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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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

90

80–90

70–79

70%

Height for age (%)

>95

95–90

89–85

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, 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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Vomiting

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 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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Diarrhoea

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

No dehydration

Mild to moderate

Severe

Risk factors? Infants 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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Abdominal pain in childhood

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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Abdominal pain in childhood

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 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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Cow’s milk allergy

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.

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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.

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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.

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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 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 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