhoea, aetiological treatment is indicated.

Transient food intolerance/allergy Transitory food allergy or intolerance is an adverse reaction to foods. The term ‘food intolerance’ is usually preferred to food allergy, in order to include pathological reactions

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mediated by nonimmune mechanisms24. Cow’s milk proteins are most frequently implicated as a cause of food intolerance during infancy. Soy protein is another common food antigen. From school age on, egg protein becomes more important. With increased consumption, sensitization from other sources becomes more frequent. It is known that gastrointestinal infections, decreased serum and secretory IgA, malnutrition, and atopic tendency are risk factors for increased intestinal permeability to food antigens. Oral tolerance does not develop and different immunological and inflammatory mechanisms occur with epithelial damage (enteropathy). Clinical symptoms depend on different factors: age, site of food antigen exposure, different pathogenetic mechanisms, and degree of the enteropathy. Symptoms can be gastrointestinal (chronic diarrhoea, failure to thrive), respiratory, or dermatological. Diagnosis is established by elimination and challenge tests. The test is positive for food intolerance when symptoms decline following dietary elimination of the suspected offending food and recur after a food challenge. A challenge should be performed with the suspected agent and with placebo. Immunological tests include: • Skin prick test with the defined antigens. • RAST: IgE class antibodies against specific food antigens. • IgG class antibodies against specific food antigens: interpretation of results will be done according clinical symptoms. • Total serum IgE. In addition, gastroenterological tests are available, such as gastric biopsy, small bowel biopsy, and stool analysis (eosinophils, blood). The definitive treatment of food allergy is strict elimination of the offending food from the diet. Food-induced intolerance is most often a temporary disease. Most children can resume consumption of the offending antigen after 1–4 years of an elimination diet.

Carbohydrate malabsorption Carbohydrate malabsorption usually presents as watery and acid stools, abdominal distension and flatulence, perianal area erythema, and failure to thrive (3.15)25. Treatment consists of the elimination of all or specific dietary carbohydrates until the diarrhoea resolves. In congenital disease, carbohydrates never will be introduced.

Congenital: • Amylase deficiency: cystic fibrosis and Schwachman–Diamond syndrome • Congenital lactase deficiency • Glucose-galactose malabsorption • Sucrose-isomaltase deficiency • Adult-type hypolactasia – Most common entity – From banal symptoms to established diarrhoea – Onset age: 5–7 years – Fluctuating prevalence: from 1–3% in North of Europe to 60% in southeast Africa

Acquired: • Lactose intolerance (secondary to a damage of the mucose that causes mucose atrophy such as viral enteritis and coeliac disease)

3.15 Carbohydrate intolerance is a common cause of chronic diarrhoea in infancy. Several different medical conditions can produce this clinical picture.

References 1 Casburn-Jones AC, Farthing MJG. Management of infectious diarrhoea. Gut 2004;53:296–305. 2 Davidson G, Barnes G, Bass D, et al. Infectious diarrhoea in children: Working Group Report of the First World Congress of Pediatric Gastroenterology, Hepatology and Nutrition. J Pediatr Gastroenterol Nutr 2002;35:S143–50. 3 Wilhelmi I, Román E, Sánchez-Fauquier A. Viruses causing gastroenteritis. Clin Microbiol Infect 2003;9:247–62. 4 AAP. Provisional Committee on Quality Improvement, Subcommittee on Acute Gastroenteritis. Practice parameter: the management of acute gastroenteritis in young children. Pediatrics 1996;97:424–33. 5 Sandhu BK, for the European Society of Pediatric Gastroenterology, Hepatology and Nutrition Working Group on Acute Diarrhoea. Practical guidelines for the management of gastroenteritis in children. J Pediatr Gastroenterol Nutr 2001;33:S36–9.

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6 King CK, Glass R, Bresee JS, Duggan C; Centers for Disease Control and Prevention. Managing acute gastroenteritis among children: oral rehydration, maintenance, and nutritional therapy. MMWR Rec Rep 2003;52(RR-16):1–16. 7 Armon K, Stephenson T, Macfaul R, et al. An evidence and consensus based guideline for acute diarrhoea management. Arch Dis Child 2001;85:132–42. 8 Rao MC. Oral rehydration therapy: new explanations for an old remedy. Ann Rev Physiol 2004;66:385–417. 9 Hoque KM, Binder J. Zinc in the treatment of acute diarrhoea: current status and assessment. Gastroenterology 2006;130:2201–5. 10 WHO/UNICEF Joint Statement. Clinical management of acute diarrhoea. The United Nations Children´s Fund/World Health Organization, 2004. WHO/FCH/CAH/04.7. 11 Szajewska H, Setty M, Mrukowicz J, Guandalini S. Probiotic in gastrointestinal diseases in children: hard and not so hard evidence of efficacy. J Pediatr Gastroenterol Nutr 2006;42:454–75. 12 Gibbons T, Fuchs GJ. Chronic enteropathy: clinical aspects. Nestle Nutr Workshop Ser Pediatr Program 2007;59:89–101; discussion 102–4. 13 Booth IW, McNeish AS. Mechanisms of diarrhoea. Ballières Clin Gastroenterol 1993;7:215–42. 14 Lee WS, Boey CC. Chronic diarrhoea in infants and young children: causes, clinical features and outcome. J Paediatr Child Health 1999;35(3):260–3. 15 Cave DR. Wireless video capsule endoscopy. Clin Perspec Gastroenterol 2002;5:203–7. 16 Seidman EG, Sant´Anna AM, Dirks MH. Potencial applications of wireless capsule endoscopy in the pediatric age group. Gastrointest Endosc Clin N Am 2004;14(1):207–17. 17 Aabakken L, Scholz T, Ostensen AB, et al. Capsule endoscopy is feasible in small children. Endoscopy 2003;35(9):798. 18 Argüelles-Arias F, Argüelles-Martín F, Caunedo A, et al. Utilidades de la cápsula endoscópica en gastroenterología pediátrica. Ann Pediatr 2003;59:586–9. 19 Argüelles-Arias F, Caunedo A, Romero J, et al. The value of capsule endoscopy in paediatric patients with a suspicion of Crohn´s disease. Endoscopy 2004;36(10):869–73.

20 Fenton TR, Harries JT, Milla PJ. Disordered small intestinal motility: a rational basis for toddlers’ diarrhoea. Gut 1983;24(10):897–903. 21 Sperber AD, Shvartzman P, Friger M, et al. A comparative reappraisal of the Rome II and Rome III diagnostic criteria: are we getting closer to the ‘true’ prevalence of irritable bowel syndrome? Eur J Gastroenterol Hepatol 2007;19(6):441–7. 22 Spiller R, Aziz Q, Creed F, et al. Guidelines for the management of irritable bowel syndrome. Gut 2007;56:1770–98. 23 Gregg CR. Enteric bacterial flora and bacterial overgrowth syndrome. Semin Gastrointest Dis 2002;13(4):200–9. 24 Assaad AH. Gastrointestinal food allergy and intolerance. Pediatr Ann 2006;35(10):718–26. 25 Kneepkens CM, Hoekstra JH. Malabsorption of carbohydrates. Nestle Nutr Workshop Ser Pediatr Program 2005;56:57–69; discussion 69–71.

Further reading Kligler B, Hanaway P, Cohrssen A. Probiotics in children. Pediatr Clin North Am 2007;54:949–67. Guarino A, Albano F, Ashkenazi S, et al. European Society for Paediatric Gastroenterology, Hepatology, and Nutrition/European Society for Paediatric Infectious Diseases evidence-based guidelines for the management of acute gastroenteritis in children in Europe: executive summary. J Pediatr Gastroenterol Nutr 2008;46:619–21. European Society for Paediatric Gastroenterology, Hepatology, and Nutrition/European Society for Paediatric Infectious Diseases. European Society for Paediatric Gastroenterology, Hepatology, and Nutrition/European Society for Paediatric Infectious Diseases evidence-based guidelines for the management of acute gastroenteritis in children in Europe. J Pediatr Gastroenterol Nutr 2008;46 suppl 2:S81–122.

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Chapter 4

Constipation Carolina Gutiérrez, MD, and Jerónimo Gonzálvez, MD

Definition and aetiology

Normal defecation and functional constipation

Constipation can be defined as the delay or difficulty in defecation occurring for ≥2 weeks and causing significant distress to the patient. As a symptom, constipation can be caused by many different disorders (Table 4.1) but 90% of all constipated children have functional constipation, with no identifiable organic or anatomical cause. Constipation is a common symptom in paediatric clinical practice, accounting for 3% of all general paediatric visits and between 10 and 25% of all cases in paediatric gastroenterology reference units.

Mechanisms of normal defecation and continence are summarized in figure 4.1. The term ‘functional constipation’ (also called idiopathic or retentive constipation or psychogenic megacolon) describes all children in whom constipation does not have an organic aetiology, and it is generally caused by a maladaptative response to defecation (4.2). In functional constipation, fear of defecation after a painful experience and repeated attempts of voluntary withholding of stools (vicious circle theory) lead to the

Table 4.1 Differential diagnosis of constipation

Functional constipation (90%) Organic constipation (10%) • Anatomical malformations – Anal stenosis – Imperforatus anus – Anterior displaced anus – Pelvic mass (sacral teratoma) • Neuromuscular disorders – Cerebral palsy, hypotonia – Disorders of the spinal cord – Myelomeningocoele – Spinal cord trauma – Spinal cord tumour – Muscular dystrophy

• Metabolic and endocrine disorders – Hypothyroidism – Renal acidosis – Diabetes insipidus – Hypercalcaemia – Hypokalaemia • Intestinal nerve or muscle disorders – Hirschsprung’s disease – Neuronal intestinal dysplasia – Chronic intestinal pseudoobstruction • Gastrointestinal diseases – Coeliac disease – Cystic fibrosis

– Cow’s milk intolerance • Abnormal abdominal musculature – Prune belly syndrome – Gastroschisis – Down syndrome • Drugs – Antacids – Codein – Phenytoin – Opiates – Antidepressants – Anticholinergics – Iron

Constipation 35

Sigmoid contraction

Painful defecation

Fear of defecation Stools in rectum Rectal distension

A faecal mass accumulates in rectum

With-holding behaviour • Temporary reflex relaxation of the IAE (RAIR) mediated by the autonomic nervous system • Stool in contact with sensitive receptors in anal canal

• Simultaneous contraction of EAE giving time to decide if circumstances are appropriate for defecation

• Functional megarectum • Loss of rectal sensitivity • Pelvic floor muscle fatigue • Anal sphincter incontinence • Overflow incontinence

4.2 Pathophysiology of functional constipation. Defecation convenient

Defecation inconvenient

• Diaphragms and abdominal muscle contraction • Increased intrarectal pressure • Puborectalis muscle relaxation • EAE relaxation • Mediated by the voluntary nervous system

• Puborectalis muscle contraction • EAE contraction • Accommodation of rectum to its contents • Mediated by the voluntary nervous system

Evacuation of stools

Defecation postponed

4.1 Normal mechanism of defecation and continence. In newborn babies and very young infants, the role played by the cerebral cortex in these events is not yet developed; therefore, defecation occurs when the internal sphincter relaxes. IAE: internal anal sphincter; EAE: external anal sphincter; RAIR: rectoanal inhibitory reflex.

formation of a functional megarectum with loss of rectal sensitivity and of the normal need to defecate. Progressive accumulation of feces in the rectum leads to pelvic floor muscle fatigue and anal sphincter poor competence, causing overflow incontinence and nonvoluntary expulsion of faeces, or encopresis. Encopresis is the involuntary loss of stool into the child’s underwear in a child with functional constipation after the acquisition of the toilet skills that are acquired by most children by the age of 4 years. Constitutional and inherited factors such as slow intrinsic motility and low fibre diet may contribute to constipation. Onset of functional constipation occurs in one of three periods: (1) in infants, often corresponding with the change from breast milk to commercial formula or introduction of solids, (2) in toddlers acquiring toilet skills, and (3) in children as school starts. Table 4.2 summarizes the main clinical symptoms and complications in children with functional constipation1. Diagnostic criteria for childhood functional gastrointestinal disorders, known as the Rome III criteria have been recently reviewed2, 3. Functional disorders of defecation include infant dyschezia and functional constipation in infants and children (Table 4.3).

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Table 4.2 Clinical symptoms and complications in children with functional constipation

• Retentive posturing: affected children are often described as standing on their toes, holding onto furniture, stiffening their legs and hiding in a corner • Infrequent and painful passage of huge stools • Abdominal pain and irritability, anal or rectal pain • Anorexia • Encopresis: sometimes is the first symptom and it is confused with chronic diarrhoea

• Urinary symptoms: – Night-time urinary incontinence – Daytime urinary incontinence – Urinary tract infection – Less frequently: vesicoureteral reflux, urinary retention, megacystis, ureteral obstruction • Immediate resolution of symptoms after the passage of a huge stool • Anal fissures • Rectal prolapse

Table 4.3 Diagnostic criteria for defecation-related childhood functional gastrointestinal disorders (Rome III)

G6. Infant dyschezia Must include both of the following in an infant younger than 6 months of age: 1 At least 10 minutes of straining and crying before successful passage of soft stools 2 No other health problems G7. Functional constipation (neonate and toddler) Must include 1 month of at least 2 of the following in infants up to 4 years of age 1 Two or fewer defecations per week 2 At least 1 episode per week of incontinence after the acquisition of toileting skills 3 History of excessive stool retention 4 History of painful or hard bowel movements 5 Presence of a large faecal mass in the rectum 6 History of large-diameter stools that may obstruct the toilet

Accompanying symptoms may include irritability, decreased appetite and/or early satiety. The accompanying symptoms disappear immediately following passage of a large stool H3a. Functional constipation (child and adolescent) Must include 2 or more of the following in a child with a developmental age of at least 4 years*: 1 Two or fewer defecations in the toilet per week 2 At least 1 episode per week of incontinence 3 History of retentive posturing or excessive volitional stooling retention 4 History of painful or hard bowel movements 5 Presence of a large faecal mass in the rectum 6 History of large diameter stools that may obstruct the toilet *Criteria fulfilled at least once per week for at least 2 months before diagnosis

Infant dyschezia Some otherwise healthy infants less than 6 months of age appear to have significant discomfort and excessive straining associated with passing soft stools. The symptoms resolve spontaneously after a few weeks and are probably related to a failure to coordinate increased intra-abdominal pressure

with pelvic floor relaxation. Parents need to be reassured that the phenomenon is part of the child’s learning process and that no intervention is necessary. Rectal stimulation should be avoided to prevent artificial sensory experiences and laxatives are unnecessary.

Constipation 37

Functional constipation The definition of functional constipation takes into account not only the frequency of stools but also the passage of painful bowel movements and stool retention with or without encopresis. Normal stool frequency ranges from four per day during the first week of life to two per day at 1 year of age. The normal adult range of three per day to three per week is attained by 4 years of age. Some breastfed babies have very infrequent stools of normal consistency without distress; these infants are usually perfectly healthy and infrequent stools relate to almost complete absorption of breast milk, leaving very little residue for stool formation.

Hirschsprung’s disease Hirschsprung’s disease, with an incidence of 1 in 5,000 live births, is the most frequent cause of lower intestinal obstruction in newborns. It is found in about 3% of children and toddlers with severe refractory constipation referred to the paediatric gastroenterologist (4.3). Hirschsprung’s disease is characterized by the absence of ganglion cells in the myenteric and submucosal plexuses of the colon leading to sustained contraction of the aganglionic segment. The bowel proximal to the aganglionic segment becomes dilated

4.3 Hirschsprung’s disease is characterized by the absence of ganglion cells in the myenteric and submucosal plexuses of the colon leading to sustained contraction of the aganglionic segment (A). The bowel proximal to the aganglionic segment becomes dilated (B) with secondary intestinal ischaemia that contributes to enterocolitis.

with secondary intestinal ischaemia that contributes to enterocolitis. The aganglionic segment begins in the internal anal sphincter and extends proximally, in 75% of cases to the rectosigmoid area, in 20% to the colon proximal to the splenic flexure, in 3–5% there is total colonic aganglionosis and, even less frequently, there is total intestinal aganglionosis. There is also a very rare form of the disease in which there is an ultra-short segment involving only the very distal 2–5 cm of the rectum. Symptoms and signs of Hirschsprung’s disease are summarized in Table 4.4. Enterocolitis is the most serious complication and it could be the first manifestation of the disease. It is characterized by the abrupt onset of fever, abdominal distention, and explosive and sometimes bloody diarrhoea, mainly in 2–3-month-old infants and is associated with a mortality of 20%. Mortality is reduced with early diagnosis of Hirschsprung’s disease.

Table 4.4 Signs and symptoms suggestive of Hirschsprung’s disease (HD) in constipated children

Symptoms • Constipation beginning early in life • Delayed passage of meconium • Failure to thrive • Abdominal distention • Absence of encopresis • Fever, bloody diarrhoea (enterocolitis) • Chronic constipation not responding to treatment Signs • Passage of liquid stools and gas after rectal digital examination • Empty rectal vault (although stool is palpable in the abdomen) • Increased anal tone • Signs of syndromes associated with HD – Down syndrome – Multiple endocrine neoplasia IIA – Congenital deafness – Waardenberg`s syndrome – Neurofibromatosis

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Diagnosis A thorough history and physical examination (including the perianal area, spine, reflexes in the distal extremities, and digital rectal examination) is generally sufficient to establish the diagnosis of functional constipation. The digital rectal examination is recommended to detect the faecal retention in the rectum typical of functional constipation. The presence of symptoms or signs suggestive of organic disease or the persistence of symptoms after treatment should lead to further evaluation. Constipation in early life is a special situation as it could be the expression of a serious congenital disorder such as Hirschsprung’s disease, meconium plugs, cystic fibrosis, anal malformations, or spinal cord anomalies, but functional constipation is the main cause. Approximately 40% of children with functional constipation develop symptoms during the first year of life4.

Laboratory tests Occult blood testing in stool is recommended in infants with constipation and in children with associated abdominal pain, failure to thrive, and intermittent diarrhoea. A positive occult blood test suggests enterocolitis or other causes of intestinal inflammation. Other laboratory tests to exclude

4.4 Abdominal X-ray showing severe faecal retention in the rectum of a child with functional constipation.

hypercalcaemia, hypothyroidism, and coeliac disease are useful in selected cases. In constipated infants, and particularly if there is delayed passage of meconium, a sweat test is recommended to exclude cystic fibrosis.

Abdominal radiographs Radiological studies are not indicated in uncomplicated constipation. An abdominal radiograph can be useful in determining the presence of faecal impaction in the child who refuses a rectal examination, and in the obese child when abdominal and rectal examination are suboptimal (4.4).

Anorectal manometry The main clinical role of anorectal manometry is in the evaluation of children with severe constipation not responding to treatment, or in those with signs or symptoms suggestive of organic disease, in which the diagnosis of Hirschsprung`s disease needs to be excluded5. Different probes for anorectal manometry are available (4.5). To exclude Hirschsprung’s disease, an Arhan type anorectal manometry probe connected to a pneumohydraulic capillary infusion system is commonly used (4.6, 4.7).

4.5 A view of an anorectal manometry station. A manometry probe is connected to a polygraph and a pneumohydraulic capillary infusion system. The room must be comfortable; playing with familiar toys or watching cartoons on television help to reduce anxiety in the child.

Constipation 39

4.6 A: Anorectal manometry probe formed by a plastic tube with four interior channels. One channel is connected to a latex balloon located in the distal segment able to distend with air (A). The second one is open to the rectal lumen (B). The third and fourth channels are covered by small latex balloons and located in the anal channel and the anal verge (C, D). A B: The B, C, and D channels transmit pressure variations in water by pressure transducers to the pneumohydraulic capillary infusion system, a low compliance system, which is able to perfuse distilled water at a rate of 0.5 ml/min. C: The electrical signals from the transducers are transmitted to a computer, which produces a graphic record of the pressures of the rectal ampulla (B), anal canal (C) and external anal sphincter (D).

D

C B

A

B

B

C

C

D

B 4.7 A: The open-tipped perfusion manometer with 4–8 channels is the most accurate for recording resting and squeeze pressures of the anal canal and to define the vector volume. B: A soft catheter with 4–8 tiny openings around its circumference provides directional pressure measurements in four quadrants of the anal sphincter. Pressures are measured using a 1 cm station or a A continuous pull through technique. This technique is especially helpful in evaluation of faecal incontinence due to postoperative states or myelomeningocoele, tethered cord, and various types of spinal cord dysfunction.

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An enema the night before the test is the recommended preparation, although some patients may need 2–3 days of enema administration to assure an empty rectal vault. Most infants and children can be tested without sedation, but fasting for 4–6 hours is also prudent in case the child needs sedative medication or it is necessary to feed infants during the test as a sedative manoeuvre. The procedure should be explained to the child and the parents to reduce anxiety and promote cooperation. Technique and interpretation are summarized in figures 4.8–4.10.

Barium enema study A barium enema study is unnecessary in most children with constipation, and is less accurate than anorectal manometry and rectal biopsy in the diagnosis of Hirschsprung’s disease5. An unprepared barium enema is useful in children with Hirschsprung’s disease to delineate the extent and the location of a transition zone between the tight aganglionic segment and the dilated proximal colon (4.11).

4.8 A: The child lies comfortably in the left lateral decubitus position and the catheter is inserted into the rectum to simultaneously measure the pressures of the rectal ampulla, anal canal, and external anal sphincter. After a 10-minute stabilization period, the following A B parameters are recorded: mean rectal ampullar resting pressure, mean anal canal resting pressure, and mean external anal sphincter resting pressure. B: Posteriorly increasing volumes of air (5–50 ml) to inflate the rectal balloon are progressively introduced. This triggers the rectoanal inhibitory reflex (RAIR), i.e the drop of anal pressure during rectal distention transmitted by the ganglion cells of the submucosal and myenteric plexus. The RAIR is present in healthy infants (even preterm older than 26 weeks gestational age) and children and in patients with functional constipation and encopresis. The amplitude of volume relaxation increases with increasing balloon distention volume. The threshold volume to elicit RAIR may be quite high in chronically constipated children; at times 120 ml is needed to demonstrate the reflex.

4.9 The RAIR is persistently absent in Hirschsprung`s disease because of the absence of ganglion cells that would transmit the distention reflex to the internal anal sphincter. The RAIR has been reported to be absent, atypical, or normal in patients with neuronal intestinal dysplasia. Barium enema and rectal biopsy to exclude Hirschsprung’s disease need to be performed in all patients with absent or atypical RAIR.

Constipation 41

4.10 In chronic refractory constipation defecatory dynamics should also be assessed; by asking the child to expel the manometric balloon, defecation is simulated. Normally, an increase in rectal pressure (Valsalva manoeuvre with abdominal compression) with a simultaneous drop in anal canal and external anal sphincter pressures (relaxation of the anal sphincter and perineal descent) are recorded. Paradoxical puborectalis contraction of the external anal sphincter can be demonstrated in children with chronic constipation and constitutes the manometric expression of the faecal retention behaviour. There is simultaneous increase in external anal sphincter, anal canal, and rectal pressures on attempted balloon expulsion. The presence of paradoxical anal contraction is correlated to severe constipation refractory to treatment. Biofeedback designed to instruct patients on sphincter relaxation may help these patients.

4.11 Barium enema in Hirschsprung’s disease (HD) showing a transition zone from aganglionic to ganglionic bowel. The arrows point to the transition zone. A normal barium enema does not rule out HD: in young infants a transition zone may not be seen simply because there has not been enough time to distend the ganglionic portion of the colon with stool. Patients with total aganglionosis may present with microcolon or normal calibre colon. It is important not to cleanse the colon in order to accentuate the transition zone and the catheter should be inserted at the end of the anal canal in order to avoid missing short-segment disease. Barium enema should not be performed in suspected enterocolitis as it can cause perforation. If the initial enema is not diagnostic a 24- and/or 48-hour followup abdominal radiograph including lateral projection could be performed. Prolonged retention of barium suggests the diagnosis of HD.

Rectal biopsy Rectal biopsy stained for acetylcholinesterase activity is the best test to rule out Hirschsprung’s disease and should be performed in infants and children with suggestive clinical data and absence or atypical RAIR in anorectal manometry5. The normal anus has a paucity or absence of ganglion cells at the level of the anal verge. To avoid missing a rare case of ultra-short segment Hirschsprung`s disease, it is recommended to perform rectal biopsy 2–3 cm above the mucocutaneous junction. The biopsy can be obtained by suction at the bedside or office, or a full-thickness biopsy can be performed. Biopsies should be deep enough to include adequate submucosa.

Occasionally suction biopsies are not diagnostic and a fullthickness biopsy is necessary (4.12). Histopathological absence of ganglion cells in the myenteric and submucosal plexus and the presence of hypertrophied nerve fibres in the lamina propria, muscularis mucosa, and submucosa are the hallmark of the disease (4.13).

Colonic transit study The estimation of total and segmentary colonic transit time is useful in two main situations: (1) to provide objective information in children who report infrequent bowel movements, but who have no objective findings of

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2 2

1

1 1

A

2 1 4.12 In infants requiring laparotomy or in definitive surgical procedure, serial, progressively proximal, fullthickness biopsies are obtained to determine the level at which ganglionic bowel begins (levelling procedure).

1 2 1

1

B 4.13 A: Normal subject. Haematoxylin and eosin stain of colonic biopsy showing myenteric plexus with ganglionic cells (2) between the circular and longitudinal muscle layers (1). B: Hirschsprung`s disease (HD). Ganglion cells are absent in the intermuscular plexus with increase in nerve fibres. Acetylcholinesterase staining of colonic biopsy in HD shows an increased submucosal nerve plexus, as most of these nerve fibres are cholinergic. The histochemical staining for acetylcholinesterase requires only the lamina propria of the mucosa, which can be obtained by suction technique. 1: Muscle layers; 2: myenteric plexus (no ganglion cells).

A

B 4.14 A gelatin capsule with 10 polyurethane radiopaque markers containing barium sulphate USP is administered at 9:00 am on each of 6 consecutive days (A). The capsules contain different marker forms (B). An anteroposterior abdominal control radiographic study is performed on day 7 (at 9:00 am).

constipation on repeated physical examination, and (2) in children with chronic constipation refractory to conventional treatment. Ingestion of radio-opaque markers followed by

abdominal radiograph to assess their progression through the colon is used to determine the colonic transit time (CTT) in patients with chronic constipation6 (4.14, 4.15). The presence of prolonged CTT in children with infrequent bowel movements constitutes an objective sign of constipation. The determination of segmental CTT is useful in chronic refractory constipation (4.16, 4.17)6.

Management Most children with functional constipation with or without encopresis will benefit from a precise, wellorganized plan including education, disimpaction, maintenance treatment, follow-up, and treatment of recurrences4, 7 (Tables 4.5–4.7). The most common reason for poor outcome is insufficient treatment, and especially the reluctance of parents and physicians to the use of

Constipation 43

4.15 To determine the segmental transit time, three areas are delineated, tracing a line joining the spinal processes of all the vertebrae to L5. Using L5 as centre, lines are in turn traced to the left anterosuperior iliac spine and to the right pelvic outlet, establishing areas corresponding to the right colon (caecum, ascending colon, proximal half of transverse colon), left colon (distal half of transverse colon, descending colon), and rectosigmoid colon. Counting the markers yield the following transit times: total colonic transit time and the segmental colonic transit times for the right colon, the left colon, and the rectosigmoid colon. These transit times are estimated using the following formula: colon transit time = (sum of the markers × [time between administration ÷ number of markers per capsule]) = sum of the markers × 2.4.

laxatives for sufficient periods of time7, 8. Maintenance therapy may be necessary for many months. Primary care providers and families should be aware that relapses are common and that difficulty with bowel movements may continue into adolescence. In children unresponsive to conventional management, consideration may be given to a time-limited trial of a cow’s milk-free diet12, 13. Biofeedback consists of teaching to recognize rectal distention, to contract and relax external anal sphincter and puborectalis muscle, and to coordinate these functions with the help of anorectal pressure recording. It has been shown to be an effective short-term treatment of children with severe intractable constipation, especially those showing distal delay in CTT and paradoxical anal contraction in anorectal manometry14. For cooperative children, anorectal biofeedback training provides auditory and visual information about anal sphincter pressure. Children learn to relax or contract the

4.16 Constipation with colonic inertia. (Total colonic transit time = 93.6 hours, right colon = 26.4 hours, left colon = 26.4 hours, rectosigmoid colon = 40.8 hours). A global delay in colonic transit may suggest the presence of a more generalized alteration in colonic motility, amenable to treatment with prokinetic drugs.

4.17 Constipation with delayed left colonic and rectosigmoid transit. (Total colonic transit time = 120 hours, right colon = 14.4 hours, left colon = 45.6 hours, rectosigmoid colon = 60 hours). A collection of markers in the left colon and rectosigmoid colon suggests outlet dysfunction such as paradoxical puborectalis contraction that could be demonstrated in anorectal manometry and may improve with various forms of biofeedback therapy.

anal sphincter to produce evacuation and continence and it can help them to reduce the threshold volume for rectal sensation (4.10).

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Table 4.5 Treatment of functional constipation Education

• Explanation of normal defecation mechanism and pathogenesis of functional constipation, including faecal soiling as an involuntary consequence of functional constipation • Try to obtain a positive and supportive attitude of parents • Explain chronicity and possible recurrences

Disimpactation if faecal impaction detected

See Table 4.6

Maintenance treatment Diet

• Increase intake of fluid, reduce dairy products. • Fibre ingestion preferably from natural food: age (years) + 5 g/day until 30 g/day9

Behavioural modification

• • • •

Medication

• Early recommendation. Continuous administration may be necessary for 3–6 months10 • Lubricants and osmotic agents are effective and safe in children11. See Table 4.7

Follow-up

Regular toilet habits Unhurried time after meals Diaries of stool frequency Reward system

• Gradual weaning of medication after months of regular defecatory habits • Treatment of recurrences

Table 4.6 Disimpactation treatment Oral >2 years Polyethylene glycol with electrolytes

25 ml/kg/h up to 1000 ml/h until clear liquid stools (premedication with metoclopramide 5 mg, usually 12–20 hours are needed)

Polyethylene glycol without electrolytes

1.5 g/kg/day for 3 days

Mineral oil

3 ml/kg/twice day for 7 days

Lactulose or sorbitol

2 ml/kg/twice day for 7 days

Senna

2–6 years: 4–7 mg/dose (2 doses) >6 years: 7–15 mg/dose (2 doses)

Rectal Glycerin suppositories Physiological enema Contraindicated: soapsuds, tap water, or magnesium enemas

Constipation 45

Table 4.7 Maintenance treatment Osmotics Magnesium hydroxide Lactulose or sorbitol Polyethylene glycol 3350 without electrolytes

Age >1 month >1 month >1 month

Dose 1–3 ml/kg/day in 1–2 doses 1–3 ml/kg/day in 1–2 doses 0.7 g/kg/day in 1–2 doses

Lubricants Mineral oil

>12 months

1–3 ml/kg/day in 1–2 doses

References 1 Loening-Baucke V. Urinary incontinence and urinary tract infection and their resolution with treatment of chronic constipation of childhood. Paediatrics 1997;100(2 Pt 1):228–32. 2 Hyman PE, Milla PJ, Benninga MA, et al. Childhood functional gastrointestinal disorders: neonate/toddler. Gastroenterology 2006;130(5):1519–26. 3 Rasquin A, Di Lorenzo C, Forbes D, et al. Childhood functional gastrointestinal disorders: child/adolescent. Gastroenterology 2006;130(5):1527–37. 4 Youssef NN, Di Lorenzo C. Childhood constipation: evaluation and treatment. J Clin Gastroenterol 2001;33(3):199–205. 5 de Lorijn F, Kremer LC, Reitsma JB, Benninga MA. Diagnostic tests in Hirschsprung disease: a systematic review. J Pediatr Gastroenterol Nutr 2006;42(5):496–505. 6 Gutierrez C, Marco A, Nogales A, Tebar R. Total and segmental colonic transit time and anorectal manometry in children with chronic idiopathic constipation. J Pediatr Gastroenterol Nutr 2002;35(1):31–8. 7 Loening-Baucke V. Polyethylene glycol without electrolytes for children with constipation and encopresis. J Pediatr Gastroenterol Nutr 2002;34(4):372–7. 8 Borowitz SM, Cox DJ, Kovatchev B, et al. Treatment of childhood constipation by primary care physicians: efficacy and predictors of outcome. Paediatrics 2005;115(4):873–7. 9 Marlett JA, McBurney MI, Slavin JL. Position of the American Dietetic Association: health implications of dietary fiber. J Am Diet Assoc 2002;102(7):993–1000. 10 Nolan T, Debelle G, Oberklaid F, Coffey C. Randomized trial of laxatives in treatment of childhood encopresis. Lancet 1991;338(8766):523–7. 11 Sharif F, Crushell E, O’Driscoll K, Bourke B. Liquid paraffin: a reappraisal of its role in the treatment of constipation. Arch Dis Child 2001;85(2):121–4.

12 Andiran F, Dayi S, Mete E. Cow’s milk consumption in constipation and anal fissure in infants and young children. J Paediatr Child Health 2003;39(5):329–31. 13 Iacono G, Cavataio F, Montalto G, et al. Intolerance of cow’s milk and chronic constipation in children. N Engl J Med 1998;339(16):1100–4. 14 Heymen S, Jones KR, Scarlett Y, Whitehead WE. Biofeedback treatment of constipation: a critical review. Dis Colon Rectum 2003;46(9):1208–17.

Further reading Baker S, Liptak G, Colletti R, et al. Constipation in infants and children: evaluation and treatment: a medical position statement of the North American Society for Pediatric Gastroenterology and Nutrition. J Pediatr Gastroenterol Nutr 1999;29:612–26. Baker SS, Liptak GS, Colletti RB, et al. Evaluation and treatment of constipation in infants and children: summary of updated recommendations of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition. J Pediatr Gastroenterol Nutr 2006;43:405–7. Loening-Baucke V. Anorectal manometry and Biofeedback training. In: Hyman PE, Di Lorenzo C (eds). Pediatric Gastrointestinal Motility Disorders. Academy Professional Information Services, New York, 1994, pp. 231–52. Loening-Baucke V. Constipation and encopresis. In: Wyllie R, Hyams JS (eds). Pediatric Gastrointestinal Disease: Pathophysiology, Diagnosis, Management. Saunders, Philadelphia 2006, pp. 177–91. Stallion A, Dough Kou T. Hirschsprung`s disease. In: Wyllie R, Hyams JS (eds). Pediatric Gastrointestinal Disease: Pathophysiology, Diagnosis, Management. Saunders, Philadelphia, 2006, pp. 735–48.

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Chapter 5

Abdominal pain in childhood Iñaki X. Irastorza Terradillos, MD, and Juan C. Vitoria Cormenzana, MD, PhD Introduction Abdominal pain is one of the most challenging symptoms in paediatric practice. Often imprecise, abdominal pain may require, especially if acute, an intense diagnostic approach in order to avoid misidentification of potentially underlying medical or surgical problems. On the other hand, chronic abdominal pain, most currently functional in origin, frequently generates a situation of familial and patient stress due to the persistent recurrence of symptoms. The paediatrician can also be affected by this stress and can be ‘forced’ to prescribe multiple unnecessary medical investigations (5.1). Understanding the neurophysiology of pain perception is crucial to making an appropriate diagnostic approach. Not

every pain perceived in the abdomen originates in the abdomen, and not every pain originating in the abdomen is perceived in the abdomen. Furthermore, characteristics of abdominal pain are very diverse; the specific pattern of abdominal pain sensation will help to establish the diagnosis. Specific types of pain receptors are located in the abdominal wall, in the mesentery, in the serosal surfaces, in the hollow viscera wall, and in the mucosal surfaces. Main receptors in each location will respond to specific stimuli types. Abdominal pain receptors can be triggered by mechanical and chemical stimuli (5.2). Mechanical stretch and chemical stimuli are the main triggers involved in visceral nociceptor activation.

Traction

Functional Histamine

Bradykinin

Functional

PGs

Contraction

Mechanical

Torsion

Chemical

Organic

Distension

Seratonin

Stretch

Chloride

Organic

Pain

Acute abdominal pain

Chronic abdominal pain

Culture

Day/night Age

5.1 Aetiology of acute and chronic abdominal pain.

Illness? Family

School

5.2 Genesis and perception of abdominal pain.

Abdominal pain in childhood 47

Pain of bilaterally innervated organs (i.e. small intestine) is perceived in the midline. Pain perceived on one side usually comes from nondigestive intra-abdominal organs (ovary, ureters, and kidneys), gallbladder, ascending and descending colon, or abdominal wall which are mainly ipsilaterally innervated.

Table 5.1 Alarm symptoms, signs, and features in recurrent abdominal pain

Pain distant from umbilicus (right upper or right lower quadrant pain) Dysphagia Persistent vomiting

Chronic abdominal pain

Gastrointestinal blood loss

Complaints of recurrent abdominal pain affect 10–40% of children and its prevalence increases with age (5.3)1. When recurrent abdominal pain was first described in 19582, only 10% of patients had a definitive diagnosis; 90% of patients remained undiagnosed or labelled as ‘suspected functional abdominal pain’. New pathological entities such as Helicobacter pylori infection or non-IgE mediated food allergies and the development of diagnostic techniques has allowed diagnosis to improve to up to 50% of patients (5.4). In order to avoid unnecessary tests a conservative approach is appropriate. Alarm symptoms, signs, and features that should make the physician suspect that the pain has an organic background are listed in Table 5.1. In their absence, pain is very likely to have a functional origin and therefore most tests will be unnecessary, leading only to increase familial anxiety.

Nocturnal and/or severe diarrhoea Hepatomegaly, splenomegaly Abdominal mass effect Family history of inflammatory bowel disease, coeliac disease, or peptic ulcer disease Arthritis Perirectal disease Involuntary weight loss Deceleration of linear growth Delayed puberty Dysuria or haematuria Respiratory symptoms Tenderness over the spine or at the costovertebral angle Unexplained fever Pain that wakes up the child

Boys Girls

Organic

Functional

0

2

4

6 8 Age (years)

10

12

5.3 Incidence of recurrent abdominal pain by age.

14

1958

Organic

Functional

2000

5.4 Aetiology of recurrent abdominal pain.

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Functional gastrointestinal disorders Functional gastrointestinal disorders (FGID) are defined as a variable combination of chronic or recurrent gastrointestinal symptoms not explained by structural or biochemical abnormalities. A symptoms-based classification, rather than a targeted organ-based one, has been set by the Rome III committee (Table 5.2) (5.5)3.

Functional dyspepsia

Table 5.2 Functional gastrointestinal disorders

Dyspepsia is pain or discomfort localized in the upper abdomen. Symptoms may vary including fullness, early satiety, bloating, nausea, retching, and vomiting. No signs or symptoms reliably differentiate functional dyspepsia from upper gastrointestinal organic disorders (Table 5.3)4.

Functional abdominal pain syndrome

Vomiting and aerophagia Adolescent rumination syndrome Cyclic vomiting syndrome Aerophagia Abdominal pain-related FGID Functional dyspepsia* Irritable bowel syndrome* Abdominal migraine* Functional abdominal pain

Functional abdominal pain

Functional dyspepsia

To establish the diagnosis of functional dyspepsia (Table 5.4) it is therefore necessary to rule out organic diseases presenting with dyspepsia, such as gastro-oesophageal reflux disease (5.6, 5.7), Helicobacter pylori infection, eosinophilic oesophagitis, and gastritis.

Abdominal migraine

Irritable bowel syndrome

Constipation and incontinence Functional constipation Nonretentive faecal incontinence Although presented as independent categories, only a minority of patients shall be classified in any of the first three specific categories (*), while most will fall within the ‘Functional abdominal pain’ open-box category

5.5 Overview of abdominal pain-related functional gastrointestinal disease.

Table 5.3 Abdominal pain-related functional gastrointestinal disorders diagnostic approach

Suspected disorder

Diagnostic tests

Functional dyspepsia

Always required

Functional abdominal pain

Depending on anamnesis

Irritable bowel syndrome

Not required

If diagnostic criteria fulfilled

Abdominal migraine

Not required

If diagnostic criteria fulfilled

No signs or symptoms reliably differentiates organic from functional

Abdominal pain in childhood 49

Table 5.4 Diagnostic criteria for functional dyspepsia

• Persistent or recurrent pain or discomfort centred in the upper abdomen (above the umbilicus) • Pain not relieved by defecation or associated with onset of a change in stool frequency or consistency • No evidence of inflammatory, anatomic, metabolic, or neoplastic process that explains subject’s symptoms All three criteria must be fulfilled at least once per week for at least 2 months

5.6 Gastro-oesophagic reflux. pH study of severe gastro-oesophagic reflux in a 7-year-old patient with epigastric pain, heartburn, and vomiting. Endoscopy of reflux oesophagitis (inset).

5.7 Gastric emptying scintigraphy. Same patient as in 5.6 after treatment with proton pump inhibitors, showing very slow gastric emptying with associated nonacid gastro-oesophageal reflux.

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Irritable bowel syndrome Irritable bowel syndrome (IBS) is characterized by episodes of recurrent abdominal pain temporally associated with altered bowel habits: either constipation or diarrhoea (Table 5.5). If the child fulfils the diagnostic criteria no further

investigations are required. Aetiology of IBS is multifactorial and not completely understood (5.8)5, 6. Available therapeutic options are summarized in Table 5.6, although most of these patients’ symptoms improve if they manage to reduce or dominate the stress intervening factors.

Table 5.5 Diagnostic criteria for IBS • Abdominal discomfort or pain associated with 2 or more of the following at least 25% of the time: – Improvement with defecation – Onset associated with a change in frequency of stool – Onset associated with a change in consistency of stool • No evidence of inflammatory, anatomic, metabolic, or neoplastic process that explains subject’s symptoms Both criteria must be fulfilled at least once per week for at least 2 months

Table 5.6 Treatment of abdominal pain-related FIGD Functional dyspepsia • Avoidance of nonsteroidal anti-inflammatory drugs • Avoidance of foods that aggravate symptoms: – Caffeine – Spicy foods – Fruit juices – Fatty foods • H2 blockers • Proton pump inhibitors • Prokinetic drugs: – Domperidone – Erythromycin – Cisapride • Psychological behavioural intervention

Abdominal migraine • Avoidance of foods containing: – Caffeine – Nitrites – Amines • Behavioural intervention • Drugs: – Pizotifen – Propanolol – Cyproheptadine – Sumatriptan Functional abdominal pain • Psychosocial intervention • Tricyclic antidepressants

Irritable bowel syndrome • Peppermint oil • Psychological behavioural intervention

• Infection • Inflammation • Trauma • Allergy

• Anxiety • Depression • Social learning of illness behaviour Genetic predisposition Psychological

Visceral hypersensitivity Irritable bowel syndrome

5.8 Aetiology of IBS. Visceral hypersensitivity, often appearing after an enteral aggression event in genetically predisposed patients, may lead under stressing circumstances to IBS.

Abdominal pain in childhood 51

Other disorders Other prevalent disorders that usually present with chronic abdominal pain and diarrhoea or constipation include:

5.9 Lactose intolerance. A: Lactose breath hydrogen test is is a noninvasive test that measures lactose nonabsorption. B: Faecal reducing substances: arrival of undigested lactose to the large bowel leads to the presence of reducing sugars in the faeces.

lactose intolerance (5.9), coeliac disease (5.10), food allergies (5.11), inflammatory bowel disease, and giardiasis (5.12).

Liquid faeces

2/3 water 1/3 faeces -ve 0%

Trace 1/4%

Negative A

+ 1/2% ?

15 drops

++ 3/4%

Clinitest Ames tablet +++ 1%

+++ 2%

Positive

B

5.11 Jejunal biopsy with flattened villi and increased inflammatory cellularity in lamina propria in cow’s milk protein enteropathy.

A

B 5.10 Coeliac disease. A: Upper gastrointestinal endoscopy in a patient with recurrent abdominal pain and positive coeliac serological markers. B: Duodenal biopsy with villous atrophy, intraepithelial lymphocytes, and crypt hyperplasia.

5.12 Intestinal biopsy showing multiple Giardia lamblia trophozoites (inset).

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Abdominal migraine Abdominal migraine is characterized by recurrent paroxysmal episodes of acute, periumbilical and noncolicky pain associated with anorexia, nausea, vomiting, headache, and pallor (Table 5.7). The origin of abdominal migraine is linked to other functional disorders like migraine headache and cyclic vomiting syndrome, and patients often progress from one to another. Abdominal migraine is one of the functional disorders that present more familial aggregation.

Familial aggregation and response to antimigraine drugs, although not included in the diagnostic criteria, support the diagnosis. Treatment options are listed in Table 5.6. A number of digestive and extradigestive conditions including renal colic, recurrent pancreatitis (5.13), choledocholithiasis, familial Mediterranean fever, Crohn’s disease (5.14), and porphyria, must be ruled out before establishing the diagnosis of abdominal migraine.

Table 5.7 Diagnostic criteria for abdominal migraine

• Paroxysmal episodes of intense, acute periumbilical pain that last for 1 hour or more • Intervening periods of usual health lasting weeks to months • Pain interferes with normal activities • Pain is associated with two or more of the following: – Anorexia

– Nausea

– Vomiting

– Headache

– Photophobia

– Pallor

• No evidence of inflammatory, anatomic, metabolic, or neoplastic process that explains subject’s symptoms All five criteria must be fulfilled at least twice in the preceding 12 months

5.13 An abdominal X-ray during an endoscopic retrograde cholangiopancreatography (ERCP) shows gallstones in bile ducts in a patient with recurrent pancreatitis. 5.14 Barium follow-through in a patient with stenosing Crohn’s disease (arrows).

Abdominal pain in childhood 53

Childhood functional abdominal pain Children with recurrent abdominal pain episodes that do not fulfil the previous categories but in whom organic pathology has been reasonably excluded fall within this category (Table 5.8). They represent the vast majority of patients consulting for recurrent abdominal pain in primary paediatric care. Functional abdominal pain syndrome has been described for a subgroup of patients with functional abdominal pain with more persistent abdominal symptoms associated with other somatic symptoms (Table 5.9). Functional abdominal pain diagnosis can be difficult to establish as there are no specific criteria as there are for other abdominal pain-related FGID. It is therefore sensible to perform some basic investigations (Table 5.10) in order to exclude an organic origin of the symptoms. Routine investigations are not required in every patient. Depending on the signs, symptoms, age, and gender of the patient it will be

reasonable to decide the laboratory and radiological tests to perform or decide if the patient requires an endoscopy. A pychosocial approach in patients with functional abdominal pain is particularly indicated because the symptoms are often associated with varying degrees of anxiety, depression, or manipulative behaviour. Behavioural intervention associated or not with antidepressant drugs is indicated in these patients7. Differential diagnosis include a wide range of digestive and nondigestive diseases such as coeliac disease (5.15), inflammatory bowel disease (5.16), food intolerances, Helicobacter pylori infection, eosinophilic enteritis, chronic pyelonephritis, and parasite infestation. However, it is important to remember that in most cases there will be no organic underlying disease and that not every endoscopic or radiological finding will prove an organic aetiology (5.17).

Table 5.8 Diagnostic criteria for functional abdominal pain

Table 5.10 Investigations in patients with suspected functional abdominal pain

• Episodic or continuous abdominal pain

• Full blood count

• Insufficient criteria for other FGID

• C-reactive protein

• No evidence of inflammatory, anatomic, metabolic, or neoplastic process that explains the subject’s symptoms

• Erythrocyte sedimentation rate • Amylase • Sugars breath hydrogen test

All three criteria must be fulfilled at least once per week for at least 2 months

• Helicobacter pylori test • Stool culture and examination for ova and parasites • Urinalysis and urine culture • Pregnancy test

Table 5.9 Diagnostic criteria for functional abdominal pain syndrome

• Barium swallow • Barium follow-through

• Functional abdominal pain at least 25% of the time and at least one of the following:

• Abdominal ultrasound scan • CT scan

– Some loss of daily activity

• MRI

– Additional somatic symptoms: headache, limb pain, or difficulty sleeping

• Endoscopy

Criteria must be fulfilled at least once per week for at least 2 months

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A 5.15 Trichobezoar removed from the stomach of a girl with recurrent abdominal pain and undiagnosed coeliac disease.

A

B

C

5.16 Same findings in barium enema (A), abdominal MRI (B) and HMPAO-Tc99m leukocytes scintigraphy (C) in a patient with ascending colon stenosing Crohn’s disease.

B

5.17 Casual findings in patients with recurrent abdominal pain. A: Ovarian cyst; B: porcelain gallbladder (arrow).

Infant colic Although it has not been proven that infant colic has a digestive or even abdominal origin, many infants with recurrent paroxysms of irritability, fussing, and crying8 episodes are referred to paediatric gastroenterologists (Tables 5.11, 5.12). The most important point is to reassure parents, to make sure they understand that colic is ‘something infants do, rather than a condition they have’9. Rhythmic

rocking and a car ride are efficient manoeuvres to calm the infant. It has been reported that milk intolerance or oesophagitis might be the cause of excessive crying. A therapeutic trial with a hydrolysed protein formula or medication to suppress gastric acid secretion would be a reasonable approach10, 11.

Abdominal pain in childhood 55

Table 5.11 Diagnostic criteria and supporting features for infant colic Diagnostic criteria • Paroxysms of irritability, fussing, or crying • Episodes lasting 3 or more hours per day and occurring at least 3 days per week for at least 1 week • No failure to thrive All the criteria must be fulfilled in infants from birth to 4 months of age Supporting features • Starts and stops suddenly • Occurs late in the day • Prolonged, inconsolable crying • Crying after feedings • Facial grimace • Abdominal distension • Increased gas • Flushing • Legs flexed over the abdomen • Rhythmic rocking and patting quietens the baby • Car riding stops the crying

References 1 Oster J. Recurrent abdominal pain, headache, and limb pains in children and adolescents. Pediatrics 1972;50:429. 2 Apley J, Naish N. Recurrent abdominal pains: a field survey of 1,000 school children. Arch Dis Child 1958;33:165–70. 3 Rasquin A, Di Lorenzo C, Forbes D, et al. Functional gastrointestinal disorders: child/adolescent. Gastroenterology 2006;130(5):1527–37. 4 Boyle JT. Recurrent abdominal pain: an update. Pediatr Rev 1997;18:310. 5 Mayer EA, Collins SM. Evolving pathophysiologic models of functional gastrointestinal disorders. Gastroenterology 2002;122:2032–48. 6 Morris-Yates A, Talley NJ, Boyce PM, et al. Evidence of a genetic contribution to functional bowel disorder. Am J Gastroenterol 1998;93:1311–17. 7 Campo JV, Bridge J, Ehmann M, et al. Recurrent abdominal pain, anxiety, and depression in primary care. Pediatrics 2004;113:817–24.

Table 5.12 Treatment of infant colic • Parent reassurance • Rhythmic rocking and patting 2–3 times per second in a quiet environment • Car ride • Time-limited therapeutic trial: – Hydrolyzed protein formula – Medication to suppress gastric acid secretion Relief of symptoms should be apparent within 48 hours

8 Wessel MA, Cobb IC, Jackson EB, et al. Paroxysmal fussing in infancy, sometimes called colic. Pediatrics 1954;14:421–34. 9 Barr RG. ‘Colic’ is something infants do, rather than a condition they ‘have’: a developmental approach to crying phenomena, patterns, pacification, and (patho)genesis. In: Barr RG, St James-Roberts I, Keefe MR (eds). New Evidence on Unexplained Early Crying: its Origins, Nature, and Management. Johnson & Johnson Pediatric Institute, Cincinnati, 2001, pp. 87–104. 10 Lothe L, Lindberg T. Cow’s milk whey protein elicits symptoms of infant colic in colicky formula-fed infants: a double blind crossover study. Pediatrics 1989;83:262–6. 11 Hyman PE, Milla PJ, Benninga MA, et al. Childhood functional gastrointestinal disorders: neonate/toddler. Gastroenterology 2006;130:1519–26.

Further reading Barad AV, Saps M. Factors influencing functional abdominal pain in children. Curr Gastroenterol Rep 2008;10:294–301. McOmber MA, Shulman RJ. Pediatric functional gastrointestinal disorders. Nutr Clin Pract 2008;23:268–74. Perez ME, Youssef NW. Dyspepsia in childhood and adolescence: insights and treatment conditions. Curr Gastroenterol Rep 2007;9;447–55.

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Chapter 6

Gastrointestinal bleeding George Gershman, MD, PhD Introduction Bleeding from the gastrointestinal (GI) tract in infants and children is always stressful and frightening for patients and their parents and challenging for a physician, especially if bleeding is severe. The attending paediatrician should act promptly and adequately to the degree of haemodynamic instability and initiate a diagnostic work-up according to the mode of presentation and common age-specific causes of GI haemorrhage.

Epidemiology The incidence of upper GI bleeding among infants and children is unknown. Epidemiological data from the UK and USA indicate that the incidence of upper GI bleeding in adults younger than 29 is approximately 18–23 per 100,000 adults per year, which is almost 4 to 5 times less than among older groups1. It is reasonable to assume that the incidence of upper GI bleeding in infants and children is even lower. However, the risk of upper GI bleeding is higher (between 6.2 and 10.2%) in infants and children admitted to paediatric intensive care units2, 3. Although rectal bleeding is quite common in paediatric practice, the epidemiology of this problem is not well established. According to published data, rectal bleeding was a chief complaint of 0.3% of all visits to a tertiary emergency department during a 10-month period4.

Haematemesis Haematemesis is the vomiting of bright-red ‘fresh’ blood, or ‘coffee ground’ emesis of dark-brown ‘old’ blood with haemoglobin (Hb) converted to haematin in the stomach by hydrochloric acid. Usually, haematemesis reflects acute bleeding from the oesophagus, stomach, or proximal duodenum. Swallowing of maternal blood in neonates, and epistaxis in older children, should be ruled out.

Melena Melena implies liquid, coal black, shiny, sticky, tarry, and foul-smelling stool. It suggests bleeding from the upper GI tract. Occasionally, the site of bleeding can be found in the ileum or right colon. However, in this case stool is black but not tarry. Melena suggests a minimum loss of 50–100 ml5 or 2% of blood volume6. Stool may remain black or tarry for a few days after massive haemorrhage, even though active bleeding has ceased.

Occult gastrointestinal bleeding Occult GI bleeding is the presence of an invisible quantity of blood in stool detected by a special technique. It is a synonym of chronic, recurrent losses of small amounts of blood, which often lead to severe microcytic anaemia.

Haematochezia Haematochezia is the passage of bright red or maroon blood from the rectum. This may be pure blood, bloody diarrhoea or blood mixed with stool. As a rule, it is a sign of lower GI bleeding from the colon or distal ileum.

Definitions Assessment There are four presentations of blood loss from the GI tract: haematemesis, melena, occult bleeding, and haematochezia.

Initial assessment of the child with suspected GI bleeding should be focused on haemodynamic stability and clues for the

Gastrointestinal bleeding 57

aetiology of bleeding. A prompt assessment of estimated blood loss and the degree of haemodynamic instability should be done using objective criteria, such as mental status, skin colour, capillary refill, pulse, blood pressure, and orthostatic manoeuvres (Table 6.1). Special attention should be focused on tachycardia and narrowed pulse pressure, which are the earliest signs of impending shock. Hypotension usually occurs in the late phase of shock in children, and is an ominous finding. The value of the initial haematocrit (Hct) may not accurately reflect the severity of blood loss. Firstly, the Hct does not fall immediately with haemorrhage due to proportionate reductions of plasma and red cell volumes. Secondly, it begins to fall due to compensatory restoration of the intravascular volume by the shift of extravascular fluids into the vascular bed. This process begins shortly after the onset of bleeding. However, it is not complete for 24–72 hours. At this point, plasma volume is larger than normal and the Hct reaches its true nadir assuming that bleeding has stopped.

Diagnosis Red food and some medications can stain stool or emesis. Cranberries, cranberry juice, cherries, strawberries, beets,

tomatoes, sweets, amoxicillin, phenytoin, and rifampin can colour stool and emesis to red or burgundy. Bismuth preparations, activated charcoal, iron, spinach, blueberries, liquorice can simulate bleeding by black staining of emesis and stool. An appropriate history, a normal physical examination, guaiac-negative stool, and/or gastroccult-negative vomitus are sufficient to rule out a true bleeding episode. It is important to remember that haematemesis and/or melena can be secondary to epistaxis. History of recent tonsillectomy and adenoidectomy or picking nose habits increases the probability of epistaxis. Thorough examination of the nose and oropharynx can help to establish the right diagnosis. Detailed history and physical examination can help to narrow the diagnostic work-up. For example, treatment with nonsteroidal anti-inflammatory drugs (NSAIDs) is a risk factor for acute gastric ulcers and bleeding from the stomach. Jaundice, hepatomegaly, spider haemangiomata, prominent vessels of the abdominal wall, or ascites are signs of chronic liver disease and suggestive of portal hypertension. Alternatively, GI bleeding in an acutely ill, febrile child with jaundice could be secondary to coagulopathy or the acute ulceration of the stomach or the duodenum due to sepsis. Careful assessment of the

Table 6.1 Manifestations of different degrees of GI blood loss Symptoms and signs

Blood loss <15%

Blood loss <30%

Blood loss >30%

Normal appearance

+

–

–

Some anxiety

±

+

+

Disorientation

–

–

+

Lethargy

–

±

+

Tachycardia

±*

++

+

Pallor

–

+

++

Livedo reticularis

–

+

++

Cold extremities

–

+

+

Capillary refill <2 sec

–

+

+

Hypotension

–

±

++

Narrowed pulse pressure

–

+

+

Elevated diastolic pressure

–

+

–

Low diastolic pressure

–

–

+

*Tachycardia could be due to agitation or anxiety in children with mild blood loss

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perineum can reveal fissures, fistulas, or perianal induration. If the source of bleeding is not obvious, the placement of a nasogastric tube is very useful. The largest bore tolerable tube should be placed for adequate gastric lavage: a 10 to 12 Fr sump tube is a reasonable choice for small children and 14 to 16 Fr for older patients. Room temperature saline is the optimal fluid for this procedure. Iced saline lavage is no longer recommended because it compromises platelet function at the bleeding site and may induce hypothermia (especially in infants) and subsequent clinically significant arrhythmia. A bloody or coffee ground aspirate indicates upper GI bleeding, if epistaxis was ruled out. The absence of blood in the stomach does not exclude upper GI bleeding, since the source of haemorrhage can be in the duodenum. The presence of coffee ground fluid in gastric aspirate, which promptly clears by gastric lavage, suggests that bleeding has stopped. Ineffective gastric lavage indicates ongoing bleeding.

The results of blood test can give some clues to the nature of bleeding. Low Hb and Hct with normal mean cell volume (MCV) are typical for recent blood loss. An elevated blood urea nitrogen (BUN) suggests volume depletion and absorption of the blood proteins in the small intestine, which support the diagnosis of upper GI bleeding. Very low Hb, Hct, and MCV in haemodynamically stable patients, is consistent with chronic GI blood loss. Knowledge of common causes of GI bleeding in age-specific groups of children helps with the diagnostic strategy (Table 6.2). Endoscopy is the method of choice for diagnosis of the specific causes of acute and chronic GI bleeding related to mucosal and submucosal lesions of GI tract. A tagged red blood cell scan and angiography are alternative methods used to diagnose children with active GI bleeding of obscure origin, especially when vascular anomalies or haemobilia are suspected.

Table 6.2 Common causes of GI bleeding in children

Age

Upper GI Bleeding

Low GI bleeding

Neonates (0–30 days)

Swallowed maternal blood Stress ulcers/sepsis Haemorrhagic gastritis Haemorrhagic disease of the newborn

Necrotizing enterocolitis Midgut volvulus Hirschsprung’s disease Vascular malformation

Infants (30 days to 6 months)

Cow’s milk or soy protein allergy Oesophagitis ‘Prolapse gastropathy’

Anal fissure Allergic proctitis or enterocolitis Nodular lymphoid hyperplasia Intussusception

Infants and children (6 months to 6 years)

Epistaxis Oesophagitis ‘Prolapse gastropathy’ Portal hypertension Drug-induced ulcers Gastritis Mallory–Weiss tear

Anal fissures Intussusception Meckel’s diverticulum Nodular lymphoid hyperplasia Polyps Infectious colitis Haemolytic uremic syndrome Henoch–Schönlein purpura

Children and teenagers (7 years to 18 years)

Epistaxis Drug-induced gastropathy and acute ulcers Peptic ulcer Oesophagitis Gastritis Portal hypertension

Infectious colitis Ulcerative colitis Crohn’s disease Anal fissure Polyps

Gastrointestinal bleeding 59

Age-associated aetiologies Neonates In the first few days of life, coffee ground emesis or bloody stools in an otherwise healthy and haemodynamically stable neonate are most likely caused by swallowed maternal blood either during delivery or breast-feeding. In such cases, the Apt-Downey test should be performed to differentiate between maternal and infant blood. Acute gastric or duodenal ulcers should be suspected in sick premature or full-term asphyxiated or septic newborns or patients with intracerebral bleeding, raised intracranial pressure, congenital heart disease, respiratory failure, or hypoglycaemia. The typical scenario includes sudden onset of haematemesis or melena and signs of haemodynamic instability. Occasionally, severe upper GI bleeding can occur in healthy full-term neonates within the first few days of life7. GI bleeding is a common manifestation of necrotizing enterocolitis (NEC). Rare causes of GI bleeding in the first month of life include Hirschsprung enterocolitis, midgut volvulus, duplication cyst, vascular malformation, and haemorrhagic disease of the newborn, particularly in breastfeeding neonates, who did not receive vitamin K.

Infants up to 6 months of age One of the leading causes of GI bleeding in infants less than 6 months of age is cow’s milk or soy protein allergy. The spectrum of symptoms includes recurrent vomiting, haematemesis, failure to thrive, and diarrhoea with guaiacpositive stools or haematochezia. Exclusively breast-fed infants may develop similar symptoms on rare occasions. An anal fissure is another common cause of bleeding in infants. The diagnosis is made by careful examination of the anus.

Intermittent rectal bleeding with streaks of frank blood mixed with normal appearing stool could be secondary to nodular lymphoid hyperplasia of the colon or terminal ileum. During endoscopy, multiple hemispheric smooth nodules less than 4 mm can be found in clusters or diffusely throughout the GI tract (6.1). It is considered to be an excessive reaction of the GI tract lymphatic tissue (lymphoid follicles and Peyer’s patches) to food-related or other antigens. Spontaneous regression of lymphoid follicles is quite common. In addition to parental reassurance, an elimination diet for nursing mothers is a reasonable initial treatment. Feeding with extensively hydrolyzed protein formula is the next step of therapy. Corticosteroid therapy is restricted to infants with a severe form of this disease, with recurrent abdominal pain, significant anaemia, persistent rectal bleeding, diarrhoea, and failure to thrive. In such cases, immunodeficiency has to be excluded. Oesophagitis should be suspected as a cause of bleeding in infants with a history of recurrent emesis and interrupted feeding patterns associated with crying, irritability, or arching (6.2). The patients with repaired oesophageal atresia with or without tracheaoesophageal fistula are at higher risk of severe reflux disease and oesophagitis. Bleeding induced by oesophagitis is usually recurrent and not intensive. The patients may have haematemesis with streaks of blood or guaiac-positive stool. Infants or older children can develop minor bleeding due to prolapse of gastric mucosa into the oesophagus through the gastro-oesophageal junction (prolapse gastropathy) (6.3). This condition is manifested by recurrent emesis with food, and appearance of brown flecks of denaturated blood at the end of vomiting. The presence of frank blood or clots at the end of recurrent emesis suggests a more serious problem such as a Mallory–Weiss tear.

6.1 Nodular lymphoid hyperplasia in an infant with recurrent episodes of rectal bleeding. Multiple, 3–4 mm, hemispheric nodules are seen in the terminal ileum (A). Similar nodules can be found in the colon or duodenum (B).

A

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Infants and children less than 7 years of age Portal hypertension The signs and symptoms of portal hypertension are a large volume haematemesis, history of omphalitis secondary to catheterization of umbilical vein, presence of splenomegaly or hepatosplenomegaly, and other stigmata of chronic liver disease such as jaundice, spider angiomas, caput medusa, and ascitis. Oesophageal varices are the most common site of bleeding in children with intrahepatic-sinusoidal and extrahepatic-presinusoidal forms of portal hypertension (6.4). Two-thirds of children with portal hypertension will bleed before 5 years of age. The diagnosis is made based on the presence of oesophageal or gastric varices (6.5) or hypertensive gastropathy (6.6) during an upper GI endoscopy.

Intussusception Intussusception, which is common in the first 2 years of life, is strongly considered in infants and children with sudden onset of severe cramping abdominal pain intercepted with pain-free episodes and currant jelly stools. A lead point is often present in children older than 2 years of age. Diagnosis is confirmed by ultrasonography demonstrating positive ‘concentric circles’ or the ‘target-shaped’ sign, or barium enema. Hydrostatic reduction of intussusceptions is successful in more than 90% of children.

Meckel’s diverticulum Meckel’s diverticulum is the most common congenital anomaly in children. It is estimated that approximately 2% of infants have a remnant of the omphalomesenteric duct.

6.2 Oesophagitis: prominent oedema, erythema and erosions in the distal oesophagus.

6.3 Prolapse gastropathy. Multiple mucosal haemorrhages in the gastric cardia due to recurrent prolapse of the affected area through the diaphragm into the oesophagus.

6.4 Oesophageal varices: enlarged tortuous veins of the distal oesophagus.

6.5 Gastric varices: multiple varices of the gastric cardia.

Gastrointestinal bleeding 61

6.6 Hypertensive gastropathy: oedematous gastric mucosa with focal erythema and multiple small mucosal haemorrhages.

6.7 A juvenile polyp of sigmoid colon: a small amount of blood is present on the head of the polyp. The adjacent area is slightly pale and has multiple small grooves, the so-called ‘goose-skin’ sign.

However, less than 5% of children will develop complications, including GI bleeding. Half of them become symptomatic in the first 2 years of life. The predominant location of Meckel’s diverticulum is the distal ileum (40–60 cm above the ileocaecal valve). Ectopic tissue is present in up to 80% of symptomatic patients. The gastric mucosa is the most common type of ectopia. The cause of bleeding is peptic ulceration at the junction of the ectopic gastric mucosa and normal ileum, the so-called marginal ulcer. The bleeding can be massive, but it may cease spontaneously secondary to contraction of the splanchnic vessels in response to hypovolemia. This phenomenon explains an intermittent nature of bleeding from Meckel’s diverticulum. Bleeding is usually painless, but sometimes coincides with recurrent abdominal pain. The diagnostic procedure of choice is a 99mTc pertechnetate scan, which has sensitivity of 85% and specificity of 95%.

composed of normal and cystically dilated crypts embedded in an abundant lamina propria. Colonoscopy is indicated due to high incidence (almost 50%) of coexisting polyps in the descending and more proximal portions of the colon. Endoscopic polypectomy is the treatment of choice. There is a general consensus that a single juvenile polyp is not a premalignant condition. Therefore, removal of a solid juvenile polyp is curative. Surveillance colonoscopy is not indicated unless the child develops a new episode of rectal bleeding.

Juvenile polyps Juvenile polyps may occur in as many as 1% of children, with peak incidence from 2 to 5 years of age. The common clinical presentation is recurrent, painless bleeding with a small amount of blood on formed stool. Diarrhoea and tenesmus can occur when the polyp is large and located in the left colon. Typical juvenile polyps are smooth, rounded, and red. Polyps less than 1 cm are usually sessile (6.7); polyps larger than 1 cm have short or long stalks. Juvenile polyps are

Haemolytic uraemic syndrome Haemolytic uraemic syndrome (HUS) should be always suspected in infants and toddlers with bloody diarrhoea, which is present in three-quarters of children with epidemic HUS. In two-thirds of these children, Escherichia coli 0157:H7 can be isolated. The cause of bloody diarrhoea in HUS is haemorrhagic colitis due to endothelial damage produced by verotoxin and chiga toxin and submucosal haemorrhages. Tenesmus is common. Diffuse, severe abdominal pain with peritoneal signs can occur. The presence of the so-called a ‘thumb printing’ sign on a barium enema or a CT scan reflects a submucosal haemorrhage of the colon. Colitis-related symptoms last no longer than a week, followed by signs of haemolytic anaemia and oliguria. Known GI complications of HUS are intussusception, pancreatitis, and intestinal obstruction. The small or large bowel perforation may occur during peritoneal dialysis.

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6.8 Henoch–Schönlein purpura: multiple submucosal haemorrhages and secondary oedema are common findings in the colon.

6.9 Helicobacter pylori gastritis: nodular appearance of the antral mucosa is a commom finding in children with HP gastritis.

Henoch–Schönlein purpura

Although peptic ulcer disease is relatively rare in paediatric patients, it comprises at least one-third of the cases of upper GI bleeding in school age children. The majority of bleeding ulcers are located in the duodenal bulb (6.10). At least 80% of bleeding episodes from duodenal ulcers cease spontaneously. However, if the bleeding is arterial, it may recur and become life threatening. Urgent endoscopy is necessary as soon as the patient becomes more stable after fluid resuscitation. The risk factors for recurrent bleeding are: large ulcer (more than 2 cm), location of the ulcer on posteroinferior wall of the duodenal bulb, blood spurting from the base of the ulcer, a visible vessel, or an adherent clot. These high-risk patients require a second-look endoscopy 24 hours after the index endoscopy, and careful observation in the intensive care unit. The most critical time for rebleeding is the first 3 days following the initial haemostasis. Haemodynamically stable children without the endoscopic risk factors for recurrent bleeding do not require endoscopic haemostasis and can be managed safely on an outpatient basis. Colitis is the most common cause of rectal bleeding in older children and teenagers. Infectious colitis is more common by far than inflammatory bowel disease. In general, bacterial colitis is an acute, self-limited disorder manifested by sudden onset of fever, tenesmus, and bloody diarrhoea lasting from 5 to 7 days. Chronic diarrhoea (lasting 2 weeks or more) is usually associated with chronic inflammatory bowel disease. Ulcerative colitis (6.11) usually

Henoch–Schönlein purpura (HSP) is most common in children less than 7 years old. The median age is 4 years. HSP should be suspected in children with sudden onset of severe diffuse abdominal pain, vomiting, and haematochezia, especially if this happens after viral illness in winter and early spring and about a week after purpuric-type skin lesions appear on the buttocks or low extremities. On rare occasions, GI manifestations may precede skin rash. Severe anaemia is uncommon. The small and/or large bowel has different degree of haemorrhagic lesions (6.8). These may be apparent on a small bowel X-ray series or barium enema with coarsening of folds and thumb printing. Abdominal pain and haematochezia is self-limited. Treatment with corticosteroids is controversial, although it may shorten the course of GI symptoms of abdominal pain by 1 or 2 days.

Children aged 7 years and older Drug-induced gastritis or acute ulcer should be strongly suspected in children who received treatment with NSAIDs or oral steroids. The degree of bleeding varies between mild to moderate. The usual clinical presentation is the sudden onset of abdominal discomfort followed by haematemesis or melena. Haemorrhage usually originates from the stomach. The incidence of NSAID-related GI bleeding is much higher in patients with Helicobacter pylori (HP) gastritis (6.9). Therefore, eradication of HP infection is recommended before long-term therapy with NSAIDs.

Gastrointestinal bleeding 63

6.10 Duodenal ulcer, with active bleeding.

6.11 Ulcerative colitis: diffuse erythema, oedema, loss of vascular pattern, and exudates are seen.

presents with insidious onset of diarrhoea, nocturnal diarrhoea, and subsequent haematochezia. Crohn’s disease has a more indolent onset associated with abdominal pain, diarrhoea, poor appetite, and weight loss. Diarrhoea is not grossly bloody unless there is bleeding from an anal fistula or left side or diffuse colitis (6.12). Differentiation between bacterial colitis and the early stage of chronic inflammatory bowel disease is always a challenge. A high index of suspicion and negative bacterial stool culture results, including Yersinia species and other rare pathogens, are essential parts of early diagnosis. The definitive diagnosis is based on the results of upper and lower GI endoscopy with multiple biopsies. Rare infectious causes of chronic diarrhoea are Yersinia enterocolitica, Mycobacterium tuberculosis, Entamoeba histolytica, Strongyloides stercoralis, and opportunistic infections in immunocompromised patients. Clostridium difficile colitis should be ruled out especially in children treated with antibiotics or hospitalized patients.

Treatment It is imperative to initiate resuscitation of a haemodynamically unstable patient almost immediately before any diagnostic procedure is considered. Two large-bore peripheral intravenous lines or a central line should be placed and secured. Blood has to be typed and cross-matched and sent for

6.12 Crohn’s disease: multiple deep, longitudinal ulcers and areas with normal appearing mucosa are typical for Crohn’s disease.

baseline laboratory assessment including liver enzymes and clotting factors. Oxygen supplementation and bolus of saline targets tissue oxygenation and restoration of circulation. The volume of isotonic solution should be sufficient to reverse tachycardia and postural hypotension. Blood transfusion is indicated for patients with persistent orthostatic hypotension after replacement of 15–20% of blood volume with isotonic solution, children with acute haemorrhage and initial Hct of

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less than 20%, and children with haemorrhagic shock. Packed red cell transfusion is the product of choice for replacement of blood loss. Matched whole blood is preferred for patients with massive bleeding. Fresh-frozen plasma is indicated for children with suspected or documented clotting factor deficiency, such as children with acute or chronic liver disease. Platelet transfusion is indicated in rare cases of severe bleeding with estimated blood loss of more than 50% of the patient’s blood volume or children with active haemorrhage and platelet count less than 50,000/mm3. Early blood transfusion is reasonable for children with active bleeding and known chronic heart or lung diseases. Monitoring of vital signs is a more accurate way to assess the effect of blood transfusion than monitoring of the Hct soon after transfusion. It is reasonable to wait 6 hours before checking posttransfusion Hct. Octreotide (a synthetic somatostatin analogue) is effective adjuvant medical therapy for severe bleeding from oesophageal or gastric varices8. It should be given to the child with active haemorrhage and any evidence of chronic liver disease or previously diagnosed portal hypertension. The initial bolus of 1 µg/kg of intravenous octreotide is followed by continues infusion of octreotide 1 µg/kg/h. The dose can be increased every 6 hours up to 5 µg/kg/h.

Endoscopic haemostasis of nonvariceal and variceal bleeding Indications for endoscopic haemostasis of nonvariceal bleeding include: • Active bleeding from the gastric or duodenal ulcer. • Stigmata of recent bleeding: a nonbleeding visible vessel in the ulcer base and a densely adherent clot. • Bleeding arteriovenous malformation. • Bleeding after polypectomy. Three methods are routinely used for endoscopic haemostasis of nonvariceal bleeding: injection of vasoconstrictive agent, thermal coagulation, and metal clips. Indications for endoscopic haemostasis of variceal bleeding include: • Active bleeding from oesophageal or gastric varices. • History of bleeding secondary to portal hypertension. • Failed surgical shunting procedure. Two different techniques are currently used for haemostasis of variceal bleeding, sclerotherapy and endoscopic variceal ligation.

References 1 Rockall TA, Logan RFA, Devlin HB, et al. Incidence of and mortality from acute upper gastrointestinal haemorrhage in the United Kingdom. BMJ 1995;311:222–6. 2 Lacroix J, Nadeau D, Laberge S, et al. Frequency of upper gastrointestinal bleeding in a pediatric intensive care unit. Crit Care Med 1992;20:35–42. 3 Chaibou M, Tucci M, Dugas MA, et al. Clinically significant upper gastrointestinal bleeding acquired in a pediatric intensive care unit: a prospective study. Pediatrics 1998;102:933–8. 4 Teach SJ, Fleisher GR. Rectal bleeding in the pediatric emergency department. Ann Emerg Med 1994;23:1252–8. 5 Gilger MA. Upper gastrointestinal bleeding. In: Walker WA, Goulet OJ, Kleinman RE, et al. (eds). Pediatric Gastrointestinal Disease: Pathophysiology, Diagnosis and Management, 4th edn. BC Decker, Hamilton, 2004, pp. 258–65. 6 Ament ME. Diagnosis and management of upper gastrointestinal tract bleeding in the pediatric patient. Pediatr Rev 1990;12:107–16. 7 Goyal A, Treem WR, Hyams JS. Severe upper gastrointestinal bleeding in healthy full-term neonates. Am J Gastr 1994;89:613–6. 8 Eroglu Y, Emerick KM, Whitingon PF, et al. Octreotide therapy for control of acute gastrointestinal bleeding in children. JPGN 2004;38:41–7.

Further reading Boyle JT. Gastrointestinal bleeding in infants and children. Pediatr Rev 2008;29:39–52. Gershman G, Ament M. Practical Pediatric Gastrointestinal Endoscopy. Blackwell Publishing, Massachusetts, 2007. Kay MH, Wyllie R. Therapeutic endoscopy for nonvariceal gastrointestinal bleeding. J Pediatr Gastroenterol Nutr 2007;45:157–71. Murphy MS. Management of bloody diarrhea in children in primary care. BMJ 2008;336:1010–15. Shamir R, Eliakim R. Capsule endoscopy in pediatric patients. World J Gastroenterol 2008;14:4152–5.

Chapter 7

65

Cow’s milk allergy Antonio Nieto, MD, PhD, and Angel Mazón, MD

Introduction Allergy to cow’s milk (CM) proteins appears mainly in infants and persists for several months or years, or may even be lifelong. Allergic reactions to CM are frequent (1–2% of infants)1–4. Cow’s milk allergy (CMA) constitutes a challenge for paediatricians, who must be aware of the condition, and know how to initiate diagnostic and therapeutic approaches.

Adverse reactions to foods The European Academy of Allergy and Clinical Immunology divides adverse reactions to foods into toxic and nontoxic. If an immunological mechanism is involved they are denominated allergic: the classic allergic reactions are termed IgE mediated (7.1), and the classic intolerance to

CM proteins is now termed non-IgE-mediated allergy (7.2). The nontoxic reactions, which are not mediated by an immunological mechanism, are now termed intolerance. Proteins are the agents that cause allergic reactions. The basic units of proteins are amino acids. The molecular weight of amino acids ranges from 89 to 204 Da. The primary structure of proteins is a chain of amino acids bound to each other through their acid (-COOH) and amino (-NH2) terminals. The amino acids can occur in short chains of 6–9 amino acids (called peptides) or long chains of hundreds of amino acids. It is important to notice the molecular weight to estimate the number of amino acids that can be found in a peptide or a protein.

Allergen

7.1 A protein which acts as an allergen is captured by an antigen-presenting cell (APC). This interacts with a nonprimed Th0 lymphocyte, which under certain conditions, such as presence of interleukin-2 and IL-4, derives into a Th2 type lymphocyte. This interacts with a B-lymphocyte that, under the influence of IL-4 and IL-13, synthesizes specific IgE against the allergen. The IgE binds to the high affinity IgE receptors on the surface of cells, such as mastocytes. Upon a subsequent contact of the allergen, this binds to two molecules of IgE, and this interaction drives the immediate release of mediators (histamine, tryptase, leukotrienes). The mediators cause the different symptoms of allergic reactions, depending on the target organ.

APC

Th0

IgE B

Mastocyte

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IL-2 IL-4

IL-13 IL-4

Release of mediators

Th2

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Milk Th2

IL-4 IL-13

IgE

Mast cell

B Histamine triptase

APC

IgG

Th0

Th1

Table 7.1 Cow’s milk proteins

Eos IL-12 IFN-γ

Bas ECP Neu MPO

7.2 Non-IgE immune responses to foods. There is no definite known intermediary pathogenic mechanism: probably cell-mediated responses are involved, or mixed responses with the involvement of both cells and immunoglobulins. These responses are mainly elicited by proteins of large molecular weight, whatever the source, but not by small molecular weight proteins or peptides, and they need a relatively large amount of protein. The interval between exposure and symptoms is longer than for IgE responses. There are several casein proteins, whose molecular weight is around 21 kD, and which comprise around 200 amino acids. Although the absolute amount of whey proteins is lower, the number of different proteins is greater as are their molecular weights (Table 7.1). A patient can be sensitized to only one or more than one protein. The human breast does not synthesize β-lactoglobulin. Thus, any content in human milk comes from the dietary intake. A regular infant formula contains about 300 mg of β-lactoglobulin per 100 ml. Human milk contains around 0.42 µg%. A few drops of formula contain as much lactoglobulin as 100 litres of human milk. These few drops contain as much lactoglobulin as the amount present in human milk that a lactating mother gives in 3 or more months. No wonder that a child who is sensitized to CM but has no symptoms while being breast-fed develops overt severe symptoms the first time that he is given a bottle of formula.

Clinical picture Group A comprises signs and symptoms associated with a demonstrated IgE sensitization to foods. These symptoms

Casein

Caseins*

21 kD

Whey

α-lactoalbumin*

15 kD

β-lactoglobulin*

36 kD

Seroalbumin

68 kD

Lactoferrin

87 kD

IgG1

160 kD

IgG2

160 kD

IgM

900 kD

IgA

400 kD

Other *Synthesized in the mammary gland

disappear when the offending food is withdrawn, and reappear when the patient is challenged with it. The classical symptoms appear immediately after ingestion or contact with the allergen. They can show as urticaria-angioedema involving skin and mucosa; digestive symptoms such as vomiting, abdominal pains or cramps, and diarrhoea, or respiratory symptoms including wheezing, difficult breathing, and rhinoconjunctivitis. The most severe disorder is anaphylaxis. Group B includes patients who often have a sensitization to foods. Some patients have an IgE sensitization, and respond to avoiding/challenging with the food in the same way that group A does. Nevertheless, other patients who are also sensitized have no clinical response to diet, and the course remains irrespective of diet. The group B includes mainly atopic dermatitis. In cases of a complete or partial response to avoiding and challenging, it is usually not immediate, but takes several hours or even days to be evident. Pathogenic mechanisms not mediated by IgE may be involved. Some infants with CMA have isolated haematochezia and are otherwise healthy. Eosinophilic infiltration of one or several portions of the digestive tract can appear in children with CMA: it is diagnosed by the eosinophilic count in biopsy samples. Depending on the affected portion it causes dysphagia, nausea, vomiting, gastro-oesophageal reflux, abdominal pain or cramps, diarrhoea of variable severity, occult or overt blood in stools. Group C includes diseases in which no IgE mechanism is identified. They have a good clinical response to the

Cow’s milk allergy 67

elimination of the offending food. The most frequent disorder in group C is what was formerly called intolerance to CM proteins. When diarrhoea is present, malabsorption can appear and lead to failure to thrive or to specific nutritional deficits. All the symptoms are very common and they are not always caused by CMA. Indications for an allergologic work-up would be those in whom the clinical history is suggestive of CMA.

Table 7.2 Clinical history

• • • • •

Antecedents of allergy Feeding: breast/mixed/formula Age at onset of symptoms Chronology and type of symptoms Amount of milk which causes symptoms

Table 7.3 Allergologic evaluation

Diagnostic approach When first facing a child with a clinical picture suspicious of CMA, the initial approach is based on a good clinical history (Table 7.2). The three first issues may orientate the physician towards a higher or lower probability of allergy, but their usefulness is very limited. The two last issues are much more informative about the suspect mechanism of reaction. It is important to try to identify if the patient has an IgE or non-IgE reaction. The allergologic tests try to identify if there is specific IgE against CM proteins5. This is accomplished with the use of skin prick tests, and the quantification of specific IgE in serum. Both tests have a good specificity but a more modest sensitivity (Table 7.3). As some patients have discordant responses in the tests, performing both gives the best yield, but even so some patients will be misclassified as non-IgE responders. The positivity of any of the tests proves that there is a sensitization to CM; the relationship of sensitization with clinical symptoms must be clarified through the interpretation of the clinical history or performing challenge tests. Sensitization to other allergens must be assessed: it is not surprising to find out that the patient is sensitized to other allergens, especially hen’s eggs. The gold standard for the diagnosis of food allergy is the double-blind placebo-controlled challenge test. This is often required for investigational studies, but in the routine clinical practice an open challenge is acceptable (Table 7.4). The protocol must be adapted to every child, taking into account the clinical history, previous reactions, and results of tests (Table 7.5). More caution must be taken for those with positive IgE tests, while those with negative tests usually tolerate greater amounts, and the protocol can be performed more rapidly. Several days must elapse until a negative response can be ascertained. The test is easily interpreted as positive when immediately evident typical reactions appear, and easily interpreted as negative when there is a long follow-up time

Prick tests (>3 mm diameter) Sensitivity 70% Specificity 83% Positive likelihood ratio 4.12 Serum specific IgE Sensitivity 0.63 Specificity 0.83 Positive likelihood ratio 3.71 Tests with other allergens

Table 7.4 Allergologic evaluation: double blind placebo controlled challenge test

Open challenge test acceptable in infants Perform if: • Adequate clinical condition • No symptoms • Symptom-free interval • Under strict medical control • No anaphylactic reactions

without symptoms. However, between these extremes are found a range of responses that are difficult to interpret. Thus, repeated challenges are sometimes needed until a clear interpretation can be reached. The positive response to the challenge test permits a diagnosis of allergy, but it cannot identify which mechanism is involved. The allergologic evaluation is complete when IgE tests and the challenge are performed (7.3).

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Table 7.5 Allergologic evaluation: challenge test and interpretation

Challenge test • Increasing amounts (from 1 drop) • 15–30 minute intervals • Assess clinical response • May take several days

Interpretation • Subjective criteria • Difficult in delayed responses • May have to be repeated • Identifies allergy, but not the mechanism

Allergy tests Prick/serum IgE

Suspect symptoms

+

–

Challenge

Challenge

+

–

+

–

IgE mediated CM allergy

Asymptomatic sensitization

Non-IgE mediated CM allergy

Current tolerance

7.3 Algorithm of the allergologic evaluation.

Treatment Treatment is based on a diet free of CM proteins. Breastfeeding must be encouraged. The lactating mother has to avoid CM proteins. If the mother has a varied diet, there is no risk of nutritional deficits, except for calcium. If breastfeeding is not possible, an alternative feeding regimen must be chosen. The two approaches are based on the modification of native CM proteins and on the use of proteins of another, not related to CM, source6, 7. To modify the CM proteins three steps are commonly used. The action of heat and hydrolysis pretends to suppress or lower the allergenicity of proteins through changes in their structure. Ultrafiltration is directed at eliminating enzymatic products used in the process of hydrolysis and

also eliminating peptides of large molecular weight. When proteins are heated, their tertiary structure is damaged. The chemical bonds are ‘broken’ and the protein is unfolded. This separates the portions which form the conformational epitopes, which lose their allergenic ability, and are unable to bind the specific IgE. Enzymes are able to break the bonds between the amino and the acid terminals of amino acids and split the proteins into smaller fragments. These resulting fragments, depending on their size, can hold one to several dozen amino acids. The breakage of the protein can result in fragments that keep whole undamaged epitopes, able to bind to the specific IgE. A fragment can be large enough to keep two or more epitopes, able to bind

Cow’s milk allergy 69

simultaneously to molecules of IgE and trigger the allergic reaction. This is called residual allergenicity, and is more probable when the molecular weight of the fragments is larger8. In elemental formulas, in which there are no peptides but only amino acids, the ability to bind IgE is nil. The first choice for IgE-mediated allergy to CM seems to be soy formula, due to the absence of allergenicity, and also the lower price. Some physicians are reluctant to use soy formula in children under 6 months of age. When choosing an extensively hydrolyzed formula, some requirements must be met and others are advisable. All peptides must have a molecular weight under 5,000 Da, and the formula must have been tested and prove to have negative results in >90% of children with CMA. The maximal admitted weight of the peptides is 5 kD, but if the distribution of molecular weight is provided the chances that residual allergenicity is present can be estimated: the higher the percentage of very small peptides, the lower the probability of residual allergenicity (Table 7.6). Table 7.7 shows the types of milk formulas used for the feeding of infants, classified according to their constituents. The regular formula used for feeding healthy infants is infant formula (IF). If lactose intolerance is present a lactose-free formula (LF) should be used; no change in proteins is required, so native whole proteins are used. When these proteins undergo a low degree hydrolysis a partially hydrolyzed (PH) formula is obtained, also known as hypoallergenic formulas. In extensively hydrolyzed (EH) formulas, proteins undergo a high degree hydrolysis. Semielemental (SE) formulas have extensively hydrolyzed proteins and also a modification in carbohydrates and lipids. The elemental formulas (EF) have modified carbohydrates and lipids and no proteins or peptides, substituted by amino

Table 7.6 Molecular weight of small peptides present in hydrolyzed milk formulas

Molecular weight

Number of amino acids

500 Da

4

1,000 Da

7

1,500 Da

11

3,000 Da

22

5,000 Da

36

9,000 Da

65

12,000 Da

88

acids. Soy formulas have modified carbohydrates and lipids, and the proteins are purified soy proteins. We would recommend the following treatment algorithm for children with CMA (7.4). The first choice for those with IgE-mediated allergy would be soy formula, and for those with non-IgE-mediated allergy would be extensively hydrolyzed (EH) formula. The response, with disappearance of symptoms, must be fast, usually within 24–48 hours. If there is no such good response in 7 days, a second choice formula should be tried. In those cases who do not respond well to the first choice, the diagnosis should be reconsidered: the second choice should be EH formula for IgE-mediated and soy formula for non-IgE-mediated allergy. If there is a lack of response to this second choice, an elemental formula should be used. Whenever the patient

Table 7.7 Types of formulas classified according to their constituents

Carbohydrate

Lipid

Protein Cow Whole

With lactose

LCT MCT

IF

Without lactose

LCT MCT

LF

Hydrolisis Low grade High grade PH

Soy/pork Hydrolisis High grade

AA Hydrolisis Total

Soy Whole

SE

EF

Soy

EH

SE

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Yes

IgE allergy

Non-IgE allergy

Soy formula

EH formula

Good response

Good response

No

Yes

No

EH formula

Soy formula

No

Good response

No

Good response

Yes

Elemental formula

Yes

Reconsider diagnosis

No

Good response

Yes

Maintain and follow

7.4 Algorithm of treatment in cow’s milk allergy.

does not respond to the selected treatment, the diagnosis should be reconsidered, especially if the child does not improve with an elemental formula. In children who have been diagnosed and are being treated for CMA a follow-up is recommended (Table 7.8) to check that the symptoms have disappeared. Care must be paid to the appearance of new symptoms that could be due to the initial allergy or to allergy to other allergens. A physical examination must be performed to rule out signs that could have passed unnoticed, as well as an assessment of the current diet and nutritional status to avoid too restrictive, unnecessary diets, which could lead to specific deficits9–13. According to an individual’s evolution of symptoms, an allergologic study and a challenge test might be indicated. If the patient has had recent symptoms related to contact or ingestion of CM, they

could be postponed. The indication of the challenge test can be guided by results of IgE tests, but in the case of non-IgE allergy these tests have no value, so its indication must be based on clinical grounds, with challenge tests every 6 months. In IgE-mediated allergy, the presence of specific IgE does not always mean that the challenge test must be postponed. Some children who have had clear allergic reactions may outgrow their symptoms and have a good tolerance to CM even if specific IgE persists for months or years after achieving tolerance. The indication can be guided by IgE tests, but must be decided by the age and the clinical symptoms of the patient, and by the experience of the physician. The prognosis of CMA is globally good. Most children will outgrow their allergy and reach good tolerance to CM, specially those with non-IgE allergy, in whom persistence of

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Table 7.8 Follow-up of allergy to cow’s milk protein

Schedule of follow-up visits • 3 months later • 6 months later • At 18 months of age • At 2 years of age • Yearly

the allergy is exceptional14. Many of those who have not reached tolerance by the age of 5 years will have lifelong allergy. Risk factors for the persistence of IgE allergy are high levels of serum total IgE, and high levels of serum specific IgE against CM proteins. A treatment that is increasingly gaining acceptance is desensitization. The usual treatment is avoidance of CM until the patient develops spontaneous tolerance. As some children do not spontaneously reach tolerance, desensitization is becoming an alternative. The patient is given gradually increasing amounts of CM, until a usual daily dose is reached, and the child then continues having that amount of CM every day. The rationale is based on the fact that very small amounts of CM are not able to trigger symptoms or, if symptoms appear, they will not be severe and can be treated with no risk for the patient.

References 1 Martín Esteban M, Bone Calvo J, Martorell Aragonés A, et al. Adverse reactions to cow’s milk proteins. Allergol et Immunopathol 1998;26:171–94. 2 Dean T. Prevalence of allergic disorders in early childhood. Pediatr Allergy Immunol 1997;8:27–31. 3 Sanz Ortega J, Martorell Aragonés A, Michavila Gómez A, Nieto García A y Grupo de Trabajo para el estudio de la Alergia Alimentaria. Estudio de la incidencia de alergia mediada por IgE frente a la proteína de la leche de vaca en el primer año de vida. An Esp Pediatr 2001;54:536–9. 4 Crespo JF, Pascual C, Burks AW, et al. Frequency of food allergy in a pediatric population from Spain. Pediatr Allergy Immunol 1995;6:39–43. 5 Baehler P, Chad Z, Gurbindo C, et al. Distinct patterns of cow’s milk allergy in infancy defined by prolonged, two stage double-blind, placebo-controlled food challenges.

Clin Exp Allergy 1996;26:254–61. 6 Host A, Koletzko B, Dreborg S, et al. Dietary products used in infants for treatment and prevention of food allergy. Arch Dis Child 1999;81:80–4. 7 American Academy of Pediatrics. Committee on Nutrition. Hypoallergenic infant formulas. Pediatrics 2000;106:346–9. 8 Caffarelli C, Pleban A, Poiesi C, et al. Determination of allergenicity to three cow’s milk hydrolysates and an amino acid-derived formula in children with cow’s milk allergy. Clin Exp Allergy 2002:32:74–9. 9 Paganus A, Juntunen-Backman K, Savilahti E. Follow-up nutritional status and dietary survey in children with cow’s milk allergy. Acta Paediatr 1992;81:518–21. 10 Isolauri E, Sütas Y, Salo M, et al. Elimination diet in cow’s milk allergy: risk for impaired growth in young children. J Pediatr 1998;132:1004–9. 11 Christie L, Hine J, Parker JG, Burks W. Food allergies in children affect nutrient intake and growth. J Am Diet Assoc 2002;102:1648–51. 12 Black RE, Williams SM, Jones IE, et al. Children who avoid drinking cow milk have low dietary calcium intakes and poor bone health. Am J Clin Nutr 2002;76:675–80. 13 Seppo L, Korpela R, Lönnerdal B, et al. A follow-up study of nutrient intake, nutritional status, and growth in infants with cow milk allergy fed either a soy formula or an extensively hydrolysed whey formula. Am J Clin Nutr 2005;82:140–5. 14 Vanto T, Helppilä S, Juntunen-Backman K, et al. Prediction of the development of tolerance to milk in children with cow’s milk hypersensivity. J Pediatr 2004;144:218–22.

Further reading Hill DJ, Murch SH, Rafferty K, et al. The efficacy of amino acid-based formulas in relieving the symptons of cow’s milk allrgy: a systematic review. Clin Exp Allergy 2007;37:808–22. Meyer R. New guidelines for managing cow’s milk allergy in infants. J Fam Health Care 2008;18:27–30. Niggemann B, Beyer K. Diagnosis of food allergy in children: toward a standarization of food challenge. J Pediatr Gastroenterol Nutr 2007;45:399–404. Vandenplas Y, Koletzo S, Isolauri E, et al. Guidelines for the diagnosis and management of cow’s milk protein allergy in infants. Arch Dis Child 2007;92:902–8.

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Chapter 8

Abdominal masses Juan A. Tovar, MD, PhD

Masses of gastrointestinal origin Tumours and cysts of the liver The liver is accessible to palpation when enlarged and therefore masses in the liver are easily detected.

Hydatic cysts These are the result of accidental ingestion of scolices of Echinoccocus granulosus, a worm that parasitizes the intestine of the dog. When the scolices are ingested by lambs or humans, they pass the intestinal barrier and are transported by the blood stream to the first or second tissular filters, respectively the liver and the lung, where a form of resistance develops forming a cyst that grows slowly. The inside of the cyst contains a white gelatinous membrane lined by a fertile proligerous layer that frees live scolices into the clear hydatic fluid. The surrounding liver parenchyma undergoes an inflammatory and fibrotic reaction (pericystic layer). Hydatic cysts are often scarcely symptomatic in children, except when they fissure causing anaphylactic reactions. They are detected by abdominal palpation and the diagnosis is confirmed by ultrasound or computed tomography (CT) scan. Specific antigenic and blood tests help to confirm the diagnosis. Treatment consists of albendazol and surgical emptying, sterilization and removal of the membrane of the cyst/s, accompanied by partial resection of the pericystic layer. Surgical removal may be performed laparoscopically.

is fusiform, in which the entire extrahepatic-biliary tract is enlarged (8.1). If not detected prenatally, this condition may become symptomatic later on as a painful mass occasionally accompanied by jaundice. CT scan and bilio-pancreatic magnetic resonance imaging (MRI) allow preoperative depiction of the anatomy of the cyst. Treatment is surgical and consists of the excision of the choledocal duct together with the gallbladder, the cystic and common hepatic duct, and of the replacement of the biliary tract by a Roux-en-Y hepaticjejunostomy performed in an open or laparoscopic operation1.

Vascular tumours of the liver (haemangioma) These are the most frequent benign liver tumours in the newborn. They may be focal, multifocal, or diffuse and each one has a different pathologic pattern2. The focal variety is

Choledocal cysts These usually originate in a defective bilio-pancreatic junction in which both ducts are confluent within the pancreas, allowing the bile and the pancreatic juice to mix and subsequently damage the choledocal wall. There are several anatomical varieties of choledocal cysts, but the most common

8.1 Choledocal cyst occupying the entire right upper quadrant of the abdomen in a 3-month-old female with palpable mass and mild icterus. She is doing well 14 years after Roux-en-Y hepatic-jejunostomy.

Abdominal masses 73

a rapidly involuting congenital haemangioma and, as well as multifocal, often creates cardiovascular compromise due to large intratumoural arteriovenous shunts. Platelet trapping and consequently coagulation disorders may occur. In contrast, the most clinically relevant feature of diffuse tumours is their large volume that creates a compartment syndrome and eventually liver failure. Ultrasonography and MRI help to delimitate the extent. Biopsy is sometimes necessary particularly in cases with unusual features. Treatment is based on the awareness of the potential regression and of their responsiveness to corticosteroids and interferon (8.2). Most of these patients, except those in whom heart failure cannot be managed, improve over a few months and have their tumours reduced to residual, partially calcified masses. Surgical removal is seldom indicated and in some rare instances of diffuse tumours, liver transplantation is unavoidable.

Mesenchymal hamartomas of the liver These are usually multicystic with solid mesenchymal components and may locate anywhere in the organ. They are

8.2 Multifocal liver haemangioma in a baby with hyperdynamic heart failure. MRI without (A) and with (B) gadolinium contrast depicts the huge vascular spaces in both lobes. He was treated with corticosteroids and interferon. Two years later (C, D), only residual vascular areas are visible and the child is healthy.

asymptomatic except when they enlarge and are detected as liver masses. Modern imaging allows accurate preoperative assessment that is helped by the near-normal levels of tumoural markers. Treatment is always surgical (8.3). When removal is complete, there is no risk of recurrence3.

Hepatoblastoma Although it is the more frequent malignant liver tumour in children, hepatoblastoma remains rare. It grows rapidly and is occasionally multicentric. It can invade the vessels and also metastasize in the regional lymph nodes or, through the liver outflow, to the lungs and elsewhere. Most cases manifest as abdominal masses detected upon palpation. Alpha-fetoprotein (AFP) is a useful marker for diagnosis and follow-up. CT scan and MRI are the cornerstones of pretreatment staging that allows selection of management protocols. We adhere to the staging of the Societé Internationale d´Oncologie Pédiatrique (SIOP). The liver is divided into two lobes by the falciform ligament and both lobes are subdivided in turn into two, to yield four segments. When

A

B

C

D

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the tumour involves one (Stage 1) or two (Stage 2) of these segments (8.4), segmentectomy or lobectomy are usually required. When three segments are involved (Stage 3), more extensive operations are necessary (8.5) and when the four segments are affected (Stage 4), liver transplantation may be the only treatment option (8.6). Complete surgical removal is always necessary for cure and preoperative chemotherapy with platinum derivatives and doxorubicin greatly helps to reduce the original extent of the tumour. More than 80% of these children are cured, including Stage 4 cases4, 5.

Hepatocarcinoma A

This is very rare in children. They are generally seen either in children with metabolic cirrhosis or sporadically in older

B A

C 8.3 A 1-year-old female with a palpable mass in the right hypochondrium and normal liver function and AFP. MRI showed a fluid-filled mass originating between the gallbladder and the falciform ligament (A). Surgical removal could be performed removing the gallbladder and a rim of liver tissue, but respecting the main vascular and biliary conduits (B, C).

B 8.4 Hepatoblastoma (HB) located in the lateral segment of the left liver lobe in a 6-month-old female (SIOP Stage 1). The tumour could be readily removed and the patient is alive and well 14 years later.

Abdominal masses 75

children and adolescents. The tumour is often multicentric and secretes AFP. It metastasizes early, often to the lungs, and responds poorly to chemotherapy. This tumour has limited surgical possibilities and the prognosis is therefore poor except in patients with metabolic cirrhosis, in whom liver transplantation for the original disease allows total removal before metastases develop6.

proximal small bowel are filled with this material, interfering with normal feeds. The bezoar is palpable as an epigastric mass. Diagnosis is confirmed by ultrasonography and sometimes by other imaging procedures. The bezoar has to be surgically removed and the patient should be provided with adequate psychological support.

Gastric tumours and cysts Gastric tumours and masses Bezoars

Duplications of this part of the gastrointestinal tract may produce palpable epigastric masses. Leiomyosarcomas, rhabdomyosarcomas, teratomas, or gastrointestinal stromal tumours (GIST) formed by C-Kit-positive cells (interstitial Cajal cells) may be occasionally observed at this level where they cause ulceration and haemorrhage7.

This condition always involves a psychopathological background. These children swallow either indigestible material (seeds, vegetal fibres that produce phytobezoar) or hair (trichobezoar). The entire gastric lumen and sometimes

A

B

8.5 Stage 3 HB before (A) and after (B) 4 cycles of platinum and doxorubicin chemotherapy. At that time right trisegmentectomy could be successfully performed.

A

B

8.6 Stage 4 HB with several nodules on both lobes (A). During liver removal for transplantation, the bilateral, inextirpable nature of the tumour could be verified (B). After transplantation, the patient is doing well.

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Duodenopancreatic tumours Pancreatic cysts The most frequent pancreatic cystic masses are pseudocysts caused by pancreatitis of traumatic or other origins. When the pancreatic ducts are disrupted by trauma or inflammation, the enzymes are spilled into the parenchyma causing a severe pancreatitis. Secondarily, areas of necrosis and eventually cysts filled with pancreatic juice may appear and occupy the retrogastric space and even extend into the thorax through the diaphragm. A palpable mass can be detected and diagnosis can be ascertained by increased enzyme levels in blood and fluid and by imaging procedures. Pancreatoblastomas and cystic and solid tumours (Frantz’s tumours) are exceedingly rare.

patients have other symptoms in addition to the mass. When the child is operated on for one of the above-mentioned acute conditions, he/she may benefit from surgical removal of the tumour when it is localized. However, in most cases the operation serves only for obtaining enough biopsy material. US, CT, and MRI, together with bone marrow aspiration and eventually contrast studies, allow diagnosis. Fine needle aspiration may be a rapid method of histopathologic diagnosis. The mainstay of treatment is chemotherapy9, 10. The current results are rapidly improving and a high proportion of these children survive.

Masses of genitourinary origin

Tumours of the jejunum, ileum, and colon Cystic lymphangioma

Malformations, tumours, and cysts of the kidney Cystic kidneys

Cystic lymphangiomas originate at the major lymphatic confluences. In the abdomen the more frequent location is the mesentery. These lymphangiomas are uni- or multiloculated. They occupy the space between both mesenteric layers and compress the bowel from the antemesenteric border. They may be voluminous and are formed by yellowish or milky fluid-filled cysts of various dimensions (8.7). They rarely cause major symptoms except those derived from intermittent torsion or bowel distension. They may be diagnosed before birth or detected incidentally for other reasons. Ultrasonography (US) depicts the cystic nature and may help to locate them. MRI is the best procedure for imaging and it can depict the nature of the contents, the presence of calcification, and the eventual association with venous or arterial components. The risks of torsion and volvulus justify prompt removal after detection. This usually entails limited bowel resection. Occasionally these tumours can be enucleated8.

Familial polycystic kidneys may appear in an infantile form, autosomal recessive pattern (mutation of PKHD1 gene in 6p), or an adult variety in which the pattern is autosomal dominant (mutation of PKD1 gene in chromosome 16). In the infantile form most patients die early after birth because of renal failure. The kidneys are enlarged and the parenchyma is replaced by multiple small cysts (8.9). This form may be accompanied in long-term survivors by progressive liver fibrosis leading to portal hypertension. Multicystic kidneys appear as malformations of one or

Lymphoma Most intraabdominal lymphomas are non-Hodgkin, B-type tumours located near the ileocaecal valve, where the density of gut-associated lymphoid tissue is higher. Epstein–Barr virus is sometimes an aetiological factor, particularly in immunosuppressed patients. The mass/masses develop rapidly, sometimes within the lumen of the terminal ileum or caecum (8.8) but more often in the mesenteric lymph nodes. Occasionally these lymphomas manifest as intussusception or acute abdominal pain suggesting appendicitis. Abdominal lymphoma is a systemic disease and most

8.7 Cystic lymphangioma of the mesentery in a 3-year-old male. The jejunal mesentery contains a huge grape of cysts filled with milky lymph. The jejunum is laminated on the surface of the tumour. Limited resection led to cure.

Abdominal masses 77

both organs. The diseased parenchyma is devoid of normal nephrons and consists of a group of cysts that form a ‘grape cluster’, and do not communicate with the ureter (8.10). Bilateral cases are incompatible with life whereas unilateral

A

ones may be detected upon fetal ultrasonography or palpated during infancy. There is associated pathology (reflux, hydronephrosis) in the contralateral kidney. The need for removal of these dysplastic masses is controversial11. It is

B

8.8 Huge Burkitt type, B-lymphoma located in the terminal ileum of a 7-year-old male. The widespread nature of the mass is depicted in A. In B, splenic infiltration is obvious.

A

B

8.9 Autopsy of a newborn female with infantile recessive polycystic disease, who died of renal failure. All organs except the kidneys were removed (A). Section of one of the kidneys shows that the renal parenchyme is replaced by multiple honeycomb cysts (B).

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8.10 Nephrectomy specimen in a case of multicystic kidney. The parenchyme is replaced by a grape cluster of fluid-filled cysts. The ureter is in apparent continuity with the kidney.

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justified in cases in which the volume is large. In all other cases laparoscopic or retroperitoneoscopic removal is an option, but the dysplastic organ can be left in place because it tends to decrease in size over time and does not cause symptoms. There is a remote risk of malignancy on these dysplastic tissues, supporting the indication for removal.

Hydronephrosis Stenosis of the uretero-pyelic junction leads to a dilated renal pelvis. The ureter is thin and the pelvis dilates progressively, laminating the renal parenchyma. Hydronephrosis is often detected prenatally by ultrasonography. Half these babies undergo regression of the dilatation, whereas in the remaining ones it persists and becomes a palpable mass with or without pain and infection. US depicts the dilated pelvis, pyelography may give some more information, but the crucial test is isotopic excretion scintigraphy (MAG3) with furosemide that provides a functional idea of the retention of urine in the pelvis and allows differentiation between simple dilatation and real obstruction. Surgical repair consists of resection of the obstructed junction and reduction of the dilated pelvis (8.11). The potential for parenchymal recovery is directly related to the duration and the severity of the obstruction.

A

Tumours of the kidney Nephroblastoma or Wilms’ tumour is a malignant neoplasia derived from the original blastema of the kidney. It appears more often in patients with some conditions such as aniridia, hemihypertrophy, Denys–Drash or Wiedeman Beckwith syndromes. It is usually unilateral, but 5% are bilateral. Some structures recalling glomeruli or tubuli may be found within the mass together with frankly malignant cells and areas of necrosis or haemorrhage. The tumour grows rapidly within the parenchyma and may invade the excretory system and/or the vessels. It metastasizes to the regional lymph nodes and to the lungs by the haematogenous route (8.12). Wilms’ tumour is generally palpated by paediatricians or parents in otherwise healthy children. Haematuria may appear rarely when the excretory system is invaded. US, CT, and MRI depict the mass which grows within the parenchyma displacing the pelvis and calices. Treatment is always surgical but it is usually performed in Europe after reducing the size of the tumour and controlling its eventual extensions with chemotherapy. In other countries surgery is performed first but although this attitude has the theoretical advantage of allowing better histological staging, it involves increased risks of tumour rupture or surgical complications. The results are similarly

B

8.11 Ultrasonographic aspect of a case of left hydronephrosis in a 3-month-old baby (A). During repair by lumbotomy, the dilated pelvis was reduced and the apparently normal uretero-pyelic junction was resected (B).

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A

B

8.12 Patient with right-sided Wilms’ tumour that displaced the aorta, vena cava, and portal axis anteriorly and to the left (A). This patient had large lung metastasis (B).

8.13 Left mesoblastic nephroma in a newborn. The tumour was very large and grossly identical to a Wilms’ tumour (A). Nephrectomy started with isolation of the renal vessels (B) prior to ligation and division.

A

B

good with both types of protocol12, 13. When metastases are present, they are treated with chemotherapy and/or radiotherapy and they can be removed surgically if limited. Mesoblastic nephroma is a benign counterpart of nephroblastoma seen in fetuses or newborns. It is grossly identical to Wilms’ tumour except for its purely mesenchymal nature. Upon section, it has a surface that resembles uterine myoma and only rarely metastasizes. Removal of the kidney with the tumour is the usual treatment (8.13).

Bladder tumours Genitourinary rhabdomyosarcomas may cause hypogastric masses. Other tumours of the bladder, such as malignant Schwannoma (neurofibrosarcoma), may arise in patients with neurofibromatosis.

Ovarian tumours Ovarian cysts are easily diagnosed by fetal ultrasound. Most are the result of follicular stimulation by maternal chorionic gonadotrophins and, except when they are twisted and

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8.14 Neonatal 6 cm ovarian cyst diagnosed 3 weeks prior to delivery. The baby was healthy but the cyst did not change in size during the ensuing 6 weeks and contained dense and cystic areas. Upon removal, it was found to correspond to a twisted ovary with a haemorrhagic follicular cyst.

8.15 Operation for twisted giant ovarian teratoma in a 12year-old female (A) and surgical specimen of dysgerminoma in a 3-year-old female (B). The contralateral ovary was normal.

A

B

devitalized, they tend to regress. Even in cases in which the blood supply is interrupted by torsion (8.14), there is a tendency to spontaneous resolution. The current attitude is to follow them ultrasonographically and to remove them only when they are large or ‘complex’14. When germ cells are not differentiated they may cause dysgerminoma. When they differentiate into embryonal tissues they cause teratomas (8.15) and when they differentiate into extraembryonal tissues they cause yolk sac (endodermal sinus) tumours and choriocarcinomas. Tumours derived from the sex cords are granulosa-theca cell tumours and Sertoli-Leydig cell tumours. Both may be

secretory and cause respectively isosexual and heretosexual precocious puberty. Finally, tumours derived from the epithelial cells are cystadenomas that may be serous or mucinous and are the equivalent of ovarian carcinomas in adult women. Ovarian tumours are more often detected as lower abdominal masses since only 10% are secreting. An increased secretion of hormones with normal gonadotrophins is suggestive of ovarian tumour. AFP is increased in malignant teratoma and in yolk sac tumours. The treatment is surgical; conservation of some ovarian tissue is advocated when possible and safe15, 16.

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Masses from other retroperitoneal organs Neuroblastoma-ganglioneuroma Tumours of neural crest origin are the second most frequent solid neoplasias in children after brain tumours. They may originate at any point in the wide variety of tissues and organs receiving the migrating neuroblasts from the neural crest, but they involve more often the adrenal medulla, the paraspinal sympathetic chains, and the nervous plexuses that surround the aorta and its main abdominal branches. These tumours range from the malignant neuroblastoma (NB) in which neuroblasts predominate and sometimes group in pseudo-rosettes, and the benign ganglioneuroma (GN) in which the neural cells are mature neurones embedded into a fibrilar supporting stroma. Most NB retain the secreting properties of the adrenal medulla and take up amine precursors while secreting catecholamines. For this reason, they may be imaged by isotope-tagged meta-iodinebenzyl-guanidine (MIBG) and they can be detected by increased urinary excretion of catecholamine metabolites. NB develops within the organ of origin, has no real capsule, spreads to the regional lymph nodes, and metastasizes by the haematogenous route to other structures such as the skin, bone marrow, liver, or bone. The primary may grow rather rapidly undergoing necrosis, haemorrhage, and calcification. Due to the secretion of amines, these patients often have symptoms like diarrhoea, hypertension, pallor and appear sick and pained, particularly when they have bone metastases. The diagnosis is based upon CT scan and MRI imaging, bone marrow aspiration, positive uptake of MIBG by the

tumour and its metastases, and detection of increased levels of catecholamines or its metabolites in serum and urine. The cellular and molecular predictors of malignity are tested on tissue samples and therefore, biopsy is advisable before starting treatment. Therapeutic protocols are currently based on postsurgical International Neuroblastoma Staging System (INSS). Stage 1 tumours are limited to the organ of origin and are completely removed. Stage 2 tumours are extended to regional lymph nodes but are removed as well. Stage 3 tumours are usually extended on both sides of the midline and cannot be removed at the first operation (8.16), Stage 4 are those with distant metastases. Both Stages 3 and 4 require aggressive chemotherapy before complete removal of the primary is attempted. Chemotherapy is continued after surgery and in Stage 4 megatherapy and bone marrow transplantation are indicated. There is another Stage 4s corresponding to metastatic disease that does not involve the bone, in babies younger than 6 months who have their tumour detected upon palpation of a massive liver enlargement that may eventually threaten survival by creating a compartment syndrome with respiratory and cardiovascular embarrassment (8.17). The current approach to this particular stage is rather conservative. The primary may or may not be removed and supportive measures are provided to allow for regression of the liver enlargement. The results are very good in Stages 1 and 2, they are improving in Stage 3 and remain poor in Stage 4. The prognosis for Stage 4s tumours ranges between those of Stages 2 and 317–19.

8.16 Pelvic Stage 2 neuroblastoma diagnosed by palpation in a 2-year-old male. The huge mass was attached to the lumbosacral spine (1) and complete removal was possible after dissecting free the right ureter (2) and the iliac artery (3) and vein (4).

3 2

4 1

A

B

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A

B 8.17 Stage 4s neonatal neuroblastoma. The patient had severe abdominal compartment syndrome (A) due to massive liver metastases of a partially cystic right adrenal primary (B, C). She died in spite of the supportive measures taken.

C

Adrenal tumours Adrenocortical carcinoma and phaeochromocytoma are very rare neoplasias in children. Teratomas are germ cell neoplasias that differentiated towards embryonal tissues. They consist of tissues derived from the three blastodermic layers that may adopt an organoid pattern and mix in amazing patterns. These tumours can be cystic and also contain bone, cartilage, or calcifications. When they have a human-like structure they are considered as a rare form of parasitic twin or ‘fetus in feto’. They are generally located in the midline in the sacrocoxigeal area where they can develop

externally, internally, or on both spaces. They are rarely retroperitoneal at any point in this body space. At birth they are generally benign although they may have immature areas. After 6 months of age, a high proportion of them become malignant and may contain areas of yolk sac (endodermal sinus) tumour and secrete AFP that is a useful marker for follow-up. Treatment is surgical and may be difficult. In malignant cases chemotherapy is required before and after surgery. The current results are quite good even in malignant cases20.

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References 1 Miyano T, Yamataka A, Kato Y, et al. Hepaticoenterostomy after excision of choledochal cyst in children: a 30-year experience with 180 cases. J Pediatr Surg 1996;31(10):1417–21. 2 Christison-Lagay ER, Burrows PE, Alomari A, et al. Hepatic hemangiomas: subtype classification and development of a clinical practice algorithm and registry. J Pediatr Surg 2007;42(1):62–7. 3 Stringer MD, Alizai NK. Mesenchymal hamartoma of the liver: a systematic review. J Pediatr Surg 2005;40(11):1681–90. 4 Czauderna P, Otte JB, Aronson DC, et al. Guidelines for surgical treatment of hepatoblastoma in the modern era: recommendations from the Childhood Liver Tumour Strategy Group of the International Society of Paediatric Oncology (SIOPEL). Eur J Cancer 2005;41(7):1031–6. 5 Otte JB, Pritchard J, Aronson DC, et al. Liver transplantation for hepatoblastoma: results from the International Society of Pediatric Oncology (SIOP) study SIOPEL-1 and review of the world experience. Pediatr Blood Cancer 2004;42(1):74–83. 6 Czauderna P. Adult type vs. childhood hepatocellular carcinoma: are they the same or different lesions? Biology, natural history, prognosis, and treatment. Med Pediatr Oncol 2002;39(5):519–23. 7 El Behery MM, Soliman HA. Primary gastric tumours in infancy and childhood. Saudi Med J 2003;24(5 Suppl):S41. 8 Steyaert H, Guitard J, Moscovici J, et al. Abdominal cystic lymphangioma in children: benign lesions that can have a proliferative course. J Pediatr Surg 1996;31(5):677–80. 9 Wright D, McKeever P, Carter R. Childhood nonHodgkin lymphomas in the United Kingdom: findings from the UK Children’s Cancer Study Group. J Clin Pathol 1997;50(2):128–34. 10 Mann G, Attarbaschi A, Steiner M, et al. Early and reliable diagnosis of non-Hodgkin lymphoma in childhood and adolescence: contribution of cytomorphology and flow cytometric immunophenotyping. Pediatr Hematol Oncol 2006;23(3):167–76.

11 Okada T, Yoshida H, Matsunaga T, et al. Multicystic dysplastic kidney detected by prenatal ultrasonography: natural history and conservative management. Pediatr Surg Int 2003;19(3):207–10. 12 Neville HL, Ritchey ML. Wilms’ tumour. Overview of National Wilms’ Tumour Study Group results. Urol Clin North Am 2000;27(3):435–42. 13 Reinhard H, Semler O, Burger D, et al. Results of the SIOP 93-01/GPOH trial and study for the treatment of patients with unilateral nonmetastatic Wilms tumour. Klin Padiatr 2004;216(3):132–40. 14 Sapin E, Bargy F, Lewin F, et al. Management of ovarian cyst detected by prenatal ultrasounds. Eur J Pediatr Surg 1994;4(3):137–40. 15 De Backer A, Madern GC, Oosterhuis JW, et al. Ovarian germ cell tumours in children: a clinical study of 66 patients. Pediatr Blood Cancer 2006;46(4):459–64. 16 Cass DL, Hawkins E, Brandt ML, et al. Surgery for ovarian masses in infants, children, and adolescents: 102 consecutive patients treated in a 15-year period. J Pediatr Surg 2001;36(5):693–9. 17 Navarro S, Amann G, Beiske K, et al. Prognostic value of International Neuroblastoma Pathology Classification in localized resectable peripheral neuroblastic tumours: a histopathologic study of localized neuroblastoma European Study Group 94.01 Trial and Protocol. J Clin Oncol 2006;24(4):695–9. 18 La Quaglia MP, Kushner BH, Su W, et al. The impact of gross total resection on local control and survival in high-risk neuroblastoma. J Pediatr Surg 2004;39(3):412–7. 19 Castel V, Tovar JA, Costa E, et al. The role of surgery in stage IV neuroblastoma. J Pediatr Surg 2002;37(11):1574–8. 20 Luo CC, Huang CS, Chu SM, et al. Retroperitoneal teratomas in infancy and childhood. Pediatr Surg Int 2005;21(7):536–40.

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Liver disorders CHOLESTASIS Piotr Socha, MD, Joanna Pawłowska, MD, and Anil Dhawan, MD, FRCPCH Jaundice and cholestasis Jaundice results from the deposition of unconjugated or conjugated bilirubin pigment in the skin and mucous membranes. Cholestasis is defined as conjugated hyperbilirubinaemia. Liver disease may present as cholestasis alone, cholestasis that accompanies liver cirrhosis or severe liver disease with liver insufficiency. Ascites, peripheral oedema, bruises and so on can be present which indicate severe liver damage. A jaundiced child with liver insufficiency requires immediate hospitalization with prompt diagnosis to find the underlying liver disease. Prothrombin time can be solely regarded as an indicator of acute liver failure.

Infancy Cholestasis should be diagnosed quickly in infancy as various diseases require immediate therapy. Numerous aetiologies make diagnosis difficult. The American Academy of Pediatrics has elaborated practical guidelines for the management of hyperbilirubinaemia in newborn infants, mainly concentrating on indirect hyperbilirubinemia1. The guidelines emphasise the importance of measuring direct bilirubin in sick infants and in those who are jaundiced at or beyond 3 weeks. If the direct or conjugated bilirubin level is elevated, additional assessment for the causes of cholestasis is recommended. For instance, hypothyroidism, galactosaemia, and tyrosinaemia should be taken into

account. Infectious diseases may also cause cholestasis, thus urinary tract infections as well as cytomegalovirus (CMV) and toxoplasmosis should be excluded. The role of CMV as the causative factor of cholestasis is still under debate, as congenital CMV infections may present with liver damage and cholestasis. It is very important to assess stool colour to make a timely diagnosis of biliary atresia (BA). BA is a relatively uncommon disease characterized by a biliary obstruction of unknown origin that presents in the neonatal period2. However, it is the most important surgically correctable cause of cholestatic jaundice in this age group and is the most common indication for liver transplantation in children. Untreated, BA leads to cirrhosis and death within the first years of life. Surgical treatment usually involves an initial attempt to restore bile flow: the Kasai portoenterostomy3 which is performed as soon after diagnosis as possible. Prognosis of the disease seems to be better in infants operated on before 90 days of age4. Other causes of cholestasis with pale stools are: Alagille syndrome, progressive familial intrahepatic cholestasis (PFIC), alpha1-antitrypsin deficiency (α1-ATD), and cystic fibrosis. Neonatal haemochromatosis, Zellweger syndrome, Niemann–Pick disease type C, and glycogen storage disease type IV should also be considered in the differential diagnosis of infantile cholestasis (Tables 9.1, 9.2).

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Table 9.1 Differential diagnosis of cholestatic liver disease of infancy

Cystic fibrosis Bile acid metabolism disturbances Peroxisomal disorders Zellweger syndrome Congenital defects of glycosylation

Extrahepatic cholestasis • Biliary atresia • Choledochal cyst • Choledocholithiasis Intrahepatic cholestasis Infectious diseases TORCH (Toxoplasmosis, Others, Rubeolla, Cytomegaloviral infection, Herpes) Other viral infections Reo Echo Parvovirus Listeria Sepsis Urinary tract infection Tuberculosis HIV

Familial cholestatic diseases Idiopathic neonatal hepatitis Progressive familial intrahepatic cholestasis Alagille syndrome Nonsyndromatic paucity of bile ducts Recurrent intrahepatic cholestasis Benign-familiar With lymphatic oedema (Aageneas syndrome) Anatomical changes Caroli disease Multicystic liver and kidney disease Chromosomal diseases Down syndrome

Metabolic diseases α1-antitrypsin deficiency Carbohydrate metabolism disturbances Galactosaemia Fructosaemia Glycogenosis: type IV Amino acid metabolism disturbances Tyrosinaemia Lipid metabolism disturbances Niemann–Pick disease Cholesterol ester storage disease Wolman disease

Other causes Hypothyroidism Histiocytosis X Necrotizing enterocolitis Parenteral nutrition-associated cholestasis Drug-induced cholestasis

Table 9.2 Diagnostic approach to cholestasis of infancy

Urgent diagnosis indicated Biliary atresia Galactosaemia Hypothyroidism Tyrosinaemia Neonatal haemochromatosis Zellweger syndrome Infections (sepsis, urinary tract infection, CMV, Toxo)

Elective diagnosis performed PFIC Alagille syndrome Cystic fibrosis Choledochal cyst (if not accompanied by cholangitis) α1-ATD Niemann–Pick disease type C Glycogen storage disease type IV

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Childhood Jaundice is uncommon in children. However, indirect hyperbilirubinaemia can be the presentation of a benign, inherited condition, Gilbert syndrome, which affects about 6% of the adult population. Mutations in hepatic enzyme isoform (1A1) belonging to the urine diphosphoglucuronate glucuronosyltransferase (UGT) family of enzymes are responsible for this condition5. Gilbert syndrome can be confirmed by molecular diagnosis but it should be suspected in an otherwise asymptomatic child whose other liver tests are normal and there are no signs of haemolysis. Several liver diseases may present with jaundice such as infection with hepatitis B, hepatitis A, and hepatitis C virus, autoimmune hepatitis, Wilson disease, and α1-ATD. Cholecystitis is a rare condition in children and acute clinical symptoms with jaundice and fever are very unusual. Choledocholithiasis is also infrequent in childhood. Familial cholestatic diseases (Alagille syndrome, PFIC) and postoperative biliary atresia may present with episodes of increased hyperbilirubinaemia or symptoms of liver insufficiency. That is why it is important to follow these patients carefully and the primary care physicians have to be aware of possible exacerbation of symptoms. Cholangitis episodes in postoperative biliary atresia require rapid diagnosis and treatment. Septic and hypoxic damage to the liver can cause cholestasis, and septicaemia seems to be a common reason for referral of a jaundiced child to liver clinics.

9.1 Typical facial appearance in a child with Alagille syndrome.

Clinical characteristic and laboratory findings Alagille syndrome Alagille syndrome can present with very early cholestasis of infancy but it may also be asymptomatic for a very long time. Liver damage may progress quickly in some patients with portal hypertension, recurrent cholangitis, and malnutrition6. Diagnosis of Alagille syndrome is aided by the presence of syndromic features, including bile duct paucity on liver histology, chronic cholestasis, cardiac murmur, vertebral abnormalities, peculiar facies, eye findings, renal disease, and xantomas7. Usually differential diagnosis is performed in early infancy when biliary atresia must be excluded. Typical facial features are a prominent forehead, pointed chin, deep set eyes, moderate hypertelorism, and a saddle or straight nose with a bulbous tip (9.1), but these features are not very typical in early infancy. The parents may also have the typical appearance (9.2) which may indicate the need to diagnose this disease. Pulmonary artery stenosis is a typical finding which may also cause a serious heart disease (9.3, 9.4). Embryotoxon posterior observed in a slit lamp is one of the most common features of the Alagille syndrome. Butterfly vertebrae observed in late infancy are also a characteristic feature (9.5). Liver biopsy is helpful to establish the diagnosis (9.6). Liver disease may slowly progress to liver insufficiency and liver transplantation may be needed. However, in most of the patients liver disease remains stable for a long time.

9.2 The parent of the child usually presents also with very typical facial appearance.

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A

B

9.3 A, B: Fallot tetralogy and pulmonary artery hypoplasia in a patient with Alagille syndrome (right ventricle angiography in a sitting-up projection of 30°). (Courtesy of the Cardiac Catheterization Laboratory, The Children’s Memorial Health Institute.)

9.5 Butterfly vertebrae in Alagille syndrome (arrows).

9.4 Scintigraphy may show peripheral stenosis of pulmonary arteries with hypoperfusion of the left lung. (Courtesy of the Radioimmunology Department, The Children’s Memorial Health Institute.)

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9.6 A: Presentation of bile duct paucity in Alagille syndrome (vein, arrow; artery, arrowhead); B: bile duct (arrow) visible in the portal space. (Courtesy of the Pathology Department, Children’s Memorial Health Institute.)

9.7 Pruritus as a presenting symptom of PFIC.

A

B

Table 9.3 Genetic background of cholestastic diseases

PFIC 1

PFIC 2

PFIC 3

Alagille syndrome

Genetics

Autosomal recessive

Autosomal recessive

Autosomal recessive

Autosomal dominant with highly variable expression

Gene

FIC 1

BSEP

MDR 3

JAG 1

Mutation on chromosome

18q 21-22

2q 24

7q 21

Short arm of chromosome 20

Gene product

P-type ATPase

Bile salt pump

Phospholipid transporter

Ligand of Notch1

Cell localization

Gut, bile duct cells, canalicular membrane

Canalicular membrane

Canalicular membrane

Liver, heart, skeletal, eye, kidney

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Progressive familial intrahepatic cholestasis

Benign recurrent intrahepatic cholestasis

PFIC is an inherited disorder where bile acid excretion is impaired (Table 9.3). This diagnosis should always be suspected in patients with high serum bile acid concentration, low/normal or elevated gamma glutamyl transpeptidase (GGT), and pruritus. Pruritus is usually the predominant symptom and skin excoriations due to itching may be observed (9.7). Short stature is a typical feature in later age (9.8). Liver histology may reveal giant cell transformation, ductular proliferation, and fibrosis (9.9). The disease may progress to end-stage liver disease. Some experience from centres in the USA and Poland points to a successful therapy with partial external biliary diversion (9.10) when performed early in the course of the disease8. PFIC also seems to be a risk factor for hepatocellular carcinoma9. In general, diagnosis of PFIC is not very urgent but doctors should be aware of the potential health effects.

Benign recurrent intrahepatic cholestasis (BRIC) is characterized by intermittent episodes of cholestasis without progression to cirrhosis. The onset of the disease usually occurs before the second decade of life. The attacks of cholestasis vary in severity and duration (from 1 to 18 months) and may be preceded by a preicteric phase with malaise, anorexia, and pruritus. Biochemically it is characterized by increased concentrations of bilirubin, serum bile acid, and alkaline phosphatase; GGT remains low. There are no pathological changes in the liver on biopsy besides some hepatocellular cholestasis. In between episodes patients are totally asymptomatic both clinically and biochemically. Treatment is symptomatic.

A

B 9.8 Short stature in a 14-year-old girl with PFIC.

9.9 Liver histology in PFIC. A: Missing bile duct in a portal space (arrow, artery; arrowhead, portal tract); B: enlargement of the portal tract with septal fibrosis (brace).

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9.10 Partial biliary diversion in a child with PFIC. Catch up growth is observed since the procedure was performed.

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Biliary atresia BA presents with cholestasis in early infancy (1–2 months of age) in an otherwise healthy child, thus diagnosis may be delayed. The most common clinical features are: jaundice with conjugated bilirubin beyond 2 weeks of life (9.11), white stools and dark urine as well as hepatomegaly, which may not always be evident. Usually a complete work-up of cholestatic diseases is performed to confirm the diagnosis and to exclude other liver diseases with early presentation. The gall bladder may not be visible on ultrasound in many patients with biliary atresia, dynamic scintigraphy (HIDA) does not show any bile passage to the gut (9.12), and liver histology may present ductal plate malformation with bile duct proliferation and fibrosis (9.13), which is regarded as a typical feature that confirms the diagnosis. It is recommended that infants with direct hyperbilirubinaemia

exceeding 2 mg/dl (34 µmol/l) over 2 weeks of age be referred to liver centres for further work-up to avoid wasting valuable time in making the diagnosis. BA may progress quickly to cirrhosis with ascites (9.14) and oesophageal varices as a consequence of portal hypertension.

Alpha-1-antytripsin deficiency α1-ATD is inherited as an autosomal codominant disorder. The most frequent and severe mutation that causes severe α1-ATD arises in the SERPINA1 gene (formerly known as PI) and gives rise to the Z allele. Determination of α-1antitrypsin phenotype but not measurement of α-1antitrypsin concentration is the way to make the final diagnosis. During the first year of life, infants with the homozygous Pi ZZ phenotype may temporarily show elevated levels of liver enzymes and cholestasis and

A 9.11 A child with biliary atresia with moderate jaundice and normal nutritional status (A), and pale stools (B). B

9.12 Dynamic scintigraphy of the liver in BA does not show any bile passage to the gut after 24 hours.

A

B

C

D

E

F

9.13 Histological evaluation of biliary atresia. A: Intracellular cholestasis (arrow); B: giant cell transformation (arrow); C: septal fibrosis (arrow); D–F: ductal plate malformation (arrows).

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9.14 Ascites in a small child with biliary atresia.

differential diagnosis with BA should be performed. In a small percentage of patients the disease may progress to liver insufficiency and liver transplantation should be considered.

Other aetiologies of cholestasis Galactosaemia and tyrosinaemia should be diagnosed very quickly, as they can be managed with a special diet and the disease may progress very rapidly. Galactosaemia is a rare disease usually presenting with prolonged prothrombin time, but most developed countries carry out newborn screening. The definitive diagnosis is done by enzymatic testing for galactose-1-phosphate-uridyltransferase activity

(UDPG)10. It is important to know that the diagnosis of galactosaemia may lead to a false result if the infant has received a blood transfusion in the preceeding 3 months as the UDPG test does not differentiate between donor or recipient enzyme levels. If the diagnosis of galactosaemia is suspected, galactose-containing feedings should be discontinued immediately and replaced by a lactose-free formula pending the results of an appropriate enzyme assay on erythrocytes to confirm the diagnosis. Hereditary tyrosinaemia may also present with jaundice and clotting disturbances. Determination of succinylacetone in the urine is a helpful diagnostic test for this disorder11. Neonatal haemochromatosis may also present acutely with liver failure and must be diagnosed very quickly. Other metabolic disorders like Niemann–Pick disease type C or glycogen storage disease type IV do not progress so rapidly and diagnosis is not so urgent. Another neonatal liver disease presenting with typical features and cholestasis is Zellweger’s syndrome (9.15), a generalized peroxisomal biogenesis disorder which is characterized by a wild spectrum of abnormalities including in the nervous system and kidneys. Patients have characteristic craniofacial abnormalities with wide fontanelle, prominent forehead, anteverted nostrils, and narrow upper lip. Hepatic involvement includes hepatomegaly and conjugated hyperbilirubinaemia due to abnormal bile acid synthesis. In some cases cirrhosis and portal hypertension has been reported in the first year of life. The administration of primary bile acids (cholic acid and chenodeoxycholic acid) may improve liver function.

9.15 Zellweger syndrome (skeletal features).

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HYPERTRANSAMINASAEMIA IN CHILDHOOD Luís Peña-Quintana, MD, and Daniel González-Santana, MD Introduction Hypertransaminasaemia in childhood is a common finding which requires a staggered study depending on the clinical features and the severity of the disease, in order to obtain a correct diagnosis12. Investigation of the liver function relies on four major signs, markers of: • Cytolysis (ALT/GPT; AST/GOT; GGT, and LDH). • Cholestasis (alkaline phosphatase; GGT; direct bilirubin; bile acids, cholesterol, and 5´ nucleotidase). • Synthetic liver function (albumin, prothrombin time, and cholinesterase). • Chronicity (immunoglobulin G and other immunoglobulins). Aminotransferases represent the integrity of liver cells. The quotient AST/ALT is normally less than 1. When it is higher than 1, it may mean that a more severe liver damage is present (Table 9.4). GGT and alkaline phosphatase increase if there is an obstruction or a damage in hepatic canaliculae (Tables 9.5, 9.6). Prothrombin time is an excellent marker of liver synthetic function, as most coagulation factors are synthesized in the liver. Prothrombin time is a measure of the extrinsic and common pathway of coagulation. Prolonged prothrombin time is a sign of an important hepatocellular dysfunction.

Symptomatology Patients with a liver disease do not present any specific symptom. Most patients are asymptomatic. An underlying liver disease can be discovered due to hypertransaminasaemia found in an ordinary blood test. Other patients may present any of the symptoms listed in Table 9.7.

Table 9.4 Characteristics of aminotransferases (normal levels ≤40 U/l) AST • Mitochondrial and cytosolic • Half-life: 48 h • Liver, heart, brain, pancreas, muscle, kidney, lung, leukocytes and erythrocytes • More unspecific ALT • Cytosolic • Half-life: 18 h • Liver. Minimal amounts in other tissues (mainly in muscles) • AST/ALT ≤1 • More specific Released into plasma during hepatocyte necrosis

Table 9.5 Characteristics of GGT • • • • • • •

Synthesized by hepatocytes and bile duct epitelium Cytolysis and cholestasis enzyme Location: kidney, heart, pancreas, brain, spleen It only increases in liver disease Greater in cholestasis and toxic hepatitis It is stimulated by: phenobarbital, phenytoin, alcohol Higher levels in plasma in prematures, newborns, and babies younger than 2 months of age

nonhepatic disorders causing acute or chronic elevation of transaminases (e.g. rotavirus infection or coeliac disease).

Viruses

Specific causes of liver disease Viral infections and drug toxicity are the main causes of acute liver disease (Table 9.8), while the list of causes of chronic disease is broader (Table 9.9). There are also some

Hepatotropic virus A, B, C, D, E, and probably G, Epstein–Barr virus (EBV), cytomegalovirus (CMV), and other viruses (herpesvirus, adenovirus, parvovirus) may produce acute hepatitis. Patients may be asymptomatic or paucisymptomatic. The classic presentation with three

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Table 9.6 Characteristics of LDH and alkaline phosphatase

LDH • ↑ in hepatic and extrahepatic damage • Less specific • Fraction 5: more liver specific Alkaline phosphatase • Synthesis in bile canaliculi membranes • Bone, kidney and small intestine • If there is no GGT rise, hepatopathy is not probable

Table 9.7 Symptomatology

Symptoms • Astenia • Anorexia • Abdominal pain • Jaundice • Choluria • Acholia • Pruritus • ↑Abdominal perimeter • Haematomas • Peripheral oedema

Signs • Hepatomegaly: – Firm: congestive – Nodular: cirrhosis – Rounded and painful: acute hepatitis

Table 9.8 Causes of acute liver disease

Table 9.9 Causes of chronic liver disease

• • • •

• • • • • • • • •

• • • •

Viral hepatitis by A, B, C, D, E, G virus Viral hepatitis by CMV, EBV Drug-induced hepatitis, alcohol Ischaemic hepatitis (heart failure, hypotension, sepsis, Budd–Chiari) Cholangitis Wilson’s disease Autoimmune hepatitis Other rare infectious agents

phases (preicteric, icteric, and posticteric or convalescent phase) is less frequent. Some patients may present prolonged abnormal liver function tests or fulminant liver failure. Only hepatitis due to B, C, D, E and G viruses can lead to chronic liver disease.

Toxic hepatitis Toxic hepatitis is less frequent in children than in adults (Table 9.10). Most patients remain asymptomatic, and it is often casually discovered by elevation of transaminases. In other cases, there are unspecific symptoms or cholestasis13. There is no specific test to diagnose toxic hepatitis.

Wilson’s disease Wilson´s disease (WD) is an autosomic recessive genetic disorder14 affecting gene ATP7B in chromosome 13q14.3. It codes for transmembrane copper transporter in hepatocytes and for excretion into the bile canaliculus as

Viral chronic liver disease Wilson’s disease α-1-antitrypsin deficiency Autoimmune hepatitis Drug/alcohol-induced hepatitis Nonalcoholic fatty liver disease Haemochromatosis Porphyrias Cystic fibrosis

Table 9.10 Hepatotoxic drugs

• • • • • • • • • • • • •

Amiodarone Anti-neoplastic drugs Azatioprine Carbamazepine Cocaine Ciclosporin Ecstasy Erythromycin Strogens Halothane Methotrexato Minocycline, penicillins Alcohol

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• • • • • • • • • • • • •

Phenobarbital Haloperidol Valproate Paracetamol Acetylsalicylic acid Ketoconazole Isoniazid Methyldopa Sulphonamide NSAIDs Verapamil Pemoline Retinoids

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9.16 Liver biopsy in a patient with autoimmune hepatitis. Piecemeal necrosis.

9.17 Liver biopsy in a patient with autoimmune hepatitis. Central–portal bridging necrosis.

well as for joining copper to coeruloplasmin. As a result, there is an abnormal accumulation of copper in liver, brain, kidney, and other organs, mitochondrial damage, and low levels of bile copper and coeruloplasmin. Prevalence in Europe is 1/30,000, with 1/100 heterozygous. In the Canary Islands, the incidence is 1/2,60015. It may present as asymptomatic hypertransaminasaemia or as chronic hepatitis, cirrhosis, or acute liver failure in childhood. In older children and adults, extrapyramidal neurological symptoms (dysarthria, dystonia, ataxia, tremor, dysphagia), psychiatric manifestations, Kayser–Fleischer ring (due to copper deposits in the Descemet corneal membrane, very specific but not pathognomonic of WD), and renal tubulopathies (with aminoaciduria and phosphaturia) are more frequent16. It is typical to find low plasma coeruloplasmin, although in 5–10% of patients it may be normal (>20 mg/dl), and decreased serum copper levels. A raised urine copper after penicillamine (higher than 100 µg/day) and an elevated liver copper concentration (higher than 250 µg/g of dry liver tissue) are helpful in diagnosis. Liver biopsy shows the stage of the disease. Genetic tests (>150 mutations) may help.

such as anti-soluble liver antigen, anti-liver cytosol, antiliver–pancreas antigen, or anti-asialoglycoprotein receptor. Anti-actine and antineutrophil cytoplasmic autoantibodies may also be useful in the diagnosis. Patients may present with acute hepatitis or as chronic hepatitis with insidious symptomatology. In other cases, it is an incidental finding. The increase in transaminases has no relationship with the degree of hepatic necrosis. Polyclonal hypergammaglobulinaemia (IgG) is often found (2–6 g/l). If the levels of IgG are low it is a sign of good response to therapy. Although the detection of autoantibodies is very useful for diagnosis, they are not specific. Therefore, autoimmune hepatitis is not excluded in the presence of low serum autoantibody titres. Liver biopsy is fundamental for diagnosis, and the findings vary from hepatitis with moderate or severe activity to cirrhosis, which is present in almost 50% of the children at diagnosis (piecemeal necrosis (9.16), lobular hepatitis [not constant], central–portal bridging necrosis) (9.17).

Autoimmune hepatitis Autoimmune hepatitis (AIH) is a chronic inflammatory disorder affecting the liver, with unknown aetiology. It may cause severe progressive liver disease and, eventually, lead to cirrhosis and liver failure. It is classified in three types17: Type 1, with positive anti-nuclear and/or anti-smooth muscle antibodies; Type 2, with positive anti-liver–kidney microsomal antibodies; and Type 3, with other antibodies,

Alpha-1-antitrypsin deficiency (α1-ATD) In this autosomal recessive disease there is a chromosome 14 mutation18 that leads to the production of abnormal and hepatotoxic α1-AT that is retained in the endoplasmic reticulum (9.18). Frequency is 1:2000 newborns. α1-AT glycoprotein may present as 100 variants, with codominant inheritance, which are classified according to the protease inhibitor (Pi) phenotype system based on their electrophoretic moiety: Pi MM variant (with normal serum concentration and normal activity), Pi null-null variant (absence of α1-AT associated with lung disease), defective

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9.18 Liver biopsy in a patient with alpha-1-antitrypsin deficiency.

variants (such as Pi Z and Pi S, with low serum concentration and lung and liver disease). MM phenotype is found in healthy individuals; ZZ phenotype causes the most severe deficiency and it represents 95% of patients. SZ phenotype may cause liver disease (neonatal cholestasis, mild dysfunction, chronic hepatitis, liver failure, cirrhosis, hepatocellular carcinoma), while MS/MZ phenotypes do not produce liver disease in children but do in adults. Diagnosis is based on a decrease in the α1 band (electrophoretic gel) (9.19), a decrease in α1-AT in blood and Pi phenotype. On the liver biopsy, an abnormal accumulation of α1-AT in liver is present.

9.19 Diagnosis of alpha-1-antitrypsin deficiency is based on a decrease in the α1 band (arrow) (readout from electrophoretic gel).

Microvesicular accumulation of fat in hepatocytes (>5%) without excessive aclcohol consumption

The main cause of chronic liver disease in pre-adolescents and adolescents

Simple steatosis

Steatohepatitis (NASH)

Nonalcoholic fatty liver disease Nonalcoholic fatty liver disease (NAFLD) includes simple fatty liver (steatosis), nonalcoholic steatohepatitis (NASH) and cirrhosis19 (9.20). Most patients with NAFLD present with obesity, mainly central adiposity20, as part of the metabolic syndrome21 (9.21). The pathology of the NAFLD in children includes: Type 1, characterized by steatosis, hepatocyte balloonization, and perisinusoidal fibrosis (similar to NAFLD in adults and more frequent in white children in both sexes), and Type 2 (infantile), characterized by steatosis, portal inflammation, and portal fibrosis (9.22) (more common in male and children of Asian, Native American, and Hispanic ethnicity)22. Clinical experience in children with NAFLD is limited. NAFLD in childhood and adolescence used to occur in the male obese patient, with AST>ALT (when hypertransaminasaemia is present), hypertriglyceridaemia,

Cirrhosis

9.20 Nonalcoholic fatty liver disease.

acanthosis nigricans (9.23), and absence of symptoms (when the disease has been diagnosed by screening tests and/or abdominal ultrasonography). Although most patients remain asymptomatic, other individuals may present with a variety of symptoms: hypertension, dyslipidaemia, insulin resistance, type 2 diabetes, and central obesity23.

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9.21 Fenotypic appearence of an adolescent with nonalcoholic fatty liver disease.

9.22 Type 2 (infantile) nonalcoholic fatty liver disease, characterized by steatosis, portal inflammation, and portal fibrosis.

9.23 Acanthosis nigricans.

9.24 Ultrasonography showing increased ecogenicity due to fat infiltration.

Transaminases can be normal or mildly elevated, persistently or intermittently (usually AST/ALT <1). In 25% of cases, patients show an increase in GGT24, 25. Imaging techniques such as ultrasonography (9.24), computed tomography, and nuclear magnetic resonance imaging do not distinguish between simple esteatosis and NASH. The gold standard test to distinguish between

simple esteatosis and NASH is liver biopsy (Table 9.11)26. It confirms diagnosis, assesses esteatosis severity, and serves as a prognostic marker. Patients with simple esteatosis have a benign course without histological progression, but patients with NAFLD may progress to cirrhosis or hepatocarcinoma (described just in adults)27.

Practical issues in a patient with increased transaminases In the differential diagnosis of hypertransaminasaemia, coeliac disease should be considered, even when there are no other symptoms28. The baseline investigations may be found in Table 9.12. If these are not enough to lead to the

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Table 9.11 Histopathological findings in nonalcoholic liver disease

9.25 Evolution to cirrhosis in a child with a severe congenital heart disease.

diagnosis, second-line investigations should be performed29. In acute hepatitis, liver biopsy should be indicated if there is unknown aetiology, prolonged hepatitis or several relapses, suspicion of underlying chronic disease, or cholestasis associated with acute cytolysis30. In chronic hepatitis, liver biopsy is essential and is indicated to investigate the aetiology, for histological diagnosis, for the prognosis based on inflammation intensity (grade) and fibrosis (stadium), and to evaluate anti-viral therapy response. Some practical considerations are: • ↑ AST isolated: macrotransaminasaemia (AST–immunoglobulin complex, without liver damage). • The degree of transaminases elevation does not correlate with prognosis. • The most frequent causes of gross elevation in transaminases in acute hypertransaminasaemia (AST/ALT >1000) are: viral hepatitis, drug and alcoholinduced hepatitis, and ischaemic hepatitis (heart failure, hypotension, sepsis, Budd–Chiari) (9.25). • In chronic hepatitis, the inversion of the quotient AST/ALT (>1), indicates a deeper damage (mitochondrial) and evolution to fibrosis-cirrhosis. • Liver transplantation is indicated if there is reduced transaminases with increased bilirrubin and decreased prothrombin time. These are signs of submassive liver necrosis and consequent hepatocellular failure. Grade III/IV encephalopathy and/or factor V <25% are clear indications for liver transplantation.

References 1 American Academy of Pediatrics. Management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation. Pediatrics 2004;114:297–316.

Steatosis Inflammation Balloonization Fibrosis Cirrhosis

Children Marked >Portal Rare >Portal Rare

Adults <Marked Lobular Frequent Lobular >Frequent

Table 9.12 Investigations to be performed in patients with increased transaminases Transaminases < twice normal: repeat probable normalization Baseline • Coagulation test • Iron, ferritin, transferrin • Immunoglobulins • Electrophoretic gel • Copper and coeruloplasmin Second line • CK, aldolase • RNA HCV; DNA HBV • Serology: CMV, EBV, herpesvirus • Autoimmunity (ANA, ASMA, LKM, citosol, AMA) • α-1-antitrypsin levels and phenotype Pi • IgA-antigliadin; IgA- antitransglutaminase • T3-T4-TSH Liver biopsy

2 Alagille D. Extrahepatic biliary atresia. Hepatology 1984;4:7S–10S. 3 Kasai M, Kimura S, Asakura Y, et al. Surgical treatment of biliary atresia. J Pediatr Surg 1968;3:665–75. 4 Altman RP, Lilly JR, Greenfeld J, et al. A multivariable risk factor analysis of the portoenterostomy (Kasai) procedure for biliary atresia: twenty-five years of experience from two centers. Ann Surg 1997;226:348–55. 5 Kaplan M, Hammerman C, Maisels MJ. Bilirubin genetics for the nongeneticist: hereditary defects of neonatal bilirubin conjugation. Pediatrics 2003;111:886–93.

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6 Quiros-Tejera R, Ament ME, Heyman MB, et al. Variable morbidity in Alagille syndrome: a review of 43 cases. J Pediatr Gastroenterol Nutr 1999;29:431–37. 7 Emerick KM, Rand EB, Goldmuntz E, et al. Features of Alagille syndrome in 92 patients: frequency and relation to prognosis. Hepatology 1999;29:822–29. 8 Whitington PF, Whitington GL. Partial external diversion of bile for the treatment of intractable pruritus associated with intrahepatic cholestasis. Gastroenterology 1988;95:130–36. 9 Knisely AS, Strautnieks SS, Meier Y, et al. Hepatocellular carcinoma in 10 children under 5 years of age with bile salt export pump deficiency. Hepatology 2006;44:478–86. 10 Schweitzer-Krantz S. Early diagnosis of inherited metabolic disorders towards improving outcome: the controversial issue of galactosaemia. Eur J Pediatr 2003;162:S50–S53. 11 Burton BK. Inborn errors of metabolism in infancy: a guide to diagnosis. Pediatrics 1998;102:1–9. 12 Suchy FJ, Sokol R, Balistreri W (eds). Liver Disease in Children, 3rd edn. Cambridge University Press, New York, 2007. 13 Impicciatore P, Choonara I, Clarkson A, et al. Incidence of adverse drug reactions in paediatric in/out-patients: a systematic review and meta-analysis of prospective studies. Br J Clin Pharmacol 2001;52:77–83. 14 Roberts EA, Schilsky ML. A practice guideline on Wilson disease. Hepatology 2003; 37:1475–92. 15 Garcia-Villarreal L, Daniels S, Shaw SH, et al. High prevalence of the very rare Wilson disease gene mutation Leu708Pro in the Island of Gran Canaria (Canary Islands, Spain): a genetic and clinical study. Hepatology 2000;32:1329–36. 16 Ferenci P, Caca K, Loudianos G, et al. Diagnosis and phenotypic classification of Wilson disease. Liver Int 2003;23:139–42. 17 Czaja AJ, Freese D. Diagnosis and treatment of autoimmune hepatitis. Hepatology 2002;36:479–97. 18 Primhak RA, Tanner MS. Alpha-1 antitrypsin deficiency. Arch Dis Child 2001;85:2–5. 19 Patton HM, Sirlin C, Behling C, et al. Pediatric nonalcoholic fatty liver disease: a critical appraisal of current data and implications for future research. J Pediatr Gastroenterol Nutr 2006;43:413–27. 20 Fishbein MH, Miner M, Mogren C, et al. The spectrum of fatty liver in obese children and the relation-ship of serum aminotransferases to severity of steatosis. J Pediatr Gastroenterol Nutr 2003;36:54–61.

21 Marchesini G, Brizi M, Bianchi G, et al. Nonalcoholic fatty liver disease: a feature of the metabolic syndrome. Diabetes 2001;50:1844–50. 22 Schwimmer JB, Behling C, Newbury R, et al. Histopathology of pediatric nonalcoholic fatty liver disease. Hepatology 2005;42:641–9. 23 Peña-Quintana L, Colino E, Montedeoca N, et al. Obesity and nonalcoholic fatty liver disease. J Pediatr Gastroenterol Nutr 2005;40:686–7. 24 Fishbein MH, Mogren C, Gleason T, et al. Relationship of hepatic steatosis to adipose tissue distribution in pediatric nonalcoholic fatty liver disease. J Pediatr Gastroenterol Nutr 2006;42:83–8. 25 Festi D, Colecchia A, Sacco T, et al. Hepatic steatosis in obese patients: clinical aspects and prognostic significance. Obesity Reviews 2004;5:27–42. 26 Joy D, Thava VR, Scott BB. Diagnosis of fatty liver disease: is biopsy necessary? Eur J Gastroenterol Hepatol 2003;15:539–43. 27 Molleston JP, White F, Teckman J, et al. Obese children with steatohepatitis can develop cirrhosis in childhood. Am J Gastroenterol 2002;97:2460–2. 28 Abdo A, Meddings J, Swain M. Liver abnormalities in celiac disease. Clin Gastroenterol Hepatol 2004;2:107–12. 29 Pratt DS, Kaplan MM. Evaluation of abnormal liverenzyme results in asymptomatic patients. N Engl J Med 2000;342:1266–71. 30 Kelly DA. Diseases of the Liver and Biliary System in Children, 2nd edn. Blackwell Science, Oxford, 2003.

Further reading Fregonese L, Stolk J. Hereditary alpha-1-antitrypsine deficiency and its clinical consequences. Orphanet J Rare Dis 2008;19(3):16. Harb R, Thomas DW. Conjugated hyperbilirubinemia: screening and treatment in older infants and children. Pediatr Rev 2007;28:83–91. Kelly DA, Devenport M. Current management of biliary atresia. Arch Dis Child 2007;92:1132–5. Moerschel SK, Cianciaruso LB, Tracy LR. A practical approach to neonatla jaundice. Am Fam Physician 2008;77:1255–62.

Chapter 10

99

Coeliac disease Isabel Polanco MD, PhD

Definition Coeliac disease (CD) is an immunologically mediated enteropathy of the small intestine, characterized by lifelong intolerance to the gliadin and related prolamines from wheat and other cereals that occurs in genetically predisposed individuals1. Symptoms result from structural damage to the mucosa of the small intestine, which may cause malabsorption. Normal mucosal architecture is restored after commencing a gluten-free diet (GFD); villous atrophy reappears when gluten is reintroduced into the diet (gluten challenge)1–3.

Epidemiology The true incidence of CD in susceptible populations may be dramatically higher than has been previously recognized1, 3, 4 and most cases remain undiagnosed, unless actively identified through mass serological screening. CD affects females more than males (ratio 2:1). A relationship between various factors and the diagnosis of CD has been described, including genetic background, quality and quantity of gluten, age at gluten introduction, and breast-feeding5–7.

administration of extra-gluten to HLA-identical siblings of coeliac patients does not always result in pathological changes to the intestine. The HLA-DQ dimmer is also strongly linked to HLA-DR status8.

Pathology The proximal mucosa of the small intestine in patients with CD becomes abnormal on gluten ingestion and small bowel biopsy is essential to confirm the diagnosis (10.1). The abnormality is characterized by stunted or even absent villi associated with an increase in crypt length and cell numbers, the so-called ‘flat mucosa’ (10.2). The flat gut lesion is characteristic, but nonspecific of CD (Table 10.1)9. All structural damage resolves on gluten withdrawal, but recurs if gluten is reintroduced to the diet. Similar intestinal changes are frequently found in dermatitis herpetiformis (DH), an intensely itchy, chronic papulovesicular skin

Genetic factors The primary association of CD is the HLA-DQ dimer DQA1*0501/DQB1*0201. The majority of patients and first-degree relatives (and up to 20% of normal controls in susceptible populations) may express this dimer on antigenpresenting cells. The possession of this haplotype is not enough to cause gluten-induced changes, and the

10.1 Histological section of a flat mucosa in untreated coeliac disease.

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10.2. Histological features. (From Am J Clin Pathol 118(3):459–63, 2002, with permission.)

Marsh I, lymphocytic enteritis

Marsh I, intraepithelial lymphocytosis

Marsh II, lymphocytic enteritis with crypt hyperplasia

Marsh IIIA, partial villous atrophy

Marsh IIIB, subtotal villous atrophy

Marsh IIIC, total villous atrophy

Table 10.1 Causes other than coeliac disease that may produce a flattened jejunal mucosa

Children • Transient gluten intolerance • Soy and cow’s protein enteropathy • Autoimmune enteropathy • Acute viral enteritis • Giardiasis • Prolonged malnutrition Adults • Zollinger–Ellison syndrome • Tropical sprue • Giardiasis • Oral contraceptives • Others

disorder, caused by granular subepithelial IgA deposits in the upper dermis. Both the cutaneous and intestinal lesions regress with a GFD. DH is now considered as a specific skin manifestation of CD.

Clinical features CD can appear with different clinical manifestations. In general, the first symptoms appear in the months following the introduction of gluten in the diet (10.3, 10.4). The earlier gluten is introduced, the shorter the interval between introduction and occurrence of the first symptoms. The first symptoms of CD, therefore, traditionally occur between 12 months and 3 years of age (Table 10.2). In a minority of children, diagnosis is not made by the age of 5 years. CD can therefore be diagnosed at any time up to adulthood, because symptoms have been either ignored or misinterpretated (e.g. short stature), because the disease is truly symptomless or when some other autoimmune disease occurs (Tables 10.3, 10.4).

Latent coeliac disease Coeliac subjects may present with a severe or mild enteropathy at different times of their life. There are in fact subjects who had a normal jejunal biopsy while taking a normal diet, and, at some other time, have had a flat jejunal biopsy which recovered on a GFD. For such subjects the definition of latent coeliac disease has been proposed. This definition can also be applied to ‘late relapsers’10–12.

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10.3 An untreated coeliac female. She is pale and looks miserable and depressed.

Table 10.2 Clinical presentation according to the age of onset of symptoms in CD

Symptoms Classic presentation Chronic diarrhoea Anorexia Abdominal distension Weight loss Vomiting Irritability/lethargy

Presentation at older age Asymptomatic Absence of diarrhoea Decreased appetite Anorexia Growth failure Pubertal delay Menstrual irregularities Abnormal (loose) stools Arthritis/arthralgia Abdominal pain Constipation

A

B

10.4 A, B: A typical 3-year-old coeliac male with active disease. Note his distended and prominent abdomen, muscle wasting, and severe malnutrition. Subcutaneus fat disappears. Muscle wasting, affecting mostly the buttocks, thighs, and shoulders, contrasts markedly with the prominent abdominal distension.

Signs Abdominal distension Buttock wasting Malnutrition/growth failure Pallor Irritability Psychomotor delay Haematomas Rickets

Glossitis, aphthous ulcers Short stature Iron deficiency anaemia Osteopaenia Bruising Arthritis/arthralgia Enamel hypoplasia Cerebral calcifications

Presentation at adulthoood Anxiety/depression Glossitis, aphthous ulcers Chronic diarrhoea Malnutrition Anorexia Spontaneous haemorrhage Abdominal pain Peripheral oedema Infertility Isolated megaloblastic Paraesthesias anaemia Nocturnal diuresis Cramps/tetany Bone pain Digital clubbing Cerebrospinal Proximal myopathy degeneration Peripheral neuropathy Variety of rashes Hyposplenism

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Table 10.3 Associated disorders found in 1010 coeliac children at the Hospital Infantil Universitario La Paz Madrid (Spain)

Table 10.4 Mode of presentation in 1010 coeliac Children at the Hospital Infantil Universitario La Paz, Madrid (Spain)

Selective IgA deficiency Dermatitis herpetiformis Diabetes mellitus Bronchial asthma Psoriasis Chronic active hepatitis Epilepsy Vitiligo Down syndrome Cardiac disease Thyroid disorders Cystic fibrosis Fibrosing alveolitis Renal tubular acidosis Spino-cerebellar degeneration

Classic presentation: 580 cases (57.4%) • Chronic diarrhoea, abdominal distention, failure to thrive, anorexia, etc.

Total

37 36 32 6 6 6 6 4 3 3 3 1 1 1 1 146

Atypical presentation: 430 cases (42.6%) • Retarded growth 90 • Anaemia 79 • Constipation 72 • Abdominal pain 57 • Abdominal distension 46 • Muscular hypotony 25 • Bleeding 23 • Oedema 20 • Aphthous stomatitis 8 • Epilepsia 6 • Ataxia 4

Diagnosis The diagnosis of coeliac disease requires both a jejunoduodenal biopsy that shows the characteristic findings of intraepithelial lymphocytosis, crypt hyperplasia, and villous atrophy (10.1) and a positive response to a GFD. The diagnostic criteria developed by the European Society for Paediatric Gastroenterology and Nutrition2 require only clinical improvement with the diet, although histological improvement on a GFD is frequently sought and is recommended in adults because villous atrophy may persist despite a clinical response to the diet. In most patients, the diagnosis is easily established. However, roughly 10% of cases are difficult to diagnose because of a lack of concordance among serologic, clinical, and histological findings1–3. The most sensitive antibody tests for the diagnosis of coeliac disease are of the IgA class. The recognition that the enzyme tissue transglutaminase is the autoantigen for the development of endomysial antibodies allowed development of automated enzyme-linked immunoassays that are less expensive than the endomysial antibody test. Overall, the sensitivity of the tests for both endomysial antibodies and anti-tissue transglutaminase antibodies is greater than 90%, and a test for either marker is considered the best means of

screening for coeliac disease (Table 10.5). The titres of endomysial antibodies and anti-tissue transglutaminase antibodies correlate with the degree of mucosal damage; as a result, the sensitivity of these antibody tests declines when a greater number of patients with lesser degrees of villous atrophy are included in studies. The various commercially available assays for anti-tissue transglutaminase antibodies have different characteristics and resultant sensitivities and specificities.

Treatment A strict GFD with exclusion of gluten from wheat, rye, barley, and oats must be recommended lifelong in both symptomatic and asymptomatic individuals. Lifelong adherence to a strict GFD should be advised to all coeliac children in order to avoid the late complications of the disease13. Adherence to a strict GFD is essential but not easy and a follow-up control by a gastroenterologist about once a year seems to be advisable. The Coeliac Patients Associations help patients to adhere to a GFD and to understand their disease better.

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Table 10.5 Serological tests for coeliac disease9

Test

Sensitivity (%)

Specificity (%)

PPV

NPD

AGA IgG

57–100

42–98

20–95

41–88

AGA IgA

53–100

65–100

s28–100

65–100

AEA IgA

75–98

96–100

98–100

80–95

Guinea pig tTG

90.2

95

Human tTG

98.5

98

PPV: positive predictive value; NPD: negative predictive value

References 1 Green P, Cellier C. Celiac disease. N Engl J Med 2007;357:1731–43. 2 Walker-Smith JA, Guandalini S, Schmitz J, et al. Revised criteria for the diagnosis of coeliac disease. Report of working group of ESPGHAN. Arch Dis Child 1990;65:909–11. 3 Troncone R, Auricchio R. Celiac disease. In: Wyllie R, Hyams JS (eds). Pediatric Gastrointestinal and Liver Disease, 3rd edn. Saunders Elsevier, The Netherlands, 2006, pp. 517–27. 4 Polanco I, De Rosa S, Jasinski C. Coeliac disease in Latin America. In: Auricchio S, Visakorpi JK (eds). Common Food Intolerance I: Epidemiology of Coeliac Disease. Dynamic Nutrition Research (series). Karger, Basel, 1992:2:10–29. 5 Polanco I, Vázquez C. The influence of breast feeding in coeliac disease. Paediat Res 1981;75:1193. 6 Polanco I, Biemond I, van Leeuwen A, et al. Glutensensitive enteropathy in Spain: genetic and environmental factors. In: McConnell RB (ed). The Genetics of Coeliac Disease. MTP Press, Lancaster, 1981, pp. 211–34. 7 Mearin ML, Biemond I, Peña AS, et al. HLA-DR phenotypes in spanish coeliac children: their contribution to the understanding of the genetics of the disease. Gut 1983;24:532–37. 8 Polanco I, Mearin ML, Larrauri J, et al. The effect of gluten supplementation in healthy siblings of children with celiac disease. Gastroenterology 1987;92:678–81. 9 Marsh MN. Gluten, major histocompatibility complex, and the small intestine. A molecular and immunologic approach to the spectrum of gluten sensitivity (celiac sprue). Gastroenterology 1992;102:330–54.

10 Polanco I, Larrauri J. Does transient gluten intolerance exist? In: Kumar PJ, Walker-Smith JA (eds). Coeliac Disease: One Hundred Years. Leeds University Press, Middlesex, 1990, pp. 226–30. 11 Kaukinen K, Collin P, Mäki M. Latent coeliac disease or coeliac disease beyond villous atrophy? Gut 2007;56:1339–40. 12 Polanco I, Larrauri J, Prieto G, et al. Severe villous atrophy appearing at different ages in two coelias siblings with identical HLA haplotypes. Acta Paediatr Belg 1980;33:276. 13 Holmes GKT. Long-term health risks for unrecognized coeliac patients. Dyn Nutr Res 1992;2:105–18.

Further reading Baldassarre M, Lanene AM, Grosso R, et al. Celiac disease: pathogenesis and novel therapeutic strategies. Endocr Metab Immune Disrd Drug Targets 2008;8:152–8. Barton SH, Murray JA. Celiac disease and autoimmunity in the gut and elsewhere. Gastroenterol Clin North Am 2008;37:411–28. Fasano A, Troncone R, Branski D. Frontiers in Celiac Disease. In: Pediatric and Adolescent Medicine, vol 12. Branski D, Kiess W (eds). Karger, Basel, 2008. Polanco I. Celiac Disease. J Pediatr Gastroenterol Nutr 2008;47(suppl 1):S3–6. Setty M, Harmaza L, Guandalini S. Celiac disease: risk assessment, diagnosis, and monitoring. Mol Diagn Ther 2008;15:289–98.

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Chapter 11

Ulcerative colitis Carlos Sierra Salinas, MD, and Javier Blasco Alonso, MD

Introduction

Pathogenesis

Ulcerative colitis (UC) is a relapsing and remitting disease characterized by acute non-infectious inflammation of the colorectal mucosa. Crohn’s disease (CrD) and UC are the two main types of inflammatory bowel disease (IBD). While children and adults develop similar symptoms, children often present with more extensive disease.

The pathogenesis remains unknown. Recent literature reports an intensive search for the antigens that trigger the immune response in inflammatory bowel disease. One hypothesis is that these triggers are microbial pathogens, as yet unidentified with an appropriate but ineffective immune response to these pathogens. Another hypothesis affirms that there are some common dietary antigens or nonpathogenic microbial agents to which the patient mounts an abnormal immune response. The autoimmune theory postulates that an antigen is expressed on the patient’s own intestinal epithelial cells and there is an immune response to antigen and own epithelium which are thus destroyed by immune mechanisms.

Epidemiology UC may appear at any age. Most of the children are between 10 and 18 years. The incidence of UC in children and adolescents per 100,000 children per year varies between 0.5 (France) and 4.3 (Norway). The incidence of UC in children has remained relatively stable. Multiple genes may contribute to the pathogenesis of UC; essential is the interaction with the environment. Among others factors, several authors have suggested the correlation with exposure to infections in the perinatal period or early life, the inverse relationship with breast-feeding, the administration of nonsteroidal anti-inflammatory drugs, and the inverse relationship with appendectomy before the age of 20 years. Evidence of higher rates of UC in urban areas raises the issue of a transmissible agent that may be responsible for the disease expression or increased susceptibility. However, no specific infectious agent has been associated with the development of the disease.

Clinical features The presentation may vary depending upon the extent of colonic involvement and the severity of inflammation. According to the extent of the disease, three subgroups have been established (11.1): • Proctitis (25%): disease limited to the rectum. • Left-sided colitis (30%): involving the descending colon up to the splenic flexure. • Pancolitis (45%): involvement proximal to the splenic flexure, usually up to the caecum.

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Table 11.1 Symptoms of ulcerative colitis

Colonic • Rectal bleeding • Diarrhoea • Tenesmus • Incontinence • Lower abdominal cramps and pain with defecation Proctitis

Left-sided colitis

Pancolitis

11.1 Extent of bowel involvement in different ulcerative colitis.

The predominant symptom is diarrhoea, which can be associated with frank blood in the stool. The patient has frequent bowel movements, which may be small in volume, as a result of irritability of the inflamed rectum. Other symptoms include abdominal or rectal pain related to defecation, fever, and weight loss (Table 11.1). Proctitis may present with tenesmus, urgency, and the passage of semi-formed stool with blood and mucus. In contrast, left-sided colitis or pancolitis may present with bloody diarrhoea and significant abdominal pain. The majority of patients will present with a history of symptoms for several weeks. For this reason growth failure is much less frequent than in children with CrD. The extent of colonic mucosal involvement and severity of disease correlate with the clinical manifestations of UC (Table 11.2)

Differential diagnosis The most difficult decision may be to establish whether the diagnosis is UC or CrD (Table 11.3). The infectious aetiologies should be investigated with stool cultures and stool test for Clostridium difficile toxins A and B. Identification of a pathogen, however, does not necessarily exclude a diagnosis of UC, as a first episode of UC may present after documented enteric infection (Table 11.4). In infancy it is important to exclude other causes of bloody diarrhoea such as allergic colitis and Hirschsprung´s colitis. Physical examination is notably less informative than in CrD, except for the demonstrations of extraintestinal manifestations that may be associated with UC.

Systemic • Tiredness • Weight loss • Fever Extraintestinal • Related to activity of colitis: – Peripheral arthritis – Erythema nodosum – Iritis, uveitis • Unrelated to activity of colitis: – Sclerosing cholangitis – Autoimmune hepatitis – Sacroileitis

Table 11.2 Disease severity at presentation

Mild • Up to 4 stools per day • Presence of blood in the stool less than daily • No systemic symptoms Moderate/severe • ≥5 stools per day • Daily presence of blood in the stool • With or without systemic symptoms Fulminant • ≥ Grossly bloody stools per day • Fever >38°C • Tachycardia • Haemoglobin ≤8 g/dl • Serum albumin ≤3.0 g/dl

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Table 11.3 Differences between UC and CrD-colitis

UC

CrD

Long latent period

No

Yes

Osteopaenia at diagnosis

No

Yes

Growth failure

No

Yes

Oral and perianal disease

No

Yes

Cytokines

↑ interleukin 4, 5;

Normal interleukin 4, 5;

normal γ interferon and

↑ γ interferon and interleukin 12

interleukin 12 Granuloma

No

Yes

Transmural inflammation

No

Yes

Table 11.4 Infectious colitis

Viral • Cytomegalovirus • HIV • HIV-related opportunistic infections Bacterial • Campylobacter • Salmonella • Shigella • Yersinia • Escherichia coli 0157:H7 and other enterohaemorrhagic E. coli • Clostridium difficile • Tuberculosis Parasitic • Entamoeba histolytica • Giardia lamblia

Initial assessment The first steps in the diagnostic work-up of children with suspected UC should include blood tests, stool examination, and bowel wall ultrasonography measurement1. There is a low diagnostic accuracy of the common laboratory parameters of inflammation such as platelet count, erythrocyte sedimentation rate, and Creactive protein. Experience with faecal calprotectin in children with suspected IBD has been encouraging and suggests that this protein is a reliable diagnostic predictor for intestinal activity, with greater sensitivity and negative predictive value compared with those of other common laboratory parameters of inflammation. However, faecal calprotectin is not disease-specific, being elevated in all kinds of intestinal inflammation such as infectious enterocolitis. The serological immune markers antiSaccharomyces cerevisiae antibodies (ASCA) and antineutrophil cytoplasmic antibody with perinuclear staining pattern (pANCA) are associated with CrD and UC, respectively, and they are rarely found in healthy controls. The ultrasonographic evaluation of the intestinal thickness has gained importance as a reliable, noninvasive imaging modality for the diagnostic and clinical follow-up of IBD patients. The combined use of faecal calprotectin, ASCA/pANCA, and bowel wall ultrasonography measurement is a useful clinical decision-making strategy. If these test results are positive, the patient would then undergo a complete evaluation2.

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Radiographic and endoscopic evaluation In the early phase, the oedema and inflammatory infiltration cause a flattening of the haustras. In the active stage there is a disseminated ulceration and loss of haustra (11.2). Deeper ulcers may undermine the mucosa, which leads to development of the characteristic collar-button ulcerations. Evaluation with colonoscopy should be performed to diagnose UC and to determine the extent and severity of UC presentation (Table 11.5) (11.3).

Table 11.5 Endoscopic staging of ulcerative colitis

Stage 0

Vessels slightly kinked, pale mucosa

Stage 1

Erythema, slight granularity

Stage 2

Individual ulcerations, no vessels visible, spontaneous bleeding

Stage 3

Larger ulcerations, spontaneous bleeding, oedematous mucosa

Histopathological findings UC is defined histologically by diffuse chronic inflammation limited to the mucosa with severe crypt cell distortion (11.4A), diffuse goblet cell depletion (mucous

depletion) (11.4B) and crypt abscesses (11.4C). Inflammation is diffuse and solely mucosal. Vascularity is increased.

11.2 Barium enema. A: Pseudopolyps; B: slight granularity; C: ulcers; D: thickening of the colonic wall.

A

B

C

D

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A

C

B

11.3 Endoscopic findings. A: Proctitis with erythematous friable mucosa and loss of vascular pattern; B: with more chronic UC, pseudopolyps may be present; C: small numerous and nonconfluents superficial ulcers; D: rectum with loss of vascular pattern, oedematous mucosa, and small ulcers.

D 11.4 Colonic biopsy of ulcerative colitis. A: Crypt cell distortion; B: diffuse goblet cell depletion (mucous depletion); C: crypt abscesses. Inflammation is diffuse and solely mucosal. Vascularity is increased.

A

C

B

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Management

References

For children with distal disease, local steroids as hydrocortisone or budesonide may be successful but rectal 5-ASA derivatives may also be tried. For mild colitis oral mesalamine (50–70 g/kg/day) or sulfasalazine (50–70 mg/kg/day) are recommended. For moderate colitis, treatment with oral steroids in a dose of 1–2 mg/kg/day up to 60 mg/day is recommended associated with mesalamine. This dose should be continued for 1–2 weeks depending upon the response. It is then tapered over the next 3 months, at first by weekly reductions by 5 mg/week and then a more gradual taper on alternate days and cessation if clinical remission is maintained. The immunomodulatory drugs azathioprine (1.5–2.5 mg/kg/day) and its metabolite 6-mercaptopurine (1.5 mg/kg/day) can reduce the disease activity and allow the withdrawal of steroid therapy in children with steroid-dependent UC. Children with severe colitis are a medical emergency and require urgent treatment with intravenous fluids, antibiotics, and intravenous steroids for 7–10 days. If the child has not responded, then intensive immunosuppression should be started with oral tacrolimus (0.12 mg/kg/day) or intravenous or oral cyclosporine (2–4 mg/kg/day). Most of children achieve clinical remission within 3–9 days. However, even if they respond to the immunosuppression the majority of patients will require colectomy a few months or years later (Table 11.6). The role of infliximab in treating paediatric UC is not well defined. In recent papers, infliximab (5 mg/kg/day) is associated with short- and long-term clinical improvement in children and adolescents with moderate to severe UC and less effective in steroid-dependent patients3.

1 Canani RB, Tanturri de Horatio L, Terrin G, et al. Combined use of noninvasive tests is useful in the initial diagnostic approach to a child with suspected inflammatory bowel disease. J Pediatr Gastroenterol Nutr 2006;42(1):9–15. 2 IBD Working Group of the ESPGHAN. Inflammatory bowel disease in children and adolescents: recommendations for diagnosis: the Porto Criteria. J Pediatr Gastroenterol Nutr 2005;41(1):1–7. 3 Mamula P, Markowitz JE, Cohen LJ, et al. Infliximab in pediatric ulcerative colitis: two year follow-up. J Pediatr Gastroenterol Nutr 2004;38(3):298–301.

Further reading Higuchi LM, Bousvaros A. Ulcerative colitis. In: Guandalini S (ed). Texbook of Paediatric Gastroenterology and Nutrition. Taylor & Francis, London 2004, pp. 385–418. McGinnis JK, Murray KF. Infliximab for ulcerative colitis in children and adolescents. J Clin Gastroenterol 2008;42: 875–9. Oliva-Hemker M, Escher JC, Moore D, et al. Refractory inflammatory bowel disease in children. J Pediatr Gastroenterol Nutr 2008;47:266–72. Van Limberger J, Russell RK, Drummond HE, et al. Definition of phenotypic characteristics of childhoodonset inflammatory bowel disease. Gastroenterology 2008;135:1114–22.

Table 11.6 Indications for colectomy in ulcerative colitis

• Fulminant colitis • Medical therapy failure • Steroid dependency • Colonic dysplasia

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Chapter 12

Crohn’s disease David Ziring, MD, and Jorge Vargas, MD

Prevalence and incidence Crohn’s disease (CrD) is a chronic, immune-mediated gastrointestinal (GI) disease and one of the inflammatory bowel diseases (IBD) (including ulcerative colitis [UC] and indeterminate colitis). IBD currently affects nearly 1 million patients in the United States, 25% of whom are children1–3. Nearly 30 patients of every 100,000 in the population are diagnosed each year, and the incidence is increasing4, 5. The prevalence of IBD is higher in industrialized nations, especially in northern latitudes4. The number of patients affected with CrD outnumbers those with UC nearly twofold2.

Aetiology

consortia have pinpointed distinct genes that are associated with the development of CrD. These include genes for proteins that sense bacterial products, like the NOD2/CARD15 gene. 40% of patients with CrD have a ‘gain of function’ mutation in NOD29, 10. These patients are more likely to have ileal disease with stricture formation11. Similarly, a genetic polymorphism has been identified in the protein encoded by the organic cation transporter gene (OCTN)12. Most recently, researchers have identified a polymorphism in the interleukin-23 (IL-23) receptor gene. This polymorphism provides protection against the development of CrD13. The IL-23 receptor is expressed by a pathogenic subset of T cells thought to be the effectors responsible for intestinal inflammation.

This disease entity stems from an abnormal host immune response to normally occurring gut constituents. Three unifying forces underlie the pathogenesis of IBD. First, at risk patients have a genetic predisposition. Next, there is an environmental trigger (or triggers, in the case of antigens borne by intestinal bacteria). Lastly, there is a dysregulation of the normal homeostasis of the intestinal immune system.

Environment

Genetics

Immunology

CrD is a polygenic disease, i.e. several genes contribute to the pathogenic immune phenotype. The role that genetic susceptibility plays in developing IBD is illustrated by its prevalence in monozygotic twins. Between 36 and 58% of affected twins have an identical twin with CrD, while nonidentical siblings have only a 4% concordance rate6–8. Many genetic susceptibility loci have been identified in patients, but over the last several years, large genetic

The intestinal immune system is incredibly complex. Several different cell types protect the mucosa from invasion by neighbouring bacteria. This ‘innate immune system’ is comprised of dendritic cells, macrophages, natural killer (NK) cells, and natural killer T (NKT) cells14. It is the first line of defence and provides the quickest response to antigen without the need for immune memory. Intestinal epithelial cells have receptors for bacterial products. Paneth cells

The rate of new diagnoses of IBD has increased 10-fold since the 1940s. Many believe that this increase is associated with our improved hygiene5. The ‘hygiene hypothesis’ posits that autoimmune disease is on the rise because regulatory cells of the developing immune systems are not educated by the normal complement of environmental bacteria.

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reside in the crypts and produce antibacterial proteins. Specialized dendritic cells are able to stick their processes in between intestinal epithelial cells and ‘sample’ gut bacteria15. The chronic inflammation of IBD is due to a loss of tolerance to these antigens. Defects have been identified in special immune suppressor cells, normally responsible for toning down the inflammatory response16, 17. The effector cells, those cells responsible for coordinating the damaging inflammation in CrD, are a special set of CD4+ T helper cells. These cells produce large amounts of proinflammatory cytokines such as tumour necrosis factor (TNF), IL-6, and IL-17.

Diagnosis The diagnosis of CrD depends on several medical modalities, including a proper history and physical examination, radiological imaging, stool testing and blood testing for indicators of inflammation, gross inspection on endoscopy, and careful analysis of the intestinal tissue biopsies obtained during endoscopy.

well as symptoms lasting in excess of 2 weeks. Also, a careful clinician will elicit any use of nonsteroidal anti-inflammatory drugs (NSAIDs) in the recent past, as NSAID enteropathy may mimic CrD. Physical examination of a patient with CrD may reveal a left lower quadrant mass with tenderness, or the presence of perianal findings such as skin tags or fistulae (12.1, 12.2). Patients with CrD may also have associated skin rashes, such as erythema nodosum, or less commonly, pyoderma gangrenosum (12.3, 12.4). Ophthalmological findings include episcleritis or uveitis. Besides typical aphthous ulcers appearing in the mouth, patients may have cheilitis, or inflammation evidenced as a red, scaly rash at the corners of the mouth. Seronegative joint pains, or arthropathies are not uncommon (12.5, 12.6). These include pauciarticular large joint arthropathy and polyarticular small joint arthropathy.

Radiology

Patients with CrD and UC typically have quite different presentations. CrD often presents with abdominal pain, weight loss, unexplained fevers, and/or a dampened growth velocity. On the other hand, patients with UC typically present with bloody diarrhoea. Differentiating acute infectious diarrhoea from CrD relies on negative cultures as

Several radiological diagnostic studies contribute information to diagnosing IBD. These include the barium contrast series and computed tomography (CT) scan (12.7, 12.8). Barium radiograph (or ‘small bowel follow through’) studies help in the diagnosis of CrD when the presence of narrowing (stenosis) or ulceration is present in the small bowel (12.9, 12.10). Stenosis, most often seen in the terminal ileum of patients with CrD, has been given the moniker ‘string sign’ (12.11, 12.12). Bowel oedema can be seen as ‘thumbprinting’ or exaggerated swollen mucosal folding. Abnormal communication between loops of bowel

12.1 Presence of perianal findings: fistulae in a young patient with Crohn’s disease (arrow).

12.2 Presence of perianal findings: skin tags in a young patient with Crohn’s disease (arrow).

History and physical examination

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12.3, 12.4 Patients with Crohn’s disease may also have associated skin rashes, such as erythema nodosum, or less commonly, pyoderma gangrenosum.

12.5, 12.6 Seronegative joint pains, or arthropathies are not uncommon. These include pauciarticular large joint arthropathy and polyarticular small joint arthropathy.

12.7, 12.8 Several radiological diagnostic studies contribute information to diagnosing IBD. These include the barium contrast series and CT scan.

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12.9 Barium radiograph studies help in the diagnosis of Crohn’s disease. Loss of haustrations (arrow) and ulcerations (asterisks) in the terminal ileum.

*

*

12.10 Barium radiograph study. Ulcerations in the terminal ileum (arrows).

12.12 Small bowel follow through study. Stenosis in the terminal ileum (‘string sign) (arrow).

12.11 CT scan may show signs of bowel inflammation (oedema) (arrow).

that stem from chronic transmural inflammation are called fistulae, and can also be noted on these barium radiographs. Some experienced groups use ultrasound as a first approach in imaging for diagnosis of CrD (12.13, 12.14). Several progressive European centres utilize magnetic resonance imaging (MRI) enterography. Cases difficult to diagnose may employ the use of radiolabeled markers, such as technetium, to tag white blood cells and localize the intestinal site of inflammation.

Stool testing Patients with CrD often have inflammation that causes the lining of the intestine to leak protein. This protein is

detected in the stool as alpha-1-antitrypsin. Other more sensitive and specific markers of inflammation that can be detected in the stool include faecal calprotectin and S100A12.

Blood testing There are several sensitive indicators of bowel inflammation that can be examined in the blood. These include the white blood cell count, platelet number, erythrocyte sedimentation rate, and C-reactive protein. Iron deficiency anaemia as evidenced by a microcytic anaemia with an elevated red blood cell differentiation width (RDW) may arise as a result of decreased oral intake, blood loss from the

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12.13 Ultrasound of thickened bowel. Relatively hypoechoic thick walls (arrows) with echogenic lumen. Coronal view.

12.14 Ultrasound of thickened bowel. Relatively hypoechoic thick walls (arrows) with echogenic lumen. Sagittal plane.

12.15 Colonoscopy in Crohn’s disease. A: Endoscopic view of ileal Crohn's disease showing oedema, hyperaemia, and confluent linear ulcerations. B: Aphtous ulcers are often seen, and these may take on a linear or a serpinginous apperarance.

A

B

GI tract, or poor iron absorption. Decreased serum albumin may similarly result from poor oral intake or protein loss from the gut. Patients may also have a decreased albumin:globulin ratio, the product of hypoalbuminaemia and increased globulin fraction due to immune activation. More recently, serological testing for antibodies directed against common bacterial antigens have helped in the diagnosis and prognosis of patients with CrD. Patients often have an elevated titre of antibodies directed against a common yeast antigen, called the anti-Saccharomyces cereviseae antibody (ASCA). Other antibodies that predict disease complications include those directed against flagellin (CBir), the outer membrane porin C on Escherichia coli (OmpC), and a common Pseudomonas antigen (I2).

Endoscopy Colonoscopy and upper endoscopy allow the clinician to obtain biopsies for histological diagnosis. Inflammation may be found anywhere along the GI tract from mouth to anus. Grossly, the inflammation is evident as discrete areas of erythema, oedema, and haemorrhage with intervening areas of normal appearing mucosa. Aphthous ulcers are often seen, and these may take on a linear or serpiginous appearance (11.15). Often, the rectum is spared gross inflammation. A skilled endoscopist typically will locate the ileocaecal valve during colonoscopy and intubate the terminal ileum, obtaining biopsies there. While patients with UC may have mild inflammation in the terminal ileum (‘backwash ileitis’),

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Management

patients with CrD may have evidence of stricture formation, granulomas, fissures, or linear ulcers. The finding of ileitis is most often associated with a diagnosis of CrD. Inflammation of the upper GI tract may be seen in as many as 30% of patients with CrD, but it has also been reported in patients with UC. Gastritis can even cause delay in gastric emptying. Approximately 12–28% of patients with CrD will have noncaseating granulomas detected in biopsies of the upper GI tract (most often in the stomach). Fewer patients have evidence of duodenal cryptitis.

At least 50% of patients with CrD will require surgical treatment (most often small bowel resection) to treat complications, such as a chronic intestinal stenosis, within the first 10 years of diagnosis, and between 70–80% of patients will eventually have surgery over the course of a lifetime18. The resected bowel specimen may have the appearance of fat on the anti-mesenteric border, termed ‘creeping fat’.

Capsule endoscopy

Medical therapy

Capsule endoscopy, an imaging modality in which the patient ingests a capsule containing a tiny camera, has proven to have remarkable sensitivity that rivals that of barium radiography. The capsule endoscope produces thousands of still digital images that must be interpreted by a skilled reader, and differentiated from normal ‘mucosal breaks’. The use of this test is limited because of its cost and the time and expertise required of the reader.

Pharmacotherapy for both the ‘induction’ and ‘maintenance’ treatment of CrD depends largely on the activity of the disease. Patients with mild disease may enter remission with a course of oral antibiotics such as ciprofloxacin or metronidazole. Other patients with mild disease may respond well to locally, topically acting aminosalicylate preparations or similar steroid derivatives such as budesonide. However, the majority of patients will require maintenance treatment with immunomodulator therapy such as 6-mercaptopurine or methotrexate. Those patients who are intolerant or unresponsive to these drugs, or who have complicated disease, may benefit from biological therapy with anti-TNF antibodies.

Histology The finding of noncaseating granulomas in the intestine of a patient who does not have chronic granulomatous disease is diagnostic for CrD (12.16, 12.17). Early findings may only show focal active inflammation associated with a lymphoid aggregate.

12.16 Medium power view of a section of colon from a patient with Crohn's disease. The mucosa shows crypt architectural distortion and an increased amount of acute and chronic inflammation in the lamina propria. No granulomas are present.

Surgery

12.17 Histological images from the ileal biopsy of a patient with Crohn’s disease. Top: a dense, chronic, inflammatory cell infiltrate, lymphoid follicles, and a granuloma (arrows) can be seen. Bottom: same sample in a higher resolution.

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References 1 Kugathasan S, Judd RH, Hoffmann RG, et al. Epidemiologic and clinical characteristics of children with newly diagnosed inflammatory bowel disease in Wisconsin: a statewide population-based study. J Pediatr 2003;143(4):525–31. 2 Baldassano RN, Piccoli DA. Inflammatory bowel disease in pediatric and adolescent patients. Gastroenterol Clin North Am 1999;28(2):445–58. 3 Loftus E. Update on incidence and prevalence of Crohn’s disease (CD) and ulcerative colitis (UC) in Olmsted county, Minnesota. Gastroenterology 2003;124(4; S1):A36. 4 Barton JR, Gillon S, Ferguson A. Incidence of inflammatory bowel disease in Scottish children between 1968 and 1983; marginal fall in ulcerative colitis, threefold rise in Crohn’s disease. Gut 1989;30(5):618–22. 5 Bach JF. The effect of infections on susceptibility to autoimmune and allergic diseases. N Engl J Med 2002;347(12):911–20. 6 Tysk C, Lindberg E, Jarnerot G, et al. Ulcerative colitis and Crohn’s disease in an unselected population of monozygotic and dizygotic twins. A study of heritability and the influence of smoking. Gut 1988;29(7):990–6. 7 Russell RK, Satsangi J. IBD: a family affair. Best Pract Res Clin Gastroenterol 2004;18(3):525–39. 8 Orholm M, Binder V, Sorensen TI, et al. Concordance of inflammatory bowel disease among Danish twins. Results of a nationwide study. Scand J Gastroenterol 2000;35(10):1075–81. 9 Hugot JP, Chamaillard M, Zouali H, et al. Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn’s disease. Nature 2001;411(6837):599–603. 10 Ogura Y, Bonen DK, Inohara N, et al. A frameshift mutation in NOD2 associated with susceptibility to Crohn’s disease. Nature 2001;411(6837):603–6. 11 Abreu MT, Taylor KD, Lin YC, et al. Mutations in NOD2 are associated with fibrostenosing disease in patients with Crohn’s disease. Gastroenterology 2002;123(3):679–88. 12 Peltekova VD, Wintle RF, Rubin LA, et al. Functional variants of OCTN cation transporter genes are associated with Crohn disease. Nat Genet 2004;36(5):471–5.

13 Duerr RH, Taylor KD, Brant SR, et al. A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science 2006;314(5804):1461–3. 14 Podolsky DK. Inflammatory bowel disease. N Engl J Med 2002;347(6):417–29. 15 Gewirtz AT, Madara JL. Periscope, up! Monitoring microbes in the intestine. Nat Immunol 2001;2(4):288–90. 16 Singh B, Read S, Asseman C, et al. Control of intestinal inflammation by regulatory T cells. Immunol Rev 2001;182:190–200. 17 Brimnes J, Allez M, Dotan I, et al. Defects in CD8+ regulatory T cells in the lamina propria of patients with inflammatory bowel disease. J Immunol 2005;174(9):5814–22. 18 Vermeire S, van Assche G, Rutgeerts P. Review article: Altering the natural history of Crohn’s disease: evidence for and against current therapies. Aliment Pharmacol Ther 2007;25(1):3–12.

Chapter 13

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Short bowel syndrome Javier Bueno, MD

Introduction

Adaptation process

Short bowel syndrome (SBS) is a transitory or permanent intestinal failure due to the anatomic loss of extensive segments of small intestine clinically manifested with diarrhoea, malabsorption, and malnutrition. SBS is the most frequent cause of intestinal failure in the paediatric population and occurs perinatally in 85%1, 2. Although it can be congenital, it occurs most frequently after small bowel resection due to gut disorders (13.1) (Table 13.1). The intestinal length in the term newborn is 2.5–3 m and between 6 and 8 m in the adult3. The definitive intestinal length to develop SBS is not well established. In adults it is considered if the intestinal length is <200 cm. In children it depends on age, but it is considered if the length is <80–100 cm, and it will be severe if <40 cm1, 2, 4. The pathophysiological consequences of a bowel resection depend on the extent and site of the intestinal resection, and the adaptability of the remaining intestine.

After a massive small bowel resection, the remnant intestine suffers an adaptation process that includes an increase in villous height and mucosal surface area, as well as in bowel luminal circumference and wall thickness5. Enteral nutrition is the principal adaptation stimuli by its trophic effect, avoiding mucosa atrophy2. It promotes the enterohepatic recirculation of biliary salts and the release of hormones and pancreato-biliary secretions that maintain the integrity and intestinal function. The length and site of resection are obviously important: ileal resection is worse tolerated than jejunal2, 6. The presence of the ileocaecal valve improves the prognosis. It increases transit time and the contact of nutrients with the mucosa. In addition, it avoids bacterial overgrowth. In children, if intestinal length is <40 cm without ileocaecal valve there is 40% of probability of permanent parenteral nutrition (PN) dependence. If the intestinal length is between 40 and 80 cm

13.1 Necrotizing enterocolitis with multiple bowel perforations resulting in short bowel syndrome.

Table 13.1 Main causes of short gut in children

• Necrotizing enterocolitis • Gastroschisis • Volvulus • Intestinal atresia • Hirschsprung´s disease • Trauma

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and the valve is present, 80% can achieve nutritional autonomy in 1 year5. Preservation of colon is not only important for the absorption of fluid and electrolytes, but it also has nutritional advantages: malabsorbed carbohydrates undergo bacterial fermentation in the residual colon where they are converted into short-chain fatty acids7. The presence of a jejunostomy or a terminal ileostomy can produce high output with dehydration and electrolytes disturbances, delaying the adaptative process (13.2)4. Bacterial overgrowth is frequent due to the absence of the ileocaecal valve, presence of intestinal strictures, and intestinal dysmotility. It can produce enteritis that worsens the adaptation process8. It is also involved in the pathogenesis of the PN-related liver failure. Established liver damage also interfere with adaptation1.

Long-term PN may be associated with complications that include recurrent central venous line sepsis and liver failure (Table 13.2). In children, hepatic dysfunction is a major problem(13.5)1, 2, 4. Patients with permanent intestinal failure sooner or later will develop cirrhosis and liver failure1. Sondheimer et al. reported that 67% of neonates with PN-dependent SBS developed cholestasis, and 17% progressed to liver failure9. Strategies to avoid or delay liver failure are shown in Table 13.3. Patients with SBS frequently develop other clinical problems which may require specific therapy (Table 13.4).

Table 13.2 Complications of parenteral nutrition use

• Sepsis • Thrombosis. Vanishing venous access • Complications related to central line insertion (embolism, haemothorax) • Liver failure • Electrolytes disturbances • Bone disease • Gallblader stones • TPN related social problems: – Limited personal(social/life) – Psychological depression – Pain medication dependance – Poor quality of life – Expensive: US$100–200,000/year

Initial supportive management Treatment of children with intestinal failure should be predicated upon three goals: (1) to keep the patient well nourished by PN, (2) to minimize the faecal losses of fluid, electrolytes, and nutrients, and (3) to enhance the natural process of intestinal adaptation whenever possible.

Parenteral nutrition Most patients require PN until their gut has undergone sufficient adaptation to allow survival on an oral diet. This period is variable and can take 18–45 months6. PN is the practice of feeding a person intravenously (13.3). It is usually administered through a permanent central line (13.4)4. Surgical venotomies should be avoided in order to preserve the veins.

13.2 End jejunostomy. The presence of a jejunostomy or a terminal ileostomy can produce high output with dehydration and electrolytes disturbances, delaying the adaptation process.

A

B

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13.3 Parenteral nutrition administration. The patient receives nutritional formulas containing glucose, amino acids, lipids, trace elements, and vitamins that are stored in sterile bags and delivered by a medical infusion pump.

A 13.4 Permanent central venous catheters. A: One B lumen subcutaneous tunnelled catheter with cuff (Broviac–Hickman); B: reservoir (Port-a-cath). Thorax X-ray with Port-a-cath in place.

A

B

13.5 PN-related liver damage. Its aetiology is multifactorial and includes alteration in gut motility which leads to intraluminal stasis which is thought to be a major aetiologic factor for bacterial overgrowth and subsequent cholestasis, especially when the ileocaecal valve is absent. Steatosis is more typical in adults. A: Cholestasis; B: steatosis.

Table 13.3 Strategies to ameliorate liver dysfunction

• Optimize PN (fewer lipids) • Cyclic parenteral nutrition • Enteral nutrition (even small amount) • Avoid bacterial overgrowth (oral decontamination) • Ursodeoxycholic acid • Avoid sepsis

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Table 13.4 Other complications related to short bowel

• Behavioural feeding problems (phobia to oral foods and hyperphagia) • Metabolic acidosis (including D-lactic acidosis) • Cholelithiasis • Urolithiasis • Electrolytes disturbances • Gastro-oesophageal reflux • Bone disease • Dystrophy • Diarrhoea • Bacterial overgrowth

13.6 Placement of a gastrostomy should be contemplated in initial surgery based on the severity of the short gut to administrate continuous enteral feeding.

Medical therapy

Enteral nutrition

Drugs that reduce motility as opioid substances (loperamide, diphenoxylate, codeine phosphate) increase the contact time between nutrients and the mucosa. Therefore, they are used to decrease the stomal output. Gastric hyperacidity and increase in serum gastrin levels are frequently observed transiently (6–12 months) following a massive bowel resection. Unless controlled with proton pump inhibitors or H2 receptor blockers, it may result in extensive gastric or duodenal ulceration. On the other hand, long-term administration can promote bacterial overgrowth. The use of cholestiramine is useful if the diarrhoea is due to the cathartic effect of unabsorbed bile salts, and to treat periostomy or perianal irritation. Ursodeoxycholic acid may improve liver dysfunction. High-volume output from a jejunostomy requires restriction of oral fluids, a high-energy iso-osmolar diet, and the use of antisecretory drugs. Ocreotride is a universal inhibitor of exocrine and endocrine gastrointestinal and pancreatic secretions. However, ocreotride is detrimental to gut adaptation because it reduces nutrient transport. In addition, it can interfere with growth.

Drip enteral nutrition can be advanced as soon as the patient can tolerate it, followed by bolus feedings (13.6). Enteral nutrition stimulates the release of pacreatico-biliary secretions that maintain the structure and function of the intestine and the release of regulatory peptides from the intestine. Specific nutrients can be delivered to the cells of the intestinal mucosa. They promote intestinal structure and function by providing substrates for the synthesis of essential molecules or by providing energy, as happens with fermentable fibre (pectin) and their products (i.e. shortchain fatty acids). The amino acid glutamine is the main fuel for enterocytes and is also a substrate for the synthesis of nucleic acids10. Medium-chain triglycerides increase the absorption of energy in SBS with a functioning colon2. Short-chain fatty acids are readily absorbed across the colonic mucosa, whereas long-chain fatty acids are not absorbed by the colon. Glucagon-like peptide-2, released by the intestinal L cells, plays a role in the trophic effect of short-chain fatty acids on intestinal adaptation. In addition, the use of either specific (e.g. intestinal growth factor-1 [IGF-1]) or general growth factors (e.g. growth hormone) can promote intestinal adaptation11, 12.

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Surgical treatment

Techniques to avoid bacterial overgrowth

When a paediatric surgeon deals with an intestinal catastrophe, it is important to be conservative and preserve as much length of the small and large intestine as possible. A ‘second look’ laparotomy is indicated because delimitation of the viable intestine will be clearer 24–48 hours later. It is a gold standard rule to try to preserve the ileocaecal valve as well as to perform jejuno-colic anastomosis whenever possible. Stomas should be reserved only in those situations in which it is strictly necessary to avoid an additional loss of intestinal length and to preserve colonic function. Patients with a jejuno-colic anastomosis rarely have problems with their fluid and electrolyte balance. Maintaining colonic continuity serves to delay gastric emptying and decreases energy/carbohydrate losses8. To evaluate the severity of the short gut syndrome, imaging studies are required. Gastrointestinal series and barium enema are crucial to study the intestinal anatomy and to rule out strictures. Abdominal ultrasounds rule out gallbladder stones or sludge. CT scan with oral contrast and 3-D reconstruction provides the same information about the pancreas. A definitive surgical treatment is indicated after failure of medical management. The type of operation will be defined by different factors: age, length, and function of remaining bowel, the presence of dilatation, bacterial overgrowth, transit time, and the development of total parenteral nutrition (TPN) related complications. In the presence of liver dysfuntion, a liver biopsy is recommended.

Techniques to slow transit time None of the following procedures have been associated with significant clinical success. • Reversed intestinal loop. It consists of the interposition of a segment of bowel in which peristalsis is in the opposite direction. The recommended minimal length of the antiperistaltic loop is 10 cm in adults and 3 cm in children13. • Isoperistaltic colon interposition. Interposition of a segment of colon between two limbs of the small bowel14. • Artificial valves. Based on the importance of the ileocaecal valve6. Although different types of valve have been created, their use has been anecdotal. When used, they are often combined with other procedures. • Recirculation circuits. The idea is to produce a loop of intestine in which nutrients can recirculate several times6. It is not used because it facilitates bacterial overgrowth.

• Enteroplasty. Dilated intestine causes stasis and ineffective peristalsis. Anti-mesenteric tapering enteroplasty is an alternative to resection in dilated bowels to preserve bowel length and improve bacterial overgrowth14. A different approach is the tapering enteroplasty with plication of the mesenteric bowel with stitches. There is a high incidence of recurrence in the long-term follow-up. • Stricturoplasty. Longitudinal stricture incision with transverse suture.

Lengthening procedures All lengthening procedures require bowel dilatation. The longitudinal lengthening procedure was described by Bianchi in 1980. It is the most commonly used method of gastrointestinal reconstruction for SBS15. The bowel is divided into two longitudinal leaves based on the bifurcated mesenteric blood supply, and then the two hemi-loops are reconnected in an isoperistaltic way in series with the rest of the intestine. There are improvements in stool output, intestinal transit time, and D-xylose and fat absorption. Recently, Waag et al. reported their experience with 25 patients with 72% survival, 17 were weaned of TPN with a mean follow-up of 6 years16. Bueno et al. have recommended avoiding the procedure in neonates, ultra-short gut, and established cirrhosis17. Complication rate is high with intestinal necrosis, leaks, strictures, and bowel obstruction. In the Kimura procedure, initially the anti-mesenteric surface of a segment of bowel is coapted to host organs such as liver and abdominal wall18. After vascular collaterals across the coaptation site have developed from these host organs, secondary longitudinal split of the bowel is performed to provide two bowel loops, one from its antimesenteric half and the other from its mesenteric half. These are arranged in series by end-to-end anastomosis to double the original bowel length. So far, there are only anecdotal reports. Serial transverse enteroplasty (STEP) is a simple and effective procedure introduced in 2003, but also requires bowel dilatation (13.7). The International STEP Registry until May 2006 has reported 38 cases19. The length of the intestine in this series was duplicated (pre-STEP 68 cm; postSTEP 115 cm). It can even be applied in intestines with prior Bianchi procedure. In the short-term follow-up it is effective; however, longer follow-up is needed. Surgical complications such as obstruction and leaks have been described.

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13.7 STEP procedure. With multiple GIA stapler shots, the dilated intestine is transected transversely from opposite directions, to create a zig-zag channel without placing the mesenteric blood supply at risk.

Small bowel transplantation Intestinal transplantation is indicated when patients developed PN complications1, 2, 4, 19. Vanishing venous access is the main indication for isolated small bowel transplantation (13.8), while recurrent sepsis and frequent hospital admission due to dehydration and electrolyte disturbances are relative indications. PN-related liver failure is an indication for combined liver–small bowel transplantation. If the whole gastrointestinal tract is affected by disease such as pseudo-obstruction and desmoid tumours the choice is multivisceral grafts. New immunosuppressant protocols, major expertise, and new strategies have contributed to dramatic improvements in survival in recent years, such that survival rates are approaching those of other solid organ transplantation. The risk of acute rejection is very high and it is the leading cause for graft and patient loss. The requirements of high doses of

immunosuppressive agents and greater incidence of sideeffects such as a high incidence of opportunistic infections and lymphoproliferative disorder are still a barrier for its success19. Endoscopic surveillance with intestinal biopsy is the only tool to detect allograft rejection. The Intestinal Transplant Registry has recently reviewed the world experience on 772 transplants in 721 paediatric recipients, with an overall survival of 55.4%20. The most common indication for transplantation was SBS. Nowadays, the 1year graft survival in experienced centres is above 80%.

References 1 Bueno J, Ohwada S, Kocoshis S, et al. Factors impacting the survival of children with intestinal failure referred for intestinal transplantation. J Pediatr Surg 1999;34(1):27–32.

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13.8 Small bowel transplantation.

2 Goulet O. Irreversible intestinal failure. J Pediatr Gastroenterol Nutr 2004;38(3):250–69. 3 FitzSimmons J, Chiin A, Shepard TH. Normal length of the human gastrointestinal tract. Pediatr Pathol 1988;8:633–41. 4 Buchman AL, Scolapio J, Fryer J. AGA technical review on SBS and intestinal transplantation. Gastroenterology 2003;124(4):1111–34. 5 Shanbonhogue L, Molenaar J. SBS: metabolic and surgical management. Br J Surg 1994;81:486–99. 6 Goulet O, Baglin-Gobet S, Talbotec C, et al. Outcome and long-term growth after extensive small bowel resection in the neonatal period: a survey of 87 children. Eur J Pediatr Surg 2005;15(2):95–101. 7 Nordgaard I, Hansen CS, Mortensen PB. Colon as a digestive organ in patients with short bowel. Lancet 1994;343:373–6. 8 Kaufman SS, Loseke CA, Lupo JV, et al. Influence of bacterial overgrowth and intestinal inflammation on duration of parenteral nutrition in children with SBS. J Pediatr 1997;131(3):356–61. 9 Sondheimer JM, Asturias E, Cadnapaphornchai M. Infection and cholestasis in neonates with intestinal resection and long-term parenteral nutrition. J Pediatr Gastroenterol Nutr 1998;27(2):131–7. 10 Michail S, Mohammadpour H, Park JH, et al. Effect of glutamine-supplemented elemental diet on mucosal adaptation after small bowel resection in rats. J Pediatr Gastroenterol Nutr 1995;21:394–8 11 Byrne TA, Persinger RL, Younf LS, et al. A new treatment for patients with short-bowel syndrome. Growth hormone, glutamine, and a modified diet. Ann Surg 1995;222:243–55.

12 Thompson JS, Langnas AN, Pinch LW, et al. Surgical approach to the SBS. Ann Surg 1995;22:600–7. 13 Zhou Y, Wu XT, Yang G, et al. Clinical evidence of growth hormone, glutamine and a modified diet for short bowel syndrome: meta-analysis of clinical trials. Asia Pac J Clin Nutr 2005;14(1):98–102. 14 Garcia VF, Templeton JM, Eichelberger MR, et al. Colon interposition for the SBS. J Pediatr Surg 1981;16(6):994–5. 15 Bianchi A. Longitudinal intestinal lengthening and tailoring: results in 20 children. J Royal Soc Med 1997;90:429–32. 16 Waag KL, Hosie S, Wessel L. What do children look like after longitudinal intestinal lengthening? Eur J Pediatr Surg 1999;9(4):260–2. 17 Bueno J, Guiterrez J, Mazariegos GV, et al. Analysis of patients with longitudinal intestinal lengthening procedure referred for intestinal transplantation. J Pediatr Surg 2001;36(1):178–83. 18 Kimura K, Soper RT. A new bowel elongation technique for the short-bowel syndrome using the isolated bowel segment Iowa models. J Pediatr Surg 1993;28(6):792–4. 19 Modi BP, Javid PJ, Jaksic T, et al. International STEP Data Registry. First report of the international serial transverse enteroplasty data registry: indications, efficacy, and complications. J Am Coll Surg 2007;204(3):365–71. 20 Reyes J, Bueno J, Kocoshis S, et al. Current status of intestinal transplantation in children. J Pediatr Surg 1998;33(2):243–54.

Further reading Ching YA, Gura K, Modi B, et al. Pediatric intestinal failure: nutrition, pharmacologic, and surgical approaches. Nutr Clin Pract 2007;22:653–63. Duro D, Kamin D, Duggan C. Overview of pediatric short bowel syndrome. J Pediatr Gastroenterol Nutr 2008;47(suppl 1):533–6. Moreno Villares JM. Parenteral nutrition-associated liver disease. Nutr Hosp 2008;23(suppl 2):25–33. Ruiz P, Kato T, Tzakis A. Current status of transplantation of the small intestine. Transplantation 2007;83:1–6.

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Chapter 14

Congenital gastrointestinal malformations Iñaki Eizaguirre, MD, and Agustín Nogués, MD Introduction

Meckel’s diverticulum

The most significant congenital gastrointestinal malformations are Meckel’s diverticulum and anorectal malformations1, 2 (Table 14.1). The majority are developmental disturbances or embryopathies. These embryopathies occur in a phase in which all the organs are forming (3rd to 8th week), thus the presence of multiple anomalies is common. Other digestive tract malformations are foetopathies, probably due to ischaemic accidents that give rise to duodenal, intestinal, and colonic or rectal atresias. The interruption of the blood supply to a segment of the primitive intestine leads to the reabsorption of that segment, with the consequent atresia. This mechanism occurs later in the foetal period and is therefore not necessarily associated with other malformations3.

This is a formation in the shape of a cone or the finger of a glove attached to the anti-mesenteric margin of the ileum (14.1A, B). It can present in a variety of anatomical forms from the complete persistence of the yolk stalk, with the discharge of intestinal fluid through the umbilicus, to the presence of a fibrous cord that can give rise to intestinal obstruction by trapping a loop of bowel. There is also an infrequent giant form of Meckel’s diverticulum, which usually gives rise to episodes of occlusion in the neonate (14.1C). Meckel’s diverticulum is found in 2% of autopsies, and is found in a 2:1 male/female ratio. It cause symptoms in only 4% of individuals; 50% have symptoms before 2 years of age and 80% before 10 years. Its histological structure is similar to that of the ileum. It can contain ectopic pancreatic tissue or gastric mucosa, explaining possible haemorrhage. Meckel’s diverticulum may present as haemorrhage (25–30%); it can invaginate and give rise to intestinal obstruction or as a diverticulitis with or without perforation. The most reliable diagnostic test is a 99mTc gamma scan (14.2). When the diverticulum contains ectopic gastric mucosa, this test shows an abnormal uptake in the centre of the abdomen. Treatment consists of resection of the diverticulum.

Table 14.1 Frequence of gastrointestinal malformations (number of cases/10,000 births)

• Meckel's diverticulum: 220 • Anorectal malformations: 3.01 • Oesophageal atresia: 2.23 • Hirschsprung's disease: 2 • Intestinal malrotation: 2 • Duodenal atresia: 1.2 • Jejuno-ileal atresia: 0.74 • Intestinal duplication: 0.6 • Colonic atresia: 0.5 • Annular pancreas: 0.18

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14.1 Meckel´s diverticulum. A: small; B: common shape; C: giant.

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14.2 Technetium isotopic scan showing an anomalous signal at the level of distal ileum (arrow).

14.3 Minimal distance between skin (marked by radioopaque reference) and air-filled rectal pouch is demonstrated in radiographic plain film.

Anorectal malformations Anorectal malformations are usually embryopathies, with associated abnormalities in 60% of cases: cardiovascular (tetralogy of Fallot); bone, particularly hemivertebrae; gastrointestinal: oesophageal atresia, duodenal atresia, Hirschsprung’s disease, or genitourinary: vesico-ureteric reflux. In 90% of cases there is an abnormal communication between the rectum and the urinary tract (in males) or the genital structures (in women). The description of the fistula gives an idea of the severity of the malformation: in males, rectoperineal, rectobulbar, rectoprostatic and rectovesical fistulae; in females, rectoperineal, rectovestibular, and rectovaginal fistulae and cloaca. All forms are considered severe with the exception of the rectoperineal forms, and require complex surgical treatment.

Diagnosis Diagnosis uses perineal examination and ultrasound. It is worth waiting 24 hours for the rectal pouch to fill, facilitating evaluation of the malformation. A flat perineum is a poor prognostic indicator as it suggests an absence of musculature. Ultrasound is used to measure the distance from the rectal pouch to the skin. When this measures more than 1 cm, it is considered a severe form (14.3).

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Treatment

Diagnosis

In the milder forms (perineal fistula or <1 cm distance on ultrasound) treatment consists of performing a direct opening of the rectal sac (cut-back). In other cases, a colostomy and, in a second phase, descent via a posterior sagittal approach (Peña’s posterior sagittal anorectoplasty).

• Prenatal ultrasound shows an absence of the gastric bubble in types I and II. • Difficulty passing a nasogastric tube (14.5, 14.6). • Plain X-ray: – Nasogastric tube. – Intestinal meteorism (III, IV, V) (14.5). – Absence of gas (types I and II) (14.6).

Oesophageal atresia Prognosis and treatment The abnormal separation of the tracheo-oesophageal bud gives rise to a large number of possible anatomical variations of this malformation, although the most frequent is type III (Table 14.2). Associated malformations are very common: bone 30%, heart defects 20%, urological 20%, digestive tract 20%, and VACTERL association: (Vertebral, Anal, Cardiac, Tracheal, oEsophageal, Renal, Limb). Patients usually present with salivation, respiratory distress, and abdominal distension (forms with a distal fistula: III, IV, V).

Survival varies from 97% in group I on the Spitz classification (weight >1500 g with no heart disease), to 47% in group II (weight <1500 g or heart disease) and 20% in group III (weight <1500 g and heart disease)2. Surgical treatment consists of a primary anastomosis when the separation between the ends allows this. Otherwise a gastrostomy and an oesophagostomy can be performed in order to replace the oesophagus later with stomach or colon. Recently, an external elongation of the two oesophageal ends has been performed in order to approximate them sufficiently to be able to perform an anastomosis4, 5.

Table 14.2 Different types of oesophageal atresia

• Type I: 8%.The two ends of the oesophagus are separated and do not communicate with the respiratory tract (no fistula) • Type II: 1%. Proximal tracheo-oesophageal fistula and blind inferior pouch • Type III: 86%. Distal tracheo-oesophageal fistula and blind superior pouch • Type IV: 1%. Proximal and distal tracheooesophageal fistulae • Type V: 1%. ‘H’ fistula. This is not a true atresia as the oesophagus is permeable (14.4) 14.4 Type V oesophageal atresia.

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14.5 Radiographic plain film in oesophageal atresia with tracheo-oesophageal fistula showing an air filled stomach and intestinal metheorism. Note the coiled feeding tube in the upper oesophageal pouch (arrow).

14.6 Radiographic plain film showing the absence of abdominal air and a feeding tube in the superior oesophageal pouch (arrows).

Hirschsprung’s disease In Hirschsprung’s disease (HD) the affected intestine presents a spastic contraction, as occurs in any denervated intestine. It is unable to dilate, giving rise to a functional obstruction (14.7). HD can affect more than one member of the same family. There is a genetic abnormality, the deletion of the long arm of chromosome 10, that is located close to the region of the RET proto-oncogene that has been found in some patients with HD6. There may be associated abnormalities including trisomy 21 and 18, anorectal atresia, von Recklinghausen’s disease, Waardenburg´s disease, or multiple endocrine neoplasia type 2.

Histopathology • • • – –

Absence of ganglion cells in the plexus. Hypertrophy of the nerve fibres. Neuronal and peptide markers: Increased acetylcholine and neuropeptide Y secretion. Decreased vasoactive intestinal peptide, substance P, and nitric oxide synthase.

Clinical presentation Functional obstruction, the intensity of which depends on the intestine affected. There are two clinical forms: neonatal, with the absence of emission of meconium in the first 24 hours and symptoms of low intestinal obstruction (abdominal distension and vomiting), and the form presenting in the older child, with severe constipation that does not resolve with the usual measures.

Complications Severe enterocolitis and sepsis, which may lead to intestinal perforation. This is a life-threatening situation that sometimes requires emergency colostomy.

Diagnosis Barium enema (14.8), anorectal manometry, demonstrating an absence of the rectoanal inhibitory reflex (14.9), and biopsy are the decisive tests.

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14.7 Hirschsprung`s disease in two patients. A: (1) Aganglionic obstructed segment corresponding to sigmoid. (2) Normal, ganglionic, descending colon. B: (1) Aganglionic rectal segment. Black arrow: place where full-thickness rectal biopsy was done. (2) Normal ganglionic sigmoid segment. White arrow: place of biopsy in the transition zone.

14.8 Barium enema in neonatal Hirschsprung’s disease. Narrow rectosigmoidium segment and dilated suprastenotic colon which presents inflammatory mucosal changes. Distention of intestinal loops.

Rectum Canal 4 Pressure mmHG escala: 10.0

Anal canal Canal 5 Pressure mmHG escala: 10.0

A Rectum Canal 4 Pressure mmHG escala: 10.0

Anal canal Canal 5 Pressure mmHG escala: 10.0

14.9 Recto-anal inhibitory reflex. A: Present; anal canal relaxation after a pressure increase in the rectum. B: Absent; no anal canal relaxation.

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Treatment The aims of the classical surgical techniques (Duhamel, Soave, Rehbein, Swenson) are to resect the aganglionic intestine, leaving 1–2 cm of the final part, necessary to guarantee continence. In recent years, new techniques and the introduction of minimally invasive surgery have led to a reduction in the age at which patients are operated on, which was classically between the 8th and 10th month. The recently described De la Torre Mondragón technique7 with or without laparoscopic assistance, is currently the most accepted technique in several paediatric surgical departments.

• Absence of the final 90° rotation: the right colon remains in the midline, fixed by peritoneal bands (Ladd’s bands) which compress and obstruct the duodenum. Treatment is by section of the bands and repositioning of the caecum in the right iliac fossa. • Internal hernias: abnormalities of the mesentery of the duodenum or right or left colon can create spaces into which the intestinal loops can prolapse as hernias. These are very variable situations which require individualized surgical approaches.

Diagnosis

Intestinal malrotation Alterations of the process of intestinal rotation and fixation during the process of re-entry of the primitive intestine into the abdominal cavity give rise to multiple types of malrotation. These are uncommon but very variable and sometimes complex abnormalities, though the clinical presentations can be summarized into three situations: • A complete absence of rotation (14.10). There is a risk of volvulus and intestinal necrosis if it is not treated in time (14.11). The symptoms include bilious vomiting and the treatment is by devolvulation and fixation in an uncomplicated position for the common mesentery, with the small intestine on the right side and the colon on the left.

A barium enema may be helpful showing the whole colon on the left (no rotation), or the caecum high close to the liver (lack of the last 90º twist). In cases of no rotation an ultrasound can show a reverse position of the mesenteric vessels with the vein situated on the left and the artery on the right.

14.11 Midgut volvulus. Intestinal necrosis, twisted mesenteric vessels (arrow). 14.10 Twisted duodenum not crossing the duodenal vessels.

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Duodenal atresia This is characterized by polyhydramnios; stomach and duodenum are dilated in the prenatal ultrasound (14.12), associated with trisomy 21 (25%) and other associated malformations present in 50% of cases (Type I). Type I is atresia in the form of a mucous membrane or diaphragm formed by the mucosa and submucosa. Externally, the only sign is a difference in diameter between the proximal and distal segments. A variation is an incomplete membrane, perforated in its centre, producing duodenal stenosis (14.13). Type II is two blind, atretic pouches connected by a fibrous cord and with an intact mesentery. Type III is two blind, disconnected, atretic pouches with a defect in the mesentery in the form of a ‘V’.

Diagnosis Patients present with bilious vomiting. Prenatal ultrasound shows a typical image of a ‘double bubble’, which is confirmed on plain X-ray and postnatal ultrasound (14.14).

14.12 Prenatal ultrasound. Stomach and duodenum are dilated.

Treatment Treatment is side-to-side anastomosis of the proximal part (proximal to the ampulla of Vater) and the distal part, distal to the ampulla. In Type 1, the operation may be limited to a simple resection of the membrane via a duodenotomy.

14.13 Duodenal dilatation caused by diaphragm. Minimal amount of contrast is delivered in the distal duodenum across a small perforation.

14.14 Radiographic plain film. Double bubble air sign in duodenal atresia. Oesophageal atresia and aspirative pneumonia in the posterior segment of the right upper lobe.

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Jejuno-ileal atresia It is a true atresia in 95% of cases. The remaining 5% are due to intestinal stenosis, i.e. a partial intraluminal occlusion. There is polyhydramnios on the prenatal ultrasound and dilated loops may be observed. Associated abnormalities are present in <10%. The Grosfeld classification2 divides this malformation into: • Type I: atresia in the form of a mucous membrane or septum with intact intestinal wall and mesentery (14.15A). • Type II: two blind, atretic pouches connected by a fibrous cord, with an intact mesentery (14.15B). • Type IIIa: two blind, disconnected, atretic pouches with a defect in the mesentery in the form of a ‘V’ (14.15C). • Type IIIb: also called ‘apple peel’. Very high jejunal atresia, close to the duodenojejunal flexure. It gives rise to a very short intestine with a large defect in the mesentery.

The intestine distal to the atresia receives a precarious, retrograde blood supply via the ileocolic, right colic, or inferior mesenteric arteries (14.15D). • Type IV: multiple atresias.

Diagnosis Diagnosis is on clinical presentation, with vomiting, which occurs earlier the higher the atresia. The plain abdominal Xray shows dilated loops, of which there are few if the atresia is in the proximal jejunum (14.16A) and many if it is ileal, more distal (14.16B). The barium enema shows a colon of small diameter due to a lack of use.

Treatment Treatment is resection of the grossly dilated loops and endto-end anastomosis.

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14.15 A: Type I ileal atresia. See the Foley catheter pulling on the membrane; B: Type II ileal atresia. C: IIIa ileal atresia. D: Type IIIb ileal atresia (apple peel).

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14.16 A: Proximal jejunum atresia; B: distal ileum atresia.

Gallbladder

Duodenum

Bladder Ileal duplication

14.17 MR T2 image shows evidence of a cystic right flank mass.

14.18 Surgical procedure revealed spherical ileal duplication.

Intestinal duplications Duplications are always situated on the mesenteric margin, can be spherical or tubular, of variable length, and can involve up to the whole length of the digestive tube (14.17, 14.18). Duplications have all the layers of the gut, including the mucosa, and often present heterotopic gastric mucosa8.

Approximately half of all duplications affected the small bowel (50%), followed in frequency by duplications of the oesophagus (20%), and of the colon. Duplications can give rise to intestinal obstruction or haemorrhage. Treatment is surgical.

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Atresia of the colon This is less frequent than the other intestinal atresias. It is associated with jejuno-ileal atresia and Hirschsprung’s disease. Prenatal ultrasound shows dilated loops of intestine. The symptoms are those of a low intestinal obstruction and the diagnosis is not difficult with plain abdominal X-rays, in which multiple dilated loops of intestines are observed. Treatment is primary anastomosis of the ends of the intestine, as long as there is no contraindication, such as perforation with peritonitis, in which case it is better to perform a colostomy with anastomosis at a later stage.

Annular pancreas The presence of pancreatic tissue around the duodenum in the form of a ring can give rise to duodenal obstruction similar to that of duodenal atresia, with which it is frequently associated. It is sometimes a casual finding. When symptoms arise, they are of a high obstruction. Surgical treatment is similar to that for duodenal atresia, with a side-to-side anastomosis between the proximal and distal segments.

6 Puri P, Shinkai T. Pathogenesis of Hirschsprung’s disease and its variants: recent progress. Semin Pediatr Surg 2004;13:6–24. 7 De la Torre-Mondragon L, Ortega-Salgado JA. Transanal endorectal pull-through for Hirschsprung’s disease. J Pediatr Surg 1998;33(8):1283–6. 8 Stern LE, Warner BD. Gastrointestinal duplications. J Pediatr Surg 2000;9:135–40.

Further reading Dasgupta R, Langer JC. Evaluation and management of persistent problems after surgery for Hirschsprung disease in a child. J Pediatr Gastroenterol Nutr 2008;46: 13–19. Keckler SJ, St Peter SD, Valusek PA, et al. VACTERL anomalies in patients with esophageal atresia: an updated delineation of the spectrum and review of the literature. Pediatr Surg Int 2007;23:309–13. Levitt AA, Peña A. Anorectal malformations. Orphanet J Rare Dis 2007;26:2–33.

References 1 EUROCAT Website Database: www.bio.medical.co.uk./eurocatline (data uploaded 17/11/2006). 2 Grosfeld JL. In: JA O’Neill Jr, MI Rowe, EW Fonkalsrud, AG Coran (eds). Pediatric Surgery, 5th edn. Mosby-Year Book, St. Louis, 1998. 3 Sadler TW. Langman´s Medical Embryology, 8th edn. Lippincot Williams & Wilkins, Philadelphia, 2003. 4 Diez-Pardo JA, Baoquan Q, Navarro C, Tovar JA. A new rodent experimental model of oesophageal atresia and tracheoesophageal fistula: preliminary report. J Pediatr Surg 1996;31:498–502. 5 Foker JE, Kendall TC, Catton K, Khan KM. A flexible approach to achieve a true primary repair for all infants with oesophageal atresia. Semin Pediatr Surg 2005;14(1):8–15.

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Chapter 15

Paediatric appendicitis Adolfo Bautista Casasnovas, MD

Introduction Acute appendicitis is a common paediatric surgical disease requiring urgent attention. Appendectomy is the most common surgical procedure performed for acute abdominal pain in children (15.1)1. The diagnosis of acute appendicitis in childhood can sometimes be difficult. The incidence of acute appendicitis has been estimated at about 1 case per 1,000 children per year, with slightly higher incidence among boys. The lifetime risk of appendicitis is estimated to be 8.67% for boys and 6.7% for girls. Incidence among preschool children is unusual, but in this age group delayed diagnosis and complications are more frequent. Around one-third of children with acute appendicitis are found to be perforated at surgery. Children who have appendicitis are twice as likely to have a positive family history as are those with right lower quadrant pain, but no appendicitis2. Early diagnosis continues to be the most important factor for prognosis. The rate of negative appendectomy is considered acceptable for up to 10% of laparotomies for suspected acute appendicitis. Paediatric surgeons performed significantly fewer negative appendectomies than general surgeons3. The development of the caecum and appendix begins in the caecal diverticulum on the anti-mesenteric side of the caudal end of the medial intestine, around the fifth week of gestation. The appendix does not elongate as rapidly as the rest of the colon. After rotation and descent, the base of the appendix is located at the posteromedial wall of the caecum about 2.5 cm below the ileocaecal valve, but this descent finishes after childhood. The variability of its descent and rotation leads to multiple possible final positions of the appendix4. The infant caecum is located in the right iliac fossa in about 55% of individuals (15.2). The blood supply

of the caecum and appendix is the appendiceal branch of the ileocolic artery, which passes behind the terminal ileum. The arterial supply is terminal, so that thrombosis leads to rapid necrosis (15.3). The malpositioned appendix may give rise to signs of inflammation in unusual locations, that make diagnosis difficult.

15.1 McBurney´s point is located two-thirds of the distance from the umbilicus to the anterior superior iliac spine.

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Ramus colicus

Ileocolic artery

Ileal 4% Retrocecal 65%

Ramus ilealis

Appendicularis artery

Pelvic 31%

15.2 Possible positions of the appendix and their relative frequency4.

15.3 Normal vascular supply of the appendix.

Pathophysiology Obstruction is a fundamental factor in the development of acute appendicitis. Obstruction increases intraluminal pressure leading to ischaemia, bacterial invasion, bacterial overgrowth, necrosis, and perforation. In the early phases, activation of receptors in the intestinal wall leads to perception of pain in the periumbilical region. In later phases, when the purulent secretion from the appendiceal wall contacts the parietal peritoneum, somatic pain fibres are triggered and the pain localizes near the appendiceal site, McBurney’s point. The characteristic organisms responsible of appendiceal inflammation are predominantly anaerobic, including Escherichia coli, Enterococcus, Bacterioides fragilis, Pseudomonas, Klebsiella, and Clostridium5. Many terms have been used to describe the pathologic stages of appendicitis, from the normal state to perforation. Only the clinically relevant distinctions of simple appendicitis (15.4) and complicated appendicitis should be made.

15.4 Typical appearance of simple appendicitis during surgery. It is possible to observe the caecum, appendix, and mesoappendix with congestion of the blood vessels and inflammatory exudates.

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Diagnosis The diagnosis of appendicitis should be based on a careful history and physical examination. The paediatric surgeon may expect to make the accurate diagnosis in 80–90% of cases. White blood count (WBC) and imaging rarely add significant information. Acute appendicitis typically occurs in older children. The incidence of appendicitis gradually increases from age 1 year onwards, peaking at around age 11–12 years. Although appendicitis is uncommon in infants, this age group has a high rate of complications because of delayed diagnosis. Difficulties of diagnosis may arise with patients younger than 2 years, and with preadolescent obese girls. In these two patient categories, analytical and imaging studies can provide additional information.

Clinical presentation The classic sequence (persistent abdominal pain, fever, and localized pain on palpation at McBurney’s point) starts with periumbilical pain, preceded by appetite loss in about 50–60% of children. The main symptom is abdominal pain, usually beginning as a vague periumbilical pain or mild gastrointestinal discomfort. After several hours, this pain gradually migrates to the right iliac fossa. Characteristically the pain is implacable and is exacerbated by movements and pressure, making ambulation painful and difficult. A child with acute appendicitis typically walks bent over and slowly. Anorexia is a helpful sign. Nausea and vomiting appear after the onset of pain. If vomiting precedes abdominal pain, other diagnoses should be considered. The last symptom in the clinical evolution is fever, which appears after pain and vomiting, and no more than 1ºC above normal. Fever higher than 39ºC is usually associated with complicated appendicitis (gangrenous and perforated). Symptoms may be influenced by the anatomical location of the appendix. Pain of a retrocaecal appendix may be in the flank or back. A pelvic appendix resting near the ureter or testicular vessels can cause urinary frequency, inguinal or testicular pain, or ureteral compression with hydronephrosis. Young patients aged 1–4 years, typically show vomiting and irritability, and draw up their legs to reduce pain. Other common manifestations include abdominal distension, diarrhoea, lethargy, and anorexia, together with fever. In 50% of cases an abdominal mass is detectable on palpation. The key point in this group of patients is vomiting.

Physical examination Palpation should always be first superficial and then deep. The palpation should start in an area without pain, and the patient’s face should be watched for signs of discomfort. In fact the important thing to look for during examination is any localized area of abdominal pain. Abdominal tenderness is the most constant physical finding. The point of maximal tenderness is localized at McBurney’s point. Associated with tenderness progressively are abdominal muscle spasms. Rebound tenderness or Blumberg’s sign (i.e. pain felt on sudden release of steady pressure in the right iliac fossa region) reflects irritation of the parietal peritoneum of the inflamed appendix, and associated fluid secretion. The routine use of rectal examination is controversial. Invariably this exploration causes discomfort to children, and pain during examination is not specific to appendicitis. It may be useful for detection of possible pelvic abscess or ovarian pathology.

Laboratory tests WBC is of limited diagnostic value. Typically leukocyte count is mildly elevated, 10,000–16,000/mm3, with increased polymorphonuclear leukocytes, neutrophils, and immature neutrophils. 20% of patients with acute appendicitis will have a normal WBC. Very high WBC suggests perforation or another diagnosis. Neutrophilia is more decisive for diagnosis than leukocytosis. In doubtful cases it is useful to monitor WBCs, as long as the patient is not receiving antibiotics. Urine sediment analyses are useful for detecting patients requiring fluid resuscitation and diseases of the urinary tract. The specific gravity and ketones are elevated. If the appendix is located adjacent to the ureter or the bladder, the red blood count and WBC in urine may be elevated.

Diagnostic imaging Imaging studies rarely add significant information in cases of classic appendicitis, and should be reserved for equivocal cases and when patient observation is indicated. Plain film, although it has a lower sensitivity and specificity, remains useful for detecting secondary problems associated with inflammation (Table 15.1) (15.5). The presence of faecalith is highly suggestive of acute appendicitis; however, faecalith is observed only in 10–15% cases of confirmed appendicitis (15.6). Ultrasonography has constituted a significant advance in the diagnosis of acute appendicitis, based on its rapidity, noninvasiveness, sensitivity (85–90%), and specificity

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Table 15.1 Abnormal signs usually found in plain film in acute appendicitis • Dilated caecum with air-fluid level • Appendiceal faecalith • Antalgic scoliosis of the right concavity • Dilated loops • Obliteration of the lower-right psoas margin

(92–96%). It is of particular value in adolescent and prepubertal girls. It should be the first approach in doubtful cases. Reports of centres with skilled radiologist often recommended ultrasonography for all children with suspected appendicitis (15.7, 15.8)6. Abdominal computed tomography (CT) with sensitivity and specificity of 98%, has become the most informative imaging technique in the study of patients with atypical manifestations (15.9)7.

• Obliteration of the preperitoneal fat line • Free peritoneal fluid • Free peritoneal air • Paucity of gas in the right-lower quadrant • Small bowel obstruction

15.5 Upright film showing multiple air–fluid levels in the small bowel and absence of gas in the colon, typical of bowel obstruction.

Differential diagnosis Appendicitis in childhood presents with uncommon features in 50% of cases, and may mimic many others diseases such as gastroenteritis, basal pneumonias, constipation, and urinary pathology (tract infections, hydronephrosis, lithiasis) (Table 15.2).

15.6 Simple radiography of the abdomen in a patient with acute appendicitis, showing appendicolith in the right iliac fossa (arrow).

15.7 Ultrasonography of a patient with acute appendicitis, showing distended noncompressible tubular structure (arrows) with faecalith (asterisk), increase in mural thickness, and inflamed periapendicular fat tissue. The most characteristic ultrasound criteria for appendicitis include the presence of noncompressible tubular structure corresponding to the inflamed appendix, with a size >6 mm in diameter, a complex mass in the right lower quadrant, faecalith, pericaecal inflammatory changes, or free peritoneal fluid.

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15.8 Ultrasonography, longitudinal and transverse view. The appendix is distended with increased wall thickness and faecalith inside.

15.9 Classic pelvic CT scan showing a distended appendix (arrow). The following findings are found in appendicitis: fluid-filled tubular structure measuring >6 mm in diameter, fat stranding, abscess or phlegmon in adjacent tissue, faecalith, and focal caecal apical thickening.

Table 15.2 Possible differential diagnoses of acute appendicitis

Urogenital tract

Small bowel diseases

• Pleuritis

• Hydronephrosis

• Gastroenteritis

• Primary peritonitis

• Urinary tract infections

• Mesenteric adenitis

• Henoch–Schönlein purpura

• Lithiasis

• Duodenal ulcer

• Viral exanthematous diseases

• Wilm’s tumour

• Meckel’s diverticulitis

• Sickle cell anaemia

• Premenstrual syndrome

• Inflammatory bowel disease

• Diabetic ketoacidosis

• Ovarian pathology

• Intussusception

• Pancreatitis

• Pelvis inflammatory disease

• Intestinal obstruction

• Omentum infarction

• Salpingitis

• Intestinal tuberculosis

• Parasitic infection

• Ectopic pregnancy

• Typhoid infection

• Abdominal migraine • Acute porphyria

Colon

Hepatobiliary

• Psoas abscess

• Appendiceal tumours

• Cholecystisis

• Burkitt´s lymphoma

• Appendiceal mucocoele

• Viral hepatitis

• Familial Mediterranean fever

• Constipation

• Cholangitis

• Haemolytic uraemic syndrome

• Crohn’s disease

• Kawasaki disease

• Intestinal obstruction

Miscellaneous

• Diverticulitis

• Cytomegalovirus

• Typhlitis

• Pneumonia

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Treatment The treatment of choice is surgical excision (appendectomy), and depends on both the general condition of the patient and the state of appendix. In many cases children are dehydrated, septic, or acidotic. Rapid administration of intravenous fluid and electrolytes (to restore acid–base balance) is essential for a successful outcome.

Antibiotics It is widely accepted that the use of antibiotics is clearly beneficial8. Antibiotics must be administered prior to skin incision. It is unnecessary to culture peritoneal fluid routinely in each case of acute appendicitis. Intraoperative cultures have not shown to alter the treatment outcome9. For many years the gold standard for complicated appendicitis was a 10-day course of ampicillin, gentamicin, and clindamicin or metronidazole; in recent years many surgeons have dropped ampicillin coverage. For simple appendicitis a single agent such as cefotetan, cefoxitin, ticarcillin/clavulanate, or piperacillin/tazobactan is typically prescribed. For complicated appendicitis a combination such as ceftriaxone/metronidazole or ticarcillin/clavulanate plus gentamicin are used10. Standard antibiotic therapy at the author’s institution is preoperative treatment with gentamicin (or tobramycin) plus metronidazole in all cases of acute appendicitis, with a low incidence (<4%) of postoperative infections and abscesses. In simple appendicitis, treatment is continued for 24–48 hours, and in complicated appendicitis for as long as 5–10 days. A prospective randomized study demonstrates equivalence between prolonged intravenous therapy and intravenous therapy followed by conversion to oral antibiotic therapy in children with perforated appendicitis11.

appendectomy if the patient improves within 24–72 hours. Interval appendectomy after nonoperative management is controversial. Indications for an open appendectomy (OA) or laparoscopic appendectomy (LA) are based on hospital personal and facilities, surgeon skills, and experience. Frequently, laparoscopic approach is avoided when bowel obstruction is present or an abdominal mass is palpable. In young and slim patients, open appendectomy through a small incision is easier and faster. Although the McBurney approach is still widely used, the author prefers a Rockey–Davis approach, transverse rightlower quadrant incision, placed above anterior superior iliac spine and lateral to rectus abdominus (15.10). When the peritoneum is exposed and incised, if free fluid is present it should be aspirated. Once the appendix is accessible the mesoappendix is taken down between clamps and divided (15.11). The appendix is released from its mesoappendix and vascular attachment and prepared for ligature (15.12). The base of the appendix is crushed with a clamp and ligated (15.13). In cases of peritonitis, if the caecum walls are thickened, congestive or friable, invagination of the appendiceal stump should be avoided. When a faecalith is present, it should be located and removed.

Appendectomy Appendectomy is not an emergency procedure, it should be treated as a semiemergency procedure. A recent study concluded that in children with acute appendicitis, delaying surgery until the daytime hours did not significantly affect operating time, perforation rate, or complications12. When the appendix is perforated, surgery is less urgent. If peritonitis is present most surgeons will proceed with appendectomy after preoperative fluid resuscitation and antibiotics have been started. Another group of surgeons will continue nonoperative management and avoid

15.10 Skin incisions: red: transverse Rockey–Davis approach; blue: oblique classic McBurney approach.

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LA is an alternative to conventional OA, but its advantages are still widely debated (Tables 15.3, 15.4). The author uses LA in obese children, and in those with suspected alternative diagnoses. LA is at least as effective as OA, with the advantage that the initial laparoscopy reduces the risk of incorrect diagnosis13. A review of 45 published trials of LA compared with OA show that LA reduced the rate of wound infections by one-half but increased the rate of intra-abdominal abscess four-fold. The most common

15.11 Complicated appendicitis: perforated appendix. Mesoappendix is exposed and prepared for division.

15.12 Perforated appendix released from its mesoappendix attachment.

15.13 The appendiceal stump is inverted and purse-string suture is tied.

Table 15.3 Advantages and disadvantages of laparoscopic appendicectomy

Advantages • Initial laparoscopy reduces the risk of incorrect diagnosis • Less traumatic • Reduction of postoperative pain and better postoperative comfort • Easy treatment of ectopic appendix • Efficient lavage of the peritoneum • Less frequent postoperative complications • Faster recovery and discharge from hospital • Lower surgical wound infection rates

Disadvantages • The operation takes longer • Higher cost • Requires paediatric surgeons with experience in this technique

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Table 15.4 Indications for laparoscopic appendectomy

• Acute appendicitis • Suspected appendicitis in patients with abdominal pain • Appendicular mass and/or peritonitis • Chronic abdominal pain • Suspected neoplasia • Incidental appendectomy during laparoscopy for other indications

technique is the three trocars technique, the sites of trocars vary depending the surgeon preferences, appendiceal position, and the presence of complications (15.14, 15.15). Independent of the type of appendectomy, the patients with simple appendicitis are usually ready to start oral fluids 8–24 hours after surgery. Intravenous fluid requirements are assessed regularly and discontinued as soon as possible. Patients can be discharged home within 48–72 hours. They may be checked after 1 week to ensure that they have no postoperative infective complications. In complicated appendicitis, antibiotic are continued depending on clinical progress. These patients may require nasogastric tubes and intravenous fluids for longer.

15.14 Possible trocar situations.

15.15 Typical appearance of appendix during laparoscopy.

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Complications The most frequent complication of acute appendicitis is infection. The risk is increased when the appendix is perforated. The overall complication rate is 10% and major complication rate of 4%. Wound infection rate should be below 4% in simple appendicitis and below 8% in complicated cases. It typically presents in the first week after surgery as localized pain, reddening, hypersensitivity, and tumefaction; spontaneous suppuration may also occur. It should be treated with antibiotics, opening the edge of the wound, or incision and drainage. Intra-abdominal abscess rate is less than 7%. The patient has persistence of pain and ileus, fever, and leukocytosis, Abscesses are usually located in the pelvis, sometimes in the subphrenic space or medial zone of the abdomen. A painful fluctuant mass can be palpated in rectal examination, if the abscess is located in Douglas’ pouch. The abscess can be treated conservatively, or drained percutaneosly under ultrasound or CT guidance or transrectally in the operating room. Exceptionally open drainage may be required (15.16). Prolonged intestinal paralysis (ileus) is directly related to peritoneal infection; the more severe the peritonitis, the

longer the period required for recovery of normal intestinal transit. Small bowel obstruction occurs in 2% of patients with complicated appendicitis, and if not responsive to medical treatment (nasogastric suction, intravenous fluids, and parenteral nutrition) may require surgery. Other unusual complications include postoperative intussusception, faecal fistulae (15.17), pylephlebitis. Some controversy exists about fertility after abdominal sepsis; different studies report than perforated appendicitis did not increase the risk of infertility14. Current mortality rates for complicated appendicitis is below 0.5%, and rather higher in children aged less than 2 years15. The incidence of postoperative complications have markedly decreased, perhaps due to the use of broadspectrum antibiotics, the progress in pre- and postoperative care, and improved anaesthesia techniques. The best results for children with appendicitis are obtained with the combination of surgical evaluation, rapid surgery when diagnosis is clear, a period of observation if diagnosis is unclear, radiology imaging if necessary, and care provided by experienced clinicians and institutions16.

B

A

15.16 Ultrasonography in a case of abdominal abscess. Situated behind the bladder. A: Abscess; B: bladder. 15.17 Faecal fistulae in a girl after complicated appendicitis with peritonitis.

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References 1 McBurney C. Experience with early operative interference in cases of diseases of the vermiform appendix. NY State J Med 1889;50:676–84. 2 Gauderer MW, Crane MM, Green JA, et al. Acute appendicitis in children: the importance of family history. J Pediatr Surg 2001;36:1214–17. 3 Somme S, To T, Langer JC. Effect of subspecialty training on outcome after pediatric appendectomy. J Pediatr Surg 2007;42:221–6. 4 Wakeley CP. The position of the vermiform appendix as ascertained by an analysis of 10,000 cases. J Anat 1933;67:277–83. 5 St Peter SD, Little DC, Calkins CM, et al. A simple and more cost-effective antibiotic regimen for perforated appendicitis. J Pediatr Surg 2006;41:1020–4. 6 Lander A. The role of imaging in children with suspected appendicitis: the UK perspective. Paediatr Radiol 2007;37:5–9. 7 Doria AS, Moineddin R, Kellenberger CJ, et al. US or CT for diagnosis of appendicitis in children and adults? A meta-analysis. Radiology 2006;241:83–94. 8 Andersen BR, Kallehave FL, Andersen HK. Antibiotics versus placebo for prevention of postoperative infection after appendicectomy. Cochrane Database Syst Rev 2005;20(3):CD001439. 9 Moawad MR, Dasmohapatra S, Justin T, et al. Value of intraoperative abdominal cavity culture in appendicectomy: a retrospective study. Int J Clin Pract 2006;60:1588–90. 10 Rodriguez JC, Buckner D, Schoenike S, et al. Comparison of two antibiotic regimens in the treatment of perforated appendicitis in paediatric patients. Int J Clin Pharmacol Ther 2000;38:492–9. 11 Rice HE, Brown RL, Gollin G, et al. Results of a pilot trial comparing prolonged intravenous antibiotics with sequential intravenous/oral antibiotics for children with perforated appendicitis. Arch Surg 2001;136:1391–5. 12 Yardeni D, Hirschl RB, Drongowski RA, et al. Delayed versus immediate surgery in acute appendicitis: do we need to operate during the night? J Pediatr Surg 2004;39:464–9. 13 Sauerland S, Lefering R, Neugebauer EA. Laparoscopic versus open surgery for suspected appendicitis. Cochrane Database Syst Rev 2004;18(4):CD001546.

14 Puri P, McGuinness EP, Guiney EJ. Fertility following perforated appendicitis in girls. J Pediatr Surg 1989;24(6):547–9. 15 Blomqvist PG, Andersson RE, Granath F, et al. Mortality after appendectomy in Sweden, 1987–1996. Ann Surg 2001;233:455–460. 16 Morrow SE, Newman KD. Current management of appendicitis. Semin Pediatr Surg 2007;16:34–40.

Further reading Bautista Casasnovas A. Acute appendicitis. In: Guandalini S (ed). Textbook of Pediatric Gastroenterology and Nutrition. Taylor & Francis, London, New York, 2004, Chapter 45, pp. 739–49. Dunn JC. Appendicitis. In: Grosfeld JL, O´Neill JA Jr, Coran AG, et al. Pediatric Surgery, 6th edn. Mosby Elsevier, Philadelphia, 2006, Chapter 98, pp. 1501–12. Ein SH. Appendicitis. In: Ashcraft KW, Murphy JP, Sharp RJ, et al. (eds). Pediatric Surgery, 3rd edn. WB Saunders Company, Philadelphia, 2000, Chapter 43, pp. 571–9. Lund DP, Folkman J. Appendicitis. In: Walker WA, Durie PR, Hamilton JR, et al. (eds). Pediatric Gastrointestinal Disease: Pathophysiology, Diagnosis and Management, 3rd edn. BC Decker, Hamilton, 2000, Chapter 48, pp. 821–9. Morrow SE, Newman KD. Appendicitis. In: Ashcraft KW, Holcomb GW, Murphy JP (eds). Pediatric Surgery, 4th edn. Elsevier Saunders, Philadelphia, 2005, Chapter 42, pp. 577–585. Stevenson RJ. Appendicitis. In: Ziegler M, Azizkhan R, Weber TR (eds). Operative Pediatric Surgery. McGrawHill Professional, New York, 2003, Chapter 60, pp. 671–89.

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Chapter 16

Paediatric clinical dietetics Amaya Peñalva Arigita, RD

Introduction Dietetics is defined as the application of the principles of nutrition to the selection of food and the feeding of individuals and groups1. Clinical dietetics covers the nutritional management of sick infants and children (either in an acute or chronic phase) to fulfill their requirements in a clinical and/or outpatient setting. This can be done in terms of adjusting the diet, adjusting menus, recommending certain foods, and/or using

commercial nutritional supplements. There are infants with certain diseases (metabolic, allergies) who need special enteral formulas to adapt the whole diet. Others may need supplementation, using nutritional modules that are added to a formula (Table 16.1). Many studies demonstrate the advantages of nutritional supplementation in different groups of patients, improving the evolution of the disease, and decreasing the incidence of

Table 16.1 Nutritional modules2

Nutrient

Module

Composition

Carbohydrates 1 g = 4 kcal

Polycose® Fantomalt® Maxijul® Dextrinomaltose Resource®

Glucose Glucose Glucose Glucose

Lipids 1 ml = 9 kcal

Resource MCT oil® Liquigen® Solagen® Supracal®

MCT MCT LCT LCT

Carbohydrates + lipids 1 g = 4.9 kcal

Duocal/Duocal MCT® Duocal liquid® (1 ml = 1.6 kcal) Energivit® PFD-1® (1 g = 5.3 kcal) PFD-2® (1 g = 4 kcal)

Glucose Glucose Glucose Glucose Glucose

Proteins 1 g = 4.0 kcal

Promod® Protifar®

Whole protein

polymers polymers polymers polymers

polymers polymers polymers polymers polymers

+ + + + +

LCT/MCT LCT/MCT LCT/MCT LCT/MCT LCT/MCT

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Table 16.2 Paediatric enteral formulae (for use in children older than 1 year)

Formula

Kcal/ml (per unit)

Proteins (g) (per unit)

Administration

Pediasure

1 (201)

5.6

Oral

Pediasure Fibre

1 (201)

5.6

Oral

Pediasure Plus

1.5 (300)

8.4

Oral

Isosource Junior

1.2 (305)

6.75

Oral

Isosource Junior Fibre

1.2 (300)

6.75

Oral

Resource CF

151/pack

4.9

Oral

Resource Protein

1.6/g (200/pot)

6 g per pot

Oral

Resource Junior

1.5 (300)

12

Oral

Fortini

1.5 (300)

6.8

Oral

Nutrini Energy

1.5 (300)

8.2

Enteral

Nutrini Energy Multi Fibre

1.5 (300)

8.2

Enteral

Novasource Junior Peptinex

1 (250)

7.5

Enteral/oral

complications3. Some children may require the use of paediatric supplements to increase their poor oral intake (Table 16.2). Other children may need a complete nutritional support via nasogastric tube (16.1), via gastrostomy (16.2), or by means of parenteral nutrition when the gastrointestinal tract is not functional. An adequate nutritional status allows a normal growth and

development. Growth can be compromised in the presence of a chronic disease especially when it coincides with peaks of growth (infancy, puberty). During growth, size increases and body composition changes. This implies certain nutritional requirements which are higher than those of the adult. Besides, the immaturity at birth involves special requirements in terms of

16.1 A nasogastric tube may be useful for supplementing the oral intake. This is a girl with failure to thrive. She has a tracheostomy due to a laryngomalacia. She takes by mouth what she can and the rest is given by the nasogastric tube.

16.2 A gastrostomy tube in a child with Menkes’ disease. As the disease progressed the child was unable to be fed normally and it became essential to find an alternative way: a gastrostomy tube placed by endoscopic procedure was the solution.

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Nutritional assessment

Clinical assessment

Anthropometry

Dietary assessment

Physical features Biochemistry Haematology

Weight/height Head circumference Mid-arm circumference Skin folds

24 hour recall 3–7 day record history (food diary) Frequency test

16.3 Algorithm of nutritional assessment. quality of nutrients, types of foods, and a limited response to overloading which can lead to complications. Therefore, there is a need to assess adequately nutritional status before starting any nutritional support.

Table 16.3 Physical signs of malnutrition4, 5 • Skin: dry, scale, paleness, bruising • Hair: thin, sparse, straight (‘lifeless’), change in colour

Nutritional assessment In the dietetic approach to a sick infant or child, it is essential to perform a correct nutritional assessment. There are a number of methods assessing specifics aspects of nutritional status, but no one measurement will give an overall picture of the status of all nutrients (16.3).

Clinical assessment This includes a complete medical history and physical examination (Table 16.3). It is important to watch out for the constitution of the child; especially differentiating those who are skinny by genetics from those who have lost muscle mass. The presence of malnutrition signs, such as abdominal distension, presence of oedema, and hepatomegaly, should be evaluated, along with mood and behaviour as children may be apathetic and irritable. Biochemistry and haematological tests are also useful (Table 16.4). Anthropometry is a physical examination which provides an indirect assessment of body composition and development. The child is growing continuously, and in each moment there is an ideal weight for a determined height. In acute malnutrition the weight may be altered maintaining the rate of height, although in a chronic state

• Lips/mouth: stomatitis, cheilosis, lingual atrophy, colour changes of tongue, problems with teeth, gums • Face: fullness of cheeks (oedematous malnutrition), thyroid enlargement • Eyes: xerosis, keratomalacia, pale conjuctiva • Nails: spoon shape, koilonychie

this rate also appears altered. This growth retardation is an important sign of malnutrition. Weight measurement is an easy and routine procedure (16.4). Children can be weighed in beam balance scales or electronic scales. Weight shows variability during the day, and it would be advisable to weigh always at the same time and with the same conditions7. Height measurement for infants and children less than 2 years old, is measured supine (16.5). From 2 years old, standing height is then measured whenever possible (16.6). Skinfolds provide information about the changes produced in the subcutaneous components of the fat and fat-free mass. There are seven sites of measure: triceps, abdomen, chest, thigh, suprailiac (iliac crest), mid-axillar, and subscapular. They are measured with a skinfold caliper. Mid-arm circumference is useful to determine the state of muscle mass, as this area is hardly affected by oedema. This measurement is used in conjunction with the skinfold

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Table 16.4 Laboratory tests (biochemical and haematological)6

Laboratory test help to define protein status, vitamin–mineral status and alterations of metabolism or organ function with nutrition implications Proteins: • Total plasma protein: serum level may detect liver function; availability of amino acids (protein intake); distribution of protein; rate of protein use by the body • Albumin: (half-life 20 days). It accounts for over 50% of total serum proteins. Low levels reflect prolonged protein depletion as it breaks down slowly. Albumin concentrations though may be depressed by many conditions besides malnutrition • Transferrin: (half-life 4–8 days). It reflects protein and iron (as it transports it) status. When an iron deficiency is present it is not a good indicator of protein status. A marked decrease means a severe malnutrition condition. It is not a good indicator of response to nutrition therapy as it responds slowly to changes in protein intake • Prealbumin: (half-life 2 days). It responds quickly to changes in protein intake and is a good indicator of nutritional therapy. There are other conditions which can lower prealbumin levels and others, such as kidney disease (treated with corticosteroids), which can elevate it • Retinol-binding protein: (half-life 12 hours). It responds quickly to changes in protein intake and is a good indicator of nutritional therapy • Serum enzymes: to monitor organ function • Urine test: to detect protein status (by urinary urea nitrogen and creatinine excretion) • Haemoglobin; haematocrit, mean corpuscular volume, mean corpuscular haemoglobin • Total lymphocyte count: when malnutrition is present there is a reduction in white blood cell count • Vitamins: water-soluble and fat-soluble • Minerals: calcium, chloride, magnesium, sodium, potassium, selenium, copper, and zinc (its deficiency retards growth and typically accompanies protein-energy malnutrition)

16.4 Infant scale (10 g precision). Ideally infants should be weighed naked or just with a clean nappy, but if this is not possible it is important to record the way the child has been measured.

16.5 Two people are needed to measure length precisely: one to hold the child in position and the other to record the measurement. Measurement of length is difficult and it requires carefully positioning of the infant, ensuring that the back, legs, and head are straight, the heels are against the footboard, the shoulders are touching the baseboard, and the crown of the head is touching the headboard.

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16.6 Standing height: the correct position is with bare feet, the back and the legs straight, the heels, buttocks, shoulder blades, and back of head touching the measurement board and the child looking straight ahead.

triceps to differentiate between lean and fat. All these anthropometric data need to be reflected in a percentiled growth chart. Many different growth charts have been published and it is important to use the correct version, adjusted to the population studied. The normal range lies between the third and 97th percentiles. Anything beyond these limits is at risk of an alteration, although marked decreases within the normal range are also a warning sign of possible nutritional problems. Weight and height are essential for estimating individual requirements. They can be estimated using the Schofield8 equations; either based on standard nomograms (RDA, WHO tables, etc.)9 or by indirect calorimetry. For protein requirements the standards are also set in this normogram, although excessive intake of protein should be checked. It has been suggested that excessive protein intake may jeopardize certain physiological functions in infants10. All the data are going to be useful to calculate the nutritional indexes that are available to determine nutritional status (Table 16.5).

Table 16.5 Nutritional indexes11 Waterloo index (weight): Weight (kg)

Waterloo index (height): x 100

Height (cm)

Weight at P50 for height

x 100

Height in P50 for age

Classification of caloric-protein malnutrition (CPM): For weight: Normal: >90% Mild CPM: 80–90% Moderate CPM: 70–79% Severe CPM: <70%

For height: Normal: >95% Mild CPM: 90–95% Moderate CPM: 85–89% Severe CPM: <85%

Z score Real anthropometric value (weight or height) – median P50 Standard deviation Classification: Risk of malnutrition: Z: –1.28 Acute malnutrition (wasting): Z <1.65 Normal range: Z ±1.28

Obesity: Z +1.65 Overnutrition: Z +1.28

Body mass index (BMI)* Weight (kg)/(height (m))2 *Using age-related centile charts (In children BMI is not related to health but only with distribution of body fat which is dependent on age)

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Dietary assessment A diet history provides a record of food intake which reflects eating habits, possible nutrient imbalances, and other factors which can affect food intake. This information will provide the background for developing discussion with the carers (usually parents) on realistic nutritional goals with a nutritional intervention (Table 16.6). This is time consuming and requires skill. There are different ways of obtaining the information depending on the need for accuracy. A 24-hour recall is the first-line approach as it is quick and easy to do by a skilled professional. The usual carers or the child are interviewed to recount what the patient normally eats in a usual day, using what has been eaten the day before. In infants, estimating food intake is particularly difficult in those taking solids as it is difficult to know how much food is lost in spitting, drooling and so on (Table 16.7). A food frequency test is used to obtain more precise information. It enables the assessor to double check the information obtained previously. A 3–7-day record history (food diary) provides an accurate account of food intake and eating behaviour. It is a good way of making the record keeper responsible for personal food choices and eating habits (in grown children).

Table 16.6 Aims of the dietary assessment

• Search for information • Analysis of the information • Dietetic diagnosis (estimating requirements, fulfillment of those requirements) • Prioritizing objectives • Dietetic intervention • Monitoring/assessment

Table 16.7 Food diary information

• Food frequency • Quality/quantity of food • Fluids/type and frequency • Feeding routine

Analysis of food intake data A skilled dietitian has to estimate quickly the amount of calories and protein intake. This can be confirmed manually by using food composition tables or using a computer dietetic analysis program. This information has its limitations as it is always an estimated approach. It can give an idea of the food ingested but not absorbed. Adequate nutrient intakes do no guarantee adequate nutrient status6. Once the calculations are made they are compared with the requirements calculated for the child. A dietetic diagnosis is made, followed by the appropriate intervention which includes the adjustment of the diet, followed by a close monitoring plan agreed and adjusted to the needs of the patient and family (Table 16.8).

Intervention Several diseases and/or the effects of treatment can result in decreased appetite, nausea, vomiting, eating difficulties, and malabsorption which can compromise the child’s nutritional state. Others such as inborn errors of metabolism

Table 16.8 Dietetic diagnosis and intervention

• Defining nutritional status • Intervention after checking nutritional requirements • Changes done in the register. Start a new register • Monitor in the outpatient clinic

(phenylketonuria, maple syrup disease) involve a thorough understanding of the deleterious effects of the precise error of metabolism. In these cases there are various approaches but often the cornerstone of treatment is diet. Substrate restriction by an individualized diet is necessary and in times of illness a careful calorie support adjustment is essential to avoid catabolism12. Furthermore, close dietary advice is necessary to address deficiencies which may develop from such a restricted diet. Other diseases may need only nutritional advice and guidance. Cases A–D are such examples.

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Case A: Fortification with nutritional modules of an infant diet Female, 3 months old, congenital heart disease Nutritional assessment Weight: 4.010 kg (
Food intake: The baby is fed by formula as breast-feeding was unsuccessful. The mother continues to offer breast-feeding, but the baby gets tired. The mother is encouraged to keep offering breast-feeding. 6x of 60 cc of infant milk 360 ml x 0.68 kcal/ml ≈ 245 kcal ≈ 61 kcal/kg/day

Analysis

Adjust the diet with a nutritional module (Duocal®) of carbohydrates and lipids: first at 3% to increase to 5%: Quantity Percentage 60 cc 3% 1.8 g *1.5 sc 5% 3g 2.5 sc

7:00 Day 1 50 ml Day 2 45 Day 3 45

10:00 40 ml 45 90

13:00 90 ml 70 65

90 cc 2.7 g ~2 sc 4.5 g ~4 sc

16:00 55 ml 75 50

120 cc 3.6 g 3 sc 6g 5 sc

19:00 90 ml 50 100

22:00 60 ml 80 80

*1 scoop (sc) = 1.2 g (each pot of different brands has its own measure) The mother is recalled for the following week and asked to register what the baby eats to evaluate progress. The mother reports that the baby is not accepting the amount prescribed, so she is encourage to add less (starting at 1% and to increase the amount until acceptance). 3:00 45 ml 55 55

Total intake 430 ml + ~4.42 g 420 ml + 3 g + 5.5 g 485 ml + 6 g + 11.4

Caloric intake (kcal) 292 + 17 = 309 286 + 11 + 21 = 318 330 + 23 + 43 = 396

Guide to colour: • Black: nothing added • Red: starts to add only 1 scoop in 90 cc (1.3%) of the nutritional module • Green: start adding 2 scoops (3%) • Blue: starts adding 3 scoops (4%) The baby is still not getting the calorie amount she needs so add some MCT oil first at 1% to be raised at 2–3% (1 ml = 8.9 kcal). This makes up to a total intake of 129 kcal/kg/d, meeting her requirements.

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Case B: Supplementation with common foods Male, 4 years old, medulloblastoma Chemotherapy has been initiated, with several visits to hospital. The boy has mild anorexia and presents with weight loss. Nutritional assessment • Weight: 15 kg (P25); Usual weight (4 months before): 17 kg (P50) • Height: 100 cm (P25) • Requirements*: *Schofield: (4 years) – Energy: 1500–1700 kcal; 130–150 Kcal/kg/day 0.082 x w (11.3 kg) + 0.545 h (0.95) + 1.730 = – Protein: minimum 30 g/day 0.9266 + 0.518 +1.730 = 3.1746 Z (weight): –1.03; Z (height): 0.65 min x 239 kcal = 758.72 kcal WI (w): 94%; WI (h): 98% x 1.5 (activity) = 1138 kcal BMI: 15 (
Food intake: The patient shows a decreased appetite, although still maintains some intake. Diet – register: 24 recall: Breakfast: Glass of milk (200 ml) Small muffin (30 g) Mid-morning snack: Nothing Dinner: Chicken soup (200 cc) + 20 g of pasta Steak (60 g) 1 fromage frais (60 g) Mid-afternoon snack: Nothing Supper: Creamed courgette (150 g) Fish in batter (50 g) 1 pear

Possible diet adaptations Breakfast: A glass of milk (150 ml) + cocoa powder (15 g) A small muffin (30 g) + marmalade (15 g)

Analysis of food intake: Energy intake: 750 kcal Protein intake: 34 g

18% 39% 43%

Carbohydrates Lipids Proteins

Analysis of food intake: Energy intake: 1485 kcal Protein intake: 56 g 15% 42% 43%

Carbohydrates Lipids Proteins

Mid-morning snack: Peanuts (25 g) Dinner: Chicken soup (200 cc) + 20 g of pasta + 30 g egg Steak (60 g) + breadcrumbs (15 g) + oil (5 cc) 1 fromage frais (60 g) + milk powder (5 g) Mid-afternoon snack: Milkshake (banana 50 g + ice-cream 60 g + hazelnuts10 g) Supper: Creamed courgette (150 g) + parmesan cheese (10 g) Fish in batter (50 g) 1 pear + condensated milk (20 g)

The boy will attend the outpatient clinic to be continuously assessed, as well as during hospitalization. Future possible adaptations may require the use of oral commercial supplements.

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Case C. Enteral and parenteral feeding supplementation Male, 2 years old. Short bowel after an intestinal resection at 2 months due to small intestinal volvulus. The boy leaves hospital with home parenteral nutrition (HPN) 7 days/week and with an elemental milk formula orally. The intake is very low and he gradually starts refusing any food by mouth at all. Then a gastrostomy is set to meet requirements enterally and to stimulate bile secretion.

Estudio Longitudinal de Crecimiento, Curvas de 0 a 18 años Instituto de Investigación sobre Crecimiento y Desarrollo FUNDACIÓN ORBEGOZO. (Bilbao-España)

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• Plotting on the growth charts is essential for performing the nutritional assessment. • Requirements are calculated by age, according to his weight. • Close monitoring is desirable (monthly until 1 year and then every 3 months)

7 months: (PN in 16 h) w = 6.1 kg; h = 63.5 cm Energy Protein Lipids Carb 90 kcal/kg/d 3 g/kg/d 1.4 g/kg/d 16 g/kg/d 540 kcal 18 g/d 8.4 g/d 96 g/d

12 months: (PN in 14 h) w = 8 kg; h = Energy Protein Lipids 90 kcal/kg/d 3 g/kg/d 1.4 g/kg/d 720 kcal 24 g/d 11.2 g/d

Oral diet: (609 kcal/16.4 g protein/19.7 g lipid/63.5 g carb) 6 btl. elemental milk formula (15%) + gluten free cereals (5%) 60 cc cereal purée 100 cc potato + carrot + 30 g chicken purée

Oral diet: (201 kcal/8.4 g protein/16.5 g lipid/32.17 g carb) 1 btl. elemental milk formula (15%) + gluten-free cereals (5%) 60 cc cereal purée 100 cc potato + carrot + 40 g chicken purée

Total intake: 1149 kcal = 188 kcal/kg/d

Total intake: 921 kcal = 115 kcal/kg/d

34 28 160

Proteins (g) Lipids (g) Carbohydrates (g)

71 cm Carb 16 g/kg/d 128 g/d

32 28 160

Proteins (g) Lipids (g) Carbohydrates (g)

The gastrostomy is set at 16 months as the child following rehabilitation continues to refuse food. It is then complementary to HPN. Furthermore keep trying with introduction of new oral food to test tolerance until he is able to decrease and at last (if possible) leave parenteral nutrition. (18 months) w = 10.3 kg; h = 71 cm PN- 7 days/week (12 h) Energy: 60 kcal/kg/d; 618 kcal Protein: 2.5g/d; 26 g Lipids: 1.5 g/kg/d; 15.45 g Carbohydrates: 21 g/kg/d; 216 g Total intake: 1140 kcal = 110 kcal/kg/d Gastrostomy: 44.5 250 cc cereal purée (with elemental milk formula 15% + cereal 12%) 30.45 Proteins (g) 250 cc savoury mashed purées (50 g protein portion) Lipids (g) 294 Energy: 523 kcal; Protein: 18.5 g/d; Lipids: 15 g; Carbohydrates: 78 g Carbohydrates (g)

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Case D: Nutritional education Male, 7 years old, encopresis. After resolving he is discharged to the outpatient clinic. Weight: 20 kg; Height: 1.17 cm; Middle arm circumference (MAC) 16.4; Tricipital skinfold (TS): 6 • Requirements (for age by WHO): 1800–2000 kcal and 24 g of protein The diet is modified during hospitalization so the child gets a personalized high fibre diet. Before discharge the child is assessed, treated, and advised on the correct diet. The mother is concerned about the child’s diet as since her divorce he is more reluctant to eat certain types of foods. She is given advice on the diet with recipes and tricks* to increase the consumption of vegetables and is referred to the outpatient clinic. After a month, at the outpatient clinic the child has normalized his bowel movements and the mother reports that the tricks have worked. The diet is explained to the child to make him participate.

*Tricks given to the mother • Adding fruit to the cereals at breakfast or to yoghourt. This can be in pieces (e.g. grapes), grated (e.g. apple) or cooked (e.g. homemade marmalade or stewed fruit). • Making fruit salads, encouraging the fruit which is liked. • Adding grated vegetables to sauces (e.g. leek, onion, and courgette to a tomato sauce for pasta). • Cooking meat, fish, or pulses stews with vegetables. If not tolerated purée in the sauce. • Including vegetables in the making of croquettes, meatballs, quiches, etc. • Adding lettuce and/or tomato to sandwiches. • Use high fibre carbohydrates (cereals, bread, pasta). In case they are not liked mix them. • Make homemade ice-creams with natural fruit juices. Always following the dietetic recommendations on healthy diet.

Occasionally

Several times daily

+ Water Healthy life-style

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Courtesy Estrategia NAOS. Ministerio de Sanidad y Consumo. Gobierno de España, 2006

Several times a week

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Conclusion The dietitian is part of a multidisciplinary team who takes care of the patient, and their role is not simply dispensing a particularly diet but to provide effective nutritional care, from advice to food provision. Many dietetic skills are unique and cannot be undertaken by other professionals. An effective nutritional support service relies heavily on dietetic expertise to optimize patient care. However, standards of practice vary significantly throughout Europe13. There are many examples where the use of dietetics in the clinical setting is essential.

11 Martinez Costa C, Sierra C, Pedrón Giner C, et al. Nutrición enteral y parenteral en pediatría. An Esp Pediatr 2000;52(Supl.3):1–33. 12 Wilken B. An introduction to nutritional treatment in inborn errors of metabolism: different disorders, different approaches. South Asia J Trop Med Pub Health 2003;34(3S):198–201. 13 Howard, JP, Jonkers-Schuietema CF, Kyle U. The role of the nutritional support dietitian in Europe. Clinical Nutrition1999;18(6):379–83.

References

Further reading

1 Martin EA (ed). Concise Medical Dictionary, 2nd edn. Oxford University Press, Oxford 1998. 2 Moreno JM, Oliveros L, Galiano MJ. Cómo enriquecer la alimentación del lactante: Uso de los módulos nutricionales. Act Pediatr Esp 2003;61(8):406–12. 3 Stratton RJ, Green CJ, Elia M. Disease-Related Malnutrition: An Evidence-Based Approach to Treatment. CABI Publishing, Oxford, 2003. 4 Golden MHN, Golden BE. Severe malnutrition. In: Garrow JS, James WPT, Ralph A (eds). Human Nutrition and Dietetics, 10th edn. Churchill Livinsgstone, Edinburgh, 2000, pp. 515–26. 5 Shaw V, Lawson M. Clinical Paediatric Dietetics, 2nd edn. Blackwell Science, Oxford, 2001. 6 Whitney EN, Cataldo CB, Rolfes SR. The nutrition care process: assessing anthropometric and biochemical data. In: Understanding Normal and Clinical Nutrition, 5th edn. Wadsworth Publishing Company, Belmont, 1998, pp. 543–58. 7 Ballabriga A, Carrascosa A. Nutrición en la Infancia y Adolescencia, 3rd edn. Nestle Nutrition Institute, Spain, 2006. 8 Schofield WN. Predicting basal metabolic rate, new standards and review of previous work. Hum Clin Nutr 1985;39C(Suppl):5–41. 9 Dewey KG, Beaton G, Fjeld C, et al. Protein requirements of infants and children. Eur J Clin Nutr 1996;50(1):119–47. 10 www.fao.org

ASPEN Board of directors. Standards for specialized nutrition support: hospitalized pediatric patients. Nutr Clin Pract 2005;20(1):103–16. Dwyer J. Dietary fibre for children: how much? Pediatrics 1995;96:1019–22. Gil Hernandez A. Bases para una alimentación complementaria adecuada de los lactantes y los niños de corta edad. An Pediatr (Barc) 2006;65(5):481–95.

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Index Note: Page numbers in italic refer to content of tables abdominal migraine 50, 52, 52 abscess, intra-abdominal 142 acanthosis nigricans 95, 96 adrenocortical carcinoma 82 Alagille syndrome 86–8, 88 alanine aminotransferase (ALT) 92, 92, 96 albumin 147 allergologic tests 67–8, 67 alpha-1-antitrypsin deficiency 90–1, 94–5 alpha fetoprotein (AFP) 73, 80, 82 aminosalicylate 115 aminotransferases 92, 92, 96 anaemia, iron deficiency 113–14 anorectal malformations 125–6 anorectal manometry 38–40 anthropometry 146 antigen-presenting cells 65 anti-neutrophil cytoplasmic antibody with perinuclear staining pattern (pANCA) 106 antireflux surgery 14, 14 anti-Saccharomyces cereviseae antibody (ASCA) 106, 114 appendectomy 134, 139–41 appendicitis, acute 134–8, 138 Apt-Downey test 59 Ascaris lumbricoides worms 54 ascites 90, 91 aspartate aminotransferase (AST) 92, 92, 96 bacteria, causing acute diarrhoea 20 bacterial overgrowth syndrome 31 barium enema 40, 41 Barrett’s oesophagus 12 behavioural modification 44 bezoars 54, 75 biliary atresia 90, 91 bladder tumours 79 bleeding, see gastrointestinal bleeding blood transfusion 63–4 blood urea nitrogen (BUN) 58 B-lymphoma 76, 77 body composition, assessment 146 body mass index (BMI) 148

bowel lengthening, procedures 121–2 bowel obstruction 12, 142 breast feeding 68 budesonide 109, 115 caloric intake 4, 8 capsule endoscopy 28–30, 115 carbohydrate intolerance 26 carbohydrate malabsorption 32 casein proteins 66 central venous catheters 119 challenge tests 32 choledocal cysts 72 cholestasis 84, 118, 119 benign recurrent intrahepatic 89 biliary atresia 90, 91 childhood 86 infancy 84–6, 85 parenteral nutrition 118, 119 progressive familial intrahepatic 88, 89 cirrhosis 97 coeliac disease 99 clinical features 7, 51, 100, 101, 101 diagnosis 102, 103 epidemiology and genetics 99 latent 100 pathology 29, 53, 54, 99–100 treatment 102 colectomy 109 colic, infant 54, 55 colitis infectious 62 see also ulcerative colitis colon biopsy 42 congenital atresia 133 tumours 76, 77 colonic transit study 41–2, 43 compartment syndrome, abdominal 81, 82 constipation definition and aetiology 34 diagnosis 38–42 differential diagnosis 34 functional 34–5, 36, 37 management 42–5, 153 cow’s milk allergy 31–2, 65–6 diagnosis 67–8, 68 management/prognosis 68–71 Crohn’s disease 110 aetiology 110–11 diagnosis 29, 52, 54, 63, 111–15 management 115 cystic fibrosis 38

defecation, normal mechanisms 35 dehydration, assessment 21 dermatitis, atopic 66 desensitization 71 diarrhoea acute 19–24, 111 chronic 25–30, 26, 62 intractable of infancy (IDI) 30–1 toddler’s 30 diet after acute diarrhoea 23 assessment 149 in failure to thrive 8–9 in functional constipation 44 gluten free 102–3 parental guidance 9, 9 dietetics defined 144 interventions 149–53 domperidone 14 Down syndrome 5 drugs antidiarrhoeal 23–4 causing gastritis 62 hepatotoxic 93 duodenal atresia 130 duplications, intestinal 132 dyschezia, infant 36, 36 dysgerminoma 80 dyspepsia, functional 48–9, 50 Echinococcus granulosus 72 emesis, coffee-ground 16, 56, 58, 59 encopresis 35, 153 enteral formulae 144–5, 145 enteral nutrition 9, 117, 120, 152 enterocolitis, necrotizing 59 enteroplasty 121 epistaxis 57 Epstein-Barr virus 76 faecal calprotectin 106, 113 faecal disimpaction 44 faecal laboratory study 22 faecal occult blood test 38 failure to thrive (FTT) aetiology 3–5 classification by pathological cause 4 definition 1, 2–3 evaluation of child 3, 5–7 management 5, 8–9 outcomes 9 Fallot tetralogy 87

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familial polycystic kidneys 76–8 feeding behaviours 9, 9 fistulae, perianal 111 food allergy/intolerance 51 classification 65–6 clinical symptoms 66–7 diagnosis 32, 67–8, 67, 68 management 68–71 transient 31–2 food diary 149, 149 food intake data, analysis 149 foods, causing stool/emesis staining 57 formulas cow’s milk allergy 69–70, 69 enteral 144–5, 145 fresh-frozen plasma 64 functional gastrointestinal disorders (FGID) 48–54 fundoplication, Nissen 14, 14 galactosaemia 91 gallbladder, porcelain 54 gallstones 52 gamma glutamyl transpeptidase 92, 92, 96 ganglioneuroma, benign 81 gastric emptying scintigraphy 49 gastric hyperacidity 120 gastric lavage 58 gastric masses/tumours 75–6 gastric mucosa, prolapse 59 gastritis, drug-induced 62 gastroenteritis management 25 viral 19–20 gastrointestinal bleeding aetiologies 58, 59–63 assessment 56–7 diagnosis 57–8, 57 epidemiology 56 treatment 63–4 gastro-oesophageal reflux 12, 13, 14, 48, 49 gastrostomy 120, 145 giardiasis 26, 51 Gilbert syndrome 86 growth, nutritional requirements 145–6 growth curves 2, 3, 148 failure to thrive 1 normal variation 4, 4 specific syndromes 5 haemangioma, liver 72–3 haematemesis 56, 57 haematochezia 56, 66

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haematocrit (Hct) 57, 58 haematuria 78 haemochromatosis, neonatal 91 haemolytic uremic syndrome 61 haemostasis, endoscopic 64 hamartomas, liver 73 heart disease, congenital 97 height, measurement 148 Helicobacter pylori gastritis 62 Henoch-Schönlein purpura 62 hepatitis 93, 94, 97 hepatobiliary dysfunction 26 hepatoblastoma 73 hepatocarcinoma 74–5 hiatal hernia 15 Hirschsprung’s disease 37, 127–9 clinical presentation 37, 127 diagnosis 38, 39, 41, 42, 127–8 treatment 129 hydatic cysts 72 hydrocortisone 109 hydronephrosis 78 hygiene, prevention of diarrhoea 24 ‘hygiene hypothesis’ 110 hypertransaminasaemia 92–7, 92, 97 hypoalbuminaemia 114 ileostomy, terminal 118 ileum, tumours 76, 77 immune responses, non-IgE 65, 66 immunomodulation therapy 109, 115 infant colic 54, 55 infantile hypertrophic pyloric stenosis 16, 17 infant scale 147 infections acute appendicitis 135 causing diarrhoea 19-20, 20, 26, 62 colitis 63, 106 inflammatory bowel disease (IBD) diagnosis 27 see also Crohn’s disease; ulcerative colitis infliximab 109 intelligence quotient (IQ) 9 interferon 73 intestinal duplications 132 intestinal length, normal newborn 117 intestinal malrotation 129 intestinal obstruction 12, 142 intractable diarrhoea of infancy (IDI) 30–1 intussusception 60 irritable bowel syndrome (IBS) 30, 50, 50 isotope-tagged meta-iodinebenzyl-guanidine (MIBG) 81 isotopic scintigraphy 78

jaundice infancy 84–6, 85 see also cholestasis jejunal mucosa, flattened 99, 100 jejuno-colic anastomosis 121 jejuno-ileal atresia 131–2 jejunostomy 118, 120 jejunum, tumours 76 juvenile polyps 61 kidney cystic 76–8 tumours 78–9 Kimura procedure 121 lactate dehydrogease (LDH) 93 β-lactoglobulin 66 lactose intolerance 51 laxatives 43, 44, 45 length, measurement 146, 147 liver, tumours and cysts 72–5, 81, 82 liver disease acute 93 chronic 57, 93 nonalcoholic fatty disease 95–6 in parenteral nutrition 118, 119 liver transplantation 74, 75, 97 lymphangioma, cystic 76 lymphoma, intra-abdominal 76, 77 McBurney’s point 134, 135 magnesium hydroxide 45 malnutrition classification 6 clinical signs 7, 146, 146 Meckel’s diverticulum 61–2, 124, 125 melena 56, 57 Menkes’ disease 145 micronutrients 23 mid arm circumference 146 milk, human 66 see also cow’s milk allergy nasogastric tube 9, 145 necrotizing enterocolitis 117 nephroblastoma (Wilms’ tumour) 78–9 nephroma, mesoblastic 79 neuroblastoma-ganglioneuroma 81–2 nodular lymphoid hyperplasia 59 nonalcoholic steatohepatitis (NASH) 95, 96 nutrition assessment 146, 149 and growth 145–6 supplementation with common foods 151 see also diet; feeding nutritional education 153

nutritional modules 144, 144, 150 octreotide 64 oesophageal atresia 59, 126–7 oesophageal varices 60 oesophagitis 13, 59, 60 oral rehydration solution (ORS) 22–3, 23, 25 ovarian cyst 54 ovarian tumours 79–80 pain, abdominal 12, 46, 53, 53 alarm symptoms 47 functional syndrome 53, 53 neurophysiology 46–7 pancreas, annular 133 pancreatic cysts 76 pancreatic insufficiency 26 pancreatitis, recurrent 52 pancreatoblastoma 76 parasites, intestinal 20 parenteral nutrition 118–19, 152 peptic ulcer disease 62–3 phaeochromocytoma 82 pH probe 13 platelet transfusion 64 polyethylene glycol 44 polyps, juvenile (colonic) 61 postenteritis syndrome 31 prealbumin 147 probiotics 23 proctitis 105, 108 prokinetic agents 14 prolapse gastropathy 59 proteins 65 allergic reactions 31–2, 65–6 modification 68–9 pseudopolyps 108 pulmonary artery hypoplasia 86, 87 pyloric stenosis 16, 17 pyloromyotomy 16, 17 pyoderma gangrenosum 111, 112 Ramstedt procedure 16, 17 rectal biopsy 41 rectal bleeding 59 rectal examination, digital 38 recto-anal inhibitory reflex (RAIR) 40, 128 regurgitation causes and incidence 11, 12 see also gastro-oesophageal reflux rehydration 22–3, 23 retinol-binding protein 147 rhabdomyosarcoma 79 rotavirus infections 19–20 Sandifer’s syndrome 12 schwannoma (neurofibrosarcoma) 79 serial transverse enteroplasty (STEP) procedure 121–2

short bowel syndrome (SBS) 117 causes 117 initial management 118–20 surgical treatment 121–3 Silver-Russell syndrome 5 skinfolds 146 skin tags, perianal 111 small bowel resection 115 adaptation process 117–18 small bowel stenosis 111, 113 small bowel transplantation 122 small villous atrophy 29 soy formulas 69 soy protein 32 steatosis 95, 96, 118, 119 stool frequency 37 stool testing 113 stricturoplasty 121 superior mesenteric artery syndrome 17, 18 teratoma 80, 82 total plasma protein 147 transferrin 147 transit time assessment 41–2, 43 techniques to slow 121 trichobezoar 54, 75 tyrosinaemia, hereditary 91 ulcerative colitis 62–3, 104–9, 105 undernutrition, see failure to thrive; malnutrition uretero-pyelic junction, stenosis 78 urticaria-angioedema 66 VACTERL association 126 varices, gastric/oesophageal 60 viral infections acute diarrhoea 19–20, 20 liver disease 92 vomiting 11, 11, 12, 14, 17 weight measurement 146, 147 normal gain 1–2, 2 Wilms’ tumour 78, 79 Wilson’s disease 92–3 wireless endoscopic capsule 28–30 Yersinia species 63 yolk sac (endodermal sinus) tumour 82 Zellweger’s syndrome 91 zinc 23