An Atlas of Investigation and Management PAEDIATRIC ...fundacioncarlosvazquez.com › frontend ›...

An Atlas of Investigation and Management

PAEDIATRIC GASTROENTEROLOGY

CLINICAL PUBLISHINGOXFORD

An Atlas of Investigation and Management

PAEDIATRICGASTROENTEROLOGY

José Manuel Moreno Villares, MD

Nutrition UnitDepartment of Paediatrics

Hospital Universitario 12 de OctubreMadrid, Spain

Isabel Polanco, MD, PhD

Professor of PaediatricsHead of Department of Paediatric Gastroenterology and Nutrition

Hospital Infantil Univeritario La PazFacultad de Medicina, Universidad Autónoma

Madrid, Spain

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


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


© 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

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.

Preface vi

Contributors vi

Abbreviations viii

1 Failure to thrive in infants and children 1JOSÉ MANUEL MORENO VILLARES, MD, AND

ANTONIO MONICA GUERRA, MD

2 Vomiting 11JOSÉ MANUEL MORENO VILLARES, MD, AND

MARÍA JOSÉ GALIANO SEGOVIA, MD

3 Diarrhoea 19Acute diarrhoea 19ENRIQUETA ROMÁN RIECHMANN, MD

Chronic diarrhoea 25ANGELES CALZADO AGRASOT, MD, BEGOÑA POLO MIQUEL, MD, AND

CARMEN RIBES-KONINCKX, MD, PHD

4 Constipation 34CAROLINA GUTIÉRREZ, MD, AND

JERÓNIMO GONZÁLVEZ, MD

5 Abdominal pain in childhood 46IÑAKI X. IRASTORZA TERRADILLOS, MD, AND

JUAN C. VITORIA CORMENZANA, MD, PHD

6 Gastrointestinal bleeding 56GEORGE GERSHMAN, MD, PHD

7 Cow’s milk allergy 65ANTONIO NIETO, MD, PHD, AND

ANGEL MAZÓN, MD

Contents

8 Abdominal masses 72JUAN A. TOVAR, MD, PhD

9 Liver disease 84Cholestasis 84PIOTR SOCHA, MD, JOANNA PAWŁOWSKA, MD, AND

ANIL DHAWAN, MD, FRCPCH

Hypertransaminasaemia in childhood 92LUÍS PEÑA-QUINTANA, MD, AND

DANIEL GONZÁLEZ-SANTANA, MD

10 Coeliac disease 99ISABEL POLANCO, MD, PHD

11 Ulcerative colitis 104CARLOS SIERRA SALINAS, MD, AND

JAVIER BLASCO ALONSO, MD

12 Crohn’s disease 110DAVID ZIRING, MD, AND

JORGE VARGAS, MD

13 Short bowel syndrome 117JAVIER BUENO, MD

14 Congenital gastrointestinal malformations 124

IÑAKI EIZAGUIRRE, MD, AND

AGUSTÍN NOGUÉS, MD

15 Paediatric appendicitis 134ADOLFO BAUTISTA CASASNOVAS, MD

16 Paediatric clinical dietetics 144AMAYA PEÑALVA ARIGITA, RD

Index 155

Contributors

Adolfo Bautista Casasnovas, MD, PhDHead of Paediatric Surgery SectionUniversity Hospital of Santiago de

CompostelaSantiago de Compostela, Spain

Javier Blasco Alonso , MDGastroenterology, Hepatology and

Nutrition DivisionHospital Materno-InfantilMálaga, Spain.

Javier Bueno , MDPaediatric Liver Transplantation UnitPaediatric Surgery DepartmentHospital Valle de HebrónBarcelona, Spain

Mª Ángeles Calzado Agrasot, MDPaediatric Gastroenterology and

Hepatology Unit Hospital La FeValencia, Spain

Anil Dhawan, MD, FRCPCHPaediatric Liver CentreInstitute of Liver StudiesVariety Club Children’s HospitalKing’s College HospitalLondon, UK

Iñaki Eizaguirre, MD, PhD Paediatric Surgery DepartmentDonostia HospitalSan Sebastian, Spain

María José Galiano Segovia, MDCentro de Salud Maria MontessoriLeganésMadrid, Spain

George Gershman, MD, PhDAssociate Professor of Pediatrics David Geffen School of MedicineChief, Division of Pediatric

Gastroenterology and NutritionHarbor-UCLA Medical Center TorranceCalifornia, USA

Jerónimo Gonzálvez Piñera, MD, PhD Associated Professor of Paediatric

SurgeryDepartment of Paediatric SurgeryUniversity General HospitalAlbacete, Spain

Management, provides concise and practical information forreaders. Topics on the three main areas of the speciality –gastroenterology, hepatology, and nutrition – constitute thebody of this book. The authors were carefully selected toprovide a comprehensive and clear account of their assignedtopics. All of them have been willing to dedicate their time,knowledge, and effort in preparing their chapters. Our mostsincere thanks to them. It has been a pleasure to work withClinical Publishing’s production team who have helped toproduce a book of outstanding quality.

We hope and expect that this Atlas will be of benefit to allphysicians dealing with gastrointestinal problems inchildren.

José Manuel Moreno Villares, MDIsabel Polanco MD, PhD

Paediatric gastroenterology emerged as a speciality in the1960s. Since then it has become an essential component ofmajor academic paediatric programmes throughout theworld. The introduction of new diagnostic techniques thatrequired special skills, as well as the development ofcomplex new therapies for children with gastrointestinaldisorders, were cornerstones in the development of thespeciality. The recognition that appropriate nurition duringinfancy and childhood is vital for health and the profoundimpact that many gastrointestinal diseases may have upongrowth also contributed to the discipline’s development.

Many excellent paediatric gastroenterology texts havebeen published since the first textbook on the subject waspublished in the early 1970s, but there are not so many basedon excellent figures and comprehensive tables. PaediatricGastroentero logy, An Atlas o f Investigation and

vi

Preface

viiContributors

Daniel González-Santana, MD Paediatric Gastroenterology DivisionLas Palmas de Gran Canaria

UniversityHospital Universitario Materno-Infantil

de CanariasSpain

Antonio Monica Guerra, MD, PhDNutrition UnitUniversity of PortoPorto, Portugal

Carolina Gutiérrez Junquera, MD, PhDAssociated Professor of PaediatricsDepartment of Pediatric

GastroenterologyUniversity General HospitalAlbacete, Spain

Iñaki X. Irastorza Terradillos, MDPaediatric Gastroenterology DivisionHospital de CrucesBilbao, Spain

Angel Mazón, MDPaediatricc Allergy DivisionHospital Infantil La FeValencia, Spain

José Manuel Moreno Villares, MDNutrition UnitDepartment of PaediatricsUniversity Hospital 12 de OctubreMadrid, Spain

Antonio Nieto , MD, PhDPaediatric Allergy DivisionHospital Infantil La FeValencia, Spain

Agustín Nogués, MD Paediatric Radiology DepartmentDonostia HospitalSan Sebastian, Spain

Joanna Pawłowska, MDDepartment of Gastroenterology,

Hepatology and ImmunologyThe Children’s Memorial Health

InstituteWarsaw, Poland

Luis Peña-Quintana, MDPaediatric Gastroenterology,

Hepatology and Nutrition DivisionUniversity HospitalUniversidad de Las Palmas de Gran

CanariaSpain

Amaya Peñalva Arigita, MDUniversity Hospital Valle de HebrónBarcelona, Spain

Isabel Polanco , MD, PhDProfessor of PaediatricsHead of Department of Paediatric

Gastroenterology and NutritionUniversity Hospital La PazUniversidad AutónomaMadrid, Spain

Begoña Polo Miquel, MDPaediatric Gastroenterology and

Hepatology DivisionHospital La FeValencia, Spain

Carmen Ribes-Koninckx, MD, PhDPaediatric Gastroenterology and

Hepatology DivisionHospital La FeValencia, Spain

Enriqueta Román Riechmann, MDDepartment of PaediatricsHospital de FuenlabradaMadrid, Spain

Carlos Sierra Salinas, MDGastroenterology, Hepatology and

Nutrition DivisionHospital Materno-InfantilMálaga, Spain

Piotr Socha, MDDepartment of Gastroenterology,

Hepatology and ImmunologyThe Children’s Memorial Health

InstituteWarsaw, Poland

Juan A. Tovar, MD, PhDProfessor and Chief, Department of

Paediatric SurgeryUniversity HospitalLa PazMadrid, Spain

Jorge Vargas, MDDivision of Gastroenterology and

NutritionDepartment of PaediatricsMattel Children’s Hospital at UCLALos Angeles, USA

Juan C. Vitoria Cormenzana, MD, PhDProfessor of PaediatricsBasque Country UniversityChief, Paediatric Gastroenterology

DivisionHospital de CrucesBilbao, Spain

David Ziring, MDDivision of Gastroenterology and

NutritionDepartment of PaediatricsMattel Children’s Hospital at UCLALos Angeles, USA

Abbreviations

viii

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 (fromula)

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 (formulas)

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

Failure to thrive in infants and children

José Manuel Moreno Villares, MD, and Antonio Monica Guerra, MD

Chapter 1

Introduction

Evaluation of growth and development in the primary caresetting is a cornerstone of paediatric care. Usually headcircumference, weight, and length are measured at birth,and then on an intermittent basis throughout the rest ofchildhood. When a divergence from the standard growthcurve occurs, in either direction, a careful assessment isrequired to determine the aetiology.

Undernutrition or ‘failure to thrive’ (FTT) is a commonnutritional problem in the infant and toddler paediatricpopulation. The identification of patients with FTT is aroutine part of residency training in paediatrics.

Inappropriate nutrient intake and growth parameters

FTT is a clinical label frequently used to describe infantsand young children, generally under 3 years, who fail togrow as expected using established growth standards for ageand gender along a period of time (usually longer than 3months) (1.1).

Weight is a measure of the varying combination of height,body fat, and muscle bulk, which makes it a lessstraightforward measure of growth than height.Nevertheless, because of its widespread availability and easeof measurement, it is the most usual tool when growthmeasure is considered. What constitutes a normal rate ofweight gain (Table 1.1)? It is often assumed that normalgrowth constitutes tracking along the birth centile. However,weight at birth is a reflection of the intrauterine environmentand is of limited prognostic value. Many children deviatefrom their earlier centile position, and this divergence may

1

1.1 Eleven-month-old boy, with growth faltering in the last

4–5 months, more severe in the last 2 weeks. Reduction

in >2 major percentiles for weight. (Courtesy Fundación

Orgebozo, Bilbao, Spain.)

not become pathological. Although the most commonlyused definition of abnormality is that falling below apredetermined centile, usually the third (1.2), this wouldinclude a number of constitutionally small children. Analternative definition applies when a child has a weight curvethat has fallen more than two standard deviations or

Failure to thrive in infants and children2

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

Table 1.1 Normal weight gain and frequency of

monitoring

1.2 An 18-week-old female, with irritability and poor weight

gain since birth. Weight below 3rd percentile. (Courtesy

Fundación Orgebozo, Bilbao, Spain.)

Definition of FTT

FTT describes an infant or child whose current weight orrate of weight gain is significantly below that expected ofsimilar children of the same age and sex. Most paedia tri ciansdiagnose FTT when a child’s weight for age falls below thefifth percentile of the standard growth charts or it crosses twomajor percentile lines (1.3). One problem arises from the useof different growth charts; misinter pretation may occur ifdifferent genetic back ground are not considered. Thisproblem may be overcome if universal growth referencescould be used. The World Health Organization (WHO) hasrecently published charts resulting from the MulticenterGrowth Reference Study, and are intended to substitute forthe National Center for Health Stat istics/WHO(NCHS/WHO) growth reference, which has beenrecommended for international use since the late 1970s(www.who.int/childgrowth/standards/curvas_por_indicadores/en/index.html) (1.4, 1.5).

FTT is not a final diagnosis but a description of a physicalstate; therefore, a cause must always be sought. Because thedescription itself is vague it has been proposed to use growthfailure or undernutrition as a diagnostic replacement forFTT.

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

1.3 Four-month-olld male. Loss of >2 major percentiles

since birth. (Courtesy Fundación Orgebozo, Bilbao,

Spain.)

Until recently, the evaluation of a child with FTT focusedon factors related to external environment or to medicalcauses. Currently, the child’s feeding behaviour and theinteraction between the caregiver and the child has taken ongreater importance. Feeding is an interactive process thatdepends upon abilities and characteristics of both theparents and the child.

Aetiology

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

Failure to thrive in infants and children 3

A

B

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

A

B

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

1.6 Aetiology of FTT.

Organiccauses

Nonorganiccauses

False failure to thrive

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


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

Genetic short Ex-premature Constitutional Catch down stature infant delay growth

Birth weight Low to normal Normal if corrected Low to normal Above expected for

for gestation genetic background

Parental percentiles Low Normal Normal Normal

Progress along Low percentile but Low if corrected May be an initial Initial fall in 6–12

percentiles do not cross but follow fall in first 6 months months and then

percentiles percentile curves and then follow follow percentiles

percentiles

Table 1.2 Normal variants of growth presenting as FTT

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

Table 1. 3. Classification of FTT by pathological causes

to be considered when making the diagnosis of FTT, forinstance, infants with intrauterine growth retardation orpremature infants.

Within the group of normal variants of growth presentingas FTT, four main patterns occur (Table 1.2)2. There arealso growth curves available for syndromes with abnormalgrowth (e.g. Down syndrome, Noonan syndrome,Prader–Willi syndrome) (1.7, 1.8). There are many reasonswhy an infant does not take on adequate nutrition. A moreuseful classification of FTT is then based onpathophysiology, as shown in Table 1.3.

Evaluation

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


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.

FFT is suspected

Basic laboratoryinvestigations

Treatment –primary care

Clinical history Physical examination

Assessment of intake

Further work up/treatment –hospital

Success

Lack of success

Follow upNutritional advice

Psychological support

Red flag signs

Nonorganic failure to thrive

Most likely normal variant of growth

Organic failure to thrive

Anomalous results?NoYes

Hospital

Dietary history

• Amount of food and/or formula

• Is the formula prepared correctly?

• Food patterns: types of foods, especially beverage

consumption (milk, juices, sodas)

Feeding history

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

• Breastfed?

• Positioning of the child

• Feeding battles

• Snacking

Past and current medical history

• Obstetric history

• Birth history, including weight and height

• Neonatal period

• Recent acute illness especially upper airway infections,

otitis, gastroenteritis

• Are they recurrent?

• Chronic medical conditions

• Past hospitalizations, injuries, accidents

• Vomiting?

Social history

• Who lives in the home?

• Who are the caregivers?

• Who helps to support the family?

• What is the child’s temperament?

• Any family problems?

Family history

• Medical conditions or FTT in siblings

• Growth pattern in other members of the family,

especially parents and siblings

• Mental illness

Table 1.4 Evaluation of medical history in FTT

Normal Mild risk Moderate risk High risk

Weight for age (%) >90 75–89 60–74 <60%

Weight for height (%) >90 80–90 70–79 70%

Height for age (%) >95 95–90 89–85 <85%

Table 1.5 Classification of undernutrition in children15, 16

The severity of a child’s undernutrition can be classifiedmost easily using the Waterlow and Gomez criteria (Table1.5), as a percentage of the median for age. Further examina -tion beyond growth should include physical examination(1.10), including inspection of any physical sign of neglect orabuse, stigmas of underlying syndromes, dysmorphicfeatures, skin rashes, and observation of feeding if possible.

1.4)3. A thorough psychosocial history is mandatory. Anaccurate assessment of growth requires the evaluation ofcurrent and past parameters including height or length,weight, and head circumference. Occasionally furtherassessments are performed such as mid-upper armcircumference, various skin fold thicknesses, bodyproportions and, if indicated, puberal assessment.


1.10 Clinical signs of malnutrition in a patient with FTT

who was found to have a coeliac disease.

Initial evaluation

• Full blood examination/erythrocyte sedimentation rate

or C-reactive protein

• Chemistry panel: urea, creatinine, lytes

• Iron status: iron, ferritin, transferrin, % saturation

• Blood glucose

• Liver function tests: GGT, SGPT, SGOT, alkaline

phospatase, bilirubin

• Urinalysis

• Urine culture

Second step

• Acid–base balance

• Immunoglobulins

• Coeliac screen

• Thyroid function test

• Bone age

• Stool microscopy and culture

Third step (if clinically indicated or abnormal data from the initial investigations)

• Metabolic screen (blood and urine for organic acids

and amino acids, ammonia, lactic/pyruvic acids,

ketone bodies in urine)

• Karyotype

• Allergy investigations

• Sweat test

• pHmetry/endoscopy

Table 1.6 Investigations in failure to thrive

7Failure to thrive in infants and children

Observing or videotaping the interaction between aparent and a child, especially during a feeding session in theoffice, may provide valuable information about the aetiologyof FTT4.

InvestigationsLaboratory evaluation should be guided by history andphysical examination findings only. A well-targeted batteryof investigations may provide guidance. There are noroutine laboratory tests that should be performed on everychild, because the majority of children with FTT have nolaboratory abnormalities. In those requiring investigation, asimple initial sequence can be performed (Table 1.6).

Treatment

Medical intervention is dictated by the disease diagnosed.Addressing identified issues of attachment and otherpsychosocial issues is crucial and often requires input froma multidisciplinary team. Most cases can be managed bynutrition intervention or feeding behaviour modification.Evaluation and treatment is generally accomplished inoutpatient settings rather than in the hospital.

Nutritional rehabilitation by means of increased caloricintake is often best supervised with the advice of anexperienced dietician, allowing exact caloric requirements tobe calculated. Asking the parent to write down the type offood and amounts a child eats over a 3-day period is one wayof quantifying caloric intake.


Dietary recommendationsChildren with FTT will need 150% of the recommendeddaily caloric intake, based on their expected, not actual,weight for height if tolerated5. As most of these children lackthe normal responses to internal hunger/satiation cues, highenergy snacks may improve their nutritional status6. Ininfants this increased caloric intake may be accomplished byconcentrating the infant formula or adding carbohydrates orlipids to the formula or the puréed foods (1.11). Toddlerscan receive more calories by adding cheese, butter, and soon to common toddler foods. In toddlers and older childrenwe can also use high-calorie milk drinks, that provide1.0–1.5 kcal/ml. Vitamin and mineral supplementation isalso sometimes required. If all these attempts fail it may benecessary to consider nasogastric tube feedings as a lastresort (1.12)7. The advantages are ensuring adequate caloricintake and decreasing or eliminating some of the emotionalstress and frustrations with feeding times. However, thereare also disadvantages, including the suppression of appetiteand sometimes the modification of feeding behaviour.

1.11 There are two ways to increase the caloric intake in an infant: to increase the strength of the regular formula or to

add caloric modules (carbohydrates or lipids or both) to the regular formula.

Infant formula 13% (68 kcal/100 ml)

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



Add maltodextrin 5 g/100 ml (20 kcal)

Add maltodextrin 5 g/100 ml (20 kcal)

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

Add modulesConcentrateformula

(powder)

1 measure in 26 ml

1 measure in 23 ml

1 measure in 20 ml

88 kcal/100 ml

104 kcal/100 ml

124 kcal/100 ml

Feeding or eating behavioursParental anxiety about a child’s FTT can be helped byreassurance. Paediatricians can intervene effectively in manyfeeding problems, providing useful guidance for parents(Table 1.7). Hospitalization is rarely required and may becounterproductive8. It may be necessary when the safety ofa child is a concern, outpatient management has failed, or ifthe FTT is severe.

Outcomes

It is ascertained that children with FTT are at risk of adverseoutcomes such as short stature, behaviour problems, anddevelopmental delay9–12. However, there are only a limitednumber of outcome studies on children with FTT, withdifferent definitions and designs, so it is difficult to make an

assessment on long-term results of FTT. Rudolph andLogan found only a small difference in intelligence quotient(IQ) (equivalent to 3 IQ points) in children with FTTcompared to their peers13. This small difference is ofquestionable clinical significance. The height and weightdifferences in their analysis were larger, but few childrenwere below the 3rd percentile at follow-up. In the light ofthese results, the aggressive approach to the identificationand management of FTT needs reassessing13.

In addition, it is often difficult to disentangle the effects ofFTT from those of the high-risk environments in whichFTT often occurs (poverty, family stress, and poor parentalcoping skills). Nevertheless, to decrease the risk of adverseeffects, it is important to recognize and treat FTT promptly.Sometimes this necessitates the intervention of community-based resources14.


1.12 In some severe FTT cases, especially if an organic

condition is underlying, it is necessary to provide enteral

nutrition through a nasogastric tube. This patient has

biliary atresia and FTT.

1 Make mealtimes pleasant

2 Avoid battles over eating. Encourage your child.

Food should be used as nourishment, not as a

reward or punishment

3 You are responsible for deciding what food your

child is offered; your child decides how much to

eat

4 Offer a variety of healthy and tasty foods

5 Establish a routine of meals and snacks and set

times

6 Recognize your child’s cues indicating hunger,

satiety, and food preferences

7 Accept your child’s wish to feed him- or herself

8 Try to eat together as a family

9 Establish a maximum time to finish a meal (for

instance 30 minutes)

10 Limit possible distractions during meals

Table 1.7 Useful guidance for parents. Tips for

preventing food hassles

10 Failure to thrive in infants and children

10 Corbett SS, Drewett RF. To what extent is failure tothrive in infancy associated with poorer cognitivedevelopment? A review and meta-analysis. J ChildPsychol Psychiatr 2004;45:641–54.

11 Zenel JA. Failure to thrive: a general pediatrician’sperspective. Pediatr Rev 1997;18: 371–8.

12 Drewett RF, Corbett SS. Cognitive and educationalattainments at school age of children who failked to thrivein infancy: a population-based study. J Child PsycholPsychiatr 1999;4:551–61.

13 Rudolf MCJ, Logan S. What is the long-term outcomefor children who fail to thrive? A systematic review. ArchDis Child 2005;90:925–31.

14 Wright CM, Callum J, Birks E, Jarvis S. Effect ofcommunity based management in failure to thrive:randomized controlled trial. BMJ 1998;317:571–4.

15 Waterlow JC. Classification and definition of protein-calorie malnutrition. BMJ 1972;3:566–9.

16 Gomez F, Ramos-Galvan R, Frenk S, Cravioto JM,Chavez R, Vazquez J. Mortality in second and thirddegree malnutrition. J Trop Paediatr 1956;2:77–83.

General reading

Frank DA, Zeisel SH. Failure to thrive. Pediatr Clin NorthAm 1988;35:1187–1206.

Jolley CD. Failure to thrive. Curr Probl Pediatr AdolescHealth Care 2003;33:183–205.

Gahagan S, Holmes R. A Stepwise approach to evaluationof undernutrition and failure to thrive. Pediatr Clin NorthAm 1998;45:169–87.

Kessler DB, Baker SS, Silverman LA. Growth assessmentand growth failure. Consensus in Paediatr 2004;1:1–28.

Conclusion

It is common to confuse the description of poor growth witha diagnosis. The term ‘failure to thrive’, although firmlyentrenched in the medical lexicon, adds little to ourunderstanding of this condition and does not guide ourapproach. Many have suggested it should be abandoned. Itrepresents a nonspecific description of symptoms ratherthan a specific condition. Paediatricians and otherhealthcare workers must come to a better understanding ofthe complex dynamics of feeding normal children. Whenfeeding and caloric issues have been ruled out, otherconsiderations should be taken into account. It is not aquestion of referring a child who is not growing well to thefeeding expert, the gastroenterologist, or theendocrinologist, but rather the recognition that a rational,sequential approach needs to be followed, to allow forinvestigation of all the possible explanations of why a childis not growing.

References

1 Krugman SD, Dubowitz H. Failure to thrive. Am FamPhys 2003;68:879–84, 886.

2 Bergman P, Graham J. An approach to ‘failure to thrive’.Aus Fam Phys 2005;34:725–9.

3 McCann JB, Stein A, Fairburn CG, Dunger DB. Eatinghabits and attitudes of mothers of children withnonorganic failure to thrive. Arch Dis Child 1994;70:34–6.

4 Satter E. The feeding relationship: problems andinterventions. J Pediatr 1990;117:S181–9.

5 Maggioni A, Lifshitz F. Nonorganic failure to thrive: anoutpatient approach. Pediatr Clin North Am1998;45:169–87.

6 Kasese-Hara M, Wright C, Drewett R. Energycompensation in young children who fail to thrive. JChild Psychol Psychiatr 2002;43:449–56.

7 Tolia V. Very early onset nonorganic failure to thrive ininfants. J Pediatr Gastroenterol Nutr 1995;20:73–80.

8 Marcovitch H. Failure to thrive. BMJ 1994;308:35–8.9 Dahl M, Kristiansson B. Early feeding problems in an

affluent society. IV. Impact of growth up to two years ofage. Acta Paediatr Scand 1987;76:881–8.

A. Gastrointestinal tract disorders

Oesophagus• Achalasia

• Gastro-oesophageal reflux (GER)

• Hiatal hernia

• Congenital vascular or mucosal

rings

• Stenosis

• Foreign body

Stomach• Pyloric stenosis

• Diaphragmatic hernia

• Peptic disease

• Antral web

Duodenum• Annular pancreas

• Duodenitis and ulcer

• Malrotation

• Superior mesenteric artery

syndrome

Intestine and colon• Atresia and stenosis

• Meconium ileus

• Malrotation, volvulus

• Duplication

• Intussusception

• Soy or cow’s milk protein

intolerance

• Coeliac disease

• Food allergy

• Hirschsprung’s disease

• Chronic intestinal pseudo-

obstruction

• Appendicitis

• Inflammatory bowel disease

• Gastroenteritis

Other abdominal organs• Hepatitis

• Gallstones

• Pancreatitis

B. Extragastrointestinal tract

disorders

• Infections: sepsis, pneumonia,

otitis, urinary tract infection,

meningitis

• Intracranial hypertension:

subdural effusion, hydrocephalus,

brain tumour

• Intoxications or drugs

• Inborn errors of metabolism

• Eating disorders

• Cyclic vomiting syndrome

Table 2.1 Causes of vomiting and regurgitation

Introduction

Vomiting is a complex behaviour composed of three linkedactivities: nausea, retching, and expulsion of stomachcontents. The vomiting act is characterized by cycles ofretching followed by forceful expulsion of gastric contentsthrough the mouth. Although it was previously thought oneor two anatomical vomiting centres existed in the centralnervous system (CNS), it is now assumed that the central

11

vomiting centres represent the integrated activity of theparaventricular nuclei arrayed along the central neuraxiscontrolling a myriad of autonomic functions1.

Vomiting may result from a variety of disorders affectingpaediatric patients (Table 2.1). History and physicalexamination may help us to distinguish nonbilious frombilious causes, i.e. proximal or distal to the ampulla of Vater.

Chapter 2

Vomiting

José Manuel Moreno Villares, MD, andMaría José Galiano Segovia, MD

Evaluation

Vomiting is a common symptom of many disease states. Thedifferential diagnosis of the child with vomiting varies withthe age of the patient. Assessment of the child with vomitingshould start with a complete history, physical examination,and description of the vomitus. Emesis of gastric contents ischaracteristic of gastric outlet obstruction, CNS masses orinfection, peptic disease, urinary tract infection, otitis, inbornerror of metabolism, or psychogenic vomiting. The child whovomits bile-stained material may have an intestinalobstruction and should be investigated urgently. The historyand physical examination are essential starting points andshould include duration of vomiting, presence of blood,abdominal pain, or fever. Pain located in the right lowerquadrant suggests appendicitis. Midline or diffuse abdominalpain suggests pancreatitis or peritonitis. Abdominaldistension suggests intestinal obstruction. Viral or bacterialgastroenteritis are usually accompanied by diarrhoea andfever. The presence of mucus and blood in the stool mayraise the suspicion of intussusception or bacterial or toxiccolitis. The evaluation of bloody vomitus start with theconfirmation that the material vomited is blood.

Imaging may help to rule out anatomical causes orintestinal obstruction. Further evaluation may include bloodcount, serum electrolytes, calcium, magnesium, blood ureanitrogen, urinalysis, and culture, and stool examination foroccult blood, leukocytes, and parasites. Specific indicationsfrom history and physical examination may result inobtaining other tests including abdominal ultrasonography,imaging of the head, test of liver function, serum amylase,toxicology screen, serum ammonia, urinary organic acids,and so on. If there is a bloody vomitus, the most productivetest is upper intestinal endoscopy.

Vomiting12

Gastro-oesophageal reflux andregurgitation

This is defined as effortless expulsion of gastric contents bythe mouth and can be asymptomatic or symptomatic.Gastro-oesophageal reflux disease (GERD) is defined asgastro-oesophageal reflux (GER) that occurs too frequentlyand damages the oesophageal mucosa leading to clinicalsymptoms. Spontaneous relaxation of the lower oesophagealsphincter is the major mechanism by which GER occurs,with or without regurgitation2. GER is a physiological eventthat can be seen in a large num ber of infants: >50% of 2-month-old infants regurgitate twice a day. The highestprevalence is at 4 months, when two-thirds of infantsregurgitate. By 1 year, <10% still present vomit ing daily.GERD affects a much smaller proportion of infants (2.1).

Symptoms/examinationThe most common symptom is postprandial regurgitation ofeffortless spit-up. Severe GERD may present with failure tothrive, oesophagitis with haematemesis, dysphagia, heart -burn or chest pain, anaemia, aspiration, chronic cough, andwheezing. Rumination is sometimes a symptom as well asneck contortions (Sandifer’s syndrome). Apnoeic episodesin neonates and very young infants can be caused by reflux.GERD is common in neurologically impaired children.

If not treated, GERD can lead to Barrett’s oesophagus.This is a metaplasia of the oesophageal squamousepithelium that transforms to specialized columnarepithelium; it is a premalignant condition associated withdysplasia and adenocarcinoma. Peptic strictures can presentin cases of severe but asymptomatic oesophagitis.

DiagnosisGER is usually diagnosed by a thorough history and physicalexamination in infants under 6 months of age. It can bediagnosed on barium swallow by observing regurgitation ofbarium from stomach to oesophagus. Nevertheless, false-posi -tive and false-negative tests are common. Nowadays, uppergastrointestinal (GI) series only serve to rule out anatomicalproblems. Ultrasonography is now used as a diagnostic tool toconfirm GER. A pH probe (prolonged monitoring ofoesophageal pH) is the best test for GERD, but it will misscases of nonacid GER (2.2). Oesophageal and gastricscintigraphy is sometimes helpful in identifying pulmonaryaspiration. Endoscopy is not diagnostic, but evidence ofoesophagitis supports the diagnosis (2.3). Impedance studiesmeasure fluid movements rather than luminal pH changes3.2.1 Reported regurgitation according to age.

0–3 4–6 7–9 10–12Age (months)

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

% p

ositiv

e

70

60

50

40

30

20

10

0

Vomiting 13

2.2 A pH probe (prolonged

monitoring of oesophageal

pH) is the best test for GER,

but it will miss cases of

nonacid GER. Top: normal

pH probe; bottom:

pathological pH probe.

(C: chest pain; H: heartburn;

M: meal; S: supine.).

A B

C D

2.3 Endoscopy is not diagnostic,

but evidence of oesophagitis

supports the diagnosis.

A: oesophagitis; B: severe

oesophagitis; C: oesophageal

stenosis secondary to

oesophagitis; D: Barrett’s

oesophagus.

11 am 3 pm 7 pm 11 pm 3 am 7 am 11 am

8

6

4

2

0

pH

SM

H

M

HH

M

9 am 1 pm 5 pm 9 pm 1 am 5 am 9 am

8

7

6

5

4

3

2

1

pH

SM M M

CCH H

TreatmentIn 85–90% of patients, GER will disappear between 6 and 12months with no treatment (2.4). Regurgitation is reduced byconservative measures such as small, frequent thickened feed -ings. H2 receptor antagonists (e.g. ranitidine, 5.0 mg/kg/d) andproton pump inhibitors (omeprazol 1 mg/kg/d) are effective incontrolling oesophagitis. Prokinetic agents such as meto -clopra mide (0.1 mg/kg/dose) or domperidone (0.2mg/kg/dose) may be used to hasten gastric emptying. Lowdoses of erythromycin may also act as a promotility agent4.

Antireflux surgery (Nissen fundoplication) is indicated inselected cases (Table 2.2) but is associated with morbidity.Neuro logically impaired children respond less well to medicaltherapy. Laparoscopic surgery has been associated withincreased repeat operations, if compared with open surgery5.

Vomiting14

2.4 Management of a vomiting infant.

1 Persistent vomiting with failure to thrive

2 Severe oesophagitis or oesophageal stricture

3 Apnoeic spells or chronic pulmonary disease

unresponsive to medical therapy

4 Large hiatal hernias, if symptomatic

Table 2.2 Indications for antireflux surgery

Recurrent vomiting

History and physical examination

Are there warning signals?

Are there signs of GERD?

Uncomplicated infantile GER‘Happy spitter’

• No test • Consider• Education – Thickened formula

– Hypoallergenic formula

Further evaluation

Further evaluation

Resolves by 18–24 hours?

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

Yes

Yes

No

No

Well childNoYes

2.5 Hiatal hernia. A: barium study; B: gastro-oesophageal junction placed into

the thorax; C: endoscopic retroview from the stomach.

Vomiting 15

Hiatal hernia

Hiatal hernia is the protrusion of a portion of the stomachinto the chest through an opening in the diaphragm (2.5).Hiatal hernias are classified as:• Para-oesophageal, if the oesophagus and the gastro-

oesophageal junction are normally placed but the gastriccardia is herniated beside the oesophagus through theoesophageal hiatus (2.6).

A

B C

A B

2.6 A: The oesophagus

and the gastro-

oesophageal junction are

normally placed but the

gastric cardia is herniated

beside the oesophagus

through the oesophageal

hiatus. B: barium study.

• Sliding, in which the gastro-oesophageal junction and aportion of the proximal stomach are herniated throughthe oesophageal hiatus. Sliding hiatal hernia is commonin childhood. It may present accompanying GER, butmany cause no symptoms.

Hernias are treated surgically if medical treatment fails6.

Infantile hypertrophic pyloric stenosis

Infantile hypertrophic pyloric stenosis is a conditionresulting from hypertrophy of the pylorus muscle in whichthe lumen becomes obstructed by mucosa (2.7). It affects1.5–4.0 per 1,000 live births, and is more common in males(4:1). There is a positive family history in 13%. Theunderlying mechanism is not understood.

Symptoms/examinationVomiting usually begins between 2 and 4 weeks of age andrapidly becomes projectile after every feeding. The vomitusis rarely bilious. Coffee-ground emesis may be seen as aresult of oesophagitis or gastritis. The infant is hungry andnurses avidly. Infants do not generally appear ill unlessundiagnosed for an extended period of time: constipation,dehydration, weight loss, fretfulness, and finally apathy canoccur. On examination, prominent gastric peristaltic wavesmay be seen after feeding. The pylorus may be palpable as asmall, hard mass or as an ‘olive’ in the right upper abdomen.

2.7 Infantile hypertrophic pyloric stenosis is a condition

resulting from hypertrophy of the pylorus muscle in which

the lumen becomes obstructed by mucosa. Laparoscopic

view.

A

B

2.8 Ultrasound images in infantile hypertrophic pyloric

stenosis. A: Longitudinal view of the pylorus showing

oval-shaped, enlarged pyloric muscle (dotted line). Pyloric

muscle length >14 mm and thickness >3–4 mm are

considered to be pyloric stenosis. B: Sagittal view of the

pyloric olive.

16 Vomiting

DiagnosisLaboratory tests demonstrate hypochloraemic, hypo -kalaemic metabolic alkalosis. Haemoconcentration isreflected by elevated haemoglobin and haematocrit values.

Ultrasound is the gold standard investigation and canreveal a thick pyloric muscle with a long pyloric channel andlarge pyloric diameter7. It shows a hypoechoic ring with ahyperdense centre, and thickness of circular muscle >4 mmin pyloric stenosis (2.8)8. A barium upper GI study revealsdelay in gastric emptying and an elongated narrowed pyloricchannel with a double tract of barium (2.9).

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

A B

2.9 Barium upper GI study. Narrowing of the pyloric

channel with a double tract of barium (‘string sign’).

2.10 A: Surgical view of hypertrophic pyloric stenosis;

B: pyloromyotomy.

of the duodenum. Treatment consists of decompression bya nasogastric tube and intravenous fluids. With improvednutrition symptoms usually resolve. Occasionally, it isnecessary to perform surgery, such as realigning theduodenum or performing a duodenojejunostomy.

Cyclic vomiting syndrome

The disorder is characterized by recurrent episodes ofnausea and vomiting without an identifiable organic cause.The episodes are of rapid onset, often starting during sleepor early morning. It may persist for hours and days. Theepisodes are separated by completely symptom-freeintervals, lasting from several weeks to more than 1 year.They may end spontaneously, may cease after a period ofsleep, or may progress to severe dehydration and electrolyteimbalance.

The pattern of inciting events and the characteristics ofthe attack are usually similar in each individual. As theclinical picture mimics migraine attack and headaches maybe present in up to 50% of patients, some authors considercyclic vomiting as abdominal migraine.

The diagnosis is based on the history, the normalphysical examination, and a meticulous evaluation of otherorganic disease causing recurrent episodes of vomiting.Diagnostic evaluations should be focused on conditionssuggested by the history. Symptomatic treatment should bestarted as early as possible after the onset of symptoms11, 12.

repair dehydration and electrolyte disturbances. The outlook is excellent following surgery. Sometimes

vomiting may persist postoperatively for a few days if thereis a long preoperative history. Mortality rates are low andusually associated with perforation or infection.

Superior mesenteric artery syndrome

This syndrome is an unusual cause of recurrent vomiting.The third part of the duodenum is obstructed as it passesbetween the superior mesenteric artery anteriorly and thevertebral column posteriorly (2.11). Rapid linear growthwithout weight gain, weight loss, scoliosis, spinal surgery,confinement to bed, and use of a body cast may predisposeto the condition10. It may present with unspecific symptomssuch as anorexia, nausea, and bilious vomiting.

Diagnosis is based on history and plain abdominal X-raythat shows a dilated stomach and proximal duodenum.Upper GI series show a partial obstruction in the third part

17Vomiting

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

and aorta, with dilatation

of the second portion of

the duodenum.

References

1 Lawes IN. The origin of the vomiting response: aneuroanatomical hypothesis. Can J Physiol Pharmacol1990;68:254–9.

2 Kumar Y, Sarvananthan R. Gastro-oesophageal reflux inchildren. Clin Evid 2005;14:349–55.

3 Vandenplas Y, Salvatore S, Devrecker T, Hauser B.Gastro-oesophageal reflux disease: oesophagealimpedance versus pH monitoring. Acta Paediatr2007;96:956–62.

4 Keady S. Update of drugs for gastro-oesophageal refluxdisease. Arch Dis Child Educ Pract Ed 2007;92:ep114–8.

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 Pract2007;57:95–8.

7 Stunden RJ, LeQuense GW, Little KET. The improvedultrasound diagnosis of pyloric stenosis. Pediatr Radiol1986;16:200–5.

8 Hernanz-Schulman M. Infantile hypertrophic pyloricstenosis. Radiology 2003;227:319–31.

9 Aldrigde RD, Mac Kinley GA, Aldridge RB. Choice ofincision: the experience and evolution of surgicalmanagement of infantile hypertrophic pyloric stenosis. JLaparoendosc Adv Surg Tech A 2007;17:131–6.

10 Lock G, Scholmerich J. Non-occlusive mesentericischemia. Hepatogastroenterology 1995;42:234–9.

11 Chow S, Golldman RD. Treating children’s cyclicvomiting. Can Fam Phys 2007;53:467–9.

12 Chepyala P, Svoboda RP, Orden KW. Treatment ofcyclic vomiting syndrome. Curr Treat OptionsGastroenterol 2007;10:273–82.

Further reading

Hassall E. Step-up and step-down approaches to treatmentof gastroesophageal reflux disease in children. CurrGastroenterol Rep 2008;10(3):324–31.

Li BU, Lefevre F, Chelimsky GG, et al. North AmericanSociety for Pediatric Gastroenterology, Hepatology, andNutrition consensus statement on the diagnosis andmanagement of cyclic vomiting syndrome. J PediatrGastroenterol Nutr 2008;47(3):379–93.

Vomiting18

A

C

50°

16°

B

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.

Outer capsid: VP 4

Outer capsid:VP 7

Middle capsid: VP 6

Segmented genome

enteric adenovirus (types 40 and 41), with some commonfeatures (Table 3.2)3.

Most common bacteria are Campylobacter spp. andSalmone lla spp., followed by Shige lla, Yersinia andEscherichia coli. The major parasitic infections are Giardiaand Cryptosporidium2.

Epidemiology

Viral gastroenteritis is the second most common disease indeveloped countries. The sporadic form affects all childrenin the first 5 years of life. Viruses are transmittedfundamentally by the faecal–oral route. There is faecal

19

Definition

Diarrhoea is a change in the individual bowel habit resultingin more frequent and/or looser stools. It expresses an acutegastrointestinal inflammation (acute gastroenteritis). Inchildhood, gastrointestinal infection is the most commoncause of acute diarrhoea worldwide1, 2.

Aetiology

In industrialized countries the most clinically significantagents in infant acute diarrhoea are viruses (Table 3.1),mainly group A rotavirus (3.1A, B). Other viruses involvedare human calicivirus (norovirus and sapovirus, formerlyknown as Norwalk and Sapporo virus), astrovirus and

Chapter 3

Diarrhoea

ACUTE DIARRHOEA

Enriqueta Román Riechmann, MD

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.)

Diarrhoea20

Viruses Bacteria• Group A rotavirus • Salmonella • Enteric adenovirus – S. typhi and paratyphi • Astrovirus – Nontyphoidal Salmonella• Human calicivirus S. enteritidis– Norovirus S. typhimurium– Sapovirus • Shigella

– Shigella sonnei• Campylobacter

Parasites – C. jejuniGiardia lamblia • Yersinia Cryptosporidium – Y. enterocolítica

parvum • Escherichia coli– Enteropathogenic E. coli – Enterotoxigenic E. coli – Enteroinvasive E. coli – Enterohaemorrhagic E. coli – Diffusely adherent E. coli – Enteroaggregative E. coli • Aeromonas

Table 3.1 Main agents of infectious acute diarrhoea

• RNA viruses (except adenovirus)

• Nonlipoproteic envelope

• Seasonal distribution

• Asymptomatic infection ⇔ severe disease

• Frequent coinfections

• Endemic, sporadic cases/epidemic, outbreaks

• Faecal–oral transmission

Table 3.2 Main features of viral agents

excretion of viral particles in the days prior to clinicalsymptoms and continuing through to its resolution.Rotavirus is a seasonal infection and in temperate climatesinfections peak during the winter months3. In bacterialenteric infection transmission can be through contaminatedwater or foodstuffs.

Pathophysiology

Diarrhoea occurs when the volume of water and electrolytespresent in the colon exceeds its capacity for absorption. Thiscan be mainly due to an increase in the secretion and/or adecrease in the absorption level of the small intestine.

Decreased intestinal absorption occurs as a result ofintestinal damage or inflammation (3.2). Viruses causingdiarrhoea infect selectively mature enterocytes, causing celllysis and producing a decrease in disaccharidase activity andin mechanisms for active sodium and water absorption. Theconsequence is a malabsorptive or osmotic diarrhoea.Diarrhoea caused by bacterial infection is most frequentlysecretory. Bacteria can activate one of the intracellularpathways leading to intestinal secretion throughenterotoxins.

A B

Clinical features

Acute diarrhoea is a self-limiting process. Viral diarrhoea istypically acute in onset, watery-like, and the faeces do notcontain mucus, blood, or white cells. Diarrhoea can lead todehydration, acidosis, and electrolyte imbalance. Vomitingappears at the beginning of the process. The most commonage is 6–24 months and rotavirus infection is associated witha more severe disease3.

In the secretory and osmotic diarrhoeas, faeces are wateryand profuse. The invasive diarrhoea is frequentlycharacterized by mucus and macroscopic blood.Nevertheless, viral gastroenteritis cannot be distinguishedfrom that caused by bacteria through clinical history orphysical examination, although some characteristics maysuggest bacterial diarrhoea (Table 3.3).

Diarrhoea 21

• Children older than 3 years

• Acute onset

• No vomiting

• Hyperthermia

• Bloody diarrhoea

• Increase in CRP

• Faecal white cells

Table 3.3 Clinical features suggestive of bacterial diarrhoea

Symptom

Body weight loss

General condition

Eyes

Tears

Mouth and tongue

Thirst

Skin fold

Fontanelle

Heart rate

Quality of pulses

Extremities

Urine output

Minimal or no dehydration<3%

Well, alert

Normal

Present

Moist

Drinks normally, not thirsty

Instant recoil

Normal

Normal

Normal

Normal capillary refill

Slightly decreased

Mild to moderatedehydration3–9%

Restless, irritable

Slightly sunken

Absent

Dry

Thirsty, eager to drink

Recoil in <2 seconds

Sunken

Normal to increased

Normal or slightly

decreased

Delayed capillary refill

<1 ml/kg/h

Severe dehydration

>9%

Lethargic or unconscious:

floppy

Deeply sunken

Absent

Very dry

Drinks poorly, unable to

drink

Recoil in >2 seconds

Sunken

Tachycardia, bradycardia in

most severe cases

Moderately decreased

Cool, mottled

<1 ml/kg/h

Table 3.4 Assessment of dehydration degree (adapted from ESPGHAN 2001and CDC report 2003)6, 7

Assessment

In most cases, a complete clinical history and a carefulphysical examination is all that is necessary4–6. These shouldrule out any life-threatening cause such as intussusception,surgical abdomen, and haemolityc–uraemic syndrome7. Theseverity of dehydration is assessed in terms of weight loss asa percentage of total body weight. An assessment ofdehydration degree can be made by diverse scales of clinicalsigns and symptoms (Table 3.4, 3.3).

Supplementary laboratory studies are usually unneces -sary. There are some recommendations on which patientsshould have blood tests (serum electrolytes, urea/creatinine,bicarbonate) (Table 3.5) and on which patients should havefaecal laboratory study (Table 3.6), as aetiology is irrelevantfor clinical management. Tests for specific pathogens

Diarrhoea22

Sunken fontanelle

Sunken eyes

Decreasedskin turgor

Dry mouth

Crying andirritablility

3.3 Signs of dehydration.

• Severe dehydration

• Moderate dehydration where clinical signs might

indicate hypernatraemia

• Moderate dehydrated patients whose histories or

physical findings are inconsistent with straightforward

diarrhoeal episodes

• History of excessive hypertonic or hypotonic fluid

ingestion

Table 3.5 Recommendations on blood tests

(adapted from AAP 1996)5, 8

• Immunocompromised

• Blood in the stool

• Uncertain diagnosis

• Severe or prolonged diarrhoea

• Hospitalization

• Recent travel abroad

Table 3.6 Recommendations for faecal laboratory

study

include stool cultures for bacteria and detection of faecalviral antigen by enzyme immunoassay (EIA), agglutinationwith latex particles, or immuno chromatography.

Treatment

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

RehydrationThe molecular process for cotransport of glucose andsodium was the basis for oral rehydration therapy (ORT)development (3.4). ORT is recommended globally for themanagement of acute diarrhoea2, 6–8.

The World Health Organization (WHO), the AmericanAcademy of Pediatrics (AAP), and the European Society ofPediatric Gastroenterology, Hepatology, and Nutrition(ESPGHAN) recommend the use of ORT in the treatmentof gastroenteritis with mild to moderate dehydration (Table3.7). Oral rehydration solution (ORS) is more physiological,cost-effective and has fewer adverse effects that intravenoustherapy. Intravenous fluids should be reserved for patientswith severe dehydration.

3.4 Diagram to show the processes involved in

cotransport of organic solutes and sodium and secondary

water absorption.

Intestinal lumen Intestinal villous cell

Na+

Substrate

D-hexosesD-glucoseD-galactose

L-amino acids

H2O

Substrate

Substrate

Na+

H2O + Na+

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

FeedingEarly feeding may decrease the intestinal permeabilitychanges induced by infection, reduce illness duration, andimprove nutritional recovery. The recommendations afterthe period of rehydration are:• Continuation of breastfeeding in all cases.• In formula-fed infants continuation of a nondiluted

formula, without restriction of lactose intake.• Resumption of full normal diet in older children, except

for avoiding foods rich in simple sugars, due to itsosmotic load.

MicronutrientsZinc has been the main micronutrient implied in thediarrhoeal process. Studies performed in developingcountries have shown its effectiveness in the treatment ofacute and persistent diarrhoea in children younger than 5

Diarrhoea 23

Sodium Potassium Chloride Base Glucose Osmolarity(mmol/l) (mmol/l) (mmol/l) (mmol/l) (mmol/l) (mOsm/l)

WHO (1975) 90 20 80 30Bic 110 310

ESPGHAN (1992) 60 20 60 10Cit 74–111 200–250

WHO (2002) 75 20 65 10Cit 75 245

Bic Bicarbonate; Cit Citrate

Table 3.7 Oral rehydration solution composition

• Severe dehydration

– Shock

– Diminished consciousness

• Persistent vomiting

• High ongoing faecal losses

(>10 ml/kg/h)

• Potential surgical pathology

• ORT previous failure

• Significant psychosocial situation

Table 3.8 Contraindications for oral rehydration therapy

years9. This has led the WHO and UNICEF to recommendtreatment with zinc in all children with diarrhoea indeveloping countries10.

ProbioticsThe addition of probiotics to milk or infant formulas or tothe rehydration solutions have shown a shortening in theduration of the diarrhoea. A moderate clinical benefit ofsome probiotics has been shown in the treatment of acutewatery diarrhoea, mainly by rotavirus in infants and youngchildren11. This effect seems to be: moderate in reducingdiarrhoea by 17–30 hours; strain dependent withLactobacillus GG most effective; not effective in bacterialinvasive diarrhoea; effective in a dose >1010 CFUs and whenit is administered early in the disease to children indeveloped countries.

DrugsAntidiarrhoeal drugs, such as inhibitors of intestinal motility(loperamide and other opiates and anticholinergics),modifiers of the intestinal secretion (bismuth salts), andadsorbent substances (cholesteramine, aluminum salts), arenot used in childhood as they have their effectiveness has notbeen demonstrated and/or they have important adverseeffects.

Effectiveness and good oral tolerance of racecadotrile (anantihypersecretor with no effect on intestinal motility) hasrecently been described. Antiemetic drugs are unnecessaryin the treatment of acute diarrhoea, although ondansetroncan sometimes be effective in diminishing vomiting and thenecessity for hospitalization. The use of antibiotics wouldonly be justified in: • Immunocompromised patients.• All cases of acute diarrhoea by Shigella, Vibrio cholerae,

and the majority of those produced by enteroinvasive andenteropathogenic E. coli and by Clostridium difficile.

• Some cases of infection by Campylobacter, by Yersinia incases of serious disease, by Salmonella in infants withbacteraemia, and in all patients younger than 3 months.

Prevention

Since the main infectious route is faecal–oral, fundamentalto prevention is to reinforce environmental hygiene, withappropriate hand cleaning and cleaning of the objects usedin the manipulation of children with diarrhoea. At presentthere are already two safe and effective vaccines againstsevere disease by the most prevalent serotypes of rotavirus inhuman pathology. Both are of oral administration in two(monovalent human, Rotarix®) or three doses (pentavalentbovine–human, Rotateq®). These vaccines can beadministered with other regular childhood vaccines.

In summary, the management of acute diarrhoea inchildren younger than 5 years should be: oral rehydrationfor 3–4 hours, followed by a fast reintroduction of usualfeeding plus ORS for maintained losses (3.5, Table 3.9).

Diarrhoea24

3.5 Management of acute diarrhoea.

Acute diarrhoea/gastroenteritis

Dehydration assessment

Mild to moderate SevereNo dehydration

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

Rehydrated?

Consider nasogastric tube or IV rehydration

Risk factors?Infants <6 months

High frequency of watery stools or vomits

DischargeObservation

at least 24 hours

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

Other causes of diarrhoea and’/or vomiting excluded

NoYes

YesNo

Diarrhoea 25

Definition and pathophysiology

Chronic diarrhoea is defined as a decrease of consistency orincrease in frequency or volume of stools lasting longer than2 weeks12. Different mechanisms can be involved in chronicdiarrhoea and usually a combination of more than one areresponsible for this alteration13:• Osmotic diarrhoea: nonabsorbed substances in the distal

bowel increases osmotic charge, pulling water along theintestinal lumen.

• Secretory diarrhoea: increased secretion of water andelectrolytes into the intestinal lumen, surpassing theabsorption capability.

• Motility alterations:– Hypermotility: unspecific chronic diarrhoea. – Hypomotility: intestinal bacterial overgrowth.• Inflammatory: enterocyte injury with inflammatory

response: humoral, cellular, and phagocytic, and withpermeability alteration and decrease in disacaridases andtransporters.

– Infectious: bacteria, parasites.– Chronic inflammatory bowel disease (IBD) (Crohn’s

disease and ulcerative colitis).• Digestion disorders (decreased enzymes, deconjugated

bile salts).

CHRONIC DIARRHOEA

Angeles Calzado Agrasot, MD, Begoña Polo Miquel, MD, and Carmen Ribes-Koninckx, MD, PhD

Aetiology

A wide variety of disorders including organ dysfunction, auto -immune diseases, and congenital alterations14 can account forchronic diarrhoea in infancy as shown in Table 3.10.

Diagnosis

A complete clinical history is mandatory. Some clinical signsand symptoms are relevant for a diagnostic approach14,including: • Nutritional repercussion. • Associated symptoms: fever, vomiting, abdominal pain,

anorexia.• Stool characteristics: blood, mucous, nondigested

substances, steatorrhoea. • Physical examination: failure to thrive, abdominal

distension, visceromegaly, tenderness, presence ofabdominal masses.

• Other organs affected, e.g. skin, respiratory system.• Age of onset: according to the age of presentation, certain

disorders are more likely to occur (Table 3.11).

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

ll Use of hypo-osmolar solution (60 mmol/l sodium, 74–111 mmol/l glucose)

lll Continuation of breast-feeding throughout

lV Early refeeding: resumption of normal diet (without restriction of lactose intake) after 4 hours rehydration

V Prevention of further dehydration by supplementing maintenance fluids with ORS (10 ml/kg/watery stool)

Vl No unnecessary medication

Table 3.9 Practical guidelines for the management of gastroenteritis in children. ‘Six pillars of good practice’

(ESPGHAN 2001)6

Diarrhoea26

Pancreatic insufficiency• Cystic fibrosis

• Schwachman syndrome

Hepatobiliary dysfunction• Deconjugated bile salts due to bacterial overgrowth

• Biliary atresia

• Cholestasis

Congenital alterations in electrolyte transport• Congenital chlorated diarrhoea

Carbohydrate intolerance• Congenital alactasia

• Secondary lactose intolerance

• Primary congenital racial intolerance

• Glucose – galactose malabsorption

Changes in mucosa• Coeliac disease

• Cow´s milk intolerance

• Soy intolerance

• Other food protein intolerance

• Congenital microvilli atrophy

• Autoimmune enteropathy

Motility disorders• Toddler´s diarrhoea

• Hyperthyroidism

• Idiopathic bowel pseudo-obstruction

• Irritable bowel syndrome

Infectious• Prolonged viral enteritis

• Salmonella• Campylobacter• Yersinia• Giardia lamblia• Cryptosporidium• Bowel bacterial overgrowth

• Pseudomembranous colitis

Anatomical or surgical disorder • Necrotizing enterocolitis

• Short bowel syndrome

• Blind loop syndrome

• Hirschprung’s disease

• Intestinal lymphangiectasia

Inflammatory• Crohn’s disease

• Ulcerative colitis

Other causes• Abetalipoproteinaemia

• Anderson disease

• Enteropathic acrodermatitis

• Immunodeficiency (congenital or acquired – HIV)

• Postenteritis diarrhoea

• Protein-losing enteropathy

• Bile acid malabsorption

Table 3.10 Aetiology of chronic diarrhoea

<1 year 1–3 years >3 years

Lactose intolerance Unspecific chronic diarrhoea Giardia lamblia

Postenteritis diarrhoea Giardia lamblia Coeliac disease

Food intolerance Coeliac disease Inflammatory bowel disease

Cystic fibrosis Infectious diarrhoea Lactose intolerance

Dietetic mistakes Postenteritis diarrhoea

Table 3.11 Aetiology according to the age at presentation

Diarrhoea 27

• Fat malabsorption• Pancreatic

insufficiency

• Protein-losingenteropathy

• Pancreatic insufficiency

• IBD• Pancreatic

insufficiency

• Carbohydratemalabsorption(glucose-galactosemalabsorption)

• >280 mOsm/l – osmoticdiarrhoea

• <280 mOsm/l –secretory diarrhoea

• Infectious diarrhoea

Parasites

• IBD• Infectious diarrhoea• Protein sensitivity

syndrome

Presence of fat • Quantitative: different

methods can be usedsuch as Van de Kamer,steatocrit

• Qualitative: Sudan

Proteins• Alpha-1-antitrypsine

clearance• Quimiotrypsine• Calprotectine • Elastase

pH <5.5Reducing substances

Osmolarity

Stool culture

Fresh view

Occult blood

Macroscopic stool aspect: consistence, mucous or blood

Nutritional status

Protein-losing enteropathy

Coeliac disease

Food allergy/foodintolerance

IBD

Haematology,biochemistry (includingproteins, albumin), iron

metabolism, vitaminlevels, immunoglobulin

levels

Total proteins, albumin

Coeliac autoantibodies (IgA antigliadin, specifictissue transglutaminase

antibodies)

IgE, prick test, foodantigen RAST

Elimination andprovocation tests

Erythrocyte sedimentationrate, C-reactive protein

level, alpha-1-glycoprotein, protein

electrophoresis

3.6 Characteristics of stools may help to diagnose chronic

diarrhoea.

3.7 Biochemical analysis in blood that may help to

diagnose the aetiology of chronic diarrhoea.

Laboratory studies• Stool analysis: faecal characteristics or faecal losses can

point to specific syndromes (3.6).• Blood studies (3.7).• Other studies:

– Exhaled hydrogen concentration test, mono/disac -charides tolerance test: carbohydrate malabsorption orbacterial overgrowth.

– Pancreatic enzymes in duodenal fluid, immunoreactivetrypsin, sweat chloride test: pancreatic insufficiency.

• Enterocyte, smooth muscle, thyroid and islet cell serumantibodies: autoimmune enteropathy.

Imaging proceduresPlain abdominal radiography may rule out anatomicaldisorders or surgical causes. An abdominal ultrasound maybe useful in anatomical or surgical disorders, in infectiousdiarrhoea, or if IBD is suspected. The use of a barium uppergastrointestinal (GI) study or a barium enema helps in thediagnosis of anatomical or surgical disorders. When IBD issuspected an upper endoscopy or a colonoscopy should beperformed and multiple biopsies taken.

3.9 Schematic diagram of a video-capsule: 1, clear

optical dome; 2, lens; 3, illuminating LEDs; 4, CMOS

imager; 5, battery; 6, ASIC transmitter; 7, antenna.

Weight, 3.7 g.

3.10 Video-capsule processor (A: workstation;

B: main screen).

3.8 The small

bowel is an area of

the intestine not

accessible to

routine endoscopic

techniques. The

recent development

of the wireless

endoscopic capsule

(A) has allowed the

possibility of

reaching these

blind areas of the

small bowel. Similar

to a large antibiotic

capsule, after being

swallowed by the

patient, the capsule

is propelled by

peristalsis. Video images are transmitted (two images per

second) from inside the body during 6–8 hours, to a sensor

array secured to the patient’s abdomen (B, C). This is then

connected to the recorder which stores the data.

Diarrhoea28

A

B

C

1

3

2

3

4 5 5 6 7

Video section

Thumbnailsection

Comment

Timebar

Video controls

A

B

The wireless endoscopic capsuleThe small bowel is an area of the intestine not accessible toroutine endoscopic techniques. However, the recentdevelopment of the wireless endoscopic capsule (EC) (3.8)has revolutionized endoscopy15. Advances in miniaturiza -tion of electronic components have allowed thedevelopment of a new type of capsule endoscope (3.9,3.10), enabling endoscopy of the whole GI tract15 with lowinvasivity. Similar to a large antibiotic capsule, after beingswallowed by the patient, the video-capsule is propelled byperistalsis and will transmit video images, 2 images persecond, from inside the body over 6–8 hours to a sensorarray fixed to the patient’s abdomen and to a recorder. Afterthe stored images are processed by a special software(RAPID™ [Reporting And Processing of Images and Data]Application Software), these can be stored as a high qualityvideo. Individual frames and short videos can be also filed;moreover, digital data allow integration into reports whichcan be stored, printed, or sent by email.

This device is therefore very useful for the diagnosis ofoccult digestive bleeding and for the diagnosis, follow-up,and extension study of IBD16–18.

Wireless EC shows great potential for the study of other

disorders such as intestinal polyps, graft versus host disease,tumours, and so on (Table 3.12). Its optimal use in paediatricpatients has not yet been established. The only actualcomplication of the procedure is related to the presence ofstrictures that may cause the capsule to be retained,necessitating removal by interventional or surgical procedures.

In chronic diarrhoea, this procedure may be useful to rule

Diarrhoea 29

Advantages

• Noninvasive

• High-quality images of the entire small bowel

• Ambulatory examination

• Imaging is possible even in the very frail patient

Disadvantage

• Patient refusal or impossibility to swallow the

capsule – the capsule can be introduced into the

stomach with a gastroscope

• The capsule is retained in the stomach, i.e. no

images of the small bowel are registered

• Small bowel strictures can contraindicate the procedure

Table 3.12 Advantages and drawbacks of the wireless EC system

3.11 Characteristic Crohn’s

disease ulcers obtained by

wireless endoscopic capsule.

A: jejunum; B: distal ileum.

A B

A B

3.12 Patchy lesions in a

young patient with coeliac

disease obtained by a

wireless endoscopic capsule.

A: villi are clearly visible in

normal jejunum; B: absence

of villi in a patient with

coeliac disease.

out a specific disorder or when other methods have failed toconfirm a diagnosis, for instance Crohn’s disease restricted toareas of the small intestine not accessible by conventionalendoscopy (3.11)19. Small villous atrophy, characteristic ofcoeliac disease, may be patchy or present in distal jejunummaking diagnosis extremely challenging by conventionalmethods (3.12). Although video-capsule endoscopy is not

Anticholinergics

5-HT4 agonistsAntidepressants

5HT agonists

Probiotics

AntibioticsProbiotics

Diet

Intestinal motility alteration

Visceral hypersensitivity

Deregulation centralnervous system and

digestive tract interaction

Low grade chronicintestinal inflammation

Bacterial overgrowth

3.13 The pharmacological treatment of irritable bowel

syndrome should be individually tailored to the most

likely physiopathological cause.

30 Diarrhoea

overgrowth, and even genetic polymorphisms(interleukin-10) have all been implicated.

Treatment consists of reassuring parents and giving somedietary advice: some patients may improve if they eliminateor restrict particular constituents of food such as lactose,fructose, sorbitol, flatulent vegetables, or fruits16. Dieteticrestrictions are applicable only if there is an improvementfollowing removal of the foodstuffs. In IBS with consti -pation, fibre intake can improve symptoms. Pharma -cological treatment depends on the putative physio -pathologic mechanisms. Different approaches can be used,but the efficacy of these treatments has not been establishedand an individual approach has to be considered (3.13)22.

Intractable diarrhoea of infancy (IDI)

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

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

Toddler’s diarrhoea

Toddler’s diarrhoea usually occurs between 6 months and 3years of age, and is the most frequent cause of chronicdiarrhoea in this age group. It usually occurs after an acutebeginning (infections, stress, antibiotic treatment). It usuallydisappears at 2–4 years old, and evolves to recoveryspontaneously. The main symptoms are 3–6 deposi tions/day,not formed, with more or less mucous and undigested foodparticles. Depositions do not occur nightly. Symptoms areintermittent and self-limited20. There is no pain orabdominal distention and it does not affect weight or height.

The physiopathology is not clear although it has beensuggested that accelerated intestinal motility or an increasein bile salt elimination are responsible. Sometimes toddler’sdiarrhoea has been related to dietary mistakes: low fat andhigh carbohydrate diet, increased fruit juice intake, orincreased water intake.

Irritable bowel syndrome (IBS)

According to Roma III21 IBS is recurrent abdominal pain ordiscomfort for at least 3 days/month in the last 3 months,associated with two or more of the following criteria:• It improves with defecation.• The onset of pain starts with a change in the frequency of

the stools.• The onset of pain starts with a change in the

characteristics of the stools.

Usual symptoms are: deposition frequency range fromfewer than three depositions in a week to more than threedepositions a day; stools can be hard, pasty, or watery; stoolevacuation with effort or urgency, with an incompleteevacuation feeling; mucous stools; abdominal distensionimpression; and nightly depositions.

There is no clear physiopathology: intestinal motilityaltera tion, visceral hypersensitivity, deregulation of thecentral nervous system and digestive tract interaction,low-grade chronic intestinal inflammation, bacterial

Microvillous inclusion disease

Epithelial dysplasia

Syndromatic diarrhoea (tufting)

Autoimmune enteropathy

Cow’s milk allergy and otherimmune-mediated disorders

Mucous stools

Choanal atresiaKeratitis

Small for gestational ageFacial dysmorphy

Abnormal hair

Extradigestive diseaseAutoimmune, autoantibodies

Occasionally bloody stool

Neonatal

1–3 months

3–12 months

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

Bacterial overgrowth syndrome

Bacterial overgrowth syndrome is due to malabsorptionresulting from poor enterocyte function and bacterialtransformation of nutrients into nonabsorbable and toxicmetabolites23. It most commonly present in infants youngerthan 2 years. It may be associated with anatomical damage,abnormal small bowel motility, and immunologicalalterations.

If bacterial overgrowth is present, there is an alteration ofthe intraluminal metabolism of carbohydrates. Carbo -hydrates are fermented into smaller osmotically activemolecules and organic acids by bacteria. Increasedosmolarity results in osmotic diarrhoea. Alteration ofintraluminal metabolism of bile acids occurs, causingdeconjugation of the bile acids. These stimulate the colon tosecrete fluid (secretory diarrhoea) and inhibit the carbo -hydrate transporters and reduce intraluminal pH levels.

Symptoms depend on the degree of mucosal damage,from abdominal pain or flatulence to severe diarrhoea withmalabsorption. The diagnosis can be established byduodenojejunal culture (≥106 UFC/ml) or exhaled hydrogenconcentration with an oral carbohydrate load. Treatmentconsists of nonintestinal absorbable antibiotics.

Postenteritis syndrome

This presents as a protracted course of acute diarrhoea orearly relapse after improvement. It usually appears in infantsand toddlers (6 months–3 years). Clinically, it presents aswatery stools with or without vomit, anorexia, and failure tothrive. There are conditioning factors such as genetics,medical conditions, the aetiology of infectious acutediarrhoea, nutritional status, and inadequate managementof acute diarrhoea (indiscriminate use of antibiotics,hypocaloric diet and excessive carbohydrate intake).

When diarrhoea is prolonged, the mucosa is damaged.Enteropathy alters secretory and absorption function andintestinal motility. The treatment consists of transientelimination of cow’s milk and lactose from the diet. If thereis a concomitant infectious cause of diarrhoea, aetiologicaltreatment is indicated.

Transient food intolerance/allergy

Transitory food allergy or intolerance is an adverse reactionto foods. The term ‘food intolerance’ is usually preferred tofood allergy, in order to include pathological reactionsmediated by nonimmune mechanisms24. Cow’s milk

31Diarrhoea

proteins are most frequently implicated as a cause of foodintolerance during infancy. Soy protein is another commonfood antigen. From school age on, egg protein becomesmore important. With increased consumption, sensitizationfrom other sources becomes more frequent.

It is known that gastrointestinal infections, decreasedserum and secretory IgA, malnutrition, and atopic tendencyare risk factors for increased intestinal permeability to foodantigens. Oral tolerance does not develop and differentimmunological and inflammatory mechanisms occur withepithelial damage (enteropathy). Clinical symptoms dependon different factors: age, site of food antigen exposure,different pathogenetic mechanisms, and degree of theenteropathy. Symptoms can be gastrointestinal (chronicdiarrhoea, failure to thrive), respiratory, or dermatological.

Diagnosis is established by elimination and challengetests. The test is positive for food intolerance whensymptoms decline following dietary elimination of thesuspected offending food and recur after a food challenge. Achallenge should be performed with the suspected agent andwith placebo. Immunological tests include: • Skin prick test with the defined antigens.• RAST: IgE class antibodies against specific food antigens.• IgG class antibodies against specific food antigens:

interpretation of results will be done according clinicalsymptoms.

• Total serum IgE.

In addition, gastroenterological tests are available, such asgastric biopsy, small bowel biopsy, and stool analysis(eosinophils, blood). The definitive treatment of foodallergy is strict elimination of the offending food from thediet. Food-induced intolerance is most often a temporarydisease. Most children can resume consumption of theoffending antigen after 1–4 years of an elimination diet.

Carbohydrate malabsorption

Carbohydrate malabsorption usually presents as watery andacid stools, abdominal distension and flatulence, perianalarea erythema, and failure to thrive (3.15)25. Treatmentconsists of the elimination of all or specific dietarycarbohydrates until the diarrhoea resolves. In congenitaldisease, carbohydrates never will be introduced.

References

1 Casburn-Jones AC, Farthing MJG. Management ofinfectious diarrhoea. Gut 2004;53:296–305.

2 Davidson G, Barnes G, Bass D, et al. Infectious diarrhoeain children: Working Group Report of the First WorldCongress of Pediatric Gastroenterology, Hepatology andNutrition. J Pediatr Gastroentero l Nutr2002;35:S143–50.

3 Wilhelmi I, Román E, Sánchez-Fauquier A. Virusescausing gastroenteritis. Clin Microb io l Infec t2003;9:247–62.

4 AAP. Provisional Committee on Quality Improvement,Subcommittee on Acute Gastroenteritis. Practiceparameter: the management of acute gastroenteritis inyoung children. Pediatrics 1996;97:424–33.

5 Sandhu BK, for the European Society of PediatricGastroenterology, Hepatology and Nutrition WorkingGroup on Acute Diarrhoea. Practical guidelines for themanagement of gastroenteritis in children. J PediatrGastroenterol Nutr 2001;33:S36–9.

Diarrhoea32

Congenital:• Amylase deficiency: cystic fibrosis and

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

to 60% in southeast Africa

Acquired:• Lactose intolerance (secondary to a damage of the

mucose that causes mucose atrophy such as viralenteritis and coeliac disease)

3.15 Carbohydrate intolerance is a common cause of

chronic diarrhoea in infancy. Several different medical

conditions can produce this clinical picture.

20 Fenton TR, Harries JT, Milla PJ. Disordered smallintestinal motility: a rational basis for toddlers’ diarrhoea.Gut 1983;24(10):897–903.

21 Sperber AD, Shvartzman P, Friger M, e t al. Acomparative reappraisal of the Rome II and Rome IIIdiagnostic criteria: are we getting closer to the ‘true’prevalence of irritable bowel syndrome? Eur JGastroenterol Hepatol 2007;19(6):441–7.

22 Spiller R, Aziz Q, Creed F, et al. Guidelines for themanagement of irritable bowel syndrome. Gut2007;56:1770–98.

23 Gregg CR. Enteric bacterial flora and bacterialovergrowth syndrome. Semin Gastro inte st Dis2002;13(4):200–9.

24 Assaad AH. Gastrointestinal food allergy andintolerance. Pediatr Ann 2006;35(10):718–26.

25 Kneepkens CM, Hoekstra JH. Malabsorption ofcarbohydrates. Nestle Nutr Workshop Ser PediatrProgram 2005;56:57–69; discussion 69–71.

Further readings

Kligler B, Hanaway P, Cohrssen A. Probiotics in children.Pediatr Clin North Am 2007;54:949–67.

Guarino A, Albano F, Ashkenazi S, et al. European Societyfor Paediatric Gastroenterology, Hepatology, andNutrition/European Society for Paediatric InfectiousDiseases evidence-based guidelines for the managementof acute gastroenteritis in children in Europe: executivesummary. J Pediatr Gastroenterol Nutr 2008;46:619–21.

European Society for Paediatric Gastroenterology,Hepatology, and Nutrition/European Society forPaediatric Infectious Diseases. European Society forPaediatric Gastroenterology, Hepatology, andNutrition/European Society for Paediatric InfectiousDiseases evidence-based guidelines for the managementof acute gastroenteritis in children in Europe. J PediatrGastroenterol Nutr 2008;46 suppl 2:S81–122.

Diarrhoea 33

6 King CK, Glass R, Bresee JS, Duggan C; Centers forDisease Control and Prevention. Managing acutegastroenteritis among children: oral rehydration,maintenance, and nutritional therapy. MMWR Rec Rep2003;52(RR-16):1–16.

7 Armon K, Stephenson T, Macfaul R, et al. An evidenceand consensus based guideline for acute diarrhoeamanagement. Arch Dis Child 2001;85:132–42.

8 Rao MC. Oral rehydration therapy: new explanations foran old remedy. Ann Rev Physiol 2004;66:385–417.

9 Hoque KM, Binder J. Zinc in the treatment of acutediarrhoea: current status and assessment.Gastroenterology 2006;130:2201–5.

10 WHO/UNICEF Joint Statement. Clinical managementof acute diarrhoea. The United Nations Children´sFund/World Health Organization, 2004.WHO/FCH/CAH/04.7.

11 Szajewska H, Setty M, Mrukowicz J, Guandalini S.Probiotic in gastrointestinal diseases in children: hard andnot so hard evidence of efficacy. J Pediatr GastroenterolNutr 2006;42:454–75.

12 Gibbons T, Fuchs GJ. Chronic enteropathy: clinicalaspects. Nestle Nutr Workshop Ser Pediatr Program2007;59:89–101; discussion 102–4.

13 Booth IW, McNeish AS. Mechanisms of diarrhoea.Ballières Clin Gastroenterol 1993;7:215–42.

14 Lee WS, Boey CC. Chronic diarrhoea in infants andyoung children: causes, clinical features and outcome. JPaediatr Child Health 1999;35(3):260–3.

15 Cave DR. Wireless video capsule endoscopy. ClinPerspec Gastroenterol 2002;5:203–7.

16 Seidman EG, Sant´Anna AM, Dirks MH. Potencialapplications of wireless capsule endoscopy in thepediatric age group. Gastrointest Endosc Clin N Am2004;14(1):207–17.

17 Aabakken L, Scholz T, Ostensen AB, et al. Capsuleendoscopy is feasible in small children. Endoscopy2003;35(9):798.

18 Argüelles-Arias F, Argüelles-Martín F, Caunedo A, etal. Utilidades de la cápsula endoscópica engastroenterología pediátrica. Ann Pediatr 2003;59:586–9.

19 Argüelles-Arias F, Caunedo A, Romero J, et al. Thevalue of capsule endoscopy in paediatric patients with asuspicion of Crohn´s disease. Endoscopy2004;36(10):869–73.

Constipation

Carolina Gutiérrez, MD, and Jerónimo Gonzálvez, MD

Chapter 434

Functional constipation (90%)

Organic constipation (10%)• Anatomical malformations

– Anal stenosis

– Imperforatus anus

– Anterior displaced anus

– Pelvic mass (sacral teratoma)

• Neuromuscular disorders

– Cerebral palsy, hypotonia

– Disorders of the spinal cord

– Myelomeningocoele

– Spinal cord trauma

– Spinal cord tumour

– Muscular dystrophy

• Metabolic and endocrine disorders

– Hypothyroidism

– Renal acidosis

– Diabetes insipidus

– Hypercalcaemia

– Hypokalaemia

• Intestinal nerve or muscle

disorders

– Hirschsprung’s disease

– Neuronal intestinal dysplasia

– Chronic intestinal pseudo-

obstruction

• Gastrointestinal diseases

– Coeliac disease

– Cystic fibrosis

– Cow’s milk intolerance

• Abnormal abdominal musculature

– Prune belly syndrome

– Gastroschisis

– Down syndrome

• Drugs

– Antacids

– Codein

– Phenytoin

– Opiates

– Antidepressants

– Anticholinergics

– Iron

Table 4.1 Differential diagnosis of constipation

Normal defecation and functionalconstipation

Mechanisms of normal defecation and continence aresummarized in figure 4.1. The term ‘functionalconstipation’ (also called idiopathic or retentive constipationor psychogenic megacolon) describes all children in whomconstipation does not have an organic aetiology, and it isgenerally caused by a maladaptative response to defecation(4.2). In functional constipation, fear of defecation after apainful experience and repeated attempts of voluntarywithholding of stools (vicious circle theory) lead to the

Definition and aetiology

Constipation can be defined as the delay or difficulty indefecation occurring for ≥2 weeks and causing significantdistress to the patient. As a symptom, constipation can becaused by many different disorders (Table 4.1) but 90% ofall constipated children have functional constipation, withno identifiable organic or anatomical cause. Constipation isa common symptom in paediatric clinical practice,accounting for 3% of all general paediatric visits andbetween 10 and 25% of all cases in paediatricgastroenterology reference units.

Constipation 35

Stools in rectumRectal distension

• Temporary reflexrelaxation of the IAE(RAIR) mediated by theautonomic nervous system

• Stool in contact withsensitive receptors inanal canal

Sigmoid contraction

• Simultaneous contraction of EAEgiving time to decide ifcircumstances areappropriate for defecation

Defecation convenient Defecation inconvenient

• Diaphragms andabdominal musclecontraction

• Increased intrarectalpressure

• Puborectalis musclerelaxation

• EAE relaxation• Mediated by the

voluntary nervous system

• Puborectalis musclecontraction

• EAE contraction• Accommodation of

rectum to its contents• Mediated by the

voluntary nervous system

Evacuation of stools Defecation postponed

4.1 Normal mechanism of defecation and continence. In

newborn babies and very young infants, the role played

by the cerebral cortex in these events is not yet

developed; therefore, defecation occurs when the internal

sphincter relaxes. IAE: internal anal sphincter; EAE:

external anal sphincter; RAIR: rectoanal inhibitory reflex.

Painful defecation

A fecal massaccumulates in

rectum

Fear of defecation

With-holding behaviour

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

4.2 Pathophysiology of functional constipation.

formation of a functional megarectum with loss of rectalsensitivity and of the normal need to defecate. Progressiveaccumulation of feces in the rectum leads to pelvic floormuscle fatigue and anal sphincter poor competence, causingoverflow incontinence and nonvoluntary expulsion offaeces, or encopresis. Encopresis is the involuntary loss ofstool into the child’s underwear in a child with functionalconstipation after the acquisition of the toilet skills that areacquired by most children by the age of 4 years.Constitutional and inherited factors such as slow intrinsicmotility and low fibre diet may contribute to constipation.

Onset of functional constipation occurs in one of threeperiods: (1) in infants, often corresponding with the changefrom breast milk to commercial formula or introduction ofsolids, (2) in toddlers acquiring toilet skills, and (3) inchildren as school starts. Table 4.2 summarizes the mainclinical symptoms and complications in children withfunctional constipation1. Diagnostic criteria for childhoodfunctional gastrointestinal disorders, known as the Rome IIIcriteria have been recently reviewed2, 3. Functional disordersof defecation include infant dyschezia and functionalconstipation in infants and children (Table 4.3).

Infant dyschezia

Some otherwise healthy infants less than 6 months of ageappear to have significant discomfort and excessive strainingassociated with passing soft stools. The symptoms resolvespontaneously after a few weeks and are probably related toa failure to coordinate increased intra-abdominal pressure

with pelvic floor relaxation. Parents need to be reassuredthat the phenomenon is part of the child’s learning processand that no intervention is necessary. Rectal stimulationshould be avoided to prevent artificial sensory experiencesand laxatives are unnecessary.

Constipation36

• Retentive posturing: affected children are often

described as standing on their toes, holding onto

furniture, stiffening their legs and hiding in a corner

• Infrequent and painful passage of huge stools

• Abdominal pain and irritability, anal or rectal pain

• Anorexia

• Encopresis: sometimes is the first symptom and it is

confused with chronic diarrhoea

• Urinary symptoms:

– Night-time urinary incontinence

– Daytime urinary incontinence

– Urinary tract infection

– Less frequently: vesicoureteral reflux, urinary retention,

megacystis, ureteral obstruction

• Immediate resolution of symptoms after the passage of

a huge stool

• Anal fissures

• Rectal prolapse

Table 4.2 Clinical symptoms and complications in children with functional constipation

G6. Infant dyscheziaMust include both of the following in an infant younger

than 6 months of age:

1 At least 10 minutes of straining and crying before

successful passage of soft stools

2 No other health problems

G7. Functional constipation (neonate and toddler)Must include 1 month of at least 2 of the following in

infants up to 4 years of age

1 Two or fewer defecations per week

2 At least 1 episode per week of incontinence after the

acquisition of toileting skills

3 History of excessive stool retention

4 History of painful or hard bowel movements

5 Presence of a large faecal mass in the rectum

6 History of large-diameter stools that may obstruct the

toilet

Accompanying symptoms may include irritability,

decreased appetite and/or early satiety. The

accompanying symptoms disappear immediately

following passage of a large stool.

H3a. Functional constipation (child and adolescent)Must include 2 or more of the following in a child with a

developmental age of at least 4 years*:

1 Two or fewer defecations in the toilet per week

2 At least 1 episode per week of incontinence

3 History of retentive posturing or excessive volitional

stooling retention

4 History of painful or hard bowel movements

5 Presence of a large faecal mass in the rectum

6 History of large diameter stools that may obstruct the

toilet

*Criteria fulfilled at least once per week for at least

2 months before diagnosis

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

Constipation 37

4.3 Hirschsprung’s

disease is

characterized by the

absence of ganglion

cells in the myenteric

and submucosal

plexuses of the colon

leading to sustained

contraction of the

aganglionic segment

(A). The bowel

proximal to the

aganglionic segment

become dilated (B)

with secondary

intestinal ischaemia

that contributes to

enterocolitis.

with secondary intestinal ischaemia that contributes toenterocolitis. The aganglionic segment begins in the internalanal sphincter and extends proximally, in 75% of cases tothe rectosigmoid area, in 20% to the colon proximal to thesplenic flexure, in 3–5% there is total colonic aganglionosisand, even less frequently, there is total intestinalaganglionosis. There is also a very rare form of the disease inwhich there is an ultra-short segment involving only the verydistal 2–5 cm of the rectum.

Symptoms and signs of Hirschsprung’s disease aresummarized in Table 4.4. Enterocolitis is the most seriouscomplication and it could be the first manifestation of thedisease. It is characterized by the abrupt onset of fever,abdominal distention, and explosive and sometimes bloodydiarrhoea, mainly in 2–3-month-old infants and isassociated with a mortality of 20%. Mortality is reducedwith early diagnosis of Hirschsprung’s disease.

Functional constipation

The definition of functional constipation takes into accountnot only the frequency of stools but also the passage ofpainful bowel movements and stool retention with orwithout encopresis. Normal stool frequency ranges fromfour per day during the first week of life to two per day at 1year of age. The normal adult range of three per day to threeper week is attained by 4 years of age. Some breastfed babieshave very infrequent stools of normal consistency withoutdistress; these infants are usually perfectly healthy andinfrequent stools relate to almost complete absorption ofbreast milk, leaving very little residue for stool formation.

Hirschsprung’s disease

Hirschsprung’s disease, with an incidence of 1 in 5000 livebirths, is the most frequent cause of lower intestinalobstruction in newborns. It is found in about 3% of childrenand toddlers with severe refractory constipation referred tothe paediatric gastroenterologist (4.3). Hirschsprung’sdisease is characterized by the absence of ganglion cells inthe myenteric and submucosal plexuses of the colon leadingto sustained contraction of the aganglionic segment. Thebowel proximal to the aganglionic segment becomes dilated Symptoms

• Constipation beginning early in life

• Delayed passage of meconium

• Failure to thrive

• Abdominal distention

• Absence of encopresis

• Fever, bloody diarrhoea (enterocolitis)

• Chronic constipation not responding to treatment

Signs• Passage of liquid stools and gas after rectal digital

examination

• Empty rectal vault (although stool is palpable in the

abdomen)

• Increased anal tone

• Signs of syndromes associated with HD

– Down syndrome

– Multiple endocrine neoplasia IIA

– Congenital deafness

– Waardenberg`s syndrome

– Neurofibromatosis

Table 4.4 Signs and symptoms suggestive of

Hirschsprung’s disease (HD) in constipated children

Diagnosis

A thorough history and physical examination (including theperianal area, spine, reflexes in the distal extremities, anddigital rectal examination) is generally sufficient to establishthe diagnosis of functional constipation. The digital rectalexamination is recommended to detect the faecal retentionin the rectum typical of functional constipation. Thepresence of symptoms or signs suggestive of organic diseaseor the persistence of symptoms after treatment should leadto further evaluation.

Constipation in early life is a special situation as it couldbe the expression of a serious congenital disorder such asHirschsprung’s disease, meconium plugs, cystic fibrosis,anal malformations, or spinal cord anomalies, but functionalconstipation is the main cause. Approximately 40% ofchildren with functional constipation develop symptomsduring the first year of life4.

Laboratory testsOccult blood testing in stool is recommended in infants withconstipation and in children with associated abdominalpain, failure to thrive, and intermittent diarrhoea. A positiveoccult blood test suggests enterocolitis or other causes ofintestinal inflammation. Other laboratory tests to exclude

hypercalcaemia, hypothyroidism, and coeliac disease areuseful in selected cases. In constipated infants, andparticularly if there is delayed passage of meconium, a sweattest is recommended to exclude cystic fibrosis.

Abdominal radiographsRadiological studies are not indicated in uncomplicatedconstipation. An abdominal radiograph can be useful indetermining the presence of faecal impaction in the childwho refuses a rectal examination, and in the obese childwhen abdominal and rectal examination are suboptimal(4.4).

Anorectal manometryThe main clinical role of anorectal manometry is in theevaluation of children with severe constipation notresponding to treatment, or in those with signs or symptomssuggestive of organic disease, in which the diagnosis ofHirschsprung`s disease needs to be excluded5. Differentprobes for anorectal manometry are available (4.5). Toexclude Hirschsprung’s disease, an Arhan type anorectalmanometry probe connected to a pneumohydraulic capillaryinfusion system is commonly used (4.6, 4.7).

Constipation38

4.4 Abdominal X-ray showing severe faecal retention in

the rectum of a child with functional constipation.

4.5 A view of an anorectal manometry station. A

manometry probe is connected to a polygraph with

pneumohydraulic capillary infusion system and pressure

transducers that transmit to a computer that generates a

graphic pressure recording. The room must be

comfortable; playing with familiar toys or watching

cartoons on television help to reduce anxiety in the child.

Constipation 39

4.7 A: The open-tipped perfusion manometer with

4–8 channels is the most accurate for recording resting

and squeeze pressures of the anal canal and to define

the vector volume. B: A soft catheter with 4–8 tiny openings

around its circumference provides directional pressure

measurements in four quadrants of the anal sphincter.

Pressures are measured using a 1 cm station or a

continuous pullthrough technique. This technique is

especially helpful in evaluation of faecal incontinence due to postoperative states or myelomeningo coele, tethered

cord, and various types of spinal cord dysfunction.

4.6 A: Anorectal manometry

probe formed by a plastic tube

with four interior channels. One

channel is connected to a latex

balloon located in the distal

segment able to distend with

air (A). The second one is open

to the rectal lumen (B). The

third and fourth channels are

covered by small latex balloons

and located in the anal channel

and the anal verge (C, D). B:

The B, C and D channels

transmit pressure variations in water by pressure transducers

to the pneumohydraulic capillary infusion system low

compliance system, able to perfuse distilled water at a rate of

0.5 ml/min. C: The electrical signals from the transducers are

transmitted to a computer, which produces a graphic record

of the pressures of rectal ampulla (B), anal canal (C) and

external anal sphincter (D).

A

C

B

B

A

B

C

D

4.9 The RAIR is persistently absent in Hirschsprung`s

disease because of the absence of ganglion cells that would

transmit the distention reflex to the internal anal sphincter.

The RAIR has been reported to be absent, atypical, or

normal in patients with neuronal intestinal dysplasia. Barium

enema and rectal biopsy to exclude Hirschsprung’s disease

need to be performed in all patients with absent or atypical

RAIR.

4.8 A: The child lies

comfortably in the left

lateral decubitus position

and the catheter is

inserted into the rectum

to simultaneously

measure the pressures

of the rectal ampulla,

anal canal, and external

anal sphincter. After a

10-minute stabilization

period, the following

parameters are

recorded: mean rectal ampullar resting pressure, mean anal canal resting pressure, and mean external anal sphincter

resting pressure. B: Posteriorly increasing volumes of air (5–50 ml) to inflate the rectal balloon are progressively

introduced. This would trigger the rectoanal inhibitory reflex (RAIR), i.e the drop of anal pressure during rectal distention

transmitted by the ganglion cells of the submucosal and myenteric plexus. The RAIR is present in healthy infants (even

preterm older than 26 weeks gestational age) and children and in patients with functional constipation and encopresis. The

amplitude of volume relaxation increases with increasing balloon distention volume. The threshold volume to elicit RAIR

may be quite high in chronically constipated children; at times 120 ml is needed to demonstrate the reflex.

An enema the night before the test is the recommendedpreparation, although some patients may need 2–3 days ofenema administration to assure an empty rectal vault. Mostinfants and children can be tested without sedation, butfasting for 4–6 hours is also prudent in case the child needssedative medication or it is necessary to feed infants duringthe test as a sedative manoeuvre. The procedure should beexplained to the child and the parents to reduce anxiety andpromote cooperation. Technique and interpretation aresummarized in figures 4.8–4.10.

Barium enema studyA barium enema study is unnecessary in most children withconstipation, and is less accurate than anorectal manometryand rectal biopsy in the diagnosis of Hirschsprung’sdisease5. An unprepared barium enema is useful in childrenwith Hirschsprung’s disease to delineate the extent and thelocation of a transition zone between the tight aganglionicsegment and the dilated proximal colon (4.11).

Constipation40

A B

Constipation 41

4.11 Barium

enema in

Hirschsprung’s

disease (HD)

showing a

transition zone

from aganglionic

to ganglionic

bowel. Arrow

points to the

transition zone.

A normal barium

enema does not

rule out HD: in

young infants a

transition zone

may not be seen

simply because there has not been enough time to

distend the ganglionic portion of the colon with stool.

Patients with total aganglionosis may present with

microcolon or normal calibre colon. It is important not to

cleanse the colon in order to accentuate the transition

zone and the catheter should be inserted at the end of the

anal canal in order to avoid missing short-segment

disease. Barium enema should not be performed in

suspected enterocolitis as it can cause perforation. If the

initial enema is not diagnostic a 24- and/or 48-hour follow-

up abdominal radiograph including lateral projection could

be performed. Prolonged retention of barium suggest the

diagnosis of HD.

Rectal biopsy Rectal biopsy stained for acetylcholinesterase activity is thebest test to rule out Hirschsprung’s disease and should beperformed in infants and children with suggestive clinicaldata and absence or atypical RAIR in anorectalmanometry5. The normal anus has a paucity or absence ofganglion cells at the level of the anal verge. To avoid missinga rare case of ultra-short segment Hirschsprung`s disease, itis recommended to perform rectal biopsy 2–3 cm above themucocutaneous junction.

The biopsy can be obtained by suction at the bedside oroffice, or a full-thickness biopsy can be performed. Biopsiesshould be deep enough to include adequate submucosa.

Occasionally suction biopsies are not diagnostic and a full-thickness biopsy is necessary (4.12). Histopathologicalabsence of ganglion cells in the myenteric and submucosalplexus and the presence of hypertrophied nerve fibres in thelamina propria, muscularis mucosa, and submucosa are thehallmark of the disease (4.13).

Colonic transit studyThe estimation of total and segmentary colonic transit timeis useful in two main situations: (1) to provide objectiveinformation in children who report infrequent bowelmovements, but who have no objective findings of

4.10 In chronic refractory constipation defecatory

dynamics should also be assessed asking the child to

expel the manometric balloon simulating defecation.

Normally, an increase in rectal pressure (Valsalva

manoeuvre with abdominal compression) with

simultaneous drop in anal canal and external anal

sphincter pressures (relaxation of the anal sphincter and

perineal descent) is recorded. Paradoxical puborectalis

contraction of the external anal sphincter can be

demonstrated in children with chronic constipation and

constitutes the manometric expression of the faecal

retention behaviour. There is simultaneous increase in

external anal sphincter, anal canal, and rectal pressures

on attempted balloon expulsion. The presence of

paradoxical anal contraction is correlated to severe

constipation refractory to treatment. Biofeedback designed

to instruct patients on sphincter relaxation may help these

patients.

Constipation42

4.12 In infants requiring laparotomy or in definitive

surgical procedure, serial, progressively proximal, full-

thickness biopsies are obtained to determine the level at

which ganglionic bowel begins (levelling procedure).

A

B

4.13 A: Normal subject. Haematoxylin and eosin stain of

colonic biopsy showing myenteric plexus with ganglionic

cells (2) between the circular and longitudinal muscle

layers (1). B: Hirschsprung`s disease (HD). Ganglion cells

are absent in the intermuscular plexus with increase in

nerve fibres. Acetylcholinesterase staining of colonic

biopsy in HD shows an increased submucosal nerve

plexus, as most of these nerve fibres are cholinergic. The

histochemical staining for acetylcholinesterase requires

only the lamina propria of the mucosa, which can be

obtained by suction technique. 1: Muscle layers;

2: myenteric plexus (no ganglion cells).

1 12

1

2

1 1

2112

A

B

4.14 A gelatin capsule with 10 polyurethane radiopaque

markers containing barium sulphate USP is administered

at 9:00 am on each of 6 consecutive days (A). The

capsules contain different marker forms (B). An

anteroposterior abdominal control radiographic study is

performed on day 7 (at 9:00 am).

constipation on repeated physical examination, and (2) inchildren with chronic constipation refractory toconventional treatment.

Ingestion of radio-opaque markers followed by

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

Management

Most children with functional constipation with orwithout encopresis will benefit from a precise, well-organized plan including education, disimpaction,maintenance treatment, follow-up, and treatment ofrecurrences4, 7 (Tab le s 4.5–4.7). The most commonreason for poor outcome is insufficient treatment, andespecially the reluctance of parents and physicians to the

Constipation 43

4.16 Constipation

with colonic inertia.

(Total colonic transit

time = 93.6 hours,

right colon = 26.4

hours, left colon =

26.4 hours,

rectosigmoid colon =

40.8 hours). A global

delay in colonic

transit may suggest

the presence of a

more generalized

alteration in colonic

motility, amenable to

treatment with

prokinetic drugs.

4.15 To determine the

segmental transit

time, three areas are

delineated, tracing a

line joining the spinal

processes of all the

vertebrae to L5.

Using L5 as centre,

lines are in turn

traced to the left

anterosuperior iliac

spine and to the right

pelvic outlet,

establishing areas

corresponding to the

right colon (caecum,

ascending colon,

proximal half of

transverse colon), left colon (distal half of transverse

colon, descending colon), and rectosigmoid colon.

Counting the markers yield the following transit times:

total colonic transit time and the segmental colonic transit

times for the right colon, the left colon, and the

rectosigmoid colon. These transit times are estimated

using the following formula: colon transit time = (sum of

the markers × [time between administration ÷ number of

markers per capsule]) = sum of the markers × 2.4.

use of laxatives for sufficient periods of time7, 8.Maintenance therapy may be necessary for many

months. Primary care providers and families should beaware that relapses are common and that difficulty withbowel movements may continue into adolescence. Inchildren unresponsive to conventional management,consideration may be given to a time-limited trial of a cow’smilk-free diet12, 13. Biofeedback consists of teaching torecognize rectal distention, to contract and relax externalanal sphincter and puborectalis muscle, and to coordinatethese functions with the help of anorectal pressurerecording. It has been shown to be an effective short-termtreatment of children with severe intractable constipation,especially those showing distal delay in CTT andparadoxical anal contraction in anorectal manometry14. Forcooperative children, anorectal biofeedback trainingprovides auditory and visual information about analsphincter pressure. Children learn to relax or contract the

4.17 Constipation

with delayed left

colonic and

rectosigmoid

transit. (Total

colonic transit time

= 120 hours, right

colon = 14.4 hours,

left colon = 45.6

hours, rectosigmoid

colon = 60 hours).

A collection of

markers in the left

colon and

rectosigmoid

suggests outlet

dysfunction such as

paradoxical

puborectalis contraction that could be demonstrated in

anorectal manometry and may improve with various

forms of biofeedback therapy.

anal sphincter to produce evacuation and continence and itcan help them to reduce the threshold volume for rectalsensation (4.10).

Constipation44

Table 4.5 Treatment of functional constipation

Education

Disimpactation if faecal

impaction detected

Maintenance treatment

Diet

Behavioural

modification

Medication

Follow-up

• Explanation of normal defecation mechanism and pathogenesis of functional constipation,

including faecal soiling as an involuntary consequence of functional constipation

• Try to obtain a positive and supportive attitude of parents

• Explain chronicity and possible recurrences

See Table 4.6

• Increase intake of fluid, reduce dairy products.

• Fibre ingestion preferably from natural food:

• Age (years) + 5 g/day until 30 g/day9

• Regular toilet habits

• Unhurried time after meals

• Diaries of stool frequency

• Reward system

• Early recommendation. Continuous administration may be necessary for 3–6 months10

• Lubricants and osmotic agents are effective and safe in children11. See Table 4.7

• Gradual weaning of medication after months of regular defecatory habits

• Treatment of recurrences

Table 4.6 Disimpactation treatment

Oral>2 years

Polyethylene glycol with electrolytes

Polyethylene glycol without electrolytes

Mineral oil

Lactulose or sorbitol

Senna

RectalGlycerin suppositories

Physiological enema

Contraindicated: soapsuds, tap water, or magnesium enemas

25 ml/kg/h up to 1000 ml/h until clear liquid stools (premedication with

metoclopramide 5 mg, usually 12–20 hours are needed)

1.5 g/kg/day for 3 days

3 ml/kg/twice day for 7 days

2 ml/kg/twice day for 7 days

2–6 years: 4–7 mg/dose (2 doses)

>6 years: 7–15 mg/dose (2 doses)

Constipation 45

Osmotics Age DoseMagnesium hydroxide >1 month 1–3 ml/kg/day in 1–2 doses

Lactulose or sorbitol >1 month 1–3 ml/kg/day in 1–2 doses

Polyethylene glycol 3350 without electrolytes >1 month 0.7 g/kg/day in 1–2 doses

LubricantsMineral oil >12 months 1–3 ml/kg/day in 1–2 doses

Table 4.7 Maintenance treatment

References

1 Loening-Baucke V. Urinary incontinence and urinarytract infection and their resolution with treatment ofchronic constipation of childhood. Paediatric s1997;100(2 Pt 1):228–32.

2 Hyman PE, Milla PJ, Benninga MA, et al. Childhoodfunctional gastrointestinal disorders: neonate/toddler.Gastroenterology 2006;130(5):1519–26.

3 Rasquin A, Di Lorenzo C, Forbes D, et al. Childhoodfunctional gastrointestinal disorders: child/adolescent.Gastroenterology 2006;130(5):1527–37.

4 Youssef NN, Di Lorenzo C. Childhood constipation:evaluation and treatment. J Clin Gastroentero l2001;33(3):199–205.

5 de Lorijn F, Kremer LC, Reitsma JB, Benninga MA.Diagnostic tests in Hirschsprung disease: a systematicreview. J Pediatr Gastroenterol Nutr 2006;42(5):496–505.

6 Gutierrez C, Marco A, Nogales A, Tebar R. Total andsegmental colonic transit time and anorectal manometryin children with chronic idiopathic constipation. J PediatrGastroenterol Nutr 2002;35(1):31–8.

7 Loening-Baucke V. Polyethylene glycol withoutelectrolytes 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 ofchildhood constipation by primary care physicians:efficacy and predictors of outcome. Paediatric s2005;115(4):873–7.

9 Marlett JA, McBurney MI, Slavin JL. Position of theAmerican Dietetic Association: health implications ofdietary 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 childhoodencopresis. Lancet 1991;338(8766):523–7.

11 Sharif F, Crushell E, O’Driscoll K, Bourke B. Liquidparaffin: a reappraisal of its role in the treatment ofconstipation. Arch Dis Child 2001;85(2):121–4.

12 Andiran F, Dayi S, Mete E. Cow’s milk consumption inconstipation and anal fissure in infants and youngchildren. J Paediatr Child Health 2003;39(5):329–31.

13 Iacono G, Cavataio F, Montalto G, et al. Intolerance ofcow’s milk and chronic constipation in children. N Engl JMed 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 infantsand children: evaluation and treatment: a medicalposition statement of the North American Society forPediatric Gastroenterology and Nutrition. J PediatrGastroenterol Nutr 1999;29:612–26.

Baker SS, Liptak GS, Colletti RB, et al. Evaluation andtreatment of constipation in infants and children:summary of updated recommendations of the NorthAmerican Society for Pediatric Gastroenterology,Hepatology, and Nutrition. J Pediatr Gastroenterol Nutr2006;43:405–7.

Loening-Baucke V. Anorectal manometry and Biofeedbacktraining. In: Hyman PE, Di Lorenzo C (eds). PediatricGastrointestinal Motility Disorders. Academy ProfessionalInformation Services, New York, 1994, pp. 231–52.

Loening-Baucke V. Constipation and encopresis. In: WyllieR, Hyams JS (eds). Pediatric Gastrointestinal Disease:Pathophysio logy, Diagnosis, Management. Saunders,Philadelphia 2006, pp. 177–91.

Stallion A, Dough Kou T. Hirschsprung`s disease. In:Wyllie R, Hyams JS (eds). Pediatric GastrointestinalDisease : Pathophysio logy, Diagnosis, Management.Saunders, Philadelphia, 2006, pp. 735–48.

Abdominal pain in childhood

Iñaki X. Irastorza Terradillos, MD, and Juan C. Vitoria Cormenzana, MD, PhD

Chapter 546

Introduction

Abdominal pain is one of the most challenging symptoms inpaediatric practice. Often imprecise, abdominal pain mayrequire, especially if acute, an intense diagnostic approach inorder to avoid misidentification of potentially underlyingmedical or surgical problems. On the other hand, chronicabdominal pain, most currently functional in origin,frequently generates a situation of familial and patient stressdue to the persistent recurrence of symptoms. Thepaediatrician can also be affected by this stress and can be‘forced’ to prescribe multiple unnecessary medicalinvestigations (5.1).

Understanding the neurophysiology of pain perception iscrucial to making an appropriate diagnostic approach. Not

every pain perceived in the abdomen originates in theabdomen, and not every pain originating in the abdomen isperceived in the abdomen. Furthermore, characteristics ofabdominal pain are very diverse; the specific pattern ofabdominal pain sensation will help to establish the diagnosis.

Specific types of pain receptors are located in theabdominal wall, in the mesentery, in the serosal surfaces, inthe hollow viscera wall, and in the mucosal surfaces. Mainreceptors in each location will respond to specific stimulitypes. Abdominal pain receptors can be triggered bymechanical and chemical stimuli (5.2). Mechanical stretchand chemical stimuli are the main triggers involved invisceral nociceptor activation.

Functional

Organic

Functional

Organic

Acute abdominal pain Chronic abdominal pain

5.1 Aetiology of acute and chronic abdominal pain.

5.2 Genesis and perception of abdominal pain.

HistamineBradykinin

PGs

Seratonin

Chloride

TractionContraction

Distension

Torsion

Stretch

Mechanical

Pain

Culture

Illness?

School

Day/night

Family

Age

Chemical

Abdominal pain in childhood 47

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

Chronic abdominal pain

Complaints of recurrent abdominal pain affect 10–40% ofchildren and its prevalence increases with age (5.3)1.

When recurrent abdominal pain was first described in19582, only 10% of patients had a definitive diagnosis; 90%of patients remained undiagnosed or labelled as ‘suspectedfunctional abdominal pain’. New pathological entities suchas Helicobacter pylori infection or non-IgE mediated foodallergies and the development of diagnostic techniques hasallowed diagnosis to improve to up to 50% of patients (5.4).

In order to avoid unnecessary tests a conservativeapproach is appropriate. Alarm symptoms, signs, andfeatures that should make the physician suspect that thepain has an organic background are listed in Table 5.1. Intheir absence, pain is very likely to have a functional originand therefore most tests will be unnecessary, leading only toincrease familial anxiety.

Organic

Functional

Organic

Functional

1958 2000

5.3 Incidence of recurrent abdominal pain by age. 5.4 Aetiology of recurrent abdominal pain.

Pain distant from umbilicus (right upper or right lower

quadrant pain)

Dysphagia

Persistent vomiting

Gastrointestinal blood loss

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

Table 5.1 Alarm symptoms, signs, and features in

recurrent abdominal pain

0 2 4 6 8 10 12 14Age (years)

Boys

Girls

Functional gastrointestinal disorders

Functional gastrointestinal disorders (FGID) are defined asa variable combination of chronic or recurrentgastrointestinal symptoms not explained by structural orbiochemical abnormalities. A symptoms-based classifica -tion, rather than a targeted organ-based one, has been set bythe Rome III committee (Table 5.2) (5.5)3.

Functional dyspepsiaDyspepsia is pain or discomfort localized in the upperabdomen. Symptoms may vary including fullness, earlysatiety, bloating, nausea, retching, and vomiting. No signs orsymptoms reliably differentiate functional dyspepsia fromupper gastrointestinal organic disorders (Table 5.3)4.

To establish the diagnosis of functional dyspepsia (Table


Vomiting and aerophagiaAdolescent rumination syndrome

Cyclic vomiting syndrome

Aerophagia

Abdominal pain-related FGIDFunctional dyspepsia*

Irritable bowel syndrome*

Abdominal migraine*

Functional abdominal pain

Constipation and incontinenceFunctional 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

Table 5.2 Functional gastrointestinal disorders

Functionalabdominal pain

Abdominalmigraine

Functionaldyspepsia

Functionalabdominal pain

syndrome

Irritable bowelsyndrome

5.5 Overview of abdominal pain-related functional

gastrointestinal disease.

Suspected disorder Diagnostic tests

Functional dyspepsia Always required No signs or symptoms reliably differentiates organic from

functional

Functional abdominal pain Depending on anamnesis

Irritable bowel syndrome Not required If diagnostic criteria fulfilled

Abdominal migraine Not required If diagnostic criteria fulfilled

Table 5.3 Abdominal pain-related functional gastrointestinal disorders diagnostic approach

5.4) it is therefore necessary to rule out organic diseasespresenting with dyspepsia, such as gastro-oesophageal refluxdisease (5.6, 5.7), Helicobacter pylori infection, eosinophilicoesophagitis, and gastritis.


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.

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).

• 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

Table 5.4 Diagnostic criteria for functional dyspepsia

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.

Irritable bowel syndromeIrritable bowel syndrome (IBS) is characterized by episodesof recurrent abdominal pain temporally associated withaltered bowel habits: either constipation or diarrhoea (Table5.5). If the child fulfils the diagnostic criteria no further


Table 5.5 Diagnostic criteria for IBS

• Anxiety• Depression• Social learning of illness

behaviour

Psychological

• 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


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

Genetic predisposition

• Infection• Inflammation• Trauma• Allergy

Visceral hypersensitivity

Irritable bowel syndrome

investigations are required. Aetiology of IBS is multifactorialand not completely understood (5.8)5, 6. Availabletherapeutic options are summarized in Table 5.6, althoughmost of these patients’ symptoms improve if they manage toreduce or dominate the stress intervening factors.

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

Irritable bowel syndrome• Peppermint oil

• 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

Table 5.6 Treatment of abdominal pain-related FIGD


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.

5.9 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.

+++

Liquidfaeces

2/3 water1/3 faeces

15 drops ClinitestAmes tablet

Negative Positive?

-ve0%

Trace1/4%

+1/2%

++3/4%

+++1%

+++2%

A B

Other disordersOther prevalent disorders that usually present with chronicabdominal pain and diarrhoea or constipation include:

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

A

B

5.11 Jejunal biopsy with flattened villi and increased

inflammatory cellularity in lamina propria in cow’s milk

protein enteropathy.

5.12 Intestinal biopsy showing multiple Giardia lambliatrophozoites (inset).

Abdominal migraineAbdominal migraine is characterized by recurrentparoxysmal episodes of acute, periumbilical and noncolickypain associated with anorexia, nausea, vomiting, headache,and pallor (Table 5.7). The origin of abdominal migraine islinked to other functional disorders like migraine headacheand cyclic vomiting syndrome, and patients often progressfrom one to another. Abdominal migraine is one of thefunctional disorders that present more familial aggregation.

Familial aggregation and response to antimigraine drugs,although not included in the diagnostic criteria, support thediagnosis. Treatment options are listed in Table 5.6.

A number of digestive and extradigestive conditionsincluding renal colic, recurrent pancreatitis (5.13),choledocholithiasis, familial Mediterranean fever, Crohn’sdisease (5.14), and porphyria, must be ruled out beforeestablishing the diagnosis of 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


All five criteria must be fulfilled at least twice in the preceding 12 months

Table 5.7 Diagnostic criteria for abdominal migraine

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.


• Episodic or continuous abdominal pain

• Insufficient criteria for other FGID

• No evidence of inflammatory, anatomic, metabolic, or

neoplastic process that explains the subject’s

symptoms

All three criteria must be fulfilled at least once per week

for at least 2 months

Table 5.8 Diagnostic criteria for functional

abdominal pain

• Functional abdominal pain at least 25% of the time

and at least one of the following:

– Some loss of daily activity

– Additional somatic symptoms: headache, limb pain, or

difficulty sleeping

Criteria must be fulfilled at least once per week for at

least 2 months.

Table 5.9 Diagnostic criteria for functional

abdominal pain syndrome

• Full blood count

• C-reactive protein

• Erythrocyte sedimentation rate

• Amylase

• Sugars breath hydrogen test

• Helicobacter pylori test

• Stool culture and examination for ova and parasites

• Urinalysis and urine culture

• Pregnancy test

• Barium swallow

• Barium follow-through

• Abdominal ultrasound scan

• CT scan

• MRI

• Endoscopy

Table 5.10 Investigations in patients with

suspected functional abdominal pain

Childhood functional abdominal painChildren with recurrent abdominal pain episodes that donot fulfil the previous categories but in whom organicpathology has been reasonably excluded fall within thiscategory (Table 5.8). They represent the vast majority ofpatients consulting for recurrent abdominal pain in primarypaediatric care.

Functional abdominal pain syndrome has been describedfor a subgroup of patients with functional abdominal painwith more persistent abdominal symptoms associated withother somatic symptoms (Table 5.9). Functional abdominalpain diagnosis can be difficult to establish as there are nospecific criteria as there are for other abdominal pain-relatedFGID. It is therefore sensible to perform some basicinvestigations (Table 5.10) in order to exclude an organicorigin of the symptoms. Routine investigations are notrequired 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 toperform or decide if the patient requires an endoscopy.

A pychosocial approach in patients with functionalabdominal pain is particularly indicated because thesymptoms are often associated with varying degrees ofanxiety, depression, or manipulative behaviour. Behaviouralintervention associated or not with antidepressant drugs isindicated in these patients7.

Differential diagnosis include a wide range of digestiveand nondigestive diseases such as coeliac disease (5.15),inflammatory bowel disease (5.16), food intolerances,Helicobacter pylori infection, eosinophilic enteritis, chronicpyelonephritis, and parasite infestation. However, it isimportant to remember that in most cases there will be noorganic underlying disease and that not every endoscopic orradiological finding will prove an organic aetiology (5.17).

5.15 Trichobezoar removed from the stomach of a girl

with recurrent abdominal pain and undiagnosed coeliac

disease.

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.

A B C

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

BA

54 Abdominal pain in childhood

Infant colic

Although it has not been proven that infant colic has adigestive or even abdominal origin, many infants withrecurrent paroxysms of irritability, fussing, and crying8

episodes are referred to paediatric gastroenterologists(Tables 5.11, 5.12). The most important point is to reassureparents, 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 tocalm the infant. It has been reported that milk intolerance oroesophagitis might be the cause of excessive crying. Atherapeutic trial with a hydrolysed protein formula ormedication to suppress gastric acid secretion would be areasonable approach10, 11.

55Abdominal pain in childhood

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

• 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

Table 5.12 Treatment of infant colic

8 Wessel MA, Cobb IC, Jackson EB, et al. Paroxysmalfussing in infancy, sometimes called colic. Pediatrics1954;14:421–34.

9 Barr RG. ‘Colic’ is something infants do, rather than acondition they ‘have’: a developmental approach to cryingphenomena, patterns, pacification, and (patho)genesis. In:Barr RG, St James-Roberts I, Keefe MR (eds). NewEvidence on Unexplained Early Crying: its Origins,Nature, and Management. Johnson & Johnson PediatricInstitute, Cincinnati, 2001, pp. 87–104.

10 Lothe L, Lindberg T. Cow’s milk whey protein elicitssymptoms of infant colic in colicky formula-fed infants: adouble blind crossover study. Pediatrics 1989;83:262–6.

11 Hyman PE, Milla PJ, Benninga MA, et al. Childhoodfunctional gastrointestinal disorders: neonate/toddler.Gastroenterology 2006;130:1519–26.

Further reading

Barad AV, Saps M. Factors influencing functionalabdominal pain in children. Curr Gastroenterol Rep2008;10:294–301.

McOmber MA, Shulman RJ. Pediatric functionalgstrointestinal disorders. Nutr Clin Pract2008;23:268–74.

Perez ME, Youssef NW. Dyspepsia in childhood andadolescence: insights and treatment conditions. CurrGastroenterol Rep 2007;9;447–55.

References

1 Oster J. Recurrent abdominal pain, headache, and limbpains in children and adolescents. Pediatrics 1972;50:429.

2 Apley J, Naish N. Recurrent abdominal pains: a field surveyof 1,000 school children. Arch Dis Child 1958;33:165–70.

3 Rasquin A, Di Lorenzo C, Forbes D, et al. Functionalgastrointestinal disorders: child/adolescent.Gastroenterology 2006;130(5):1527–37.

4 Boyle JT. Recurrent abdominal pain: an update. PediatrRev 1997;18:310.

5 Mayer EA, Collins SM. Evolving pathophysiologicmodels of functional gastrointestinal disorders.Gastroenterology 2002;122:2032–48.

6 Morris-Yates A, Talley NJ, Boyce PM, et al. Evidence of agenetic contribution to func tional bowel disorder. Am JGastroenterol 1998;93:1311–17.

7 Campo JV, Bridge J, Ehmann M, et al. Recurrentabdominal pain, anxiety, and depression in primary care.Pediatrics 2004;113:817–24.

Gastrointestinalbleeding

George Gershman, MD, PhD

Chapter 656

HaematemesisHaematemesis is the vomiting of bright-red ‘fresh’ blood, or‘coffee ground’ emesis of dark-brown ‘old’ blood withhaemoglobin (Hb) converted to haematin in the stomach byhydrochloric acid. Usually, haematemesis reflects acutebleeding from the oesophagus, stomach, or proximalduodenum. Swallowing of maternal blood in neonates, andepistaxis in older children, should be ruled out.

MelenaMelena implies liquid, coal black, shiny, sticky, tarry, andfoul-smelling stool. It suggests bleeding from the upper GItract. Occasionally, the site of bleeding can be found in theileum or right colon. However, in this case stool is black butnot tarry. Melena suggests a minimum loss of 50–100 ml5 or2% of blood volume6. Stool may remain black or tarry for afew days after massive haemorrhage, even though activebleeding has ceased.

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

HaematocheziaHaematochezia is the passage of bright red or maroon bloodfrom the rectum. This may be pure blood, bloody diarrhoeaor blood mixed with stool. As a rule, it is a sign of lower GIbleeding from the colon or distal ileum.

Assessment

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

Introduction

Bleeding from the gastrointestinal (GI) tract in infants andchildren is always stressful and frightening for patients andtheir parents and challenging for a physician, especially ifbleeding is severe. The attending paediatrician should actpromptly and adequately to the degree of haemodynamicinstability and initiate a diagnostic work-up according to themode of presentation and common age-specific causes of GIhaemorrhage.

Epidemiology

The incidence of upper GI bleeding among infants andchildren is unknown. Epidemiological data from the UKand USA indicate that the incidence of upper GI bleeding inadults younger than 29 is approximately 18–23 per 100,000adults per year, which is almost 4 to 5 times less than amongolder groups1. It is reasonable to assume that the incidenceof upper GI bleeding in infants and children is even lower.However, the risk of upper GI bleeding is higher (between6.2 and 10.2%) in infants and children admitted topaediatric intensive care units2, 3.

Although rectal bleeding is quite common in paediatricpractice, the epidemiology of this problem is not wellestablished. According to published data, rectal bleedingwas a chief complaint of 0.3% of all visits to a tertiaryemergency department during a 10-month period4.

Definitions

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

Gastrointestinal bleeding 57

Symptoms and signs Blood loss <15% Blood loss <30% Blood loss >30%

Normal appearance + – –

Some anxiety ± + +

Disorientation – – +

Lethargy – ± +

Tachycardia ±* ++ +

Pallor – + ++

Livedo reticularis – + ++

Cold extremities – + +

Capillary refill <2 sec – + +

Hypotension – ± ++

Narrowed pulse pressure – + +

Elevated diastolic pressure – + –

Low diastolic pressure – – +

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

Table 6.1 Manifestations of different degrees of GI blood loss

tomatoes, sweets, amoxicillin, phenytoin, and rifampin cancolour stool and emesis to red or burgundy. Bismuthpreparations, activated charcoal, iron, spinach, blueberries,liquorice can simulate bleeding by black staining of emesisand stool. An appropriate history, a normal physical exam -ina tion, guaiac-negative stool, and/or gastroccult-negativevomitus are sufficient to rule out a true bleeding episode.

It is important to remember that haematemesis and/ormelena can be secondary to epistaxis. History of recenttonsillectomy and adenoidectomy or picking nose habitsincreases the probability of epistaxis. Thorough examinationof the nose and oropharynx can help to establish the rightdiagnosis.

Detailed history and physical examination can help tonarrow the diagnostic work-up. For example, treatmentwith nonsteroidal anti-inflammatory drugs (NSAIDs) is arisk factor for acute gastric ulcers and bleeding from thestomach. Jaundice, hepatomegaly, spider haemangiomata,prominent vessels of the abdominal wall, or ascites are signsof chronic liver disease and suggestive of portalhypertension. Alternatively, GI bleeding in an acutely ill,febrile child with jaundice could be secondary tocoagulopathy or the acute ulceration of the stomach or theduodenum due to sepsis. Careful assessment of the

the aetiology of bleeding. A prompt assessment of estimatedblood loss and the degree of haemodynamic instabilityshould be done using objective criteria, such as mentalstatus, skin colour, capillary refill, pulse, blood pressure, andorthostatic manoeuvres (Table 6.1). Special attentionshould be focused on tachycardia and narrowed pulsepressure, which are the earliest signs of impending shock.Hypotension usually occurs in the late phase of shock inchildren, and is an ominous finding. The value of the initialhaematocrit (Hct) may not accurately reflect the severity ofblood loss. Firstly, the Hct does not fall immediately withhaemorrhage due to proportionate reductions of plasma andred cell volumes. Secondly, it begins to fall due tocompensatory restoration of the intravascular volume by theshift of extravascular fluids into the vascular bed. Thisprocess begins shortly after the onset of bleeding. However,it is not complete for 24–72 hours. At this point, plasmavolume is larger than normal and the Hct reaches its truenadir assuming that bleeding has stopped.

Diagnosis

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

Age Upper GI Bleeding Low GI bleeding

Neonates (0–30 days) Swallowed maternal blood Necrotizing enterocolitis

Stress ulcers/sepsis Midgut volvulus

Haemorrhagic gastritis Hirschsprung’s disease

Haemorrhagic disease of the newborn Vascular malformation

Infants (30 days to Cow’s milk or soy protein allergy Anal fissure

6 months) Oesophagitis Allergic proctitis or enterocolitis

‘Prolapse gastropathy’ Nodular lymphoid hyperplasia

Intussusception

Infants and children Epistaxis Anal fissures

(6 months to 6 years) Oesophagitis Intussusception

‘Prolapse gastropathy’ Meckel’s diverticulum

Portal hypertension Nodular lymphoid hyperplasia

Drug-induced ulcers Polyps

Gastritis Infectious colitis

Mallory–Weiss tear Haemolytic uremic syndrome

Henoch–Schönlein purpura

Children and teenagers Epistaxis Infectious colitis

(7 years to 18 years) Drug-induced gastropathy and acute ulcers Ulcerative colitis

Peptic ulcer Crohn’s disease

Oesophagitis Anal fissure

Gastritis Polyps

Portal hypertension

Table 6.2 Common causes of GI bleeding in children

58 Gastrointestinal bleeding

The results of blood test can give some clues to the natureof bleeding. Low Hb and Hct with normal mean cell volume(MCV) are typical for recent blood loss. An elevated bloodurea nitrogen (BUN) suggests volume depletion andabsorption of the blood proteins in the small intestine,which support the diagnosis of upper GI bleeding. Very lowHb, Hct, and MCV in haemodynamically stable patients, isconsistent with chronic GI blood loss. Knowledge ofcommon causes of GI bleeding in age-specific groups ofchildren helps with the diagnostic strategy (Table 6.2).

Endoscopy is the method of choice for diagnosis of thespecific causes of acute and chronic GI bleeding related tomucosal and submucosal lesions of GI tract. A tagged redblood cell scan and angiography are alternative methodsused to diagnose children with active GI bleeding of obscureorigin, especially when vascular anomalies or haemobilia aresuspected.

perineum can reveal fissures, fistulas, or perianal induration.If the source of bleeding is not obvious, the placement of a

nasogastric tube is very useful. The largest bore tolerable tubeshould be placed for adequate gastric lavage: a 10 to 12 Frsump tube is a reasonable choice for small children and 14 to16 Fr for older patients. Room temperature saline is theoptimal fluid for this procedure. Iced saline lavage is no longerrecommended because it compromises platelet function at thebleeding site and may induce hypothermia (especially ininfants) and subsequent clinically significant arrhythmia. Abloody or coffee ground aspirate indicates upper GI bleeding,if epistaxis was ruled out. The absence of blood in thestomach does not exclude upper GI bleeding, since the sourceof haemorrhage can be in the duodenum. The presence ofcoffee ground fluid in gastric aspirate, which promptly clearsby gastric lavage, suggests that bleeding has stopped.Ineffective gastric lavage indicates ongoing bleeding.

59Gastrointestinal bleeding

6.1 Nodular lymphoid

hyperplasia in infant with

recurrent episodes of rectal

bleeding. Multiple, 3–4 mm,

hemispheric nodules are seen

in the terminal ileum (A).

Similar nodules can be found in

the colon or duodenum (B).

Age-associated aetiologies

NeonatesIn the first few days of life, coffee ground emesis or bloodystools in an otherwise healthy and haemodynamically stableneonate are most likely caused by swallowed maternal bloodeither during delivery or breast-feeding. In such cases, theApt-Downey test should be performed to differentiatebetween maternal and infant blood. Acute gastric orduodenal ulcers should be suspected in sick premature orfull-term asphyxiated or septic newborns or patients withintracerebral bleeding, raised intracranial pressure,congenital heart disease, respiratory failure, or hypo -glycaemia. The typical scenario includes sudden onset ofhaematemesis or melena and signs of haemodynamicinstability. Occasionally, severe upper GI bleeding can occurin healthy full-term neonates within the first few days of life7.

GI bleeding is a common manifestation of necrotizingenterocolitis (NEC). Rare causes of GI bleeding in the firstmonth of life include Hirschsprung enterocolitis, midgutvolvulus, duplication cyst, vascular malformation, andhaemorrhagic disease of the newborn, particularly in breast-feeding neonates, who did not receive vitamin K.

Infants up to 6 months of ageOne of the leading causes of GI bleeding in infants less than6 months of age is cow’s milk or soy protein allergy. Thespectrum of symptoms includes recurrent vomiting,haematemesis, failure to thrive, and diarrhoea with guaiac-positive stools or haematochezia. Exclusively breast-fedinfants may develop similar symptoms on rare occasions. Ananal fissure is another common cause of bleeding in infants.The diagnosis is made by careful examination of the anus.

Intermittent rectal bleeding with streaks of frank bloodmixed with normal appearing stool could be secondary tonodular lymphoid hyperplasia of the colon or terminal ileum.During endoscopy, multiple hemispheric smooth nodules lessthan 4 mm can be found in clusters or diffusely throughout theGI tract (6.1). It is considered to be an excessive reaction ofthe GI tract lymphatic tissue (lymphoid follicles and Peyer’spatches) to food-related or other antigens. Spontaneousregres sion of lymphoid follicles is quite common. In additionto parental reassurance, an elimina tion diet for nursingmothers is a reasonable initial treatment. Feeding with exten -sively hydrolyzed protein formula is the next step of therapy.Corticosteroid therapy is restricted to infants with a severeform of this disease, with recurrent abdominal pain, signifi cantanaemia, persistent rectal bleeding, diarrhoea, and failure tothrive. In such cases, immunodeficiency has to be excluded.

Oesophagitis should be suspected as a cause of bleedingin infants with a history of recurrent emesis and interruptedfeeding patterns associated with crying, irritability, orarching (6.2). The patients with repaired oesophagealatresia with or without tracheaoesophageal fistula are athigher risk of severe reflux disease and oesophagitis.Bleeding induced by oesophagitis is usually recurrent andnot intensive. The patients may have haematemesis withstreaks of blood or guaiac-positive stool.

Infants or older children can develop minor bleeding dueto prolapse of gastric mucosa into the oesophagus throughthe gastro-oesophageal junction (prolapse gastropathy)(6.3). This condition is manifested by recurrent emesis withfood, and appearance of brown flecks of denaturated bloodat the end of vomiting. The presence of frank blood or clotsat the end of recurrent emesis suggests a more seriousproblem such as a Mallory–Weiss tear.

A B

6.3 Prolapse gastropathy. Multiple mucosal haemorrhages

in the gastric cardia due to recurrent prolapse of the

affected area through the diaphragm into the oesophagus.


6.2 Oesophagitis: prominent oedema, erythema and

erosions in the distal oesophagus.

6.4 Oesophageal varices: enlarged tortuous veins of the

distal oesophagus.

6.5 Gastric varices: multiple varices of the gastric cardia.

Infants and children less than 7 years of agePortal hypertensionThe signs and symptoms of portal hypertension are a largevolume haematemesis, history of omphalitis secondary tocatheterization of umbilical vein, presence of splenomegaly orhepatosplenomegaly, and other stigmata of chronic liverdisease such as jaundice, spider angiomas, caput medusa, andascitis. Oesophageal varices are the most common site ofbleeding in children with intrahepatic-sinusoidal andextrahepatic-presinusoidal forms of portal hypertension (6.4).Two-thirds of children with portal hypertension will bleedbefore 5 years of age. The diagnosis is made based on thepresence of oesophageal or gastric varices (6.5) or hypertensivegastropathy (6.6) during an upper GI endoscopy.

IntussusceptionIntussusception, which is common in the first 2 years of life,is strongly considered in infants and children with suddenonset of severe cramping abdominal pain intercepted withpain-free episodes and currant jelly stools. A lead point isoften present in children older than 2 years of age. Diagnosisis confirmed by ultrasonography demonstrating positive‘concentric circles’ or the ‘target-shaped’ sign, or bariumenema. Hydrostatic reduc tion of intussusceptions issuccessful in more than 90% of children.

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


6.6 Hypertensive gastropathy: oedematous gastric

mucosa with focal erythema and multiple small mucosal

haemorrhages.

6.7 A juvenile polyp of sigmoid colon: a small amount of

blood is present on the head of the polyp. The adjacent

area is slightly pale and has multiple small grooves, so-

called ‘goose-skin’ sign.

However, less than 5% of children will developcomplications, including GI bleeding. Half of them becomesymptomatic in the first 2 years of life. The predominantlocation of Meckel’s diverticulum is the distal ileum (40–60cm above the ileocaecal valve). Ectopic tissue is present inup to 80% of symptomatic patients. The gastric mucosa isthe most common type of ectopia. The cause of bleeding ispeptic ulceration at the junction of the ectopic gastricmucosa and normal ileum, the so-called marginal ulcer. Thebleeding can be massive, but it may cease spontaneouslysecondary to contraction of the splanchnic vessels inresponse to hypovolemia. This phenomenon explains anintermittent nature of bleeding from Meckel’s diverticulum.Bleeding is usually painless, but sometimes coincides withrecurrent abdominal pain. The diagnostic procedure ofchoice is a 99mTc pertechnetate scan, which has sensitivity of85% and specificity of 95%.

Juvenile polypsJuvenile polyps may occur in as many as 1% of children, withpeak incidence from 2 to 5 years of age. The common clinicalpresentation is recurrent, painless bleeding with a smallamount of blood on formed stool. Diarrhoea and tenesmuscan occur when the polyp is large and located in the left colon.

Typical juvenile polyps are smooth, rounded, and red.Polyps less than 1 cm are usually sessile (6.7); polyps largerthan 1 cm have short or long stalks. Juvenile polyps are

composed of normal and cystically dilated crypts embeddedin an abundant lamina propria. Colonoscopy is indicateddue to high incidence (almost 50%) of coexisting polyps inthe descending and more proximal portions of the colon.

Endoscopic polypectomy is the treatment of choice. Thereis a general consensus that a single juvenile polyp is not apremalignant condition. Therefore, removal of a solid juvenilepolyp is curative. Surveillance colonoscopy is not indicatedunless the child develops a new episode of rectal bleeding.

Haemolytic uraemic syndrome Haemolytic uraemic syndrome (HUS) should be alwayssuspected in infants and toddlers with bloody diarrhoea,which is present in three-quarters of children with epidemicHUS. In two-thirds of these children, Escherichia coli0157:H7 can be isolated. The cause of bloody diarrhoea inHUS is haemorrhagic colitis due to endothelial damageproduced by verotoxin and chiga toxin and submucosalhaemorrhages. Tenesmus is common. Diffuse, severeabdominal pain with peritoneal signs can occur.

The presence of the so-called a ‘thumb printing’ sign on abarium enema or a CT scan reflects a submucosal haemorr -hage of the colon. Colitis-related symptoms last no longerthan a week, followed by signs of haemolytic anaemia andoliguria. Known GI complications of HUS are intussuscep -tion, pancreatitis, and intestinal obstruction. The small orlarge bowel perforation may occur during peritoneal dialysis.

6.8 Henoch–Schönlein purpura: multiple submucosal

haemorrhages and secondary oedema are common

findings in the colon.

6.9 Helicobacter pylori gastritis: nodular appearance of

the antral mucosa is a commom finding in children with

HP gastritis.


Although peptic ulcer disease is relatively rare inpaediatric patients, it comprises at least one-third of thecases of upper GI bleeding in school age children. Themajority of bleeding ulcers are located in the duodenal bulb(6.10). At least 80% of bleeding episodes from duodenalulcers cease spontaneously. However, if the bleeding isarterial, it may recur and become life threatening. Urgentendoscopy is necessary as soon as the patient becomes morestable after fluid resuscitation.

The risk factors for recurrent bleeding are: large ulcer(more than 2 cm), location of the ulcer on posteroinferiorwall of the duodenal bulb, blood spurting from the base ofthe ulcer, a visible vessel, or an adherent clot. These high-riskpatients require a second-look endoscopy 24 hours after theindex endoscopy, and careful observation in the intensivecare unit. The most critical time for rebleeding is the first 3days following the initial haemostasis. Haemo dynamicallystable children without the endoscopic risk factors forrecurrent bleeding do not require endoscopic haemostasisand can be managed safely on an outpatient basis.

Colitis is the most common cause of rectal bleeding inolder children and teenagers. Infectious colitis is morecommon by far than inflammatory bowel disease. Ingeneral, bacterial colitis is an acute, self-limited disordermanifested by sudden onset of fever, tenesmus, and bloodydiarrhoea lasting from 5 to 7 days. Chronic diarrhoea(lasting 2 weeks or more) is usually associated with chronicinflammatory bowel disease. Ulcerative colitis (6.11) usually

Henoch–Schönlein purpuraHenoch–Schönlein purpura (HSP) is most common inchildren less than 7 years old. The median age is 4 years.HSP should be suspected in children with sudden onset ofsevere diffuse abdominal pain, vomiting, and haemato -chezia, especially if this happens after viral illness in winterand early spring and about a week after purpuric-type skinlesions appear on the buttocks or low extremities. On rareoccasions, GI manifestations may precede skin rash. Severeanaemia is uncommon. The small and/or large bowel hasdifferent degree of haemorrhagic lesions (6.8). These maybe apparent on a small bowel X-ray series or barium enemawith coarsening of folds and thumb printing. Abdominalpain and haematochezia is self-limited. Treatment withcorticosteroids is controversial, although it may shorten thecourse of GI symptoms of abdominal pain by 1 or 2 days.

Children aged 7 years and olderDrug-induced gastritis or acute ulcer should be stronglysuspected in children who received treatment with NSAIDsor oral steroids. The degree of bleeding varies between mildto moderate. The usual clinical presentation is the suddenonset of abdominal discomfort followed by haematemesis ormelena. Haemorrhage usually originates from the stomach.The incidence of NSAID-related GI bleeding is muchhigher in patients with Helicobacter pylori (HP) gastritis(6.9). Therefore, eradication of HP infection isrecommended before long-term therapy with NSAIDs.

63Gastrointestinal bleeding

6.10 Duodenal ulcer, with active bleeding. 6.11 Ulcerative colitis: diffuse erythema, oedema, loss of

vascular pattern, and exudates are seen.

6.12 Crohn’s disease: multiple deep, longitudinal ulcers

and areas with normal appearing mucosa are typical for

Crohn’s disease.

presents with insidious onset of diarrhoea, nocturnaldiarrhoea, and subsequent haematochezia. Crohn’s diseasehas a more indolent onset associated with abdominal pain,diarrhoea, poor appetite, and weight loss. Diarrhoea is notgrossly bloody unless there is bleeding from an anal fistulaor left side or diffuse colitis (6.12).

Differentiation between bacterial colitis and the earlystage of chronic inflammatory bowel disease is always achallenge. A high index of suspicion and negative bacterialstool culture results, including Yersinia species and otherrare pathogens, are essential parts of early diagnosis. Thedefinitive diagnosis is based on the results of upper andlower GI endoscopy with multiple biopsies. Rare infectiouscauses of chronic diarrhoea are Yersinia enterocolitica,Mycobacterium tuberculo sis, Entamoeba histo lytica,Strongyloides stercoralis, and opportunistic infections inimmunocompromised patients. Clostridium difficile colitisshould be ruled out especially in children treated withantibiotics or hospitalized patients.

Treatment

It is imperative to initiate resuscitation of a haemodynamicallyunstable patient almost immediately before any diagnosticprocedure is considered. Two large-bore peripheralintravenous lines or a central line should be placed andsecured. Blood has to be typed and cross-matched and sent forbaseline laboratory assessment including liver enzymes and

clotting factors. Oxygen supplementation and bolus of salinetargets tissue oxygenation and restoration of circulation. Thevolume of isotonic solution should be sufficient to reversetachycardia and postural hypotension. Blood transfusion isindicated for patients with persistent orthostatic hypotensionafter replacement of 15–20% of blood volume with isotonicsolution, children with acute haemorrhage and initial Hct ofless than 20%, and children with haemorrhagic shock. Packed


References

1 Rockall TA, Logan RFA, Devlin HB, et al. Incidence ofand mortality from acute upper gastrointestinalhaemorrhage in the United Kingdom. BMJ1995;311:222–6.

2 Lacroix J, Nadeau D, Laberge S, et al. Frequency of uppergastrointestinal bleeding in a pediatric intensive care unit.Crit Care Med 1992;20:35–42.

3 Chaibou M, Tucci M, Dugas MA, et al. Clinicallysignificant upper gastrointestinal bleeding acquired in apediatric intensive care unit: a prospective study.Pediatrics 1998;102:933–8.

4 Teach SJ, Fleisher GR. Rectal bleeding in the pediatricemergency department. Ann Emerg Med1994;23:1252–8.

5 Gilger MA. Upper gastrointestinal bleeding. In: WalkerWA, Goulet OJ, Kleinman RE, et al. (eds). PediatricGastrointestinal Disease: Pathophysiology, Diagnosis andManagement, 4th edn. BC Decker, Hamilton, 2004, pp.258–65.

6 Ament ME. Diagnosis and management of uppergastrointestinal tract bleeding in the pediatric patient.Pediatr Rev 1990;12:107–16.

7 Goyal A, Treem WR, Hyams JS. Severe uppergastrointestinal bleeding in healthy full-term neonates.Am J Gastr 1994;89:613–6.

8 Eroglu Y, Emerick KM, Whitingon PF, et al. Octreotidetherapy for control of acute gastrointestinal bleeding inchildren. JPGN 2004;38:41–7.

Further reading

Boyle JT. Gastrointestinal bleeding in infants and children.Pediatr Rev 2008;29:39–52.

Gershman G, Ament M. Practical Pediatric GastrointestinalEndoscopy. Blackwell Publishing, Massachusetts, 2007.

Kay MH, Wyllie R. Therapeutic endoscopy for nonvaricealgastrointestinal bleeding. J Pediatr Gastroenterol Nutr2007;45:157–71.

Murphy MS. Management of bloody diarrhea in children inprimary care. BMJ 2008;336:1010–15.

Shamir R, Eliakim R. Capsule endoscopy in pediatricpatients. World J Gastroenterol 2008;14:4152–5.

red cell transfusion is the product of choice for replacement ofblood loss. Matched whole blood is preferred for patients withmassive bleeding. Fresh-frozen plasma is indicated for childrenwith suspected or documented clotting factor deficiency, suchas children with acute or chronic liver disease. Platelettransfusion is indicated in rare cases of severe bleeding withestimated blood loss of more than 50% of the patient’s bloodvolume or children with active haemorrhage and platelet countless than 50,000/mm3. Early blood transfusion is reasonablefor children with active bleeding and known chronic heart orlung diseases. Monitoring of vital signs is a more accurate wayto assess the effect of blood transfusion than monitoring of theHct soon after transfusion. It is reasonable to wait 6 hoursbefore checking posttransfusion Hct.

Octreotide (a synthetic somatostatin analogue) is effectiveadjuvant medical therapy for severe bleeding fromoesophageal or gastric varices8. It should be given to thechild with active haemorrhage and any evidence of chronicliver disease or previously diagnosed portal hypertension.The initial bolus of 1 µg/kg of intravenous octreotide isfollowed by continues infusion of octreotide 1 µg/kg/h. Thedose can be increased every 6 hours up to 5 µg/kg/h.

Endoscopic haemostasis of nonvaricealand variceal bleeding

Indications for endoscopic haemostasis of nonvaricealbleeding include:• Active bleeding from the gastric or duodenal ulcer.• Stigmata of recent bleeding: a nonbleeding visible vessel

in the ulcer base and a densely adherent clot. • Bleeding arteriovenous malformation.• Bleeding after polypectomy.

Three methods are routinely used for endoscopichaemostasis of nonvariceal bleeding: injection ofvasoconstrictive agent, thermal coagulation, and metal clips.

Indications for endoscopic haemostasis of varicealbleeding include:• Active bleeding from oesophageal or gastric varices.• History of bleeding secondary to portal hypertension.• Failed surgical shunting procedure.

Two different techniques are currently used forhaemostasis of variceal bleeding, sclerotherapy andendoscopic variceal ligation.

APCTh0

IL-2IL-4

Th2

IL-13IL-4

B

7.1 A protein which acts as an allergen is captured by an

antigen-presenting cell (APC). This interacts with a non-

primed Th0 lymphocyte, which under certain conditions,

such as presence of interleukin-2 and IL-4 derives into a

Th2 type lymphocyte. This interacts with a B-lymphocyte

that, under the influence of IL-4 and IL-13, synthesizes

specific IgE against the allergen. The IgE binds to the high

affinity IgE receptors on the surface of cells like mastocytes.

Upon a subsequent contact of the allergen, this binds to two

molecules of IgE, and this interaction drives the immediate

release of mediators (histamine, tryptase, leukotrienes). The

mediators cause the different symptoms of allergic

reactions, depending on the target organ.

IgE

Release ofmediators

Allergen

Mastocyte

they are denominated allergic: the classic allergic reactionsare termed IgE mediated (7.1), and the classic intolerance toCM proteins is now termed non-IgE-mediated allergy (7.2).The nontoxic reactions, which are not mediated by animmunological mechanism, are now termed intolerance.

Proteins are the agents that cause allergic reactions. Thebasic units of proteins are amino acids. The molecularweight of amino acids ranges from 89 to 204 Da. Theprimary structure of proteins is a chain of amino acidsbound to each other through their acid (-COOH) andamino (-NH2) terminals. The amino acids can occur inshort chains of 6–9 amino acids (called peptides) or longchains of hundreds of amino acids. It is important to noticethe molecular weight to estimate the number of amino acidsthat can be found in a peptide or a protein.

65

Introduction

Allergy to cow’s milk (CM) proteins appears mainly ininfants and persists for several months or years, or may evenbe lifelong. Allergic reactions to CM are frequent (1–2% ofinfants)1–4. Cow’s milk allergy (CMA) constitutes achallenge for paediatricians, who must be aware of thecondition, and know how to initiate diagnostic andtherapeutic approaches.

Adverse reactions to foods

The European Academy of Allergy and ClinicalImmunology divides adverse reactions to foods into toxicand nontoxic. If an immunological mechanism is involved

Chapter 7

Cow’s milk allergy

Antonio Nieto, MD, PhD, and Angel Mazón, MD

Milk

APC

Th1

Th0

Th2

IL-4IL-13

B

IgG

IgEMast cell

Histamine triptase

IL-12IFN-γ

ECP

MPONeu

BasEos

7.2 Non-IgE immune responses to foods. There is no

definite known intermediary pathogenic mechanism:

probably cell-mediated responses are involved, or mixed

responses with the involvement of both cells and

immunoglobulins. These responses are mainly elicited by

proteins of large molecular weight, whatever the source,

but not by small molecular weight proteins or peptides,

and they need a relatively large amount of protein. The

interval between exposure and symptoms is longer than

for IgE responses.

Casein Caseins* 21 kD

Whey α-lactoalbumin* 15 kD

β-lactoglobulin* 36 kD

Seroalbumin 68 kD

Lactoferrin 87 kD

IgG1 160 kD

IgG2 160 kD

IgM 900 kD

IgA 400 kD

Other

*Synthesized in the mammary gland

Table 7.1 Cow’s milk proteins

disappear when the offending food is withdrawn, andreappear when the patient is challenged with it. The classicalsymptoms appear immediately after ingestion or contact withthe allergen. They can show as urticaria-angioedema involv -ing skin and mucosa; digestive symptoms such as vomit ing,abdominal pains or cramps, and diarrhoea, or respiratorysymptoms including wheezing, difficult breath ing, andrhinoconjunctivitis. The most severe disorder is anaphylaxis.

Group B includes patients who often have a sensitization tofoods. Some patients have an IgE sensitization, and respond toavoiding/challenging with the food in the same way that groupA does. Nevertheless, other patients who are also sensitizedhave no clinical response to diet, and the course remainsirrespective of diet. The group B includes mainly atopicdermatitis. In cases of a complete or partial response toavoiding and challenging, it is usually not immediate, but takesseveral hours or even days to be evident. Pathogenicmechanisms not mediated by IgE may be involved. Someinfants with CMA have isolated haematochezia and areotherwise healthy. Eosinophilic infiltration of one or severalportions of the digestive tract can appear in children withCMA: it is diag nosed by the eosinophilic count in biopsysamples. Depending on the affected portion it causesdysphagia, nausea, vomiting, gastro-oesophageal reflux,abdominal pain or cramps, diarrhoea of variable severity,occult or overt blood in stools.

Group C includes diseases in which no IgE mechanism isidentified. They have a good clinical response to the

66 Cow’s milk allergy

There are several casein proteins, whose molecularweight is around 21 kD, and which comprise around 200amino acids. Although the absolute amount of wheyproteins is lower, the number of different proteins is greateras are their molecular weights (Table 7.1). A patient can besensitized to only one or more than one protein.

The human breast does not synthesize β-lactoglobulin.Thus, any content in human milk comes from the dietaryintake. A regular infant formula contains about 300 mg ofβ-lactoglobulin per 100 ml. Human milk contains around0.42 μg%. A few drops of formula contain as much lacto -globulin as 100 litres of human milk. These few drops con -tain as much lactoglobulin as the amount present in humanmilk that a lactating mother gives in 3 or more months. Nowonder that a child who is sensitized to CM but has nosymptoms while being breast-fed develops overt severesymptoms the first time that he is given a bottle of formula.

Clinical picture

Group A comprises signs and symptoms associated with ademonstrated IgE sensitization to foods. These symptoms

• Antecedents of allergy

• Feeding: breast/mixed/formula

• Age at onset of symptoms

• Chronology and type of symptoms

• Amount of milk which causes symptoms

Table 7.2 Clinical history

Prick tests (>3 mm diameter)Sensitivity 70%

Specificity 83%

Positive likelihood ratio 4.12

Serum specific IgESensitivity 0.63

Specificity 0.83

Positive likelihood ratio 3.71

Tests with other allergens

Table 7.3 Allergologic evaluation

without symptoms. However, between these extremes arefound a range of responses that are difficult to interpret. Thus,repeated challenges are sometimes needed until a clearinterpretation can be reached. The positive response to thechallenge test permits a diagnosis of allergy, but it cannotidentify which mechanism is involved. The allergologicevaluation is com plete when IgE tests and the challenge areperformed (7.3).

Open challenge test acceptable in infants

Perform if:

• Adequate clinical condition

• No symptoms

• Symptom-free interval

• Under strict medical control

• No anaphylactic reactions

Table 7.4 Allergologic evaluation: double blind

placebo controlled challenge test

67Cow’s milk allergy

elimination of the offending food. The most frequentdisorder in group C is what was formerly called intoleranceto CM proteins. When diarrhoea is present, malabsorptioncan appear and lead to failure to thrive or to specificnutritional deficits.

All the symptoms are very common and they are notalways caused by CMA. Indications for an allergologicwork-up would be those in whom the clinical history issuggestive of CMA.

Diagnostic approach

When first facing a child with a clinical picture suspicious ofCMA, the initial approach is based on a good clinical history(Table 7.2). The three first issues may orientate the physiciantowards a higher or lower probability of allergy, but theirusefulness is very limited. The two last issues are much moreinformative about the suspect mechanism of reaction.

It is important to try to identify if the patient has an IgE ornon-IgE reaction. The allergologic tests try to identify if thereis specific IgE against CM proteins5. This is accomplishedwith the use of skin prick tests, and the quantification ofspecific IgE in serum. Both tests have a good specificity buta more modest sensitivity (Table 7.3). As some patients havediscordant responses in the tests, performing both gives thebest yield, but even so some patients will be misclassified asnon-IgE responders. The positivity of any of the tests provesthat there is a sensitization to CM; the relationship ofsensitization with clinical symptoms must be clarifiedthrough the interpretation of the clinical history orperforming challenge tests. Sensitization to other allergensmust be assessed: it is not surprising to find out that thepatient is sensitized to other allergens, especially hen’s eggs.

The gold standard for the diagnosis of food allergy is thedouble-blind placebo-controlled challenge test. This is oftenrequired for investigational studies, but in the routine clinicalpractice an open challenge is acceptable (Table 7.4). Theprotocol must be adapted to every child, taking into accountthe clinical history, previous reactions, and results of tests(Table 7.5). More caution must be taken for those with posi -tive IgE tests, while those with negative tests usually tolerategreater amounts, and the protocol can be performed morerapidly. Several days must elapse until a negative response canbe ascertained. The test is easily interpreted as positive whenimmediately evident typical reactions appear, and easilyinterpreted as negative when there is a long follow-up time

Treatment

Treatment is based on a diet free of CM proteins. Breast-feeding must be encouraged. The lactating mother has toavoid CM proteins. If the mother has a varied diet, there isno risk of nutritional deficits, except for calcium. If breast-feeding is not possible, an alternative feeding regimen mustbe chosen. The two approaches are based on themodification of native CM proteins and on the use ofproteins of another, not related to CM, source6, 7.

To modify the CM proteins three steps are commonlyused. The action of heat and hydrolysis pretends to suppressor lower the allergenicity of proteins through changes intheir structure. Ultrafiltration is directed at eliminatingenzymatic products used in the process of hydrolysis and

Cow’s milk allergy68

Challenge test• Increasing amounts (from 1 drop)

• 15–30 minute intervals

• Assess clinical response

• May take several days

Interpretation• Subjective criteria

• Difficult in delayed responses

• May have to be repeated

• Identifies allergy, but not the mechanism

Table 7.5 Allergologic evaluation: challenge test and interpretation

Allergy testsPrick/serum IgE

+ –

Challenge Challenge

IgE mediated CM allergy

Asymptomatic sensitization

Non-IgE mediated CM allergy

Current tolerance

+ – –+

Suspect symptoms

7.3 Algorithm of the allergologic evaluation.

also eliminating peptides of large molecular weight.When proteins are heated, their tertiary structure is

damaged. The chemical bonds are ‘broken’ and the proteinis unfolded. This separates the portions which form theconformational epitopes, which lose their allergenic ability,and are unable to bind the specific IgE. Enzymes are able tobreak the bonds between the amino and the acid terminalsof amino acids and split the proteins into smaller fragments.These resulting fragments, depending on their size, can holdone to several dozen amino acids. The breakage of theprotein can result in fragments that keep whole undamagedepitopes, able to bind to the specific IgE. A fragment can belarge enough to keep two or more epitopes, able to bind

simultaneously to molecules of IgE and trigger the allergicreaction. This is called residual allergenicity, and is moreprobable when the molecular weight of the fragments islarger8. In elemental formulas, in which there are nopeptides but only amino acids, the ability to bind IgE is nil.

The first choice for IgE-mediated allergy to CM seems tobe soy formula, due to the absence of allergenicity, and alsothe lower price. Some physicians are reluctant to use soyformula in children under 6 months of age. When choosingan extensively hydrolyzed formula, some requirements mustbe met and others are advisable. All peptides must have amolecular weight under 5,000 Da, and the formula musthave been tested and prove to have negative results in >90%of children with CMA. The maximal admitted weight of thepeptides is 5 kD, but if the distribution of molecular weightis provided the chances that residual allergenicity is presentcan be estimated: the higher the percentage of very smallpeptides, the lower the probability of residual allergenicity(Table 7.6). Table 7.7 shows the types of milk formulas usedfor the feeding of infants, classified according to theirconstituents. The regular formula used for feeding healthyinfants is infant formula (IF). If lactose intolerance ispresent a lactose-free formula (LF) should be used; nochange in proteins is required, so native whole proteins areused. When these proteins undergo a low degree hydrolysisa partially hydrolyzed (PH) formula is obtained, also knownas hypoallergenic formulas. In extensively hydrolyzed (EH)formulas, proteins undergo a high degree hydrolysis. Semi-elemental (SE) formulas have extensively hydrolyzedproteins and also a modification in carbohydrates and lipids.The elemental formulas (EF) have modified carbohydratesand lipids and no proteins or peptides, substituted by amino

acids. Soy formulas have modified carbohydrates and lipids,and the proteins are purified soy proteins.

We would recommend the following treatment algorithmfor children with CMA (7.4). The first choice for those withIgE-mediated allergy would be soy formula, and for thosewith non-IgE-mediated allergy would be extensivelyhydrolyzed (EH) formula. The response, withdisappearance of symptoms, must be fast, usually within24–48 hours. If there is no such good response in 7 days, asecond choice formula should be tried. In those cases whodo not respond well to the first choice, the diagnosis shouldbe reconsidered: the second choice should be EH formulafor IgE-mediated and soy formula for non-IgE-mediatedallergy. If there is a lack of response to this second choice,an elemental formula should be used. Whenever the patient

Cow’s milk allergy 69

Molecular weight Number of amino acids

500 Da 4

1000 Da 7

1500 Da 11

3000 Da 22

5000 Da 36

9000 Da 65

12,000 Da 88

Table 7.6 Molecular weight of small peptides

present in hydrolyzed milk formulas

Carbohydrate Lipid ProteinCow Soy/pork AA SoyWhole Hydrolisis Hydrolisis Hydrolisis Whole

Low grade High grade High grade Total

With lactose LCT IF PH EH

MCT

Without lactose LCT LF

MCT SE SE EF Soy

Table 7.7 Types of formulas classified according to their constituents

does not respond to the selected treatment, the diagnosisshould be reconsidered, especially if the child does notimprove with an elemental formula.

In children who have been diagnosed and are being treatedfor CMA a follow-up is recommended (Table 7.8) to checkthat the symptoms have disappeared. Care must be paid to theappearance of new symptoms that could be due to the initialallergy or to allergy to other allergens. A physical examinationmust be performed to rule out signs that could have passedunnoticed, as well as an assessment of the current diet andnutritional status to avoid too restrictive, unnecessary diets,which could lead to specific deficits9–13. According to anindividual’s evolution of symptoms, an allergologic study anda challenge test might be indicated. If the patient has hadrecent symptoms related to contact or ingestion of CM, they

Cow’s milk allergy70

IgE allergy

Soy formula

Good response

EH formula

Good response

Reconsider diagnosis

Non-IgE allergy

EH formula

Good response

Soy formula

Good response

Elemental formula

Good response

No No

Yes Yes

Yes

No

Maintain and follow

YesNo No

Yes

7.4 Algorithm of treatment in cow’s milk allergy.

could be postponed. The indication of the challenge test canbe guided by results of IgE tests, but in the case of non-IgEallergy these tests have no value, so its indication must bebased on clinical grounds, with challenge tests every 6 months.In IgE-mediated allergy, the presence of specific IgE does notalways mean that the challenge test must be postponed. Somechildren who have had clear allergic reactions may outgrowtheir symptoms and have a good tolerance to CM even ifspecific IgE persists for months or years after achievingtolerance. The indication can be guided by IgE tests, but mustbe 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 childrenwill outgrow their allergy and reach good tolerance to CM,specially those with non-IgE allergy, in whom persistence of

the allergy is exceptional14. Many of those who have notreached tolerance by the age of 5 years will have lifelongallergy. Risk factors for the persistence of IgE allergy arehigh levels of serum total IgE, and high levels of serumspecific IgE against CM proteins.

A treatment that is increasingly gaining acceptance isdesensitization. The usual treatment is avoidance of CMuntil the patient develops spontaneous tolerance. As somechildren do not spontaneously reach tolerance,desensitization is becoming an alternative. The patient isgiven gradually increasing amounts of CM, until a usualdaily dose is reached, and the child then continues havingthat amount of CM every day. The rationale is based on thefact that very small amounts of CM are not able to triggersymptoms or, if symptoms appear, they will not be severeand 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 etImmunopathol 1998;26:171–94.

2 Dean T. Prevalence of allergic disorders in earlychildhood. Pediatr Allergy Immunol 1997;8:27–31.

3 Sanz Ortega J, Martorell Aragonés A, Michavila GómezA, Nieto García A y Grupo de Trabajo para el estudio dela Alergia Alimentaria. Estudio de la incidencia de alergiamediada por IgE frente a la proteína de la leche de vacaen el primer año de vida. An Esp Pediatr 2001;54:536–9.

4 Crespo JF, Pascual C, Burks AW, et al. Frequency of foodallergy in a pediatric population from Spain. PediatrAllergy Immunol 1995;6:39–43.

5 Baehler P, Chad Z, Gurbindo C, et al. Distinct patternsof cow’s milk allergy in infancy defined by prolonged, twostage 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 foodallergy. Arch Dis Child 1999;81:80–4.

7 American Academy of Pediatrics. Committee onNutrition. Hypoallergenic infant formulas. Pediatrics2000;106:346–9.

8 Caffarelli C, Pleban A, Poiesi C, et al. Determination ofallergenicity to three cow’s milk hydrolysates and anamino acid-derived formula in children with cow’s milkallergy. Clin Exp Allergy 2002:32:74–9.

9 Paganus A, Juntunen-Backman K, Savilahti E. Follow-upnutritional status and dietary survey in children withcow’s milk allergy. Acta Paediatr 1992;81:518–21.

10 Isolauri E, Sütas Y, Salo M, et al. Elimination diet incow’s milk allergy: risk for impaired growth in youngchildren. J Pediatr 1998;132:1004–9.

11 Christie L, Hine J, Parker JG, Burks W. Food allergiesin children affect nutrient intake and growth. J Am DietAssoc 2002;102:1648–51.

12 Black RE, Williams SM, Jones IE, et al. Children whoavoid drinking cow milk have low dietary calcium intakesand poor bone health. Am J Clin Nutr 2002;76:675–80.

13 Seppo L, Korpela R, Lönnerdal B, et al. A follow-upstudy of nutrient intake, nutritional status, and growth ininfants with cow milk allergy fed either a soy formula oran extensively hydrolysed whey formula. Am J Clin Nutr2005;82:140–5.

14 Vanto T, Helppilä S, Juntunen-Backman K, et al.Prediction of the development of tolerance to milk inchildren with cow’s milk hypersensivity. J Pediatr2004;144:218–22.

Further reading

Hill DJ, Murch SH, Rafferty K, et al. The efficacy of aminoacid-based formulas in relieving the symptons of cow’smilk allrgy: a systematic review. Clin Exp Allergy2007;37:808–22.

Meyer R. New guidelines for managing cow’s milk allergy ininfants. J Fam Health Care 2008;18:27–30.

Niggemann B, Beyer K. Diagnosis of food allergy inchildren: toward a standarization of food challenge. JPediatr Gastroenterol Nutr 2007;45:399–404.

Vandenplas Y, Koletzo S, Isolauri E, et al. Guidelines for thediagnosis and management of cow’s milk protein allergyin infants. Arch Dis Child 2007;92:902–8.

Cow’s milk allergy 71

Schedule of follow-up visits

• 3 months later

• 6 months later

• At 18 months of age

• At 2 years of age

• Yearly

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

Abdominal masses

Juan A. Tovar, MD, PhD

Chapter 872

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.

is fusiform, in which the entire extrahepatic-biliary tract isenlarged (8.1). If not detected prenatally, this condition maybecome symptomatic later on as a painful mass occasionallyaccompanied by jaundice. CT scan and bilio-pancreaticmagnetic resonance imaging (MRI) allow preoperativedepiction of the anatomy of the cyst. Treatment is surgical andconsists of the excision of the choledocal duct together with thegallbladder, the cystic and common hepatic duct, and of thereplacement of the biliary tract by a Roux-en-Y hepatic-jejunostomy performed in an open or laparoscopic operation1.

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

Masses of gastrointestinal origin

Tumours and cysts of the liverThe liver is accessible to palpation when enlarged andtherefore masses in the liver are easily detected.

Hydatic cystsThese are the result of accidental ingestion of scolices ofEchinoccocus granulosus, a worm that parasitizes theintestine of the dog. When the scolices are ingested by lambsor humans, they pass the intestinal barrier and aretransported by the blood stream to the first or secondtissular filters, respectively the liver and the lung, where aform of resistance develops forming a cyst that grows slowly.The inside of the cyst contains a white gelatinous membranelined by a fertile proligerous layer that frees live scolices intothe clear hydatic fluid. The surrounding liver parenchymaundergoes an inflammatory and fibrotic reaction (pericysticlayer). Hydatic cysts are often scarcely symptomatic inchildren, except when they fissure causing anaphylacticreactions. They are detected by abdominal palpation andthe diagnosis is confirmed by ultrasound or computedtomography (CT) scan. Specific antigenic and blood testshelp 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.

Choledocal cystsThese usually originate in a defective bilio-pancreatic junctionin which both ducts are confluent within the pancreas,allowing the bile and the pancreatic juice to mix andsubsequently damage the choledocal wall. There are severalanatomical varieties of choledocal cysts, but the most common

Abdominal masses 73

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.

a rapidly involuting congenital haemangioma and, as well asmultifocal, often creates cardiovascular compromise due tolarge intratumoural arteriovenous shunts. Platelet trappingand consequently coagulation disorders may occur. Incontrast, the most clinically relevant feature of diffusetumours is their large volume that creates a compartmentsyndrome and eventually liver failure.

Ultrasonography and MRI help to delimitate the extent.Biopsy is sometimes necessary particularly in cases withunusual features. Treatment is based on the awareness ofthe potential regression and of their responsiveness tocorticosteroids 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 reducedto residual, partially calcified masses. Surgical removal isseldom indicated and in some rare instances of diffusetumours, liver transplantation is unavoidable.

Mesenchymal hamartomas of the liverThese are usually multicystic with solid mesenchymalcomponents and may locate anywhere in the organ. They are

asymptomatic except when they enlarge and are detected asliver masses. Modern imaging allows accurate preoperativeassessment that is helped by the near-normal levels oftumoural markers. Treatment is always surgical (8.3). Whenremoval is complete, there is no risk of recurrence3.

Hepatoblastoma Although it is the more frequent malignant liver tumour inchildren, hepatoblastoma remains rare. It grows rapidly andis occasionally multicentric. It can invade the vessels andalso metastasize in the regional lymph nodes or, through theliver outflow, to the lungs and elsewhere. Most casesmanifest as abdominal masses detected upon palpation.Alpha-fetoprotein (AFP) is a useful marker for diagnosisand follow-up.

CT scan and MRI are the cornerstones of pretreatmentstaging that allows selection of management protocols. Weadhere to the staging of the Societé Internationaled´Oncologie Pédiatrique (SIOP). The liver is divided intotwo lobes by the falciform ligament and both lobes aresubdivided in turn into two, to yield four segments. When

A B

C D

the tumour involves one (Stage 1) or two (Stage 2) of thesesegments (8.4), segmentectomy or lobectomy are usuallyrequired. When three segments are involved (Stage 3), moreextensive operations are necessary (8.5) and when the foursegments are affected (Stage 4), liver transplantation may bethe only treatment option (8.6). Complete surgical removalis always necessary for cure and preoperative chemotherapywith platinum derivatives and doxorubicin greatly helps toreduce the original extent of the tumour. More than 80% ofthese children are cured, including Stage 4 cases4, 5.

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

Abdominal masses74

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).

A

B

C

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.

A

B

Abdominal masses 75

proximal small bowel are filled with this material, interferingwith normal feeds. The bezoar is palpable as an epigastricmass. Diagnosis is confirmed by ultrasonography andsometimes by other imaging procedures.

The bezoar has to be surgically removed and the patientshould be provided with adequate psychological support.

Gastric tumours and cystsDuplications of this part of the gastrointestinal tract mayproduce palpable epigastric masses. Leiomyosarcomas,rhabdomyosarcomas, teratomas, or gastrointestinal stromaltumours (GIST) formed by C-Kit-positive cells (interstitialCajal cells) may be occasionally observed at this level wherethey cause ulceration and haemorrhage7.

children and adolescents. The tumour is often multicentricand secretes AFP. It metastasizes early, often to the lungs,and responds poorly to chemotherapy. This tumour haslimited surgical possibilities and the prognosis is thereforepoor except in patients with metabolic cirrhosis, in whomliver transplantation for the original disease allows totalremoval before metastases develop6.

Gastric tumours and masses BezoarsThis condition always involves a psychopathologicalbackground. These children swallow either indigestiblematerial (seeds, vegetal fibres that produce phytobezoar) orhair (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, unextirpable

nature of the tumour could be verified (B). After transplantation, the patient is doing well.

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.

76 Abdominal masses

Duodenopancreatic tumoursPancreatic cystsThe most frequent pancreatic cystic masses are pseudocystscaused by pancreatitis of traumatic or other origins. Whenthe pancreatic ducts are disrupted by trauma orinflammation, the enzymes are spilled into the parenchymacausing a severe pancreatitis. Secondarily, areas of necrosisand eventually cysts filled with pancreatic juice may appearand occupy the retrogastric space and even extend into thethorax through the diaphragm. A palpable mass can bedetected and diagnosis can be ascertained by increasedenzyme levels in blood and fluid and by imaging procedures.

Pancreatoblastomas and cystic and solid tumours(Frantz’s tumours) are exceedingly rare.

Tumours of the jejunum, ileum, and colonCystic lymphangiomaCystic lymphangiomas originate at the major lymphaticconfluences. In the abdomen the more frequent location isthe mesentery. These lymphangiomas are uni- ormultiloculated. They occupy the space between bothmesenteric layers and compress the bowel from the ante-mesenteric border. They may be voluminous and are formedby yellowish or milky fluid-filled cysts of various dimensions(8.7). They rarely cause major symptoms except thosederived from intermittent torsion or bowel distension.

They may be diagnosed before birth or detectedincidentally for other reasons. Ultrasonography (US)depicts the cystic nature and may help to locate them. MRIis the best procedure for imaging and it can depict thenature of the contents, the presence of calcification, and theeventual association with venous or arterial components.

The risks of torsion and volvulus justify prompt removalafter detection. This usually entails limited bowel resection.Occasionally these tumours can be enucleated8.

LymphomaMost intraabdominal lymphomas are non-Hodgkin, B-typetumours located near the ileocaecal valve, where the densityof gut-associated lymphoid tissue is higher. Epstein–Barrvirus is sometimes an aetiological factor, particularly inimmunosuppressed patients. The mass/masses developrapidly, sometimes within the lumen of the terminal ileum orcaecum (8.8) but more often in the mesenteric lymph nodes.Occasionally these lymphomas manifest as intussusceptionor acute abdominal pain suggesting appendicitis.

Abdominal lymphoma is a systemic disease and most

patients have other symptoms in addition to the mass. Whenthe child is operated on for one of the above-mentionedacute conditions, he/she may benefit from surgical removalof the tumour when it is localized. However, in most casesthe operation serves only for obtaining enough biopsymaterial. US, CT, and MRI, together with bone marrowaspiration and eventually contrast studies, allow diagnosis.Fine needle aspiration may be a rapid method of histo -pathologic diagnosis. The mainstay of treatment ischemotherapy9, 10. The current results are rapidly improv -ing and a high proportion of these children survive.

Masses of genitourinary origin

Malformations, tumours, and cysts of the kidneyCystic kidneysFamilial polycystic kidneys may appear in an infantile form,autosomal recessive pattern (mutation of PKHD1 gene in6p), or an adult variety in which the pattern is autosomaldominant (mutation of PKD1 gene in chromosome 16). Inthe infantile form most patients die early after birth becauseof renal failure. The kidneys are enlarged and theparenchyma is replaced by multiple small cysts (8.9). Thisform may be accompanied in long-term survivors byprogressive liver fibrosis leading to portal hypertension.

Multicystic kidneys appear as malformations of one or

77Abdominal masses

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

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

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).

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

A B8.10 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.

justified in cases in which the volume is large. In all othercases laparoscopic or retroperitoneoscopic removal is anoption, but the dysplastic organ can be left in place becauseit tends to decrease in size over time and does not causesymptoms. There is a remote risk of malignancy on thesedysplastic tissues, supporting the indication for removal.

HydronephrosisStenosis of the uretero-pyelic junction leads to a dilatedrenal pelvis. The ureter is thin and the pelvis dilatesprogressively, laminating the renal parenchyma.Hydronephrosis is often detected prenatally byultrasonography. Half these babies undergo regression of thedilatation, whereas in the remaining ones it persists andbecomes a palpable mass with or without pain and infection.

US depicts the dilated pelvis, pyelography may give somemore information, but the crucial test is isotopic excretionscintigraphy (MAG3) with furosemide that provides afunctional idea of the retention of urine in the pelvis andallows differentiation between simple dilatation and realobstruction. Surgical repair consists of resection of theobstructed junction and reduction of the dilated pelvis(8.11). The potential for parenchymal recovery is directlyrelated to the duration and the severity of the obstruction.

Tumours of the kidneyNephroblastoma or Wilms’ tumour is a malignant neoplasiaderived from the original blastema of the kidney. It appearsmore often in patients with some conditions such as aniridia,hemihypertrophy, Denys–Drash or Wiedeman Beckwithsyndromes. It is usually unilateral, but 5% are bilateral.Some structures recalling glomeruli or tubuli may be foundwithin the mass together with frankly malignant cells andareas of necrosis or haemorrhage. The tumour grows rapidlywithin the parenchyma and may invade the excretory systemand/or the vessels. It metastasizes to the regional lymphnodes and to the lungs by the haematogenous route (8.12).Wilms’ tumour is generally palpated by paediatricians orparents in otherwise healthy children. Haematuria mayappear rarely when the excretory system is invaded. US, CT,and MRI depict the mass which grows within theparenchyma displacing the pelvis and calices.

Treatment is always surgical but it is usually performed inEurope after reducing the size of the tumour and controllingits eventual extensions with chemotherapy. In othercountries surgery is performed first but although thisattitude has the theoretical advantage of allowing betterhistological staging, it involves increased risks of tumourrupture or surgical complications. The results are similarly

Abdominal masses78

A 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).

Abdominal masses 79

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).

A 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.

good with both types of protocol12, 13. When metastases arepresent, they are treated with chemotherapy and/orradiotherapy and they can be removed surgically if limited.

Mesoblastic nephroma is a benign counterpart ofnephroblastoma seen in fetuses or newborns. It is grosslyidentical to Wilms’ tumour except for its purelymesenchymal nature. Upon section, it has a surface thatresembles uterine myoma and only rarely metastasizes.Removal of the kidney with the tumour is the usualtreatment (8.13).

Bladder tumoursGenitourinary rhabdomyosarcomas may cause hypogastricmasses. Other tumours of the bladder, such as malignantSchwannoma (neurofibrosarcoma), may arise in patientswith neurofibromatosis.

Ovarian tumoursOvarian cysts are easily diagnosed by fetal ultrasound. Mostare the result of follicular stimulation by maternal chorionicgonadotrophins and, except when they are twisted and

8.15 Operation for

twisted giant ovarian

teratoma in a 12-

year-old female (A)

and surgical

specimen of

dysgerminoma in a

3-year-old female

(B). The contra -

lateral ovary was

normal.

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 along 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.

A B

secretory and cause respectively isosexual and heretosexualprecocious puberty. Finally, tumours derived from theepithelial cells are cystadenomas that may be serous ormucinous and are the equivalent of ovarian carcinomas inadult women.

Ovarian tumours are more often detected as lowerabdominal masses since only 10% are secreting. Anincreased secretion of hormones with normalgonadotrophins is suggestive of ovarian tumour. AFP isincreased in malignant teratoma and in yolk sac tumours.The treatment is surgical; conservation of some ovariantissue is advocated when possible and safe15, 16.

80 Abdominal masses

devitalized, they tend to regress. Even in cases in which theblood supply is interrupted by torsion (8.14), there is atendency to spontaneous resolution. The current attitude isto follow them ultrasonographically and to remove themonly when they are large or ‘complex’14.

When germ cells are not differentiated they may causedysgerminoma. When they differentiate into embryonaltissues they cause teratomas (8.15) and when theydifferentiate into extraembryonal tissues they cause yolk sac(endodermal sinus) tumours and choriocarcinomas.

Tumours derived from the sex cords are granulosa-thecacell tumours and Sertoli-Leydig cell tumours. Both may be

81Abdominal masses

tumour and its metastases, and detection of increased levelsof catecholamines or its metabolites in serum and urine. Thecellular and molecular predictors of malignity are tested ontissue samples and therefore, biopsy is advisable beforestarting treatment.

Therapeutic protocols are currently based on postsurgicalInternational Neuroblastoma Staging System (INSS). Stage 1tumours are limited to the organ of origin and are completelyremoved. Stage 2 tumours are extended to regional lymphnodes but are removed as well. Stage 3 tumours are usuallyextended on both sides of the midline and cannot be removedat the first operation (8.16), Stage 4 are those with distantmetastases. Both Stages 3 and 4 require aggressive chemo -therapy before complete removal of the primary is attempted.Chemotherapy is continued after surgery and in Stage 4megatherapy and bone marrow transplantation are indicated.There is another Stage 4s corresponding to metastatic diseasethat does not involve the bone, in babies younger than 6months who have their tumour detected upon palpation of amassive liver enlargement that may eventually threatensurvival by creating a compartment syndrome with respiratoryand cardiovascular embarrassment (8.17). The currentapproach to this particular stage is rather conservative. Theprimary may or may not be removed and supportive measuresare provided to allow for regression of the liver enlargement.

The results are very good in Stages 1 and 2, they areimproving in Stage 3 and remain poor in Stage 4. Theprognosis for Stage 4s tumours ranges between those ofStages 2 and 317–19.

Masses from other retroperitoneal organs

Neuroblastoma-ganglioneuromaTumours of neural crest origin are the second most frequentsolid neoplasias in children after brain tumours. They mayoriginate at any point in the wide variety of tissues andorgans receiving the migrating neuroblasts from the neuralcrest, but they involve more often the adrenal medulla, theparaspinal sympathetic chains, and the nervous plexusesthat surround the aorta and its main abdominal branches.

These tumours range from the malignant neuroblastoma(NB) in which neuroblasts predominate and sometimesgroup in pseudo-rosettes, and the benign ganglioneuroma(GN) in which the neural cells are mature neuronesembedded into a fibrilar supporting stroma. Most NB retainthe secreting properties of the adrenal medulla and take upamine precursors while secreting catecholamines. For thisreason, they may be imaged by isotope-tagged meta-iodine-benzyl-guanidine (MIBG) and they can be detected byincreased urinary excretion of catecholamine metabolites.

NB develops within the organ of origin, has no realcapsule, spreads to the regional lymph nodes, andmetastasizes by the haematogenous route to other structuressuch as the skin, bone marrow, liver, or bone. The primarymay grow rather rapidly undergoing necrosis, haemorrhage,and calcification. Due to the secretion of amines, thesepatients often have symptoms like diarrhoea, hypertension,pallor and appear sick and pained, particularly when theyhave bone metastases.

The diagnosis is based upon CT scan and MRI imaging,bone marrow aspiration, positive uptake of MIBG by the

A B

8.16 Pelvic Stage 2

neuroblastoma

diagnosed by palpation

in a 2-year-old male.

The huge mass was

attached to the lumbo-

sacral spine (1) and

complete removal was

possible after dissecting

free the right ureter (2)

and the iliac artery (3)

and vein (4).

1

2

3

4

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

82 Abdominal masses

Adrenal tumoursAdrenocortical carcinoma and phaeochromocytoma arevery rare neoplasias in children. Teratomas are germ cellneoplasias that differentiated towards embryonal tissues.They consist of tissues derived from the three blastodermiclayers that may adopt an organoid pattern and mix inamazing patterns. These tumours can be cystic and alsocontain bone, cartilage, or calcifications. When they have ahuman-like structure they are considered as a rare form ofparasitic twin or ‘fetus in feto’. They are generally located inthe midline in the sacrocoxigeal area where they can develop

externally, internally, or on both spaces. They are rarelyretroperitoneal at any point in this body space.

At birth they are generally benign although they may haveimmature areas. After 6 months of age, a high proportion ofthem become malignant and may contain areas of yolk sac(endodermal sinus) tumour and secrete AFP that is a usefulmarker for follow-up.

Treatment is surgical and may be difficult. In malignantcases chemotherapy is required before and after surgery. Thecurrent results are quite good even in malignant cases20.

11 Okada T, Yoshida H, Matsunaga T, et al. Multicysticdysplastic kidney detected by prenatal ultrasonography:natural history and conservative management. PediatrSurg Int 2003;19(3):207–10.

12 Neville HL, Ritchey ML. Wilms’ tumour. Overview ofNational Wilms’ Tumour Study Group results. Urol ClinNorth Am 2000;27(3):435–42.

13 Reinhard H, Semler O, Burger D, et al. Results of theSIOP 93-01/GPOH trial and study for the treatment ofpatients with unilateral nonmetastatic Wilms tumour.Klin Padiatr 2004;216(3):132–40.

14 Sapin E, Bargy F, Lewin F, et al. Management ofovarian cyst detected by prenatal ultrasounds. Eur JPediatr 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 of66 patients. Pediatr Blood Cancer 2006;46(4):459–64.

16 Cass DL, Hawkins E, Brandt ML, et al. Surgery forovarian masses in infants, children, and adolescents: 102consecutive patients treated in a 15-year period. J PediatrSurg 2001;36(5):693–9.

17 Navarro S, Amann G, Beiske K, et al. Prognostic valueof International Neuroblastoma Pathology Classificationin localized resectable peripheral neuroblastic tumours: ahistopathologic study of localized neuroblastomaEuropean Study Group 94.01 Trial and Protocol. J ClinOncol 2006;24(4):695–9.

18 La Quaglia MP, Kushner BH, Su W, et al. The impactof gross total resection on local control and survival inhigh-risk neuroblastoma. J Pediatr Surg2004;39(3):412–7.

19 Castel V, Tovar JA, Costa E, et al. The role of surgeryin stage IV neuroblastoma. J Pediatr Surg2002;37(11):1574–8.

20 Luo CC, Huang CS, Chu SM, et al. Retroperitonealteratomas in infancy and childhood. Pediatr Surg Int2005;21(7):536–40.

83Abdominal masses

References

1 Miyano T, Yamataka A, Kato Y, et al. Hepatico -enterostomy after excision of choledochal cyst inchildren: a 30-year experience with 180 cases. J PediatrSurg 1996;31(10):1417–21.

2 Christison-Lagay ER, Burrows PE, Alomari A, et al.Hepatic hemangiomas: subtype classification anddevelopment of a clinical practice algorithm and registry.J Pediatr Surg 2007;42(1):62–7.

3 Stringer MD, Alizai NK. Mesenchymal hamartoma ofthe liver: a systematic review. J Pediatr Surg2005;40(11):1681–90.

4 Czauderna P, Otte JB, Aronson DC, et al. Guidelines forsurgical treatment of hepatoblastoma in the modern era:recommendations from the Childhood Liver TumourStrategy Group of the International Society of PaediatricOncology (SIOPEL). Eur J Cancer 2005;41(7):1031–6.

5 Otte JB, Pritchard J, Aronson DC, e t al. Livertransplantation for hepatoblastoma: results from theInternational Society of Pediatric Oncology (SIOP) studySIOPEL-1 and review of the world experience. PediatrBlood Cancer 2004;42(1):74–83.

6 Czauderna P. Adult type vs. childhood hepatocellularcarcinoma: are they the same or different lesions? Biology,natural history, prognosis, and treatment. Med PediatrOncol 2002;39(5):519–23.

7 El Behery MM, Soliman HA. Primary gastric tumours ininfancy and childhood. Saudi Med J 2003;24(5Suppl):S41.

8 Steyaert H, Guitard J, Moscovici J, et al. Abdominalcystic lymphangioma in children: benign lesions that canhave a proliferative course. J Pediatr Surg1996;31(5):677–80.

9 Wright D, McKeever P, Carter R. Childhood non-Hodgkin lymphomas in the United Kingdom: findingsfrom the UK Children’s Cancer Study Group. J ClinPathol 1997;50(2):128–34.

10 Mann G, Attarbaschi A, Steiner M, et al. Early andreliable diagnosis of non-Hodgkin lymphoma inchildhood and adolescence: contribution ofcytomorphology and flow cytometric immuno pheno -typing. Pediatr Hematol Oncol 2006;23(3):167–76.

Liver disorders

Chapter 984

account. Infectious diseases may also cause cholestasis, thusurinary tract infections as well as cytomegalovirus (CMV)and toxoplasmosis should be excluded. The role of CMV asthe causative factor of cholestasis is still under debate, ascongenital CMV infections may present with liver damageand cholestasis. It is very important to assess stool colour tomake a timely diagnosis of biliary atresia (BA). BA is arelatively uncommon disease characterized by a biliaryobstruction of unknown origin that presents in the neonatalperiod2. However, it is the most important surgicallycorrectable cause of cholestatic jaundice in this age groupand is the most common indication for liver transplantationin children. Untreated, BA leads to cirrhosis and deathwithin the first years of life. Surgical treatment usuallyinvolves an initial attempt to restore bile flow: the Kasaiportoenterostomy3 which is performed as soon afterdiagnosis as possible. Prognosis of the disease seems to bebetter in infants operated on before 90 days of age4. Othercauses of cholestasis with pale stools are: Alagille syndrome,progressive familial intrahepatic cholestasis (PFIC), alpha-1-antitrypsin deficiency (α1-ATD), and cystic fibrosis.Neonatal haemochromatosis, Zellweger syndrome,Niemann–Pick disease type C, and glycogen storage diseasetype IV should also be considered in the differentialdiagnosis of infantile cholestasis (Tables 9.1, 9.2).

Jaundice and cholestasis

Jaundice results from the deposition of unconjugated orconjugated bilirubin pigment in the skin and mucousmembranes. Cholestasis is defined as conjugatedhyperbilirubinaemia. Liver disease may present ascholestasis alone, cholestasis that accompanies liver cirrhosisor severe liver disease with liver insufficiency. Ascites,peripheral oedema, bruises and so on can be present whichindicate severe liver damage. A jaundiced child with liverinsufficiency requires immediate hospitalization withprompt diagnosis to find the underlying liver disease.Prothrombin time can be solely regarded as an indicator ofacute liver failure.

InfancyCholestasis should be diagnosed quickly in infancy asvarious diseases require immediate therapy. Numerousaetiologies make diagnosis difficult. The American Academyof Pediatrics has elaborated practical guidelines for themanagement of hyperbilirubinaemia in newborn infants,mainly concentrating on indirect hyperbilirubinemia1. Theguidelines emphasise the importance of measuring directbilirubin in sick infants and in those who are jaundiced at orbeyond 3 weeks. If the direct or conjugated bilirubin level iselevated, additional assessment for the causes of cholestasisis recommended. For instance, hypothyroidism,galactosaemia, and tyrosinaemia should be taken into

CHOLESTASIS

Piotr Socha, MD, Joanna Pawłowska, MD,and Anil Dhawan, MD, FRCPCH

Liver disorders 85

Extrahepatic cholestasis• Biliary atresia

• Choledochal cyst

• Choledocholithiasis

Intrahepatic cholestasisInfectious diseasesTORCH (Toxoplasmosis, Others, Rubeolla,

Cytomegaloviral infection, Herpes)

Other viral infections

Reo

Echo

Parvovirus

Listeria

Sepsis

Urinary tract infection

Tuberculosis

HIV

Metabolic diseasesα1-antytrypsin 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

Cystic fibrosis

Bile acid metabolism disturbances

Peroxisomal disorders

Zellweger syndrome

Congenital defects of glycosylation

Familial cholestatic diseasesIdiopathic 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 diseasesDown syndrome

Other causesHypothyroidism

Histiocytosis X

Necrotizing enterocolitis

Parenteral nutrition-associated cholestasis

Drug-induced cholestasis

Table 9.1 Differential diagnosis of cholestatic liver disease of infancy

Urgent diagnosis indicatedBiliary atresia

Galactosaemia

Hypothyroidism

Tyrosinaemia

Neonatal haemochromatosis

Zellweger syndrome

Infections (sepsis, urinary tract infection, CMV, Toxo)

Elective diagnosis performedPFIC

Alagille syndrome

Cystic fibrosis

Choledochal cyst (if not accompanied by cholangitis)

α1-ATD

Niemann–Pick disease type C

Glycogen storage disease type IV

Table 9.2 Diagnostic approach to cholestasis of infancy

9.2 The parent

of the child

usually presents

also with very

typical facial

appearance.

9.1 Typical facial

appearance in a

child with Alagille

syndrome.

86 Liver disorders

Clinical characteristic and laboratoryfindings

Alagille syndromeAlagille syndrome can present with very early cholestasis ofinfancy but it may also be asymptomatic for a very long time.Liver damage may progress quickly in some patients withportal hypertension, recurrent cholangitis, and malnutrition6.Diagnosis of Alagille syndrome is aided by the presence ofsyndromic features, including bile duct paucity on liverhistology, chronic cholestasis, cardiac murmur, vertebralabnormalities, peculiar facies, eye findings, renal disease, andxantomas7. Usually differential diagnosis is performed in earlyinfancy when biliary atresia must be excluded.

Typical facial features are a prominent forehead, pointedchin, deep set eyes, moderate hypertelorism, and a saddle orstraight nose with a bulbous tip (9.1), but these features arenot very typical in early infancy. The parents may also havethe typical appearance (9.2) which may indicate the need todiagnose this disease. Pulmonary artery stenosis is a typicalfinding which may also cause a serious heart disease (9.3,9.4). Embryotoxon posterior observed in a slit lamp is oneof the most common features of the Alagille syndrome.Butterfly vertebrae observed in late infancy are also acharacteristic feature (9.5). Liver biopsy is helpful toestablish the diagnosis (9.6). Liver disease may slowlyprogress to liver insufficiency and liver transplantation maybe needed. However, in most of the patients liver diseaseremains stable for a long time.

ChildhoodJaundice is uncommon in children. However, indirecthyper bilirubinaemia can be the presentation of a benign,inherited condition, Gilbert syndrome, which affects about6% of the adult population. Mutations in hepatic enzymeisoform (1A1) belonging to the urine diphosphoglucuronateglucuronosyltransferase (UGT) family of enzymes areresponsible for this condition5. Gilbert syndrome can beconfirmed by molecular diagnosis but it should be suspectedin an otherwise asymptomatic child whose other liver testsare normal and there are no signs of haemolysis.

Several liver diseases may present with jaundice such asinfection with hepatitis B, hepatitis A, and hepatitis C virus,autoimmune hepatitis, Wilson disease, and α1-ATD.Cholecystitis is a rare condition in children and acuteclinical 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 episodesof increased hyperbilirubinaemia or symptoms of liverinsufficiency. That is why it is important to follow thesepatients carefully and the primary care physicians have to beaware of possible exacerbation of symptoms. Cholangitisepisodes in postoperative biliary atresia require rapiddiagnosis and treatment. Septic and hypoxic damage to theliver can cause cholestasis, and septicaemia seems to be acommon reason for referral of a jaundiced child to liverclinics.

87Liver disorders

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 30°. (Courtesy of the Cardiac Catheterization Laboratory, The Children’s Memorial Health

Institute).

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.)

9.5 Butterfly

vertebrae in

Alagille

syndrome.

9.7 Pruritus as a

presenting symptom

of PFIC.

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.)

Liver disorders88

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 18q 21-22 2q 24 7q 21 Short arm of

chromosome chromosome 20

Gene product P-type ATPase Bile salt pump Phospholipid Ligand of Notch1

transporter

Cell localization Gut, bile duct Canalicular Canalicular Liver, heart, skeletal,

cells, canalicular membrane membrane eye, kidney

membrane

Table 9.3 Genetic background of cholestastic diseases

A

B

Liver disorders 89

Progressive familial intrahepatic cholestasisPFIC is an inherited disorder where bile acid excretion isimpaired (Table 9.3). This diagnosis should always besuspected in patients with high serum bile acid concentra -tion, low/normal or elevated gamma glutamyl trans -peptidase (GGT), and pruritus.

Pruritus is usually the predominant symptom and skinexcoriations due to itching may be observed (9.7). Shortstature is a typical feature in later age (9.8). Liver histologymay reveal giant cell transformation, ductular proliferation,and fibrosis (9.9). The disease may progress to end-stage liverdisease. Some experience from centres in the USA and Polandpoints to a successful therapy with partial external biliarydiversion (9.10) when performed early in the course of thedisease8. PFIC also seems to be a risk factor for hepato cellularcarcinoma9. In general, diagnosis of PFIC is not very urgentbut doctors should be aware of the potential health effects.

Benign recurrent intrahepatic cholestasisBenign recurrent intrahepatic cholestasis (BRIC) ischaracterized by intermittent episodes of cholestasis withoutprogression to cirrhosis. The onset of the disease usuallyoccurs before the second decade of life. The attacks ofcholestasis vary in severity and duration (from 1 to 18months) and may be preceded by a preicteric phase withmalaise, anorexia, and pruritus. Biochemically it ischaracterized by increased concentrations of bilirubin,serum bile acid, and alkaline phosphatase; GGT remainslow. There are no pathological changes in the liver on biopsybesides some hepatocellular cholestasis. In betweenepisodes patients are totally asymptomatic both clinicallyand biochemically. Treatment is symptomatic.

9.10 Partial biliary

diversion in a child with

PFIC. Catch up growth is

observed since the

procedure was performed.

9.8 Short stature in a

14-year-old girl with

PFIC.

A

B

9.9 Liver histology in PFIC. A: Missing bile duct in a portal

space (arrow, artery; arrowhead, portal truct);

B: enlargement of the portal truct with septal fibrosis

(brace).

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

Liver disorders90

exceeding 2 mg/dl (34 μmol/l) over 2 weeks of age bereferred to liver centres for further work-up to avoid wastingvaluable time in making the diagnosis. BA may progressquickly to cirrhosis with ascites (9.14) and oesophagealvarices as a consequence of portal hypertension.

Alpha-1-antytripsin deficiencyα1-ATD is inherited as an autosomal codominant disorder.The most frequent and severe mutation that causes severeα1-ATD arises in the SERPINA1 gene (formerly known asPI) and gives rise to the Z allele. Determination of α-1-antitrypsin phenotype but not measurement of α-1-antitrypsin concentration is the way to make the finaldiagnosis. During the first year of life, infants with thehomozygous Pi ZZ phenotype may temporarily showelevated levels of liver enzymes and cholestasis and

A

B

9.11 A child with biliary atresia with moderate jaundice

and normal nutritional status (A), and pale stools (B).

9.12 Dynamic scintigraphy of the

liver in BA does not show any bile

passage to the gut after 24 hours.

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).

A B C

D E F

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

Other aetiologies of cholestasisGalactosaemia and tyrosinaemia should be diagnosed veryquickly, as they can be managed with a special diet and thedisease may progress very rapidly. Galactosaemia is a raredisease usually presenting with prolonged prothrombintime, but most developed countries carry out newbornscreening. The definitive diagnosis is done by enzymatictesting for galactose-1-phosphate-uridyltransferase activity

Liver disorders 91

9.14 Ascites in a small child with biliary atresia.

(UDPG)10. It is important to know that the diagnosis ofgalactosaemia may lead to a false result if the infant hasreceived a blood transfusion in the preceeding 3 months asthe UDPG test does not differentiate between donor orrecipient enzyme levels. If the diagnosis of galactosaemia issuspected, galactose-containing feedings should bediscontinued immediately and replaced by a lactose-freeformula pending the results of an appropriate enzyme assayon erythrocytes to confirm the diagnosis.

Hereditary tyrosinaemia may also present with jaundiceand clotting disturbances. Determination of succinylacetonein the urine is a helpful diagnostic test for this disorder11.Neonatal haemochromatosis may also present acutely withliver failure and must be diagnosed very quickly. Othermetabolic disorders like Niemann–Pick disease type C orglycogen storage disease type IV do not progress so rapidlyand diagnosis is not so urgent.

Another neonatal liver disease presenting with typicalfeatures and cholestasis is Zellweger’s syndrome (9.15), ageneralized peroxisomal biogenesis disorder which ischaracterized by a wild spectrum of abnormalities includingin the nervous system and kidneys. Patients havecharacteristic craniofacial abnormalities with widefontanelle, prominent forehead, anteverted nostrils, andnarrow upper lip. Hepatic involvement includeshepatomegaly and conjugated hyperbilirubinaemia due toabnormal bile acid synthesis. In some cases cirrhosis andportal hypertension has been reported in the first year of life.The administration of primary bile acids (cholic acid andchenodeoxycholic acid) may improve liver function.

9.15 Zellweger syndrome (skeletal features).

Liver disorders92

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 9.4 Characteristics of aminotransferases

(normal levels ≤40 U/l)

• 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

Table 9.5 Characteristics of GGT

Introduction

Hypertransaminasaemia in childhood is a common findingwhich requires a staggered study depending on the clinicalfeatures and the severity of the disease, in order to obtain acorrect diagnosis12. Investigation of the liver function relieson 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 immuno -

globulins).

Aminotransferases represent the integrity of liver cells. Thequotient AST/ALT is normally less than 1. When it is higherthan 1, it may mean that a more severe liver damage is present(Table 9.4). GGT and alkaline phosphatase increase if there isan obstruction or a damage in hepatic canaliculae (Tables 9.5,9.6). Prothrombin time is an excellent marker of liver syntheticfunction, as most coagulation factors are synthesized in theliver. Prothrombin time is a measure of the extrinsic andcommon pathway of coagulation. Prolonged prothrombintime is a sign of an important hepatocellular dysfunction.

Symptomatology

Patients with a liver disease do not present any specificsymptom. Most patients are asymptomatic. An underlyingliver disease can be discovered due to hyper trans -aminasaemia found in an ordinary blood test. Other patientsmay present any of the symptoms listed in Table 9.7.

Specific causes of liver disease

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

HYPERTRANSAMINASAEMIA IN CHILDHOOD

Luís Peña-Quintana, MD, and Daniel González-Santana, MD

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

VirusesHepatotropic virus A, B, C, D, E, and probably G,Epstein–Barr virus (EBV), cytomegalovirus (CMV), andother viruses (herpesvirus, adenovirus, parvovirus) mayproduce acute hepatitis. Patients may be asymptomatic orpaucisymptomatic. The classic presentation with three

Liver disorders 93

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 9.6 Characteristics of LDH and alkaline

phosphatase

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 9.7 Symptomatology

• 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

Table 9.8 Causes of acute liver disease

• 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 9.9 Causes of chronic liver disease

phases (preicteric, icteric, and posticteric or convalescentphase) is less frequent. Some patients may presentprolonged abnormal liver function tests or fulminant liverfailure. Only hepatitis due to B, C, D, E and G viruses canlead to chronic liver disease.

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

Wilson’s diseaseWilson´s disease (WD) is an autosomic recessive geneticdisorder14 affecting gene ATP7B in chromosome 13q14.3.It codes for transmembrane copper transporter inhepatocytes and for excretion into the bile canaliculus as

• Amiodarone

• Anti-neoplastic drugs

• Azatioprine

• Carbamazepine

• Cocaine

• Ciclosporin

• Ecstasy

• Erythromycin

• Strogens

• Halothane

• Methotrexato

• Minocycline, penicillins

• Alcohol

• Phenobarbital

• Haloperidol

• Valproate

• Paracetamol

• Acetylsalicylic acid

• Ketoconazole

• Isoniazid

• Methyldopa

• Sulphonamide

• NSAIDs

• Verapamil

• Pemoline

• Retinoids

Table 9.10 Hepatotoxic drugs

9.16 Liver biopsy in a patient with autoimmune hepatitis.

Piecemeal necrosis.

94 Liver disorders

such as anti-soluble liver antigen, anti-liver cytosol, anti-liver–pancreas antigen, or anti-asialoglycoprotein receptor.Anti-actine and antineutrophil cytoplasmic autoantibodiesmay also be useful in the diagnosis. Patients may presentwith acute hepatitis or as chronic hepatitis with insidioussymptomatology. In other cases, it is an incidental finding.

The increase in transaminases has no relationship withthe degree of hepatic necrosis. Polyclonal hypergamma -globulinaemia (IgG) is often found (2–6 g/l). If the levels ofIgG are low it is a sign of good response to therapy.

Although the detection of autoantibodies is very useful fordiagnosis, they are not specific. Therefore, autoimmunehepatitis is not excluded in the presence of low serumautoantibody titres. Liver biopsy is fundamental fordiagnosis, and the findings vary from hepatitis withmoderate or severe activity to cirrhosis, which is present inalmost 50% of the children at diagnosis (piecemeal necrosis(9.16), lobular hepatitis [not constant], central–portalbridging necrosis) (9.17).

Alpha-1-antitrypsin deficiency (α1-ATD)In this autosomal recessive disease there is a chromosome14 mutation18 that leads to the production of abnormal andhepatotoxic α1-AT that is retained in the endoplasmicreticulum (9.18). Frequency is 1:2000 newborns.α1-AT glycoprotein may present as 100 variants, with

codominant inheritance, which are classified according tothe protease inhibitor (Pi) phenotype system based on theirelectrophoretic moiety: Pi MM variant (with normal serumconcentration and normal activity), Pi null-null variant(absence of α1-AT associated with lung disease), defective

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 lowlevels of bile copper and coeruloplasmin.

Prevalence in Europe is 1/30,000, with 1/100heterozygous. In the Canary Islands, the incidence is1/2,60015. It may present as asymptomatic hypertrans -aminasaemia or as chronic hepatitis, cirrhosis, or acute liverfailure in childhood. In older children and adults,extrapyramidal neurological symptoms (dysarthria,dystonia, ataxia, tremor, dysphagia), psychiatric manifesta -tions, Kayser–Fleischer ring (due to copper deposits in theDescemet corneal membrane, very specific but notpathognomonic of WD), and renal tubulopathies (withaminoaciduria and phosphaturia) are more frequent16.

It is typical to find low plasma coeruloplasmin, althoughin 5–10% of patients it may be normal (>20 mg/dl), anddecreased serum copper levels. A raised urine copper afterpenicillamine (higher than 100 μg/day) and an elevated livercopper concentration (higher than 250 μg/g of dry livertissue) are helpful in diagnosis. Liver biopsy shows the stageof the disease. Genetic tests (>150 mutations) may help.

Autoimmune hepatitis Autoimmune hepatitis (AIH) is a chronic inflammatorydisorder affecting the liver, with unknown aetiology. It maycause severe progressive liver disease and, eventually, lead tocirrhosis and liver failure. It is classified in three types17:Type 1, with positive anti-nuclear and/or anti-smoothmuscle antibodies; Type 2, with positive anti-liver–kidneymicrosomal antibodies; and Type 3, with other antibodies,

9.17 Liver biopsy in a patient with autoimmune hepatitis.

Central–portal bridging necrosis.

95Liver disorders

9.18 Liver biopsy in a patient with alpha-1-antitrypsine

deficiency.

9.19 Diagnosis of alpha-1-antitrypsine deficiency is based

on a decrease in the α1 band (arrow) (readout from

electrophoretic gel).

variants (such as Pi Z and Pi S, with low serumconcentration and lung and liver disease). MM phenotype isfound in healthy individuals; ZZ phenotype causes the mostsevere deficiency and it represents 95% of patients. SZphenotype may cause liver disease (neonatal cholestasis,mild dysfunction, chronic hepatitis, liver failure, cirrhosis,hepatocellular carcinoma), while MS/MZ phenotypes donot 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 bloodand Pi phenotype. On the liver biopsy, an abnormalaccumulation of α1-AT in liver is present.

Nonalcoholic fatty liver diseaseNonalcoholic fatty liver disease (NAFLD) includes simplefatty liver (steatosis), nonalcoholic steatohepatitis (NASH)and cirrhosis19 (9.20). Most patients with NAFLD presentwith obesity, mainly central adiposity20, as part of themetabolic syndrome21 (9.21).

The pathology of the NAFLD in children includes: Type1, characterized by steatosis, hepatocyte balloonization, andperisinusoidal fibrosis (similar to NAFLD in adults andmore 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 andchildren of Asian, Native American, and Hispanicethnicity)22.

Clinical experience in children with NAFLD is limited.NAFLD in childhood and adolescence used to occur in themale obese patient, with AST>ALT (whenhypertransaminasaemia is present), hypertriglyceridaemia,

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)

Cirrhosis

9.20 Nonalcoholic fatty liver disease.

acanthosis nigricans (9.23), and absence of symptoms(when the disease has been diagnosed by screening testsand/or abdominal ultrasonography). Although most patientsremain asymptomatic, other individuals may present with avariety of symptoms: hypertension, dyslipidaemia, insulinresistance, type 2 diabetes, and central obesity23.

9.21 Fenotypic

appearence of an

adolescent with

nonalcoholic fatty liver

disease.

Liver disorders96

Transaminases can be normal or mildly elevated,persistently or intermittently (usually AST/ALT <1). In25% of cases, patients show an increase in GGT24, 25.Imaging techniques such as ultrasonography (9.24),computed tomography, and nuclear magnetic resonanceimaging do not distinguish between simple esteatosis andNASH. The gold standard test to distinguish between

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.

simple esteatosis and NASH is liver biopsy (Table 9.11)26.It confirms diagnosis, assesses esteatosis severity, and servesas a prognostic marker. Patients with simple esteatosis havea benign course without histological progression, butpatients with NAFLD may progress to cirrhosis orhepatocarcinoma (described just in adults)27.

Practical issues in a patient withincreased transaminases

In the differential diagnosis of hypertransaminasaemia,coeliac disease should be considered, even when there areno other symptoms28. The baseline investigations may befound in Table 9.12. If these are not enough to lead to the

Liver disorders 97

9.25 Evolution to cirrhosis in a child with a severe

congenital heart disease.

Children AdultsSteatosis Marked <Marked

Inflammation >Portal Lobular

Ballonization Rare Frequent

Fibrosis >Portal Lobular

Cirrhosis Rare >Frequent

Table 9.11 Histopathological findings in

nonalcoholic liver disease

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

Table 9.12 Investigations to be performed in

patients with increased transaminasesdiagnosis, second-line investigations should be performed29.In acute hepatitis, liver biopsy should be indicated if there isunknown aetiology, prolonged hepatitis or several relapses,suspicion of underlying chronic disease, or cholestasisassociated with acute cytolysis30.

In chronic hepatitis, liver biopsy is essential and isindicated to investigate the aetiology, for histologicaldiagnosis, for the prognosis based on inflammation intensity(grade) and fibrosis (stadium), and to evaluate anti-viraltherapy response. Some practical considerations are:• ↑ AST isolated: macrotransaminasaemia (AST–immu no -

globulin complex, without liver damage).• The degree of transaminases elevation does not correlate

with prognosis.• The most frequent causes of gross elevation in

transaminases in acute hypertransaminasaemia (AST-ALT >1000) are: viral hepatitis, drug and alcohol-induced hepatitis, and ischaemic hepatitis (heart failure,hypotension, sepsis, Budd–Chiari).

• In chronic hepatitis, the inversion of the quotientAST/ALT (>1), indicates a deeper damage (mito -chondrial) and evolution to fibrosis-cirrhosis (9.25).

• Liver transplantation is indicated if there is reducedtransaminases with increased bilirrubin and decreasedprothrombin time. These are signs of submassive livernecrosis and consequent hepatocellular failure. GradeIII/IV encephalopathy and/or factor V <25% are clearindications for liver transplantation.

References

1 American Academy of Pediatrics. Management ofhyperbilirubinemia in the newborn infant 35 or moreweeks of gestation. Pediatrics 2004;114:297–316.

2 Alagille D. Extrahepatic biliary atresia. Hepato logy1984;4:7S–10S.

3 Kasai M, Kimura S, Asakura Y, et al. Surgical treatmentof biliary atresia. J Pediatr Surg 1968;3:665–75.

4 Altman RP, Lilly JR, Greenfeld J, et al. A multivariablerisk factor analysis of the portoenterostomy (Kasai)procedure for biliary atresia: twenty-five years ofexperience from two centers. Ann Surg1997;226:348–55.

5 Kaplan M, Hammerman C, Maisels MJ. Bilirubin geneticsfor the nongeneticist: hereditary defects of neonatalbilirubin conjugation. Pediatrics 2003;111:886–93.

21 Marchesini G, Brizi M, Bianchi G, et al. Nonalcoholicfatty liver disease: a feature of the metabolic syndrome.Diabetes 2001;50:1844–50.

22 Schwimmer JB, Behling C, Newbury R, e t al.Histopathology of pediatric nonalcoholic fatty liverdisease. Hepatology 2005;42:641–9.

23 Peña-Quintana L, Colino E, Montedeoca N, et al.Obesity and nonalcoholic fatty liver disease. J PediatrGastroenterol Nutr 2005;40:686–7.

24 Fishbein MH, Mogren C, Gleason T, et al. Relationshipof hepatic steatosis to adipose tissue distribution inpediatric nonalcoholic fatty liver disease. J PediatrGastroenterol Nutr 2006;42:83–8.

25 Festi D, Colecchia A, Sacco T, et al. Hepatic steatosis inobese patients: clinical aspects and prognosticsignificance. Obesity Reviews 2004;5:27–42.

26 Joy D, Thava VR, Scott BB. Diagnosis of fatty liverdisease: is biopsy necessary? Eur J Gastroenterol Hepatol2003;15:539–43.

27 Molleston JP, White F, Teckman J, et al. Obese childrenwith steatohepatitis can develop cirrhosis in childhood.Am J Gastroenterol 2002;97:2460–2.

28 Abdo A, Meddings J, Swain M. Liver abnormalities inceliac disease. Clin Gastroentero l Hepato l2004;2:107–12.

29 Pratt DS, Kaplan MM. Evaluation of abnormal liver-enzyme results in asymptomatic patients. N Engl J Med2000;342:1266–71.

30 Kelly DA. Diseases of the Liver and Biliary System inChildren, 2nd edn. Blackwell Science, Oxford, 2003.

Further reading

Fregonese L, Stolk J. Hereditary alpha-1-antitrypsinedeficiency and its clinical consequences. Orphanet J RareDis 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 biliaryatresia. Arch Dis Child 2007;92:1132–5.

Moerschel SK, Cianciaruso LB, Tracy LR. A practicalapproach to neonatla jaundice. Am Fam Physician2008;77:1255–62.

98 Liver disorders

6 Quiros-Tejera R, Ament ME, Heyman MB, et al.Variable morbidity in Alagille syndrome: a review of 43cases. J Pediatr Gastroenterol Nutr 1999;29:431–37.

7 Emerick KM, Rand EB, Goldmuntz E, et al. Features ofAlagille syndrome in 92 patients: frequency and relationto prognosis. Hepatology 1999;29:822–29.

8 Whitington PF, Whitington GL. Partial externaldiversion of bile for the treatment of intractable pruritusassociated with intrahepatic cholestasis. Gastroenterology1988;95:130–36.

9 Knisely AS, Strautnieks SS, Meier Y, et al. Hepatocellularcarcinoma in 10 children under 5 years of age with bile saltexport pump deficiency. Hepatology 2006;44:478–86.

10 Schweitzer-Krantz S. Early diagnosis of inheritedmetabolic disorders towards improving outcome: thecontroversial issue of galactosaemia. Eur J Pediatr2003;162:S50–S53.

11 Burton BK. Inborn errors of metabolism in infancy: aguide to diagnosis. Pediatrics 1998;102:1–9.

12 Suchy FJ, Sokol R, Balistreri W (eds). Liver Disease inChildren, 3rd edn. Cambridge University Press, NewYork, 2007.

13 Impicciatore P, Choonara I, Clarkson A, et al. Incidenceof adverse drug reactions in paediatric in/out-patients: asystematic review and meta-analysis of prospectivestudies. Br J Clin Pharmacol 2001;52:77–83.

14 Roberts EA, Schilsky ML. A practice guideline onWilson disease. Hepatology 2003; 37:1475–92.

15 Garcia-Villarreal L, Daniels S, Shaw SH, et al. Highprevalence of the very rare Wilson disease gene mutationLeu708Pro in the Island of Gran Canaria (CanaryIslands, Spain): a genetic and clinical study. Hepatology2000;32:1329–36.

16 Ferenci P, Caca K, Loudianos G, et al. Diagnosis andphenotypic classification of Wilson disease. Liver Int2003;23:139–42.

17 Czaja AJ, Freese D. Diagnosis and treatment ofautoimmune hepatitis. Hepatology 2002;36:479–97.

18 Primhak RA, Tanner MS. Alpha-1 antitrypsindeficiency. Arch Dis Child 2001;85:2–5.

19 Patton HM, Sirlin C, Behling C, et al. Pediatricnonalcoholic fatty liver disease: a critical appraisal ofcurrent data and implications for future research. JPediatr Gastroenterol Nutr 2006;43:413–27.

20 Fishbein MH, Miner M, Mogren C, et al. The spectrumof fatty liver in obese children and the relation-ship ofserum aminotransferases to severity of steatosis. J PediatrGastroenterol Nutr 2003;36:54–61.

10.1 Histological section of a flat mucosa in untreated

coeliac disease.

99

administration of extra-gluten to HLA-identical siblings ofcoeliac patients does not always result in pathologicalchanges to the intestine. The HLA-DQ dimmer is alsostrongly linked to HLA-DR status8.

Pathology

The proximal mucosa of the small intestine in patients withCD becomes abnormal on gluten ingestion and small bowelbiopsy is essential to confirm the diagnosis (10.1). Theabnormality is characterized by stunted or even absent villiassociated with an increase in crypt length and cell numbers,the so-called ‘flat mucosa’ (10.2). The flat gut lesion ischaracteristic, but nonspecific of CD (Table 10.1)9.

All structural damage resolves on gluten withdrawal, butrecurs if gluten is reintroduced to the diet. Similar intestinalchanges are frequently found in dermatitis herpetiformis(DH), an intensely itchy, chronic papulovesicular skin

Definition

Coeliac disease (CD) is an immunologically mediatedenteropathy of the small intestine, characterized by lifelongintolerance to the gliadin and related prolamines from wheatand other cereals that occurs in genetically predisposedindividuals1. Symptoms result from structural damage to themucosa of the small intestine, which may causemalabsorption. Normal mucosal architecture is restoredafter commencing a gluten-free diet (GFD); villous atrophyreappears when gluten is reintroduced into the diet (glutenchallenge)1–3.

Epidemiology

The true incidence of CD in susceptible populations may be dramatically higher than has been previouslyrecognized1, 3, 4 and most cases remain undiagnosed, unlessactively identified through mass serological screening. CDaffects females more than males (ratio 2:1).

A relationship between various factors and the diagnosisof CD has been described, including genetic background,quality and quantity of gluten, age at gluten introduction,and breast-feeding5–7.

Genetic factors

The primary association of CD is the HLA-DQ dimerDQA1*0501/DQB1*0201. The majority of patients andfirst-degree relatives (and up to 20% of normal controls insusceptible populations) may express this dimer on antigen-presenting cells. The possession of this haplotype is notenough to cause gluten-induced changes, and the

Chapter 10

Coeliac disease

Isabel Polanco MD, PhD

10.2. Histological

features. (From Horvath

K. Recent Advances inPediatrics, 2002.)

Clinical features

CD can appear with different clinical manifestations. Ingeneral, the first symptoms appear in the months followingthe introduction of gluten in the diet (10.3, 10.4). Theearlier gluten is introduced, the shorter the interval betweenintroduction and occurrence of the first symptoms. The firstsymptoms of CD, therefore, traditionally occur between 12months and 3 years of age (Table 10.2).

In a minority of children, diagnosis is not made by the ageof 5 years. CD can therefore be diagnosed at any time up toadulthood, because symptoms have been either ignored ormisinterpretated (e.g. short stature), because the disease istruly symptomless or when some other autoimmune diseaseoccurs (Tables 10.3, 10.4).

Latent coeliac disease

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

Coeliac disease100

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

Table 10.1 Causes other than coeliac disease that

may produce a flattened jejunal mucosa

disorder, caused by granular subepithelial IgA deposits inthe upper dermis. Both the cutaneous and intestinal lesionsregress with a GFD. DH is now considered as a specific skinmanifestation of CD.

Normal 0 Infiltrative 1 Hyperplastic 2

Partial atrophy 3a Subtotal atrophy 3b Total atrophy 3c

10.4 A, B: A typical 3-year-old coeliac boy 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.

Coeliac disease 101

10.3 An untreated coeliac girl.

She is pale and looks miserable

and depressed.

A B

Symptoms SignsClassic presentationChronic diarrhoea Abdominal distension

Anorexia Buttock wasting

Abdominal distension Malnutrition/growth failure

Weight loss Pallor

Vomiting Irritability

Irritability/lethargy Psychomotor delay

Haematomas

Rickets

Presentation at older ageAsymptomatic Glossitis, aphthous ulcers

Absence of diarrhoea Short stature

Decreased appetite Iron deficiency anaemia

Anorexia Osteopaenia

Growth failure Bruising

Pubertal delay Arthritis/arthralgia

Menstrual irregularities Enamel hypoplasia

Abnormal (loose) stools Cerebral calcifications

Arthritis/arthralgia

Abdominal pain

Constipation

Presentation at adulthooodAnxiety/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

Table 10.2 Clinical presentation according to the

age of onset of symptoms in CD

Selective IgA deficiency 37

Dermatitis herpetiformis 36

Diabetes mellitus 32

Bronchial asthma 6

Psoriasis 6

Chronic active hepatitis 6

Epilepsy 6

Vitiligo 4

Down syndrome 3

Cardiac disease 3

Thyroid disorders 3

Cystic fibrosis 1

Fibrosing alveolitis 1

Renal tubular acidosis 1

Spino-cerebellar degeneration 1

Total 146

Table 10.3 Associated disorders found in

1010 coeliac children at the Hospital Infantil

Universitario La Paz Madrid (Spain)

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

thrive, anorexia, etc.

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

Table 10.4 Mode of presentation in 1010 coeliac

Children at the Hospital Infantil Universitario

La Paz, Madrid (Spain)

screening for coeliac disease (Table 10.5). The titres ofendomysial antibodies and anti-tissue transglutaminaseantibodies correlate with the degree of mucosal damage; asa result, the sensitivity of these antibody tests declines whena greater number of patients with lesser degrees of villousatrophy are included in studies. The various commerciallyavailable assays for anti-tissue transglutaminase antibodieshave different characteristics and resultant sensitivities andspecificities.

Treatment

A strict GFD with exclusion of gluten from wheat, rye,barley, and oats must be recommended lifelong in bothsymptomatic and asymptomatic individuals. Lifelongadherence to a strict GFD should be advised to all coeliacchildren in order to avoid the late complications of thedisease13. Adherence to a strict GFD is essential but noteasy and a follow-up control by a gastroenterologist aboutonce a year seems to be advisable. The Coeliac PatientsAssociations help patients to adhere to a GFD and tounderstand their disease better.

102 Coeliac disease

Diagnosis

The diagnosis of coeliac disease requires both a jejuno-duodenal biopsy that shows the characteristic findings ofintraepithelial lymphocytosis, crypt hyperplasia, and villousatrophy (10.1) and a positive response to a GFD. Thediagnostic criteria developed by the European Society forPaediatric Gastroenterology and Nutrition2 require onlyclinical improvement with the diet, although histologicalimprovement on a GFD is frequently sought and isrecommended in adults because villous atrophy may persistdespite a clinical response to the diet. In most patients, thediagnosis is easily established. However, roughly 10% ofcases are difficult to diagnose because of a lack ofconcordance among serologic, clinical, and histologicalfindings1–3.

The most sensitive antibody tests for the diagnosis ofcoeliac disease are of the IgA class. The recognition that theenzyme tissue transglutaminase is the autoantigen for thedevelopment of endomysial antibodies allowed developmentof automated enzyme-linked immunoassays that are lessexpensive than the endomysial antibody test. Overall, thesensitivity of the tests for both endomysial antibodies andanti-tissue transglutaminase antibodies is greater than 90%,and a test for either marker is considered the best means of

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

Table 10.5 Serological tests for coeliac disease9

103Coeliac disease

10 Polanco I, Larrauri J. Does transient gluten intoleranceexist? In: Kumar PJ, Walker-Smith JA (eds). CoeliacDisease: One Hundred Years. Leeds University Press,Middlesex, 1990, pp. 226–30.

11 Kaukinen K, Collin P, Mäki M. Latent coeliac diseaseor coeliac disease beyond villous atrophy? Gut2007;56:1339–40.

12 Polanco I, Larrauri J, Prieto G, et al. Severe villousatrophy appearing at different ages in two coelias siblingswith identical HLA haplotypes. Acta Paediatr Belg1980;33:276.

13 Holmes GKT. Long-term health risks for unrecognizedcoeliac 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. EndocrMetab Immune Disrd Drug Targets 2008;8:152–8.

Barton SH, Murray JA. Celiac disease and autoimmunity inthe gut and elsewhere. Gastroenterol Clin North Am2008;37:411–28.

Fasano A, Troncone R, Branski D. Frontiers in CeliacDisease. In: Pediatric and Adolescent Medicine, vol 12. Branski D, Kiess W (eds). Karger, Basel, 2008.

Polanco I. Celiac Disease. J Pediatr Gastroenterol Nutr2008;47(suppl 1):S3–6.

Setty M, Harmaza L, Guandalini S. Celiac disease: riskassessment, diagnosis, and monitoring. Mol Diagn Ther2008;15:289–98.

References

1 Green P, Cellier C. Celiac disease. N Engl J Med2007;357:1731–43.

2 Walker-Smith JA, Guandalini S, Schmitz J, et al. Revisedcriteria for the diagnosis of coeliac disease. Report ofworking group of ESPGHAN. Arch Dis Child1990;65:909–11.

3 Troncone R, Auricchio R. Celiac disease. In: Wyllie R,Hyams JS (eds). Pediatric Gastrointestinal and LiverDisease, 3rd edn. Saunders Elsevier, The Netherlands,2006, pp. 517–27.

4 Polanco I, De Rosa S, Jasinski C. Coeliac disease in LatinAmerica. In: Auricchio S, Visakorpi JK (eds). CommonFood 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 incoeliac disease. Paediat Res 1981;75:1193.

6 Polanco I, Biemond I, van Leeuwen A, et al. Gluten-sensitive enteropathy in Spain: genetic and environmentalfactors. In: McConnell RB (ed). The Genetics of CoeliacDisease. MTP Press, Lancaster, 1981, pp. 211–34.

7 Mearin ML, Biemond I, Peña AS, et al. HLA-DRphenotypes in spanish coeliac children: their contributionto the understanding of the genetics of the disease. Gut1983;24:532–37.

8 Polanco I, Mearin ML, Larrauri J, et al. The effect ofgluten supplementation in healthy siblings of childrenwith celiac disease. Gastroenterology 1987;92:678–81.

9 Marsh MN. Gluten, major histocompatibility complex,and the small intestine. A molecular and immunologicapproach to the spectrum of gluten sensitivity (celiacsprue). Gastroenterology 1992;102:330–54.

Ulcerative colitis

Carlos Sierra Salinas, MD, andJavier Blasco Alonso, MD

Chapter 11104

Pathogenesis

The pathogenesis remains unknown. Recent literaturereports an intensive search for the antigens that trigger theimmune response in inflammatory bowel disease. Onehypothesis is that these triggers are microbial pathogens, asyet unidentified with an appropriate but ineffective immuneresponse to these pathogens. Another hypothesis affirmsthat there are some common dietary antigens ornonpathogenic microbial agents to which the patientmounts an abnormal immune response. The autoimmunetheory postulates that an antigen is expressed on thepatient’s own intestinal epithelial cells and there is animmune response to antigen and own epithelium which arethus destroyed by immune mechanisms.

Clinical features

The presentation may vary depending upon the extent ofcolonic involvement and the severity of inflammation.According to the extent of the disease, three subgroups havebeen 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.

Introduction

Ulcerative colitis (UC) is a relapsing and remitting diseasecharacterized by acute non-infectious inflammation of thecolorectal mucosa. Crohn’s disease (CrD) and UC are thetwo main types of inflammatory bowel disease (IBD). Whilechildren and adults develop similar symptoms, childrenoften present with more extensive disease.

Epidemiology

UC may appear at any age. Most of the children arebetween 10 and 18 years. The incidence of UC in childrenand adolescents per 100,000 children per year variesbetween 0.5 (France) and 4.3 (Norway). The incidence ofUC in children has remained relatively stable. Multiplegenes may contribute to the pathogenesis of UC; essential isthe interaction with the environment. Among others factors,several authors have suggested the correlation with exposureto infections in the perinatal period or early life, the inverserelationship with breast-feeding, the administration ofnonsteroidal anti-inflammatory drugs, and the inverserelationship with appendectomy before the age of 20 years.

Evidence of higher rates of UC in urban areas raises theissue of a transmissible agent that may be responsible for thedisease expression or increased susceptibility. However, nospecific infectious agent has been associated with thedevelopment of the disease.

Ulcerative colitis 105

Proctitis Left-sided colitis Pancolitis

11.1 Extent of bowel involvement in different ulcerative

colitis.

Colonic• Rectal bleeding

• Diarrhoea

• Tenesmus

• Incontinence

• Lower abdominal cramps and pain with defecation

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 11.1 Symptoms of ulcerative colitis

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

Table 11.2 Disease severity at presentation

The predominant symptom is diarrhoea, which can beassociated with frank blood in the stool. The patient hasfrequent bowel movements, which may be small in volume,as a result of irritability of the inflamed rectum. Othersymptoms include abdominal or rectal pain related todefecation, fever, and weight loss (Table 11.1).

Proctitis may present with tenesmus, urgency, and thepassage of semi-formed stool with blood and mucus. Incontrast, left-sided colitis or pancolitis may present withbloody diarrhoea and significant abdominal pain. Themajority of patients will present with a history of symptomsfor several weeks. For this reason growth failure is much lessfrequent than in children with CrD. The extent of colonicmucosal involvement and severity of disease correlate withthe clinical manifestations of UC (Table 11.2)

Differential diagnosis

The most difficult decision may be to establish whether thediagnosis is UC or CrD (Table 11.3). The infectiousaetiologies should be investigated with stool cultures andstool test for Clostridium diffic ile toxins A and B.Identification of a pathogen, however, does not necessarilyexclude a diagnosis of UC, as a first episode of UC maypresent after documented enteric infection (Table 11.4). Ininfancy it is important to exclude other causes of bloodydiarrhoea such as allergic colitis and Hirschsprung´s colitis.

Physical examination is notably less informative than inCrD, except for the demonstrations of extraintestinalmanifestations that may be associated with UC.

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 11.3 Differences between UC and CrD-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

Table 11.4 Infectious colitis

106 Ulcerative colitis

Initial assessment

The first steps in the diagnostic work-up of children withsuspected UC should include blood tests, stoolexamination, and bowel wall ultrasonographymeasurement1. There is a low diagnostic accuracy of thecommon laboratory parameters of inflammation such asplatelet count, erythrocyte sedimentation rate, and C-reactive protein. Experience with faecal calprotectin inchildren with suspected IBD has been encouraging andsuggests that this protein is a reliable diagnostic predictor forintestinal activity, with greater sensitivity and negativepredictive value compared with those of other commonlaboratory parameters of inflammation. However, faecalcalprotectin is not disease-specific, being elevated in allkinds of intestinal inflammation such as infectiousenterocolitis. The serological immune markers anti-Saccharomyces cerevisiae antibodies (ASCA) and anti-neutrophil cytoplasmic antibody with perinuclear stainingpattern (pANCA) are associated with CrD and UC,respectively, and they are rarely found in healthy controls.The ultrasonographic evaluation of the intestinal thicknesshas gained importance as a reliable, noninvasive imagingmodality for the diagnostic and clinical follow-up of IBDpatients. The combined use of faecal calprotectin,ASCA/pANCA, and bowel wall ultrasonographymeasurement is a useful clinical decision-making strategy. Ifthese test results are positive, the patient would thenundergo a complete evaluation2.

107Ulcerative colitis

11.2 Barium enema.

A: Pseudopolyps;

B: slight granularity;

C: ulcers; D: thickening

of the colonic wall.

Radiographic and endoscopic evaluation

In the early phase, the oedema and inflammatory infiltrationcause a flattening of the haustras. In the active stage there isa disseminated ulceration and loss of haustra (11.2). Deeperulcers may undermine the mucosa, which leads todevelopment of the characteristic collar-button ulcerations.Evaluation with colonoscopy should be performed todiagnose UC and to determine the extent and severity ofUC presentation (Table 11.5) (11.3).

Histopathological findings

UC is defined histologically by diffuse chronicinflammation limited to the mucosa with severe crypt celldistortion (11.4A), diffuse goblet cell depletion (mucous

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

Table 11.5 Endoscopic staging of ulcerative colitis

A B

C D

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

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.

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.


A B

C D

A B

C


References

1 Canani RB, Tanturri de Horatio L, Terrin G, et al.Combined use of noninvasive tests is useful in the initialdiagnostic approach to a child with suspectedinflammatory bowel disease. J Pediatr Gastroenterol Nutr2006;42(1):9–15.

2 IBD Working Group of the ESPGHAN. Inflammatorybowel disease in children and adolescents:recommendations for diagnosis: the Porto Criteria. JPediatr Gastroenterol Nutr 2005;41(1):1–7.

3 Mamula P, Markowitz JE, Cohen LJ, et al. Infliximab inpediatric ulcerative colitis: two year follow-up. J PediatrGastroenterol Nutr 2004;38(3):298–301.

Further reading

Higuchi LM, Bousvaros A. Ulcerative colitis. In:Guandalini S (ed). Texbook o f PaediatricGastroentero logy and Nutrition. Taylor & Francis,London 2004, pp. 385–418.

McGinnis JK, Murray KF. Infliximab for ulcerative colitis inchildren and adolescents. J Clin Gastroenterol 2008;42:875–9.

Oliva-Hemker M, Escher JC, Moore D, et al. Refractoryinflammatory bowel disease in children. J PediatrGastroenterol Nutr 2008;47:266–72.

Van Limberger J, Russell RK, Drummond HE, et al.Definition of phenotypic characteristics of childhood-onset inflammatory bowel disease. Gastroentero logy2008;135:1114–22.

• Fulminant colitis

• Medical therapy failure

• Steroid dependency

• Colonic dysplasia

Table 11.6 Indications for colectomy in

ulcerative colitis

Management

For children with distal disease, local steroids ashydrocortisone or budesonide may be successful but rectal 5-ASA derivatives may also be tried. For mild colitis oralmesalamine (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 to60 mg/day is recommended associated with mesalamine.This dose should be continued for 1–2 weeks dependingupon the response. It is then tapered over the next 3 months,at first by weekly reductions by 5 mg/week and then a moregradual taper on alternate days and cessation if clinicalremission is maintained. The immunomodulatory drugsazathioprine (1.5–2.5 mg/kg/day) and its metabolite 6-mercaptopurine (1.5 mg/kg/day) can reduce the diseaseactivity and allow the withdrawal of steroid therapy inchildren with steroid-dependent UC. Children with severecolitis are a medical emergency and require urgent treatmentwith intravenous fluids, antibiotics, and intravenous steroidsfor 7–10 days. If the child has not responded, then intensiveimmunosuppression should be started with oral tacrolimus(0.12 mg/kg/day) or intravenous or oral cyclosporine (2–4mg/kg/day). Most of children achieve clinical remissionwithin 3–9 days. However, even if they respond to theimmunosuppression the majority of patients will requirecolectomy a few months or years later (Table 11.6).

The role of infliximab in treating paediatric UC is notwell defined. In recent papers, infliximab (5 mg/kg/day) isassociated with short- and long-term clinical improvementin children and adolescents with moderate to severe UC andless effective in steroid-dependent patients3.

Crohn’s disease

David Ziring, MD, and Jorge Vargas, MD

Chapter 12110

consortia have pinpointed distinct genes that are associatedwith the development of CrD. These include genes forproteins that sense bacterial products, like theNOD2/CARD15 gene. 40% of patients with CrD have a‘gain of function’ mutation in NOD29, 10. These patients aremore likely to have ileal disease with stricture formation11.

Similarly, a genetic polymorphism has been identified inthe protein encoded by the organic cation transporter gene(OCTN)12. Most recently, researchers have identified apolymorphism in the interleukin-23 (IL-23) receptor gene.This polymorphism provides protection against thedevelopment of CrD13. The IL-23 receptor is expressed bya pathogenic subset of T cells thought to be the effectorsresponsible for intestinal inflammation.

EnvironmentThe rate of new diagnoses of IBD has increased 10-foldsince the 1940s. Many believe that this increase is associatedwith our improved hygiene5. The ‘hygiene hypothesis’ positsthat autoimmune disease is on the rise because regulatorycells of the developing immune systems are not educated bythe normal complement of environmental bacteria.

ImmunologyThe intestinal immune system is incredibly complex.Several different cell types protect the mucosa from invasionby neighbouring bacteria. This ‘innate immune system’ iscomprised of dendritic cells, macrophages, natural killer(NK) cells, and natural killer T (NKT) cells14. It is the firstline of defence and provides the quickest response to antigenwithout the need for immune memory. Intestinal epithelialcells have receptors for bacterial products. Paneth cells

Prevalence and incidence

Crohn’s disease (CrD) is a chronic, immune-mediatedgastrointestinal (GI) disease and one of the inflammatorybowel diseases (IBD) (including ulcerative colitis [UC] andindeterminate colitis). IBD currently affects nearly 1 millionpatients in the United States, 25% of whom are children1–3.Nearly 30 patients of every 100,000 in the population arediagnosed each year, and the incidence is increasing4, 5. Theprevalence of IBD is higher in industrialized nations,especially in northern latitudes4. The number of patientsaffected with CrD outnumbers those with UC nearly two-fold2.

Aetiology

This disease entity stems from an abnormal host immuneresponse to normally occurring gut constituents. Threeunifying forces underlie the pathogenesis of IBD. First, atrisk patients have a genetic predisposition. Next, there is anenvironmental trigger (or triggers, in the case of antigensborne by intestinal bacteria). Lastly, there is a dysregulationof the normal homeostasis of the intestinal immune system.

GeneticsCrD is a polygenic disease, i.e. several genes contribute tothe pathogenic immune phenotype. The role that geneticsusceptibility plays in developing IBD is illustrated by itsprevalence in monozygotic twins. Between 36 and 58% ofaffected twins have an identical twin with CrD, whilenonidentical siblings have only a 4% concordance rate6–8.

Many genetic susceptibility loci have been identified inpatients, but over the last several years, large genetic

Crohn’s disease 111

well as symptoms lasting in excess of 2 weeks. Also, a carefulclinician will elicit any use of nonsteroidal anti-inflammatorydrugs (NSAIDs) in the recent past, as NSAID enteropathymay mimic CrD.

Physical examination of a patient with CrD may reveal aleft lower quadrant mass with tenderness, or the presence ofperianal 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, pyodermagangrenosum (12.3, 12.4). Ophthalmological findingsinclude episcleritis or uveitis. Besides typical aphthousulcers appearing in the mouth, patients may have cheilitis,or inflammation evidenced as a red, scaly rash at the cornersof the mouth. Seronegative joint pains, or arthropathies arenot uncommon (12.5, 12.6). These include pauciarticularlarge joint arthropathy and polyarticular small jointarthropathy.

RadiologySeveral radiological diagnostic studies contributeinformation to diagnosing IBD. These include the bariumcontrast 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 ofnarrowing (stenosis) or ulceration is present in the smallbowel (12.9, 12.10). Stenosis, most often seen in theterminal ileum of patients with CrD, has been given themoniker ‘string sign’ (12.11, 12.12). Bowel oedema can beseen as ‘thumbprinting’ or exaggerated swollen mucosalfolding. Abnormal communication between loops of bowel

reside in the crypts and produce antibacterial proteins.Specialized dendritic cells are able to stick their processes inbetween intestinal epithelial cells and ‘sample’ gutbacteria15. The chronic inflammation of IBD is due to a lossof tolerance to these antigens. Defects have been identifiedin special immune suppressor cells, normally responsible fortoning down the inflammatory response16, 17.

The effector cells, those cells responsible for coordinatingthe damaging inflammation in CrD, are a special set ofCD4+ T helper cells. These cells produce large amounts ofproinflammatory cytokines such as tumour necrosis factor(TNF), IL-6, and IL-17.

Diagnosis

The diagnosis of CrD depends on several medicalmodalities, including a proper history and physicalexamination, radiological imaging, stool testing and bloodtesting for indicators of inflammation, gross inspection onendoscopy, and careful analysis of the intestinal tissuebiopsies obtained during endoscopy.

History and physical examinationPatients with CrD and UC typically have quite differentpresentations. CrD often presents with abdominal pain,weight loss, unexplained fevers, and/or a dampened growthvelocity. On the other hand, patients with UC typicallypresent with bloody diarrhoea. Differentiating acuteinfectious diarrhoea from CrD relies on negative cultures as

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).

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.

112 Crohn’s disease

113Crohn’s disease

12.9 Barium radiograph

studies help in the diagnosis of

Crohn’s disease. Lost of

haustrations (arrow) and ulcers

(asterisks) in terminal ileum.

12.10 Barium radiograph study.

Ulcerations in terminal ileum

(arrows).

12.11 CT scan may show signs of bowel inflammation

(oedema) (arrow).

that stem from chronic transmural inflammation are calledfistulae, and can also be noted on these barium radiographs.Some experienced groups use ultrasound as a first approachin imaging for diagnosis of CrD (12.13, 12.14).

Several progressive European centres utilize magneticresonance imaging (MRI) enterography. Cases difficult todiagnose may employ the use of radiolabeled markers, suchas technetium, to tag white blood cells and localize theintestinal site of inflammation.

Stool testingPatients with CrD often have inflammation that causes thelining of the intestine to leak protein. This protein is

detected in the stool as alpha-1-antitrypsin. Other moresensitive and specific markers of inflammation that can bedetected in the stool include faecal calprotectin andS100A12.

Blood testingThere are several sensitive indicators of bowel inflammationthat can be examined in the blood. These include the whiteblood cell count, platelet number, erythrocytesedimentation rate, and C-reactive protein. Iron deficiencyanaemia as evidenced by a microcytic anaemia with anelevated red blood cell differentiation width (RDW) mayarise as a result of decreased oral intake, blood loss from the

**

12.12 Small bowel

follow through study.

Stenosis in the

terminal ileum (‘string

sign) (arrow).

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

12.13 Ultrasound of thickened bowel. Relatively

hypoechoic thick walls (arrows) with echogenic lumen.

Coronal view.

A B

114 Crohn’s disease

EndoscopyColonoscopy and upper endoscopy allow the clinician toobtain biopsies for histological diagnosis. Inflammation maybe found anywhere along the GI tract from mouth to anus.Grossly, the inflammation is evident as discrete areas oferythema, oedema, and haemorrhage with intervening areasof normal appearing mucosa. Aphthous ulcers are oftenseen, and these may take on a linear or serpiginousappearance (11.15). Often, the rectum is spared grossinflammation.

A skilled endoscopist typically will locate the ileocaecalvalve during colonoscopy and intubate the terminal ileum,obtaining biopsies there. While patients with UC may havemild inflammation in the terminal ileum (‘backwash ileitis’),

GI tract, or poor iron absorption. Decreased serum albuminmay similarly result from poor oral intake or protein lossfrom the gut. Patients may also have a decreasedalbumin:globulin ratio, the product of hypoalbuminaemiaand increased globulin fraction due to immune activation.

More recently, serological testing for antibodies directedagainst common bacterial antigens have helped in thediagnosis and prognosis of patients with CrD. Patients oftenhave an elevated titre of antibodies directed against acommon yeast antigen, called the anti-Saccharomycescereviseae antibody (ASCA). Other antibodies that predictdisease complications include those directed against flagellin(CBir), the outer membrane porin C on Escherichia coli(OmpC), and a common Pseudomonas antigen (I2).

12.14 Ultrasound of thickened bowel. Relatively

hypoechoic thick walls (arrows) with echogenic lumen.

Sagittal plane.

115Crohn’s disease

patients with CrD may have evidence of stricture formation,granulomas, fissures, or linear ulcers. The finding of ileitis ismost often associated with a diagnosis of CrD.

Inflammation of the upper GI tract may be seen in asmany as 30% of patients with CrD, but it has also beenreported in patients with UC. Gastritis can even cause delayin gastric emptying. Approximately 12–28% of patients withCrD will have noncaseating granulomas detected in biopsiesof the upper GI tract (most often in the stomach). Fewerpatients have evidence of duodenal cryptitis.

Capsule endoscopyCapsule endoscopy, an imaging modality in which thepatient ingests a capsule containing a tiny camera, hasproven to have remarkable sensitivity that rivals that ofbarium radiography. The capsule endoscope producesthousands of still digital images that must be interpreted bya skilled reader, and differentiated from normal ‘mucosalbreaks’. The use of this test is limited because of its cost andthe time and expertise required of the reader.

HistologyThe finding of noncaseating granulomas in the intestine of apatient who does not have chronic granulomatous disease isdiagnostic for CrD (12.16, 12.17). Early findings may onlyshow focal active inflammation associated with a lymphoidaggregate.

Management

SurgeryAt least 50% of patients with CrD will require surgicaltreatment (most often small bowel resection) to treat compli -cations, such as a chronic intestinal stenosis, within the first10 years of diagnosis, and between 70–80% of patients willeventually have surgery over the course of a lifetime18. Theresected bowel specimen may have the appearance of fat onthe anti-mesenteric border, termed ‘creeping fat’.

Medical therapyPharmacotherapy for both the ‘induction’ and‘maintenance’ treatment of CrD depends largely on theactivity of the disease. Patients with mild disease may enterremission with a course of oral antibiotics such asciprofloxacin or metronidazole. Other patients with milddisease may respond well to locally, topically actingaminosalicylate preparations or similar steroid derivativessuch as budesonide. However, the majority of patients willrequire maintenance treatment with immunomodulatortherapy such as 6-mercaptopurine or methotrexate. Thosepatients who are intolerant or unresponsive to these drugs,or who have complicated disease, may benefit frombiological therapy with anti-TNF antibodies.

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.

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.

References

1 Kugathasan S, Judd RH, Hoffmann RG, e t al.Epidemiologic and clinical characteristics of children withnewly diagnosed inflammatory bowel disease inWisconsin: a statewide population-based study. J Pediatr2003;143(4):525–31.

2 Baldassano RN, Piccoli DA. Inflammatory bowel diseasein pediatric and adolescent patients. Gastroenterol ClinNorth Am 1999;28(2):445–58.

3 Loftus E. Update on incidence and prevalence of Crohn’sdisease (CD) and ulcerative colitis (UC) in Olmstedcounty, Minnesota. Gastroentero logy 2003;124(4;S1):A36.

4 Barton JR, Gillon S, Ferguson A. Incidence ofinflammatory bowel disease in Scottish children between1968 and 1983; marginal fall in ulcerative colitis, three-fold rise in Crohn’s disease. Gut 1989;30(5):618–22.

5 Bach JF. The effect of infections on susceptibility toautoimmune and allergic diseases. N Engl J Med2002;347(12):911–20.

6 Tysk C, Lindberg E, Jarnerot G, et al. Ulcerative colitisand Crohn’s disease in an unselected population ofmonozygotic and dizygotic twins. A study of heritabilityand the influence of smoking. Gut 1988;29(7):990–6.

7 Russell RK, Satsangi J. IBD: a family affair. Best PractRes Clin Gastroenterol 2004;18(3):525–39.

8 Orholm M, Binder V, Sorensen TI, et al. Concordance ofinflammatory bowel disease among Danish twins. Resultsof a nationwide study. Scand J Gastroentero l2000;35(10):1075–81.

9 Hugot JP, Chamaillard M, Zouali H, et al. Association ofNOD2 leucine-rich repeat variants with susceptibility toCrohn’s disease. Nature 2001;411(6837):599–603.

10 Ogura Y, Bonen DK, Inohara N, et al. A frameshiftmutation in NOD2 associated with susceptibility toCrohn’s disease. Nature 2001;411(6837):603–6.

11 Abreu MT, Taylor KD, Lin YC, et al. Mutations inNOD2 are associated with fibrostenosing disease inpatients with Crohn’s disease. Gastroentero logy2002;123(3):679–88.

12 Peltekova VD, Wintle RF, Rubin LA, et al. Functionalvariants of OCTN cation transporter genes are associatedwith Crohn disease. Nat Genet 2004;36(5):471–5.

13 Duerr RH, Taylor KD, Brant SR, et al. A genome-wideassociation study identifies IL23R as an inflammatorybowel disease gene. Science 2006;314(5804):1461–3.

14 Podolsky DK. Inflammatory bowel disease. N Engl JMed 2002;347(6):417–29.

15 Gewirtz AT, Madara JL. Periscope, up! Monitoringmicrobes in the intestine. Nat Immuno l2001;2(4):288–90.

16 Singh B, Read S, Asseman C, et al. Control of intestinalinflammation by regulatory T cells. Immuno l Rev2001;182:190–200.

17 Brimnes J, Allez M, Dotan I, et al. Defects in CD8+regulatory T cells in the lamina propria of patients withinflammatory bowel disease. J Immuno l2005;174(9):5814–22.

18 Vermeire S, van Assche G, Rutgeerts P. Review article:Altering the natural history of Crohn’s disease: evidencefor and against current therapies. Aliment PharmacolTher 2007;25(1):3–12.

Crohn’s disease116

Short bowel syndrome

Javier Bueno, MD

Chapter 13117

Introduction

Short bowel syndrome (SBS) is a transitory or permanentintestinal failure due to the anatomic loss of extensivesegments of small intestine clinically manifested withdiarrhoea, malabsorption, and malnutrition. SBS is themost frequent cause of intestinal failure in the paediatricpopulation and occurs perinatally in 85%1, 2. Although itcan be congenital, it occurs most frequently after smallbowel resection due to gut disorders (13.1) (Table 13.1).

The intestinal length in the term newborn is 2.5–3 m andbetween 6 and 8 m in the adult3. The definitive intestinallength to develop SBS is not well established. In adults it isconsidered if the intestinal length is <200 cm. In children itdepends on age, but it is considered if the length is <80–100cm, and it will be severe if <40 cm1, 2, 4. The patho -physiological consequences of a bowel resection depend onthe extent and site of the intestinal resection, and theadaptability of the remaining intestine.

Adaptation process

After a massive small bowel resection, the remnant intestinesuffers an adaptation process that includes an increase invillous height and mucosal surface area, as well as in bowelluminal circumference and wall thickness5.

Enteral nutrition is the principal adaptation stimuli by itstrophic effect, avoiding mucosa atrophy2. It promotes theenterohepatic recirculation of biliary salts and the release ofhormones and pancreato-biliary secretions that maintain theintegrity and intestinal function. The length and site ofresection are obviously important: ileal resection is worsetolerated than jejunal2, 6. The presence of the ileocaecalvalve improves the prognosis. It increases transit time andthe contact of nutrients with the mucosa. In addition, itavoids bacterial overgrowth. In children, if intestinal lengthis <40 cm without ileocaecal valve there is 40% ofprobability of permanent parenteral nutrition (PN)dependence. If the intestinal length is between 40 and 80 cm

• Necrotizing enterocolitis

• Gastroschisis

• Volvulus

• Intestinal atresia

• Hirschsrpung´s disease

• Trauma

Table 13.1 Main causes of short gut in children13.1 Necrotizing

enterocolitis with

multiple bowel

perforations

resulting in short

bowel syndrome.

13.2 End jejunostomy.

The presence of a

jejunostomy or a

terminal ileostomy can

produce high output

with dehydration and

electrolytes

disturbances, delaying

the adaptation

process.

and the valve is present, 80% can achieve nutritionalautonomy in 1 year5.

Preservation of colon is not only important for theabsorption of fluid and electrolytes, but it also hasnutritional advantages: malabsorbed carbohydrates undergobacterial fermentation in the residual colon where they areconverted into short-chain fatty acids7. The presence of ajejunostomy or a terminal ileostomy can produce highoutput with dehydration and electrolytes disturbances,delaying the adaptative process (13.2)4.

Bacterial overgrowth is frequent due to the absence of theileocaecal valve, presence of intestinal strictures, andintestinal dysmotility. It can produce enteritis that worsensthe adaptation process8. It is also involved in thepathogenesis of the PN-related liver failure. Established liverdamage also interfere with adaptation1.

Initial supportive management

Treatment of children with intestinal failure should bepredicated upon three goals: (1) to keep the patient wellnourished by PN, (2) to minimize the faecal losses of fluid,electrolytes, and nutrients, and (3) to enhance the naturalprocess of intestinal adaptation whenever possible.

Parenteral nutritionMost patients require PN until their gut has undergonesufficient adaptation to allow survival on an oral diet. Thisperiod is variable and can take 18–45 months6. PN is thepractice of feeding a person intravenously (13.3). It isusually administered through a permanent central line4

(13.4). Surgi cal venotomies should be avoided in order to

Short bowel syndrome118

preserve the veins. Long-term PN may be associated with complications that

include recurrent central venous line sepsis and liver failure(Table 13.2). In children, hepatic dysfunction is a majorprob lem(13.5)1, 2, 4. Patients with permanent intestinalfailure sooner or later will develop cirrhosis and liverfailure1. Sondheimer et al. reported that 67% of neonateswith PN-dependent SBS developed cholestasis, and 17%progressed to liver failure9. Strategies to avoid or delay liverfailure are shown in Table 13.3. Patients with SBSfrequently develop other clinical problems which mayrequire specific therapy (Table 13.4).

A B

• Sepsis

• Thrombosis. Vanishing venous access

• Complications related to central line insertion

(embolism, haemothorax)

• Liver failure

• Electrolytes disturbances

• Bone disease

• Gallblader stones

• TPN related social problems:

– Limited personal(social/life)

– Psychological depression

– Pain medication dependance

– Poor quality of life

– Expensive: US$100–200,000/year

Table 13.2 Complications of parenteral nutrition use

13.4 Permanent central

venous catheters. A: One

lumen subcutaneous

tunnelled catheter with cuff (Broviac–Hickman); B:

reservoir (Port-a-cath). Thorax X-ray with Port-a-cath in

place.

13.3 Parenteral

nutrition

administration. The

patient receives

nutritional formulas

containing glucose,

amino acids, lipids,

trace elements,

and vitamins that

are stored in sterile

bags and delivered

by a medical

infusion pump.

Short bowel syndrome 119

A

A B

13.5 PN-related liver damage. Its aetiology is multifactorial and includes alteration in gut motility which leads to

intraluminal stasis which is thought to be a major aetiologic factor for bacterial overgrowth and subsequent cholestasis,

especially when the ileocaecal valve is absent. Steatosis is more typical in adults. A: Cholestasis; B: steatosis.

B

• Optimize PN (fewer lipids)

• Cyclic parenteral nutrition

• Enteral nutrition (even small amount)

• Avoid bacterial overgrowth (oral decontamination)

• Ursodeoxycholic acid

• Avoid sepsis

Table 13.3 Strategies to ameliorate liver dysfunction

Short bowel syndrome120

Medical therapy Drugs that reduce motility as opioid substances(loperamide, diphenoxylate, codeine phosphate) increasethe contact time between nutrients and the mucosa.Therefore, they are used to decrease the stomal output.Gastric hyperacidity and increase in serum gastrin levels arefrequently observed transiently (6–12 months) following amassive bowel resection. Unless controlled with protonpump inhibitors or H2 receptor blockers, it may result inextensive gastric or duodenal ulceration. On the other hand,long-term administration can promote bacterial overgrowth.The use of cholestiramine is useful if the diarrhoea is due tothe cathartic effect of unabsorbed bile salts, and to treatperiostomy or perianal irritation. Ursodeoxycholic acid mayimprove liver dysfunction.

High-volume output from a jejunostomy requiresrestriction of oral fluids, a high-energy iso-osmolar diet, andthe use of antisecretory drugs. Ocreotride is a universalinhibitor of exocrine and endocrine gastrointestinal andpancreatic secretions. However, ocreotride is detrimental togut adaptation because it reduces nutrient transport. Inaddition, it can interfere with growth.

• Behavioural feeding problems (phobia to oral foods

and hyperphagia)

• Metabolic acidosis (including D-lactic acidosis)

• Cholelithiasis

• Urolithiasis

• Electrolytes disturbances

• Gastro-oesophageal reflux

• Bone disease

• Dystrophy

• Diarrhoea

• Bacterial overgrowth

Table 13.4 Other complications related to

short bowel

Enteral nutritionDrip enteral nutrition can be advanced as soon as thepatient can tolerate it, followed by bolus feedings (13.6).Enteral nutrition stimulates the release of pacreatico-biliarysecretions that maintain the structure and function of theintestine and the release of regulatory peptides from theintestine. Specific nutrients can be delivered to the cells ofthe intestinal mucosa. They promote intestinal structureand function by providing substrates for the synthesis ofessential molecules or by providing energy, as happens withfermentable fibre (pectin) and their products (i.e. short-chain fatty acids). The amino acid glutamine is the main fuelfor enterocytes and is also a substrate for the synthesis ofnucleic acids10. Medium-chain triglycerides increase theabsorption of energy in SBS with a functioning colon2.Short-chain fatty acids are readily absorbed across thecolonic mucosa, whereas long-chain fatty acids are notabsorbed by the colon. Glucagon-like peptide-2, released bythe intestinal L cells, plays a role in the trophic effect ofshort-chain fatty acids on intestinal adaptation. In addition,the use of either specific (e.g. intestinal growth factor-1[IGF-1]) or general growth factors (e.g. growth hormone)can promote intestinal adaptation11, 12.

13.6 Placement of a gastrostomy should be contemplated

in initial surgery based on the severity of the short gut to

administrate continuous enteral feeding.

Surgical treatment

When a paediatric surgeon deals with an intestinalcatastrophe, it is important to be conservative and preserveas much length of the small and large intestine as possible .A ‘second look’ laparotomy is indicated becausedelimitation of the viable intestine will be clearer 24–48hours later. It is a gold standard rule to try to preserve theileocaecal valve as well as to perform jejuno-colicanastomosis whenever possible. Stomas should be reservedonly in those situations in which it is strictly necessary toavoid an additional loss of intestinal length and to preservecolonic function. Patients with a jejuno-colic anastomosisrarely have problems with their fluid and electrolyte balance.Maintaining colonic continuity serves to delay gastricemptying and decreases energy/carbohydrate losses8.

To evaluate the severity of the short gut syndrome,imaging studies are required. Gastrointestinal series andbarium enema are crucial to study the intestinal anatomyand to rule out strictures. Abdominal ultrasounds rule outgallbladder stones or sludge. CT scan with oral contrast and3-D reconstruction provides the same information about thepancreas.

A definitive surgical treatment is indicated after failure ofmedical management. The type of operation will be definedby different factors: age, length, and function of remainingbowel, the presence of dilatation, bacterial overgrowth,transit time, and the development of total parenteralnutrition (TPN) related complications. In the presence ofliver dysfuntion, a liver biopsy is recommended.

Techniques to slow transit time None of the following procedures have been associated withsignificant clinical success.• Reversed intestinal loop. It consists of the interposition of

a segment of bowel in which peristalsis is in the oppositedirection. The recommended minimal length of the anti-peristaltic loop is 10 cm in adults and 3 cm in children13.

• Isoperistaltic colon interposition. Interposition of asegment of colon between two limbs of the small bowel14.

• Artificial valves. Based on the importance of theileocaecal valve6. Although different types of valve havebeen created, their use has been anecdotal. When used,they are often combined with other procedures.

• Recirculation circuits. The idea is to produce a loop ofintestine in which nutrients can recirculate several times6.It is not used because it facilitates bacterial overgrowth.

Techniques to avoid bacterial overgrowth• Enteroplasty. Dilated intestine causes stasis and

ineffective peristalsis. Anti-mesenteric taperingenteroplasty is an alternative to resection in dilatedbowels to preserve bowel length and improve bacterialovergrowth14. A different approach is the taperingenteroplasty with plication of the mesenteric bowel withstitches. There is a high incidence of recurrence in thelong-term follow-up.

• Stricturoplasty. Longitudinal stricture incision withtransverse suture.

Lengthening procedures All lengthening procedures require bowel dilatation.

The longitudinal lengthening procedure was described byBianchi in 1980. It is the most commonly used method ofgastrointestinal reconstruction for SBS15. The bowel isdivided into two longitudinal leaves based on the bifurcatedmesenteric blood supply, and then the two hemi-loops arereconnected in an isoperistaltic way in series with the rest ofthe intestine. There are improvements in stool output,intestinal transit time, and D-xylose and fat absorption.Recently, Waag et al. reported their experience with 25patients with 72% survival, 17 were weaned of TPN with amean follow-up of 6 years16. Bueno et al. have recom -mended avoiding the procedure in neonates, ultra-short gut,and established cirrhosis17. Complication rate is high withintestinal necrosis, leaks, strictures, and bowel obstruction.

In the Kimura procedure, initially the anti-mesentericsurface of a segment of bowel is coapted to host organs suchas liver and abdominal wall18. After vascular collateralsacross the coaptation site have developed from these hostorgans, secondary longitudinal split of the bowel isperformed to provide two bowel loops, one from its anti-mesenteric half and the other from its mesenteric half.These are arranged in series by end-to-end anastomosis todouble the original bowel length. So far, there are onlyanecdotal reports.

Serial transverse enteroplasty (STEP) is a simple andeffective procedure introduced in 2003, but also requiresbowel dilatation (13.7). The International STEP Registryuntil May 2006 has reported 38 cases19. The length of theintestine in this series was duplicated (pre-STEP 68 cm; post-STEP 115 cm). It can even be applied in intestines with priorBianchi procedure. In the short-term follow-up it is effective;however, longer follow-up is needed. Surgical compli cationssuch as obstruction and leaks have been described.

Short bowel syndrome 121

13.7 STEP procedure. With multiple GIA stapler shots, the dilated intestine is transected

transversally from opposite directions, to create a zig-zag channel without placing the

mesenteric blood supply at risk.

A B

C D

immunosuppressive agents and greater incidence of side-effects such as a high incidence of opportunistic infectionsand lymphoproliferative disorder are still a barrier for itssuccess19. Endoscopic surveillance with intestinal biopsy isthe only tool to detect allograft rejection. The IntestinalTransplant Registry has recently reviewed the worldexperience on 772 transplants in 721 paediatric recipients,with an overall survival of 55.4%20. The most commonindication for transplantation was SBS. Nowadays, the 1-year graft survival in experienced centres is above 80%.

References

1 Bueno J, Ohwada S, Kocoshis S, et al. Factors impactingthe survival of children with intestinal failure referred forintestinal transplantation. J Pediatr Surg1999;34(1):27–32.

122 Short bowel syndrome

Small bowel transplantationIntestinal transplantation is indicated when patientsdeveloped PN complications1, 2, 4, 19. Vanishing venousaccess is the main indication for isolated small boweltransplantation (13.8), while recurrent sepsis and frequenthospital admission due to dehydration and electrolytedisturbances are relative indications. PN-related liver failureis an indication for combined liver–small boweltransplantation. If the whole gastrointestinal tract is affectedby disease such as pseudo-obstruction and desmoidtumours the choice is multivisceral grafts.

New immunosuppressant protocols, major expertise, andnew strategies have contributed to dramatic improvementsin survival in recent years, such that survival rates areapproaching those of other solid organ transplantation. Therisk of acute rejection is very high and it is the leading causefor graft and patient loss. The requirements of high doses of

13.8 Small bowel transplantation.

123Short bowel syndrome

12 Thompson JS, Langnas AN, Pinch LW, et al. Surgicalapproach to the SBS. Ann Surg 1995;22:600–7.

13 Zhou Y, Wu XT, Yang G, et al. Clinical evidence ofgrowth hormone, glutamine and a modified diet for shortbowel syndrome: meta-analysis of clinical trials. Asia PacJ Clin Nutr 2005;14(1):98–102.

14 Garcia VF, Templeton JM, Eichelberger MR, et al.Colon interposition for the SBS. J Pediatr Surg1981;16(6):994–5.

15 Bianchi A. Longitudinal intestinal lengthening andtailoring: results in 20 children. J Royal Soc Med1997;90:429–32.

16 Waag KL, Hosie S, Wessel L. What do children look likeafter longitudinal intestinal lengthening? Eur J PediatrSurg 1999;9(4):260–2.

17 Bueno J, Guiterrez J, Mazariegos GV, et al. Analysis ofpatients with longitudinal intestinal lengtheningprocedure referred for intestinal transplantation. J PediatrSurg 2001;36(1):178–83.

18 Kimura K, Soper RT. A new bowel elongationtechnique for the short-bowel syndrome using theisolated bowel segment Iowa models. J Pediatr Surg1993;28(6):792–4.

19 Modi BP, Javid PJ, Jaksic T, et al. International STEPData Registry. First report of the international serialtransverse enteroplasty data registry: indications, efficacy,and complications. J Am Coll Surg 2007;204(3):365–71.

20 Reyes J, Bueno J, Kocoshis S, et al. Current status ofintestinal transplantation in children. J Pediatr Surg1998;33(2):243–54.

Further reading

Moreno Villares JM. Parenteral nutrition-associated liverdisease. Nutr Hosp 2008;23(suppl 2):25–33.

Duro D, Kamin D, Duggan C. Overview of pediatric shortbowel syndrome. J Pediatr Gastroentero l Nutr2008;47(suppl 1):533–6.

Ching YA, Gura K, Modi B, et al. Pediatric intestinalfailure: nutrition, pharmacologic, and surgicalapproaches. Nutr Clin Pract 2007;22:653–63.

Ruiz P, Kato T, Tzakis A. Current status of transplantationof the small intestine. Transplantation 2007;83:1–6.

2 Goulet O. Irreversible intestinal failure. J PediatrGastroenterol Nutr 2004;38(3):250–69.

3 FitzSimmons J, Chiin A, Shepard TH. Normal length ofthe human gastrointestinal tract. Pediatr Patho l1988;8:633–41.

4 Buchman AL, Scolapio J, Fryer J. AGA technical reviewon SBS and intestinal transplantation. Gastroenterology2003;124(4):1111–34.

5 Shanbonhogue L, Molenaar J. SBS: metabolic andsurgical management. Br J Surg 1994;81:486–99.

6 Goulet O, Baglin-Gobet S, Talbotec C, et al. Outcomeand long-term growth after extensive small bowelresection in the neonatal period: a survey of 87 children.Eur J Pediatr Surg 2005;15(2):95–101.

7 Nordgaard I, Hansen CS, Mortensen PB. Colon as adigestive organ in patients with short bowel. Lancet1994;343:373–6.

8 Kaufman SS, Loseke CA, Lupo JV, et al. Influence ofbacterial overgrowth and intestinal inflammation onduration of parenteral nutrition in children with SBS. JPediatr 1997;131(3):356–61.

9 Sondheimer JM, Asturias E, Cadnapaphornchai M.Infection and cholestasis in neonates with intestinalresection and long-term parenteral nutrition. J PediatrGastroenterol Nutr 1998;27(2):131–7.

10 Michail S, Mohammadpour H, Park JH, et al. Effect ofglutamine-supplemented elemental diet on mucosaladaptation after small bowel resection in rats. J PediatrGastroenterol Nutr 1995;21:394–8

11 Byrne TA, Persinger RL, Younf LS, et al. A newtreatment for patients with short-bowel syndrome.Growth hormone, glutamine, and a modified diet. AnnSurg 1995;222:243–55.

Congenitalgastrointestinal malformations

Iñaki Eizaguirre, MD, and Agustín Nogués, MD

Chapter 14124

• Meckel's diverticulum: 220

• Anorectal malformations: 3.01

• Oesophageal atresia: 2.23

• Hirschsprung's disease: 2

• Intestinal malrotation: 2

• Duodenal atresia: 1.2

• Jejuno-ileal atresia: 0.74

• Intestinal duplication: 0.6

• Colonic atresia: 0.5

• Annular pancreas: 0.18

Table 14.1 Frequence of gastrointestinal

malformations (number of cases/10,000 births)

Introduction

The most significant congenital gastrointestinalmalformations are Meckel’s diverticulum and anorectalmalformations1, 2 (Table 14.1). The majority are develop -mental disturbances or embryopathies. Theseembryopathies occur in a phase in which all the organs areforming (3rd to 8th week), thus the presence of multipleanomalies is common. Other digestive tract malformationsare foetopathies, probably due to ischaemic accidents thatgive rise to duodenal, intestinal, and colonic or rectalatresias. The interruption of the blood supply to a segmentof the primitive intestine leads to the reabsorption of thatsegment, with the consequent atresia. This mechanismoccurs later in the foetal period and is therefore notnecessarily associated with other malformations3.

Meckel’s diverticulum

This is a formation in the shape of a cone or the finger of aglove attached to the anti-mesenteric margin of the ileum(14.1A, B). It can present in a variety of anatomical formsfrom the complete persistence of the yolk stalk, with thedischarge of intestinal fluid through the umbilicus, to thepresence of a fibrous cord that can give rise to intestinalobstruction by trapping a loop of bowel. There is also aninfrequent giant form of Meckel’s diverticulum, whichusually gives rise to episodes of occlusion in the neonate(14.1C)

Meckel’s diverticulum is found in 2% of autopsies, and isfound in a 2:1 male/female ratio. It cause symptoms in only4% of individuals; 50% have symptoms before 2 years of ageand 80% before 10 years. Its histological structure is similarto that of the ileum. It can contain ectopic pancreatic tissueor gastric mucosa, explaining possible haemorrhage.Meckel’s diverticulum may present as haemorrhage(25–30%); it can invaginate and give rise to intestinalobstruction or as a diverticulitis with or without perforation

The most reliable diagnostic test is a 99mTc gamma scan(14.2). When the diverticulum contains ectopic gastricmucosa, this test shows an abnormal uptake in the centre ofthe abdomen. Treatment consists of resection of thediverticulum.

Congenital gastrointestinal malformations 125

14.1 Meckel´s

diverticulum. A: small;

B: common shape;

C: giant.

Anorectal malformations

Anorectal malformations are usually embryopathies, withassociated abnormalities in 60% of cases: cardiovascular(tetralogy of Fallot); bone, particularly hemivertebrae;gastrointestinal: oesophageal atresia, duodenal atresia,Hirschsprung’s disease, or genitourinary: vesico-uretericreflux. In 90% of cases there is an abnormal communicationbetween the rectum and the urinary tract (in males) or thegenital structures (in women). The description of the fistulagives an idea of the severity of the malformation: in males,rectoperineal, rectobulbar, rectoprostatic and rectovesicalfistulae; in females, rectoperineal, rectovestibular, andrectovaginal fistulae and cloaca. All forms are consideredsevere with the exception of the rectoperineal forms, andrequire complex surgical treatment.

DiagnosisDiagnosis uses perineal examination and ultrasound. It isworth waiting 24 hours for the rectal pouch to fill,facilitating evaluation of the malformation. A flat perineumis a poor prognostic indicator as it suggests an absence ofmusculature. Ultrasound is used to measure the distancefrom the rectal pouch to the skin. When this measures morethan 1 cm, it is considered a severe form (14.3).

A B C

14.2 Technetium

isotopic scan shows

an anomalous signal

at the level of distal

ileum.

14.3 Minimal distance between skin (marked by radio-

opaque reference) and air-filled rectal pouch is

demonstrated in Rx plain film.

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

Oesophageal atresia

The abnormal separation of the tracheo-oesophageal budgives rise to a large number of possible anatomical variationsof this malformation, although the most frequent is type III(Table 14.2). Associated malformations are very common:bone 30%, heart defects 20%, urological 20%, digestivetract 20%, and VACTERL association: (Vertebral, Anal,Cardiac, Tracheal, oEsophageal, Renal, Limb).

Patients usually present with salivation, respiratorydistress, and abdominal distension (forms with a distalfistula: III, IV, V).

Diagnosis• Prenatal ultrasound shows an absence of the gastric

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

Prognosis and treatmentSurvival varies from 97% in group I on the Spitzclassification (weight >1500 g with no heart disease), to 47%in group II (weight <1500 g or heart disease) and 20% ingroup III (weight <1500 g and heart disease)2.

Surgical treatment consists of a primary anastomosiswhen the separation between the ends allows this. Otherwisea gastrostomy and an oesophagostomy can be performed inorder to replace the oesophagus later with stomach or colon.Recently, an external elongation of the two oesophagealends has been performed in order to approximate themsufficiently to be able to perform an anastomosis4, 5.

Congenital gastrointestinal malformations126

• Type I: 8%.The two ends of the oesophagus are

separated and do not communicate with the

respiratory tract (no fistula)

• Type II: 1%. Proximal tracheo-oesophageal fistula

and blind inferior pouch

• Type III: 86%. Distal tracheo-oesophageal fistula

and blind superior pouch

• Type IV: 1%. Proximal and distal tracheo-

oesophageal fistulae

• Type V: 1%. ‘H’ fistula. This is not a true atresia as

the oesophagus is permeable (14.4)

Table 14.2 Different types of oesophageal atresia

14.4 Type V oesophageal atresia.


14.5 Radiographic plain film in oesophageal atresia with

tracheo-oesophageal fistula. Reports air filled stomach

and intestinal metheorism. Note the coiled feeding tube in

the upper pouch oesophagus.

14.6 Radiographic plain film showing absence of

abdominal air and feeding tube in the superior

oesophageal pouch.

Hirschsprung’s disease

In Hirschsprung’s disease (HD) the affected intestinepresents a spastic contraction, as occurs in any denervatedintestine. It is unable to dilate, giving rise to a functionalobstruction (14.7). HD can affect more than one member ofthe same family. There is a genetic abnormality, the deletionof the long arm of chromosome 10, that is located close tothe region of the RET proto-oncogene that has been foundin some patients with HD6. There may be associatedabnormalities including trisomy 21 and 18, anorectalatresia, von Recklinghausen’s disease, Waardenburg´sdisease, or multiple endocrine neoplasia type 2.

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

nitric oxide synthase.

Clinical presentationFunctional obstruction, the intensity of which depends onthe intestine affected. There are two clinical forms:neonatal, with the absence of emission of meconium in thefirst 24 hours and symptoms of low intestinal obstruction(abdominal distension and vomiting), and the formpresenting in the older child, with severe constipation thatdoes not resolve with the usual measures.

ComplicationsSevere enterocolitis and sepsis, which may lead to intestinalperforation. This is a life-threatening situation thatsometimes requires emergency colostomy.

DiagnosisBarium enema (14.8), anorectal manometry, demonstratingan absence of the rectoanal inhibitory reflex (14.9), andbiopsy are the decisive tests.

14.8 Barium

enema in neonatal

Hirschsprung’s

disease. Narrow

rectosigmoidium

segment and

dilated

suprastenotic colon

which presents

inflammatory

mucosal changes.

Distention of

intestinal loops.

A B

14.7 Hirschsprung`s disease in two patients. A: (1) Aganglionic obstructed segment corresponding to sigmoid. (2) Normal,

ganglionic, descending colon. B: (1) Aganglionic rectal segment. Black arrow: place where full-thickness rectal biopsy was

done. (2) Normal ganglionic sigmoid segment. White arrow: place of biopsy in the transition zone.

1

2

1

2

A

B

14.9 Recto-anal inhibitory reflex. A: Present; anal canal

relaxation after a pressure increase in the rectum. B: Absent;

no anal canal relaxation.

Rectum

Anal canal

Rectum

Anal canal

128 Congenital gastrointestinal malformations

Canal 4PressuremmHGescala: 10.0




129Congenital gastrointestinal malformations

• Absence of the final 90° rotation: the right colon remainsin the midline, fixed by peritoneal bands (Ladd’s bands)which compress and obstruct the duodenum. Treatmentis by section of the bands and repositioning of the caecumin the right iliac fossa.

• Internal hernias: abnormalities of the mesentery of theduodenum or right or left colon can create spaces intowhich the intestinal loops can prolapse as hernias. Theseare very variable situations which require individualizedsurgical approaches.

DiagnosisA barium enema may be helpful showing the whole colon onthe left (no rotation), or the caecum high close to the liver(lack of the last 90º twist). In cases of no rotation anultrasound can show a reverse position of the mesentericvessels with the vein situated on the left and the artery on theright.

TreatmentThe aims of the classical surgical techniques (Duhamel,Soave, Rehbein, Swenson) are to resect the aganglionicintestine, leaving 1–2 cm of the final part, necessary toguarantee continence. In recent years, new techniques andthe introduction of minimally invasive surgery have led to areduction in the age at which patients are operated on,which was classically between the 8th and 10th month. Therecently described De la Torre Mondragón technique7 withor without laparoscopic assistance, is currently the mostaccepted technique in several paediatric surgicaldepartments.

Intestinal malrotation

Alterations of the process of intestinal rotation and fixationduring the process of re-entry of the primitive intestine intothe abdominal cavity give rise to multiple types ofmalrotation. These are uncommon but very variable andsometimes complex abnormalities, though the clinicalpresentations can be summarized into three situations:• A complete absence of rotation (14.10). There is a risk of

volvulus and intestinal necrosis if it is not treated in time(14.11). The symptoms include bilious vomiting and thetreatment is by devolvulation and fixation in an uncompli -cated position for the common mesentery, with the smallintestine on the right side and the colon on the left.

14.10 Twisted duodenum not crossing the duodenal

vessels.

14.11 Midgut volvulus. Intestinal necrosis, twisted

mesenteric vessels (arrow).

14.12 Prenatal ultrasound. Stomach and duodenum are

dilated.

Duodenal atresia

This is characterized by polyhydramnios; stomach andduodenum are dilated in the prenatal ultrasound (14.12),associated with trisomy 21 (25%) and other associatedmalformations present in 50% of cases (Type I).

Type I is atresia in the form of a mucous membrane ordiaphragm formed by the mucosa and submucosa.Externally, the only sign is a difference in diameter betweenthe proximal and distal segments. A variation is anincomplete membrane, perforated in its centre, producingduodenal stenosis (14.13).

Type II is two blind, atretic pouches connected by afibrous cord and with an intact mesentery. Type III is twoblind, disconnected, atretic pouches with a defect in themesentery in the form of a ‘V’.

DiagnosisPatients present with bilious vomiting. Prenatal ultrasoundshows a typical image of a ‘double bubble’, which isconfirmed on plain X-ray and postnatal ultrasound (14.14).

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


14.13 Duodenal dilatation caused by diaphragm. Minimal

amount of contrast is delivered in distal duodenum across

a small perforation.

14.14 Radiographic plain film. Double

bubble air sign in duodenal atresia.

Oesophageal atresia and aspirative

pneumonia in posterior segment of right

upper lobe.


14.15 A: Type I ileal atresia. See the Foley catheter pulling on the membrane; B: Type II ileal atresia.

C: IIIa ileal atresia. D: Type IIIb ileal atresia (apple peel).

Jejuno-ileal atresia

It is a true atresia in 95% of cases. The remaining 5% aredue to intestinal stenosis, i.e. a partial intraluminalocclusion. There is polyhydramnios on the prenatalultrasound and dilated loops may be observed. Associatedabnormalities are present in <10%. The Grosfeldclassification2 divides this malformation into:• Type I: atresia in the form of a mucous membrane or

septum with intact intestinal wall and mesentery(14.15A).

• Type II: two blind, atretic pouches connected by a fibrouscord, with an intact mesentery (14.15B).

• Type IIIa: two blind, disconnected, atretic pouches witha defect in the mesentery in the form of a ‘V’ (14.15C).

• Type IIIb: also called ‘apple peel’. Very high jejunalatresia, close to the duodenojejunal flexure. It gives rise toa very short intestine with a large defect in the mesentery.

The intestine distal to the atresia receives a precarious,retrograde blood supply via the ileocolic, right colic, orinferior mesenteric arteries (14.15D).

• Type IV: multiple atresias.

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

TreatmentTreatment is resection of the grossly dilated loops and end-to-end anastomosis.

A B

C D

14.16 A: Proximal jejunum atresia;

B: distal ileum atresia.

Intestinal duplications

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

Approximately half of all duplications affected the smallbowel (50%), followed in frequency by duplications of theoesophagus (20%), and of the colon. Duplications can giverise to intestinal obstruction or haemorrhage. Treatment issurgical.


A B

14.17 MR T2 image shows evidence of a cystic right flank

mass.

14.18 Surgical procedure revealed spherical

ileal duplication.

Bladder

Ilealduplication

Duodenum

Gallbladder


6 Puri P, Shinkai T. Pathogenesis of Hirschsprung’s diseaseand its variants: recent progress. Semin Pediatr Surg2004;13:6–24.

7 De la Torre-Mondragon L, Ortega-Salgado JA.Transanal endorectal pull-through for Hirschsprung’sdisease. J Pediatr Surg 1998;33(8):1283–6.

8 Stern LE, Warner BD. Gastrointestinal duplications. JPediatr Surg 2000;9:135–40.

Further reading

Dasgupta R, Langer JC. Evaluation and management ofpersistent problems after surgery for Hirschsprungdisease in a child. J Pediatr Gastroenterol Nutr 2008;46:13–19.

Keckler SJ, St Peter SD, Valusek PA, et al. VACTERLanomalies in patients with esophageal atresia: an updateddelineation of the spectrum and review of the literature.Pediatr Surg Int 2007;23:309–13.

Levitt AA, Peña A. Anorectal malformations. Orphanet JRare Dis 2007;26:2–33.

Atresia of the colon

This is less frequent than the other intestinal atresias. It isassociated with jejuno-ileal atresia and Hirschsprung’sdisease. Prenatal ultrasound shows dilated loops ofintestine. The symptoms are those of a low intestinalobstruction and the diagnosis is not difficult with plainabdominal X-rays, in which multiple dilated loops ofintestines are observed.

Treatment is primary anastomosis of the ends of theintestine, as long as there is no contraindication, such asperforation with peritonitis, in which case it is better toperform a colostomy with anastomosis at a later stage.

Annular pancreas

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

References

1 EUROCAT Website Database:www.bio.medical.co.uk./eurocatline (data uploaded17/11/2006).

2 Grosfeld JL. In: JA O’Neill Jr, MI Rowe, EW Fonkalsrud,AG Coran (eds). Pediatric Surgery, 5th edn. Mosby-YearBook, St. Louis, 1998.

3 Sadler TW. Langman´s Medical Embryology, 8th edn.Lippincot Williams & Wilkins, Philadelphia, 2003.

4 Diez-Pardo JA, Baoquan Q, Navarro C, Tovar JA. A newrodent experimental model of oesophageal atresia andtracheoesophageal fistula: preliminary report. J PediatrSurg 1996;31:498–502.

5 Foker JE, Kendall TC, Catton K, Khan KM. A flexibleapproach to achieve a true primary repair for all infantswith oesophageal atresia. Semin Pediatr Surg2005;14(1):8–15.

Paediatric appendicitis

Adolfo Bautista Casasnovas, MD

Chapter 15134

15.1 McBurney´s point is located two-thirds of the

distance from the umbilicus to the anterior superior iliac

spine.

Introduction

Acute appendicitis is a common paediatric surgical diseaserequiring urgent attention. Appendectomy is the mostcommon surgical procedure performed for acute abdominalpain in children (15.1)1. The diagnosis of acute appendicitisin childhood can sometimes be difficult.

The incidence of acute appendicitis has been estimated atabout 1 case per 1,000 children per year, with slightly higherincidence among boys. The lifetime risk of appendicitis isestimated to be 8.67% for boys and 6.7% for girls. Incidenceamong preschool children is unusual, but in this age groupdelayed diagnosis and complications are more frequent.Around one-third of children with acute appendicitis arefound to be perforated at surgery.

Children who have appendicitis are twice as likely to havea positive family history as are those with right lowerquadrant pain, but no appendicitis2. Early diagnosiscontinues to be the most important factor for prognosis.The rate of negative appendectomy is considered acceptablefor up to 10% of laparotomies for suspected acuteappendicitis. Paediatric surgeons performed significantlyfewer negative appendectomies than general surgeons3.

The development of the caecum and appendix begins inthe caecal diverticulum on the anti-mesenteric side of thecaudal end of the medial intestine, around the fifth week ofgestation. The appendix does not elongate as rapidly as therest of the colon. After rotation and descent, the base of theappendix is located at the posteromedial wall of the caecumabout 2.5 cm below the ileocaecal valve, but this descentfinishes after childhood. The variability of its descent androtation leads to multiple possible final positions of theappendix4. The infant caecum is located in the right iliacfossa in about 55% of individuals (15.2). The blood supply

of the caecum and appendix is the appendiceal branch of theileocolic artery, which passes behind the terminal ileum.The arterial supply is terminal, so that thrombosis leads torapid necrosis (15.3). The malpositioned appendix may giverise to signs of inflammation in unusual locations, that makediagnosis difficult.

Paediatric appendicitis 135

Retrocecal65%

Ileal 4%

Pelvic 31%

15.2 Possible positions of appendix and their relative

frequency4.

15.3 Normal vascular supply of the appendix.

IleocolicarteryRamus

colicus

Ramusilealis

Appendicularis artery

15.4 Typical appearance of simple appendicitis during

surgery. It is possible to observe the caecum, appendix,

and mesoappendix with congestion of the blood vessels

and inflammatory exudates.

Pathophysiology

Obstruction is a fundamental factor in the development ofacute appendicitis. Obstruction increases intraluminalpressure leading to ischaemia, bacterial invasion, bacterialovergrowth, necrosis, and perforation.

In the early phases, activation of receptors in theintestinal wall leads to perception of pain in theperiumbilical region. In later phases, when the purulentsecretion from the appendiceal wall contacts the parietalperitoneum, somatic pain fibres are triggered and the painlocalizes near the appendiceal site, McBurney’s point. Thecharacteristic organisms responsible of appendicealinflammation are predominantly anaerobic, includingEscherichia co li, Enterococcus, Bacterio ides fragilis,Pseudomonas, Klebsiella, and Clostridium5.

Many terms have been used to describe the pathologicstages of appendicitis, from the normal state to perforation.Only the clinically relevant distinctions of simpleappendicitis (15.4) and complicated appendicitis should bemade.

136 Paediatric appendicitis

Physical examinationPalpation should always be first superficial and then deep.The palpation should start in an area without pain, and thepatient’s face should be watched for signs of discomfort. Infact the important thing to look for during examination isany localized area of abdominal pain. Abdominal tendernessis the most constant physical finding. The point of maximaltenderness is localized at McBurney’s point. Associated withtenderness progressively are abdominal muscle spasms.Rebound tenderness or Blumberg’s sign (i.e. pain felt onsudden release of steady pressure in the right iliac fossaregion) reflects irritation of the parietal peritoneum of theinflamed appendix, and associated fluid secretion.

The routine use of rectal examination is controversial.Invariably this exploration causes discomfort to children,and pain during examination is not specific to appendicitis.It may be useful for detection of possible pelvic abscess orovarian pathology.

Laboratory testsWBC is of limited diagnostic value. Typically leukocytecount is mildly elevated, 10,000–16,000/mm3, withincreased polymorphonuclear leukocytes, neutrophils, andimmature neutrophils. 20% of patients with acuteappendicitis will have a normal WBC. Very high WBCsuggests perforation or another diagnosis.

Neutrophilia is more decisive for diagnosis thanleukocytosis. In doubtful cases it is useful to monitor WBCs,as long as the patient is not receiving antibiotics. Urinesediment analyses are useful for detecting patients requiringfluid resuscitation and diseases of the urinary tract. Thespecific gravity and ketones are elevated. If the appendix islocated adjacent to the ureter or the bladder, the red bloodcount and WBC in urine may be elevated.

Diagnostic imagingImaging studies rarely add significant information in cases ofclassic appendicitis, and should be reserved for equivocal casesand when patient observation is indicated. Plain film, althoughit has a lower sensitivity and specificity, remains useful fordetecting secondary problems associated with inflam mation(Table 15.1) (15.5). The presence of faecalith is highlysuggestive of acute appendicitis; however, faecalith is observedonly in 10–15% cases of confirmed appendicitis (15.6).

Ultrasonography has constituted a significant advance inthe diagnosis of acute appendicitis, based on its rapidity,noninvasiveness, sensitivity (85–90%), and specificity

Diagnosis

The diagnosis of appendicitis should be based on a carefulhistory and physical examination. The paediatric surgeonmay expect to make the accurate diagnosis in 80–90% ofcases. White blood count (WBC) and imaging rarely addsignificant information.

Acute appendicitis typically occurs in older children. Theincidence of appendicitis gradually increases from age 1 yearonwards, peaking at around age 11–12 years. Althoughappendicitis is uncommon in infants, this age group has ahigh rate of complications because of delayed diagnosis.Difficulties of diagnosis may arise with patients youngerthan 2 years, and with preadolescent obese girls. In thesetwo patient categories, analytical and imaging studies canprovide additional information.

Clinical presentationThe classic sequence (persistent abdominal pain, fever, andlocalized pain on palpation at McBurney’s point) starts withperiumbilical pain, preceded by appetite loss in about50–60% of children. The main symptom is abdominal pain,usually beginning as a vague periumbilical pain or mildgastrointestinal discomfort. After several hours, this paingradually migrates to the right iliac fossa. Characteristicallythe pain is implacable and is exacerbated by movements andpressure, making ambulation painful and difficult. A childwith acute appendicitis typically walks bent over and slowly.Anorexia is a helpful sign. Nausea and vomiting appear afterthe onset of pain. If vomiting precedes abdominal pain,other diagnoses should be considered.

The last symptom in the clinical evolution is fever, whichappears after pain and vomiting, and no more than 1ºCabove normal. Fever higher than 39ºC is usually associatedwith complicated appendicitis (gangrenous and perforated).Symptoms may be influenced by the anatomical location ofthe appendix. Pain of a retrocaecal appendix may be in theflank or back. A pelvic appendix resting near the ureter ortesticular vessels can cause urinary frequency, inguinal ortesticular pain, or ureteral compression with hydro -nephrosis. Young patients aged 1–4 years, typically showvomiting and irritability, and draw up their legs to reducepain. Other common manifestations include abdominaldistension, diarrhoea, lethargy, and anorexia, together withfever. In 50% of cases an abdominal mass is detectable onpalpation. The key point in this group of patients isvomiting.

137Paediatric appendicitis

15.7 Ultrasonography of a patient with acute appendicitis, showing

distended noncompressible tubular structure with faecalith, increase

in mural thickness, and inflamed periapendicular fat tissue. The most

characteristic ultrasound criteria for appendicitis include the presence

of noncompressible tubular structure corresponding to the inflamed

appendix, with a size greater than 6 mm in diameter, a complex mass

in the right lower quadrant, faecalith, pericaecal inflammatory

changes, or free peritoneal fluid.

15.5 Upright film

shows multiple

air-fluid levels in

small bowel and

absence of gas

in colon. Typical

of bowel

obstruction.

15.6 Simple

radiography of

the abdomen in a

patient with acute

appendicitis,

showing

appendicolith in

the right iliac

fossa.

• Dilated caecum with air-fluid level

• Appendiceal faecalith

• Antalgic scoliosis of the right concavity

• Dilated loops

• Obliteration of the lower-right psoas margin

• Obliteration of the preperitoneal fat line

• Free peritoneal fluid

• Free peritoneal air

• Paucity of gas in the right-lower quadrant

• Small bowel obstruction

Table 15.1 Abnormal signs usually found in plain

film in acute appendicitis

(92–96%). It is of particular value in adolescent andprepubertal girls. It should be the first approach in doubtfulcases. Reports of centres with skilled radiologist oftenrecommended ultrasonography for all children withsuspected appendicitis (15.7, 15.8)6.

Abdominal computed tomography (CT) with sensitivityand specificity of 98%, has become the most informativeimaging technique in the study of patients with atypicalmanifestations (15.9)7.

Differential diagnosisAppendicitis in childhood presents with uncommon featuresin 50% of cases, and may mimic many others diseases suchas gastroenteritis, basal pneumonias, constipation, andurinary pathology (tract infections, hydronephrosis,lithiasis) (Table 15.2).

Paediatric appendicitis138

15.8 Ultrasonography, longitudinal and transverse view.

The appendix is distended with increased wall thickness

and faecalith inside.

15.9 Classic pelvic CT scan shows a distended appendix.

The following findings are found in appendicitis: fluid-filled

tubular structure measuring >6 mm in maximum diameter,

fat stranding, abscess or phlegmon in adjacent tissue,

faecalith, and focal caecal apical thickening.

Urogenital tract • Hydronephrosis

• Urinary tract infections

• Lithiasis

• Wilm’s tumour

• Premenstrual syndrome

• Ovarian pathology

• Pelvis inflammatory disease

• Salpingitis

• Ectopic pregnancy

Colon • Appendiceal tumours

• Appendiceal mucocoele

• Constipation

• Crohn’s disease

• Intestinal obstruction

• Diverticulitis

• Typhlitis

Small bowel diseases• Gastroenteritis

• Mesenteric adenitis

• Duodenal ulcer

• Meckel’s diverticulitis

• Inflammatory bowel disease

• Intussusception

• Intestinal obstruction

• Intestinal tuberculosis

• Typhoid infection

Hepatobiliary• Cholecystisis

• Viral hepatitis

• Cholangitis

Miscellaneous• Cytomegalovirus

• Pneumonia

• Pleuritis

• Primary peritonitis

• Henoch–Schönlein purpura

• Viral exanthematous diseases

• Sickle cell anaemia

• Diabetic ketoacidosis

• Pancreatitis

• Omentum infarction

• Parasitic infection

• Abdominal migraine

• Acute porphyria

• Psoas abscess

• Burkitt´s lymphoma

• Familial Mediterranean fever

• Haemolytic uraemic syndrome

• Kawasaki disease

Table 15.2 Possible differential diagnoses of acute appendicitis


15.10 Skin incisions: red: transverse Rockey–Davis

approach; Blue: oblique classic McBurney approach.

appendectomy if the patient improves within 24–72 hours.Interval appendectomy after nonoperative management iscontroversial.

Indications for an open appendectomy (OA) orlaparoscopic appendectomy (LA) are based on hospitalpersonal and facilities, surgeon skills, and experience.Frequently, laparoscopic approach is avoided when bowelobstruction is present or an abdominal mass is palpable. Inyoung and slim patients, open appendectomy through asmall incision is easier and faster.

Although the McBurney approach is still widely used, theauthor prefers a Rockey–Davis approach, transverse right-lower quadrant incision, placed above anterior superior iliacspine and lateral to rectus abdominus (15.10). When theperitoneum is exposed and incised, if free fluid is present itshould be aspirated. Once the appendix is accessible themesoappendix is taken down between clamps and divided(15.11). The appendix is released from its mesoappendixand vascular attachment and prepared for ligature (15.12).The base of the appendix is crushed with a clamp andligated (15.13). In cases of peritonitis, if the caecum wallsare thickened, congestive or friable, invagination of theappendiceal stump should be avoided. When a faecalith ispresent, it should be located and removed.

Treatment

The treatment of choice is surgical excision(appendectomy), and depends on both the generalcondition of the patient and the state of appendix. In manycases children are dehydrated, septic, or acidotic. Rapidadministration of intravenous fluid and electrolytes (torestore acid–base balance) is essential for a successfuloutcome.

Antibiotics It is widely accepted that the use of antibiotics is clearlybeneficial8. Antibiotics must be administered prior to skinincision. It is unnecessary to culture peritoneal fluidroutinely in each case of acute appendicitis. Intraoperativecultures have not shown to alter the treatment outcome9.

For many years the gold standard for complicatedappendicitis was a 10-day course of ampicillin, gentamicin,and clindamicin or metronidazole; in recent years manysurgeons have dropped ampicillin coverage. For simpleappendicitis a single agent such as cefotetan, cefoxitin,ticarcillin/clavulanate, or piperacillin/tazobactan is typicallyprescribed. For complicated appendicitis a combinationsuch as ceftriaxone/metronidazole or ticarcillin/clavulanateplus gentamicin are used10.

Standard antibiotic therapy at the author’s institution ispreoperative treatment with gentamicin (or tobramycin)plus metronidazole in all cases of acute appendicitis, with alow incidence (<4%) of postoperative infections andabscesses. In simple appendicitis, treatment is continued for24–48 hours, and in complicated appendicitis for as long as5–10 days. A prospective randomized study demonstratesequivalence between prolonged intravenous therapy andintravenous therapy followed by conversion to oralantibiotic therapy in children with perforated appendicitis11.

AppendectomyAppendectomy is not an emergency procedure, it should betreated as a semiemergency procedure. A recent studyconcluded that in children with acute appendicitis, delayingsurgery until the daytime hours did not significantly affectoperating time, perforation rate, or complications12. Whenthe appendix is perforated, surgery is less urgent. Ifperitonitis is present most surgeons will proceed withappendectomy after preoperative fluid resuscitation andantibiotics have been started. Another group of surgeonswill continue nonoperative management and avoid

15.12 Perforated

appendix released

from its

mesoappendix

attachment.

15.11 Complicated appendicitis: perforated appendix.

mesoappendix is exposed and prepared for division.

15.13 The

appendiceal

stump is inverted

and purse-string

suture is tied.

Advantages• Initial laparoscopy reduces the risk of incorrect

diagnosis

• Less traumatic

• Reduction of postoperative pain and better

postoperative comfort

• Easy treatment of ectopic appendix

• Efficient lavage of the peritoneum

• Less frequent postoperative complications

• Faster recovery and discharge from hospital

• Lower surgical wound infection rates

Disadvantages • The operation takes longer

• Higher cost

• Requires paediatric surgeons with experience in this

technique

Table 15.3 Advantages and disadvantages of laparoscopic appendicectomy

LA is an alternative to conventional OA, but itsadvantages are still widely debated (Tables 15.3, 15.4). Theauthor uses LA in obese children, and in those withsuspected alternative diagnoses. LA is at least as effective asOA, with the advantage that the initial laparoscopy reducesthe risk of incorrect diagnosis13. A review of 45 publishedtrials of LA compared with OA show that LA reduced therate of wound infections by one-half but increased the rateof intra-abdominal abscess four-fold. The most common

140 Paediatric appendicitis

141Paediatric appendicitis

• Acute appendicitis

• Suspected appendicitis in patients with abdominal

pain

• Appendicular mass and/or peritonitis

• Chronic abdominal pain

• Suspected neoplasia

• Incidental appendectomy during laparoscopy for other

indications

Table 15.4 Indications for laparoscopic

appendectomy

technique is the three trocars technique, the sites of trocarsvary depending the surgeon preferences, appendicealposition, and the presence of complications (15.14, 15.15).

Independent of the type of appendectomy, the patientswith simple appendicitis are usually ready to start oral fluids8–24 hours after surgery. Intravenous fluid requirements areassessed regularly and discontinued as soon as possible.Patients can be discharged home within 48–72 hours. Theymay be checked after 1 week to ensure that they have nopostoperative infective complications.

In complicated appendicitis, antibiotic are continueddepending on clinical progress. These patients may requirenasogastric tubes and intravenous fluids for longer.

15.14 Possible trocar situations.

15.15 Typical appearance of appendix during laparoscopy.

Complications

The most frequent complication of acute appendicitis isinfection. The risk is increased when the appendix isperforated. The overall complication rate is 10% and majorcomplication rate of 4%.

Wound infection rate should be below 4% in simpleappendicitis and below 8% in complicated cases. It typicallypresents in the first week after surgery as localized pain,reddening, hypersensitivity, and tumefaction; spontaneoussuppuration may also occur. It should be treated withantibiotics, opening the edge of the wound, or incision anddrainage.

Intra-abdominal abscess rate is less than 7%. The patienthas persistence of pain and ileus, fever, and leukocytosis,Abscesses are usually located in the pelvis, sometimes in thesubphrenic space or medial zone of the abdomen. A painfulfluctuant mass can be palpated in rectal examination, if theabscess is located in Douglas’ pouch. The abscess can betreated conservatively, or drained percutaneosly underultrasound or CT guidance or transrectally in the operatingroom. Exceptionally open drainage may be required (15.16).

Prolonged intestinal paralysis (ileus) is directly related toperitoneal infection; the more severe the peritonitis, the

Paediatric appendicitis142

15.16 Ultrasonography in a case of abdominal abscess.

Situated behind the bladder. A: Abscess; B: bladder.

15.17 Faecal fistulae in a girl after complicated

appendicitis with peritonitis.

longer the period required for recovery of normal intestinaltransit.

Small bowel obstruction occurs in 2% of patients withcomplicated appendicitis, and if not responsive to medicaltreatment (nasogastric suction, intravenous fluids, andparenteral nutrition) may require surgery.

Other unusual complications include postoperativeintussusception, faecal fistulae (15.17), pylephlebitis. Somecontroversy exists about fertility after abdominal sepsis;different studies report than perforated appendicitis did notincrease the risk of infertility14.

Current mortality rates for complicated appendicitis isbelow 0.5%, and rather higher in children aged less than 2years15. The incidence of postoperative complications havemarkedly decreased, perhaps due to the use of broad-spectrum antibiotics, the progress in pre- and postoperativecare, and improved anaesthesia techniques. The best resultsfor children with appendicitis are obtained with thecombination of surgical evaluation, rapid surgery whendiagnosis is clear, a period of observation if diagnosis isunclear, radiology imaging if necessary, and care providedby experienced clinicians and institutions16.


14 Puri P, McGuinness EP, Guiney EJ. Fertility followingperforated appendicitis in girls. J Pediatr Surg1989;24(6):547–9.

15 Blomqvist PG, Andersson RE, Granath F, et al.Mortality after appendectomy in Sweden, 1987–1996.Ann Surg 2001;233:455–460.

16 Morrow SE, Newman KD. Current management ofappendicitis. Semin Pediatr Surg 2007;16:34–40.

Further reading

Bautista Casasnovas A. Acute appendicitis. In: GuandaliniS (ed). Textbook of Pediatric Gastroenterology andNutrition. Taylor & Francis, London, New York, 2004,Chapter 45, pp. 739–49.

Dunn JC. Appendicitis. In: Grosfeld JL, O´Neill JA Jr,Coran AG, et al. Pediatric Surgery, 6th edn. MosbyElsevier, Philadelphia, 2006, Chapter 98, pp. 1501–12.

Ein SH. Appendicitis. In: Ashcraft KW, Murphy JP, SharpRJ, et al. (eds). Pediatric Surgery, 3rd edn. WB SaundersCompany, Philadelphia, 2000, Chapter 43, pp. 571–9.

Lund DP, Folkman J. Appendicitis. In: Walker WA, DuriePR, Hamilton JR, et al. (eds). Pediatric GastrointestinalDisease: Pathophysiology, Diagnosis and Management,3rd edn. BC Decker, Hamilton, 2000, Chapter 48, pp.821–9.

Morrow SE, Newman KD. Appendicitis. In: Ashcraft KW,Holcomb GW, Murphy JP (eds). Pediatric Surgery, 4thedn. Elsevier Saunders, Philadelphia, 2005, Chapter 42,pp. 577–585.

Stevenson RJ. Appendicitis. In: Ziegler M, Azizkhan R,Weber TR (eds). Operative Pediatric Surgery. McGraw-Hill Professional, New York, 2003, Chapter 60, pp.671–89.

References

1 McBurney C. Experience with early operativeinterference in cases of diseases of the vermiformappendix. NY State J Med 1889;50:676–84.

2 Gauderer MW, Crane MM, Green JA, et al. Acuteappendicitis in children: the importance of family history.J Pediatr Surg 2001;36:1214–17.

3 Somme S, To T, Langer JC. Effect of subspecialtytraining on outcome after pediatric appendectomy. JPediatr Surg 2007;42:221–6.

4 Wakeley CP. The position of the vermiform appendix asascertained by an analysis of 10,000 cases. J Anat1933;67:277–83.

5 St Peter SD, Little DC, Calkins CM, et al. A simple andmore cost-effective antibiotic regimen for perforatedappendicitis. J Pediatr Surg 2006;41:1020–4.

6 Lander A. The role of imaging in children with suspectedappendicitis: the UK perspective. Paediatr Radio l2007;37:5–9.

7 Doria AS, Moineddin R, Kellenberger CJ, et al. US orCT for diagnosis of appendicitis in children and adults? Ameta-analysis. Radiology 2006;241:83–94.

8 Andersen BR, Kallehave FL, Andersen HK. Antibioticsversus placebo for prevention of postoperative infectionafter appendicectomy. Cochrane Database Syst Rev2005;20(3):CD001439.

9 Moawad MR, Dasmohapatra S, Justin T, et al. Value ofintraoperative abdominal cavity culture inappendicectomy: a retrospective study. Int J Clin Pract2006;60:1588–90.

10 Rodriguez JC, Buckner D, Schoenike S, e t al.Comparison of two antibiotic regimens in the treatmentof perforated appendicitis in paediatric patients. Int J ClinPharmacol Ther 2000;38:492–9.

11 Rice HE, Brown RL, Gollin G, et al. Results of a pilottrial comparing prolonged intravenous antibiotics withsequential intravenous/oral antibiotics for children withperforated appendicitis. Arch Surg 2001;136:1391–5.

12 Yardeni D, Hirschl RB, Drongowski RA, et al. Delayedversus immediate surgery in acute appendicitis: do weneed to operate during the night? J Pediatr Surg2004;39:464–9.

13 Sauerland S, Lefering R, Neugebauer EA. Laparoscopicversus open surgery for suspected appendicitis. CochraneDatabase Syst Rev 2004;18(4):CD001546.

Paediatric clinicaldietetics

Amaya Peñalva Arigita, RD

Chapter 16144

Nutrient Module Composition

Carbohydrates Polycose® Glucose polymers

1 g = 4 kcal Fantomalt® Glucose polymers

Maxijul® Glucose polymers

Dextrinomaltose Resource® Glucose polymers

Lipids Resource MCT oil® MCT

1 ml = 9 kcal Liquigen® MCT

Solagen® LCT

Supracal® LCT

Carbohydrates + lipids Duocal/Duocal MCT® Glucose polymers + LCT/MCT

1 g = 4.9 kcal Duocal liquid® (1 ml = 1.6 kcal) Glucose polymers + LCT/MCT

Energivit® Glucose polymers + LCT/MCT

PFD-1® (1 g = 5.3 kcal) Glucose polymers + LCT/MCT

PFD-2® (1 g = 4 kcal) Glucose polymers + LCT/MCT

Proteins Promod®

1 g = 4.0 kcal Protifar® Whole protein

Table 16.1 Nutritional modules2

supplements.There are infants with certain diseases (metabolic,

allergies) who need special enteral formulas to adapt thewhole diet. Others may need supplementation, usingnutritional modules that are added to a formula (Table 16.1).

Many studies demonstrate the advantages of nutritionalsupplementation in different groups of patients, improvingthe evolution of the disease, and decreasing the incidence of

Introduction

Dietetics is defined as the application of the principles ofnutrition to the selection of food and the feeding ofindividuals and groups1. Clinical dietetics covers thenutritional management of sick infants and children (eitherin an acute or chronic phase) to fulfill their requirements ina clinical and/or outpatient setting. This can be done interms of adjusting the diet, adjusting menus, recommendingcertain foods, and/or using commercial nutritional

Paediatric clinical dietetics 145

complications3. Some children may require the use ofpaediatric supplements to increase their poor oral intake(Table 16.2). Other children may need a completenutritional support via nasogastric tube (16.1), viagastrostomy (16.2), or by means of parenteral nutritionwhen the gastrointestinal tract is not functional. Anadequate nutritional status allows a normal growth and

Formula Kcal/ml (per unit) Proteins (g) (per unit) Administration

Pediasure 1 (201) 5.6 Oral

Pediasure Fibre 1 (201) 5.6 Oral

Pediasure Plus 1.5 (300) 8.4 Oral

Isosource Junior 1.2 (305) 6.75 Oral

Isosource Junior Fibre 1.2 (300) 6.75 Oral

Resource CF 151/pack 4.9 Oral

Resource Protein 1.6/g (200/pot) 6 g per pot Oral

Resource Junior 1.5 (300) 12 Oral

Fortini 1.5 (300) 6.8 Oral

Nutrini Energy 1.5 (300) 8.2 Enteral

Nutrini Energy Multi Fibre 1.5 (300) 8.2 Enteral

Novasource Junior Peptinex 1 (250) 7.5 Enteral/oral

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

development. Growth can be compromised in the presenceof a chronic disease especially when it coincides with peaksof growth (infancy, puberty).

During growth, size increases and body compositionchanges. This implies certain nutritional requirementswhich are higher than those of the adult. Besides, theimmaturity at birth involves special requirements in terms of

16.1 A nasogastric tube may be useful for supplementing

the oral intake. This is a girl with failure to thrive. She has

a tracheostomy due to a laryngomalacia. She takes by

mouth what she can and the rest is given by the

nasogastric tube.

16.2 A gastrostomy tube in a child with Menkes’ disease.

As the disease progressed the child was unable to be fed

normally and it became essential to find an alternative

way: a gastrostomy tube placed by endoscopic procedure

was the solution.

quality of nutrients, types of foods, and a limited response tooverloading which can lead to complications. Therefore,there is a need to assess adequately nutritional status beforestarting any nutritional support.

Nutritional assessment

In the dietetic approach to a sick infant or child, it isessential to perform a correct nutritional assessment. Thereare a number of methods assessing specifics aspects ofnutritional status, but no one measurement will give anoverall picture of the status of all nutrients (16.3).

Clinical assessment

This includes a complete medical history and physicalexamination (Table 16.3). It is important to watch out forthe constitution of the child; especially differentiating thosewho are skinny by genetics from those who have lost musclemass. The presence of malnutrition signs such as abdominaldistension, presence of oedema, and hepatomegaly, shouldbe evaluated, along with mood and behaviour as childrenmay be apathetic and irritable. Biochemistry andhaematological tests are also useful (Table 16.4)

Anthropometry is a physical examination which providesan indirect assessment of body composition anddevelopment. The child is growing continuously, and ineach moment there is an ideal weight for a determinedheight. In acute malnutrition the weight may be alteredmaintaining the rate of height, although in a chronic state


this rate also appears altered. This growth retardation is animportant sign of malnutrition.

Weight measurement is an easy and routine procedure(16.4). Children can be weighed in beam balance scales orelectronic scales. Weight shows variability during the day,and it would be advisable to weigh always at the same timeand with the same conditions7. Height measurement forinfants and children less than 2 years old, is measuredsupine (16.5). From 2 years old, standing height is thenmeasured whenever possible (16.6).

Skinfolds provide information about the changesproduced in the subcutaneous components of the fat andfat-free mass. There are seven sites of measure: triceps,abdomen, chest, thigh, suprailiac (iliac crest), mid-axillar,and subscapular. They are measured with a skinfold caliper.Mid-arm circumference is useful to determine the state ofmuscle mass, as this area is hardly affected by oedema. Thismeasurement is used in conjunction with the skinfold

Nutritiional assessment

Clinical assessment Anthropometry Dietary assessment

Physical featuresBiochemistryHaematology

Weight/heightHead circumference

Mid-arm circumferenceSkin folds

24 hour recall3–7 day record history (food diary)

Frequency test

16.3 Algorithm of nutritional assessment.

• Skin: dry, scale, paleness, bruising

• Hair: thin, sparse, straight (‘lifeless’), change in colour

• Lips/mouth: stomatitis, cheilosis, lingual atrophy,

colour changes of tongue, problems with teeth, gums

• Face: fullness of cheeks (oedematous malnutrition),

thyroid enlargement

• Eyes: xerosis, keratomalacia, pale conjuctiva

• Nails: spoon shape, koilonychie

Table 16.3 Physical signs of malnutrition4, 5


Table 16.4 Laboratory tests (biochemical and haematological)6

Laboratory test help to define protein status, vitamin–mineral status and alterations of metabolism or organ function

with nutrition implications

Proteins:

• Total plasma protein: serum level may detect liver function; availability of amino acids (protein intake); distribution of

protein; rate of protein use by the body

• Albumin: (half-life 20 days). It accounts for over 50% of total serum proteins. Low levels reflect prolonged protein

depletion as it breaks down slowly. Albumin concentrations though may be depressed by many conditions besides

malnutrition

• Transferrin: (half-life 4–8 days). It reflects protein and iron (as it transports it) status. When an iron deficiency is

present it is not a good indicator of protein status. A marked decrease means a severe malnutrition condition. It is

not a good indicator of response to nutrition therapy as it responds slowly to changes in protein intake.

• Prealbumin: (half-life 2 days). It responds quickly to changes in protein intake and is a good indicator of nutritional

therapy. There are other conditions which can lower prealbumin levels and others, such as kidney disease (treated

with corticosteroids), which can elevate it

• Retinol-binding protein: (half-life 12 hours). It responds quickly to changes in protein intake and is a good indicator

of nutritional therapy.

• Serum enzymes: to monitor organ function

• Urine test: to detect protein status (by urinary urea nitrogen and creatinine excretion)

• Haemoglobin; haematocrit, mean corpuscular volume, mean corpuscular haemoglobin

• Total lymphocyte count: when malnutrition is present there is a reduction in white blood cell count

• Vitamins: water-soluble and fat-soluble

• Minerals: calcium, chloride, magnesium, sodium, potassium, selenium, copper, and zinc (its deficiency retards

growth and typically accompanies protein-energy malnutrition)

16.4 Infant scale (10 g precision). Ideally infants should

be weighed naked or just with a clean nappy, but if it is

not possible it is important to record the way it has been

measured.

16.5 Two people are needed to measure length precisely:

one to hold the child in position and the other to record

the measurement. Measurement of length is difficult and it

requires carefully positioning of the infant, ensuring that

the back, legs, and head are straight, the heels are

against the footboard, the shoulders are touching the

baseboard, and the crown of the head is touching the

headboard.

16.6 Standing height:

the correct position is

with bare feet, the back

and the legs straight,

the heels, buttocks,

shoulder blades, and

back of head touching

the measurement

board and the child

looking straight ahead.


triceps to differentiate between lean and fat.All these anthropometric data need to be reflected in a

percentiled growth chart. Many different growth charts havebeen published and it is important to use the correct version,adjusted to the population studied. The normal range liesbetween the third and 97th percentiles. Anything beyondthese limits is at risk of an alteration, although markeddecreases within the normal range are also a warning sign ofpossible nutritional problems.

Weight and height are essential for estimating individualrequirements. They can be estimated using the Schofield8

equations; either based on standard nomograms (RDA,WHO tables, etc.)9 or by indirect calorimetry. For proteinrequirements the standards are also set in this normogram,although excessive intake of protein should be checked. It hasbeen suggested that excessive protein intake may jeopardizecertain physiological functions in infants10. All the data aregoing to be useful to calculate the nutritional indexes that areavailable to determine nutritional status (Table 16.5).

Waterloo index (weight): Waterloo index (height):Weight (kg) x 100 Height (cm) x 100

Weight at P50 for height Height in P50 for age

Classification of caloric-protein malnutrition (CPM): For weight: For height:

Normal: >90% Normal: >95%

Mild CPM: 80–90% Mild CPM: 90–95%

Moderate CPM: 70–79% Moderate CPM: 85–89%

Severe CPM: <70% Severe CPM: <85%

Z scoreReal anthropometric value (weight or height) – median P50

Standard deviation

Classification: Risk of malnutrition: Z: –1.28 Obesity: Z +1.65

Acute malnutrition (wasting): Z <1.65 Overnutrition: Z +1.28

Normal range: Z ±1.28

Body mass index (BMI)*

Weight (kg)/(height (m))2

*Using age-related centile charts (In children BMI is not related to health but only with distribution of body fat which is

dependent on age)

Table 16.5 Nutritional indexes11


Dietary assessment

A diet history provides a record of food intake which reflectseating habits, possible nutrient imbalances, and otherfactors which can affect food intake. This information willprovide the background for developing discussion with thecarers (usually parents) on realistic nutritional goals with anutritional intervention (Table 16.6). This is timeconsuming and requires skill. There are different ways ofobtaining the information depending on the need foraccuracy.

A 24-hour recall is the first-line approach as it is quickand easy to do by a skilled professional. The usual carers orthe child are interviewed to recount what the patientnormally eats in a usual day, using what has been eaten theday before. In infants, estimating food intake is particularlydifficult in those taking solids as it is difficult to know howmuch food is lost in spitting, drooling and so on (Table16.7). A food frequency test is used to obtain more preciseinformation. It enables the assessor to double check theinformation obtained previously. A 3–7-day record history(food diary) provides an accurate account of food intake andeating behaviour. It is a good way of making the recordkeeper responsible for personal food choices and eatinghabits (in grown children).

Analysis of food intake dataA skilled dietitian has to estimate quickly the amount ofcalories and protein intake. This can be confirmed manuallyby using food composition tables or using a computerdietetic analysis program. This information has itslimitations as it is always an estimated approach. It can givean idea of the food ingested but not absorbed. Adequatenutrient intakes do no guarantee adequate nutrient status6.

Once the calculations are made they are compared withthe requirements calculated for the child. A dieteticdiagnosis is made, followed by the appropriate interventionwhich includes the adjustment of the diet, followed by aclose monitoring plan agreed and adjusted to the needs ofthe patient and family (Table 16.8).

Intervention

Several diseases and/or the effects of treatment can result indecreased appetite, nausea, vomiting, eating difficulties, andmalabsorption which can compromise the child’s nutritional

• Search for information

• Analysis of the information

• Dietetic diagnosis (estimating requirements,

fulfillment of those requirements)

• Prioritizing objectives

• Dietetic intervention

• Monitoring/assessment

Table 16.6 Aims of the dietary assessment

• Food frequency

• Quality/quantity of food

• Fluids/type and frequency

• Feeding routine

Table 16.7 Food diary information

• Defining nutritional status

• Intervention after checking nutritional requirements

• Changes done in the register. Start a new register

• Monitor in the outpatient clinic

Table 16.8 Dietetic diagnosis and intervention

state. Others such as inborn errors of metabolism(phenylketonuria, maple syrup disease) involve a thoroughunderstanding of the deleterious effects of the precise errorof metabolism. In these cases there are various approachesbut often the cornerstone of treatment is diet. Substraterestriction by an individualized diet is necessary and in timesof illness a careful calorie support adjustment is essential toavoid catabolism12. Furthermore, close dietary advice isnecessary to address deficiencies which may develop fromsuch a restricted diet. Other diseases may need only nutri -tional advice and guidance. Cases A–D are such examples.


Case A: Fortification with nutritional modules of an infant dietFemale, 3 months old, congenital heart disease

Nutritional assessmentWeight: 4.010 kg (<P3); Height: 55.5 cm (<P3); HC: 39 cm (P10)

• Requirements*:

– Energy: 125–131 kcal/kg/day

– Protein: 10 g per day

Z (weight): –3.11 (<P3); Z (height): –2.04 (<P3)

W.I. (w): 77%; W.I. (h): 94%

BMI: 12.5 (<P3)

Food intake: The baby is fed by formula as breastfeeding was unsuccessful. The mother continues to offer

breastfeeding, but the baby gets tired. The mother is encouraged to keep offering breast-feeding.

6 x of 60 cc of infant milk

Adjust the diet with a nutritional module (Duocal®) of carbohydrates and lipids: first at 3% to increase to 5%:

QuantityPercentage 60 cc 90 cc 120 cc

3% 1.8 g 2.7 g 3.6 g

*1.5 sc ~2 sc 3 sc

5% 3 g 4.5 g 6 g

2.5 sc ~4 sc 5 sc

7:00 10:00 13:00 16:00 19:00 22:00 3:00 Total intake Caloric intake (kcal)Day 1 50 ml 40 ml 90 ml 55 ml 90 ml 60 ml 45 ml 430 ml + ~4.42 g 292 + 17 = 309

Day 2 45 45 70 75 50 80 55 420 ml + 3 g + 5.5 g 286 + 11 + 21 = 318

Day 3 45 90 65 50 100 80 55 485 ml + 6 g + 11.4 330 + 23 + 43 = 396

Guide to colour:• Black: nothing added

• Red: starts to add only 1 scoop in 90 cc (1.3%) of the nutritional module

• Green: start adding 2 scoops (3%)

• Blue: starts adding 3 scoops (4%)

The baby is still not getting the calorie amount she needs so add some MCT oil first at 1% to be raised at 2–3% (1 ml = 8.9 kcal). This makes up to a total intake of 129 kcal/kg/d, meeting her requirements.

Analysis360 ml x 0.68 kcal/ml

≈ 245 kcal ≈ 61 kcal/kg/day

*Schofield: (3 months)

0.068 x w (4.01 kg) + 4.281 x h (0.555) -1.730 = 0.9186 x

239 kcal = 219.5 kcal

x 1.6 (activity) = 351.2 kcal

x stress (1.3–1.5) ≈ 500– 527 kcal

*1 scoop (sc) = 1.2 g (each pot of different

brands has its own measure)

The mother is recalled for the following week and

asked to register what the baby eats to evaluate

progress. The mother reports that the baby is not

accepting the amount prescribed, so she is encourage

to add less (starting at 1% and to increase the amount

until acceptance).


Case B: Supplementation with common foodsMale, 4 years old, medulloblastoma

Chemotherapy has been initiated, with several visits to hospital. The boy has mild anorexia and presents with

weight loss.

Nutritional assessment• Weight: 15 kg (P25); Usual weight (4 months before): 17 kg (P50)

• Height: 100 cm (P25)

• Requirements*:

– Energy: 1500–1700 kcal; 130–150 Kcal/kg/day

– Protein: minimum 30 g/day

Z (weight): –1.03; Z (height): 0.65 min

WI (w): 94%; WI (h): 98%

BMI: 15 (<P10–25)

Food intake: The patient shows a decreased appetite, although still maintains some intake.

Diet – register: 24 recall:

Breakfast:Glass of milk (200 ml)

Small muffin (30 g)

Mid-morning snack:Nothing

Dinner:Chicken soup (200 cc) +

20 g of pasta

Steak (60 g)

1 fromage frais (60 g)

Mid-afternoon snack:Nothing

Supper: Creamed courgette (150 g)

Fish in batter (50 g)

1 pear

The boy will attend the outpatient clinic to be continuously assessed, as well as during hospitalization. Future

possible adaptations may require the use of oral commercial supplements.

*Schofield: (4 years)

0.082 x w (11.3 kg) + 0.545 h (0.95) + 1.730 =

0.9266 + 0.518 +1.730 = 3.1746

x 239 kcal = 758.72 kcal

x 1.5 (activity) = 1138 kcal

x stress (1.3–1.5) = 1500–1700 kcal

Possible diet adaptations

Breakfast:A glass of milk (150 ml) + cocoa powder

(15 g) A small muffin (30 g) + marmalade (15 g)

Mid-morning snack:Peanuts (25 g)

Dinner:Chicken soup (200 cc) + 20 g of pasta +

30 g eggSteak (60 g) + breadcrumbs (15 g) + oil

(5 cc)1 fromage frais (60 g) + milk powder (5 g)

Mid-afternoon snack:Milkshake (banana 50 g + icecream 60 g

+ hazelnuts10 g)

Supper: Creamed courgette (150 g) + parmesan

cheese (10 g)Fish in batter (50 g)

1 pear + condensated milk (20 g)

Analysis of food intake:Energy intake: 750 kcal

Protein intake: 34 g

Analysis of food intake:Energy intake: 1485 kcal

Protein intake: 56 g

18%

39%

43%

Carbohydrates

Lipids

Proteins

15%

43%

42%Carbohydrates

Lipids

Proteins


Case C. Enteral and parenteral feeding supplementation Male, 2 years old. Short bowel after an intestinal

resection at 2 months due to small intestinal volvulus. The

boy leaves hospital with home parenteral nutrition (HPN)

7 days/week and with an elemental milk formula orally.

The intake is very low and he gradually starts refusing

any food by mouth at all. Then a gastrostomy is set to

meet requirements enterally and to stimulate bile secretion.

• Plotting on the growth charts is essential for performing

the nutritional assessment.

• Requirements are calculated by age, according to his

weight.

• Close monitoring is desirable (monthly until 1 year and

then every 3 months)

7 months: (PN in 16 h) w = 6.1 kg; h = 63.5 cm

Energy Protein Lipids Carb90 kcal/kg/d 3 g/kg/d 1.4 g/kg/d 16 g/kg/d

540 kcal 18 g/d 8.4 g/d 96 g/d

Oral diet:(609 kcal/16.4 g protein/19.7 g lipid/63.5 g carb)

6 btl. elemental milk formula (15%) + gluten free

cereals (5%)

60 cc cereal purée

100 cc potato + carrot + 30 g chicken purée

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

12 months: (PN in 14 h) w = 8 kg; h = 71 cm

Energy Protein Lipids Carb90 kcal/kg/d 3 g/kg/d 1.4 g/kg/d 16 g/kg/d

720 kcal 24 g/d 11.2 g/d 128 g/d

Oral diet:(201 kcal/8.4 g protein/16.5 g lipid/32.17 g carb)

1 btl. elemental milk formula (15%) + gluten-free

cereals (5%)

60 cc cereal purée

100 cc potato + carrot + 40 g chicken purée

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

The gastrostomy is set at 16 months as the child following rehabilitation continues to refuse food. It is then

complementary to HPN. Furthermore keep trying with introduction of new oral food to test tolerance until

he is able to decrease and at last (if possible) leave parenteral nutrition.

(18 months) w = 10.3 kg; h = 71 cm PN- 7 days/week (12 h)

Energy: 60 kcal/kg/d; 618 kcal Protein: 2.5g/d; 26 g Lipids: 1.5 g/kg/d; 15.45 g Carbohydrates: 21 g/kg/d; 216 g

Total intake: 1140 kcal = 110 kcal/kg/dGastrostomy:250 cc cereal purée (with elemental milk formula 15% + cereal 12%)

250 cc savoury mashed purées (50 g protein portion)

Energy: 523 kcal; Protein: 18.5 g/d; Lipids: 15 g; Carbohydrates: 78 g

Proteins (g)

Lipids (g)

Carbohydrates (g)160

32

28

34

28160

Proteins (g)

Lipids (g)

Carbohydrates (g)

294

44.530.45 Proteins (g)

Lipids (g)

Carbohydrates (g)

Co

urt

esy F

un

da

ció

n O

rge

bo

zo

, B

ilba

o,

Sp

ain


Case D: Nutritional education Male, 7 years old, encopresis. After resolving he is discharged to the outpatient clinic.

Weight: 20 kg; Height: 1.17 cm; Middle arm circumference (MAC) 16.4; Tricipital skinfold (TS): 6

• Requirements (for age by WHO): 1800–2000 kcal and 24 g of protein

The diet is modified during hospitalization so the child gets a personalized high fibre diet. Before discharge the child

is assessed, treated, and advised on the correct diet.

The mother is concerned about the child’s diet as since her divorce he is more reluctant to eat certain types of

foods. She is given advice on the diet with recipes and tricks* to increase the consumption of vegetables and is

referred to the outpatient clinic.

After a month, at the outpatient clinic the child has normalized his bowel movements and the mother reports that

the tricks have worked. The diet is explained to the child to make him participate.

*Tricks given to the mother

• Adding fruit to the cereals at breakfast or to yoghourt. This can be in pieces (e.g. grapes), grated (e.g.

apple) or cooked (e.g. homemade marmalade or stewed fruit).

• Making fruit salads, encouraging the fruit which is liked.

• Adding grated vegetables to sauces (e.g. leek, onion, and courgette to a tomato sauce for pasta).

• Cooking meat, fish, or pulses stews with vegetables. If not tolerated purée in the sauce.

• Including vegetables in the making of croquettes, meatballs, quiches, etc.

• Adding lettuce and/or tomato to sandwiches.

• Use high fibre carbohydrates (cereals, bread, pasta). In case they are not liked mix them.

• Make homemade ice-creams with natural fruit juices.

Always following the dietetic recommendations on healthy diet.

Occasionally

Several times a week

Several times daily

+ Water

Healthy life-style

Court

esy E

str

ate

gia

NA

OS

. M

inis

terio d

e S

anid

ad y

Consum

o.

Gobie

rno d

e E

spaña,

2006

Conclusion

The dietitian is part of a multidisciplinary team who takescare of the patient, and their role is not simply dispensing aparticularly diet but to provide effective nutritional care,from advice to food provision. Many dietetic skills areunique and cannot be undertaken by other professionals. Aneffective nutritional support service relies heavily on dieteticexpertise to optimize patient care. However, standards ofpractice vary significantly throughout Europe13. There aremany examples where the use of dietetics in the clinicalsetting is essential.

References

1 Martin EA (ed). Concise Medical Dictionary, 2nd edn.Oxford University Press, Oxford 1998.

2 Moreno JM, Oliveros L, Galiano MJ. Cómo enriquecer laalimentación del lactante: Uso de los módulosnutricionales. Act Pediatr Esp 2003;61(8):406–12.

3 Stratton RJ, Green CJ, Elia M. Disease-Re latedMalnutrition: An Evidence-Based Approach toTreatment. CABI Publishing, Oxford, 2003.

4 Golden MHN, Golden BE. Severe malnutrition. In:Garrow JS, James WPT, Ralph A (eds). HumanNutrition and Die te tic s, 10th edn. ChurchillLivinsgstone, Edinburgh, 2000, pp. 515–26.

5 Shaw V, Lawson M. Clinical Paediatric Dietetics, 2ndedn. Blackwell Science, Oxford, 2001.

6 Whitney EN, Cataldo CB, Rolfes SR. The nutrition careprocess: assessing anthropometric and biochemical data.In: Understanding Normal and Clinical Nutrition, 5thedn. Wadsworth Publishing Company, Belmont, 1998,pp. 543–58.

7 Ballabriga A, Carrascosa A. Nutrición en la Infancia yAdolescencia, 3rd edn. Nestle Nutrition Institute, Spain,2006.

8 Schofield WN. Predicting basal metabolic rate, newstandards and review of previous work. Hum Clin Nutr1985;39C(Suppl):5–41.

9 Dewey KG, Beaton G, Fjeld C, e t al. Proteinrequirements of infants and children. Eur J Clin Nutr1996;50(1):119–47.

10 www.fao.org

11 Martinez Costa C, Sierra C, Pedrón Giner C, et al.Nutrición enteral y parenteral en pediatría. An EspPediatr 2000;52(Supl.3):1–33.

12 Wilken B. An introduction to nutritional treatment ininborn errors of metabolism: different disorders, differentapproaches. South Asia J Trop Med Pub Health2003;34(3S):198–201.

13 Howard, JP, Jonkers-Schuietema CF, Kyle U. The roleof the nutritional support dietitian in Europe. ClinicalNutrition1999;18(6):379–83.

Further reading

ASPEN Board of directors. Standards for specializednutrition support: hospitalized pediatric patients. NutrClin Pract 2005;20(1):103–16.

Dwyer J. Dietary fibre for children: how much? Pediatrics1995;96:1019–22.

Gil Hernandez A. Bases para una alimentacióncomplementaria adecuada de los lactantes y los niños decorta edad. An Pediatr (Barc) 2006;65(5):481–95.


An Atlas of Investigation and Management PAEDIATRIC ...fundacioncarlosvazquez.com › frontend ›...

Documents

Transcript of An Atlas of Investigation and Management PAEDIATRIC ...fundacioncarlosvazquez.com › frontend ›...