An Atlas of Investigation and Management PAEDIATRIC

An Atlas of Investigation and Management PAEDIATRIC GASTROENTEROLOGY

José Manuel Moreno Villares, MD Nutrition Unit Department of Paediatrics Hospital Universitario 12 de Octubre Madrid, Spain

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

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First published 2009

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Preface vi 8 Abdominal masses 72 JUAN A. TOVAR, MD, PhD Contributors vi 9 Liver disease 84 Abbreviations viii Cholestasis 84 PIOTR SOCHA, MD, 1 Failure to thrive in infants and children 1 JOANNA PAWŁOWSKA, MD, AND JOSÉ MANUEL MORENO VILLARES, MD, AND ANIL DHAWAN, MD, FRCPCH ANTONIO MONICA GUERRA, MD Hypertransaminasaemia in childhood 92 LUÍS PEÑA-QUINTANA, MD, AND 2 Vomiting 11 DANIEL GONZÁLEZ-SANTANA, MD JOSÉ MANUEL MORENO VILLARES, MD, AND MARÍA JOSÉ GALIANO SEGOVIA, MD 10 Coeliac disease 99 ISABEL POLANCO, MD, PHD 3 Diarrhoea 19 Acute diarrhoea 19 11 Ulcerative colitis 104 ENRIQUETA ROMÁN RIECHMANN, MD CARLOS SIERRA SALINAS, MD, AND Chronic diarrhoea 25 JAVIER BLASCO ALONSO, MD ANGELES CALZADO AGRASOT, MD, BEGOÑA POLO MIQUEL, MD, AND 12 Crohn’s disease 110 CARMEN RIBES-KONINCKX, MD, PHD DAVID ZIRING, MD, AND JORGE VARGAS, MD 4 Constipation 34 CAROLINA GUTIÉRREZ, MD, AND 13 Short bowel syndrome 117 JERÓNIMO GONZÁLVEZ, MD JAVIER BUENO, MD

5 Abdominal pain in childhood 46 14 Congenital gastrointestinal IÑAKI X. IRASTORZA TERRADILLOS, MD, AND malformations 124 JUAN C. VITORIA CORMENZANA, MD, PHD IÑAKI EIZAGUIRRE, MD, AND AGUSTÍN NOGUÉS, MD 6 Gastrointestinal bleeding 56 GEORGE GERSHMAN, MD, PHD 15 Paediatric appendicitis 134 ADOLFO BAUTISTA CASASNOVAS, MD 7 Cow’s milk allergy 65 ANTONIO NIETO, MD, PHD, AND 16 Paediatric clinical dietetics 144 ANGEL MAZÓN, MD AMAYA PEÑALVA ARIGITA, RD

Index 155 vi Preface

Paediatric gastroenterology emerged as a speciality in the Management, provides concise and practical information for 1960s. Since then it has become an essential component of readers. Topics on the three main areas of the speciality – major academic paediatric programmes throughout the gastroenterology, hepatology, and nutrition – constitute the world. The introduction of new diagnostic techniques that body of this book. The authors were carefully selected to required special skills, as well as the development of provide a comprehensive and clear account of their assigned complex new therapies for children with gastrointestinal topics. All of them have been willing to dedicate their time, disorders, were cornerstones in the development of the knowledge, and effort in preparing their chapters. Our most speciality. The recognition that appropriate nurition during sincere thanks to them. It has been a pleasure to work with infancy and childhood is vital for health and the profound Clinical Publishing’s production team who have helped to impact that many gastrointestinal diseases may have upon produce a book of outstanding quality. growth also contributed to the discipline’s development. We hope and expect that this Atlas will be of benefit to all Many excellent paediatric gastroenterology texts have physicians dealing with gastrointestinal problems in been published since the first textbook on the subject was children. published in the early 1970s, but there are not so many based on excellent figures and comprehensive tables. Paediatric José Manuel Moreno Villares, MD Gastroenterology, An Atlas of Investigation and Isabel Polanco MD, PhD

Contributors

Adolfo Bautista Casasnovas, MD, PhD Mª Ángeles Calzado Agrasot, MD María José Galiano Sego via, MD Head of Paediatric Surgery Section Paediatric Gastroenterology and Centro de Salud Maria Montessori University Hospital of Santiago de Hepatology Unit Leganés Compostela Hospital La Fe Madrid, Spain Santiago de Compostela, Spain Valencia, Spain George Gershman, MD, PhD Javier Blasco Alo nso , MD Anil Dhawan, MD, FRCPCH Associate Professor of Pediatrics Gastroenterology, Hepatology and Paediatric Liver Centre David Geffen School of Medicine Nutrition Division Institute of Liver Studies Chief, Division of Pediatric Hospital Materno-Infantil Variety Club Children’s Hospital Gastroenterology and Nutrition Málaga, Spain. King’s College Hospital Harbor-UCLA Medical Center London, UK Torrance Javier Bueno, MD California, USA Paediatric Liver Transplantation Unit Iñaki Eizaguirre, MD, PhD Paediatric Surgery Department Paediatric Surgery Department Jerónimo Gonzálvez Piñera, MD, PhD Hospital Valle de Hebrón Donostia Hospital Associated Professor of Paediatric Barcelona, Spain San Sebastian, Spain Surgery Department of Paediatric Surgery University General Hospital Albacete, Spain Contributors vii

Daniel González-Santana, MD Joanna Pawłowska, MD Carlos Sierra Salinas, MD Paediatric Gastroenterology Division Department of Gastroenterology, Gastroenterology, Hepatology and Las Palmas de Gran Canaria Hepatology and Immunology Nutrition Division University The Children’s Memorial Health Hospital Materno-Infantil Hospital Universitario Materno-Infantil Institute Málaga, Spain de Canarias Warsaw, Poland Spain Piotr Socha, MD Luis Peña-Quintana, MD Department of Gastroenterology, Antonio Monica Guerra, MD, PhD Paediatric Gastroenterology, Hepatology and Immunology Nutrition Unit Hepatology and Nutrition Division The Children’s Memorial Health University of Porto University Hospital Institute Porto, Portugal Universidad de Las Palmas de Gran Warsaw, Poland Canaria Carolina Gutiérrez Junquera, MD, PhD Spain Juan A. To var, MD, PhD Associated Professor of Paediatrics Professor and Chief, Department of Department of Pediatric Am aya Peñalva Arigita, MD Paediatric Surgery Gastroenterology University Hospital Valle de Hebrón University Hospital University General Hospital Barcelona, Spain La Paz Albacete, Spain Madrid, Spain Isabel Polanco, MD, PhD Iñaki X. Irastorza Terradillos, MD Professor of Paediatrics Jorge Vargas, MD Paediatric Gastroenterology Division Head of Department of Paediatric Division of Gastroenterology and Hospital de Cruces Gastroenterology and Nutrition Nutrition Bilbao, Spain University Hospital La Paz Department of Paediatrics Universidad Autónoma Mattel Children’s Hospital at UCLA Angel Mazón, MD Madrid, Spain Los Angeles, USA Paediatricc Allergy Division Hospital Infantil La Fe Begoña Polo Miquel, MD Juan C. Vito ria Co rm enzana, MD, PhD Valencia, Spain Paediatric Gastroenterology and Professor of Paediatrics Hepatology Division Basque Country University José Manuel Moreno Villares, MD Hospital La Fe Chief, Paediatric Gastroenterology Nutrition Unit Valencia, Spain Division Department of Paediatrics Hospital de Cruces University Hospital 12 de Octubre Carmen Ribes-Koninckx, MD, PhD Bilbao, Spain Madrid, Spain Paediatric Gastroenterology and Hepatology Division David Ziring, MD Antonio Nieto, MD, PhD Hospital La Fe Division of Gastroenterology and Paediatric Allergy Division Valencia, Spain Nutrition Hospital Infantil La Fe Department of Paediatrics Valencia, Spain Enriqueta Román Riechmann, MD Mattel Children’s Hospital at UCLA Department of Paediatrics Los Angeles, USA Agustín Nogués, MD Hospital de Fuenlabrada Paediatric Radiology Department Madrid, Spain Donostia Hospital San Sebastian, Spain viii Abbreviations

α1-ATD alpha-1-antitrypsin deficiency FGID functional gastrointestinal NKT natural killer T cells AAP American Academy of Pediatrics disorders NPD negative predictive value AFP alpha-fetoprotein FTT failure to thrive NSAID nonsteroidal anti-inflammatory AIH autoimmune hepatitis GER gastro-oesophageal reflux drug ALT alanine aminotransferase GERD gastro-oesophageal reflux disease OA open appendectomy AMA antimitocondrial antibodies GFD gluten-free diet OCTN organic cation transporter gene ANA antinuclear antibodies GGT gamma glutamyl transpeptidase ORS oral rehydration solution APC antigen-presenting cell GI gastrointestinal ORT oral rehydration therapy ASCA anti-Saccharomyces cerevisiae GIST gastrointestinal stromal tumour pANCA anti-neutrophil cytoplasmic antibodies GN ganglioneuroma antibody with perinuclear staining ASMA antismooth muscle Hb haemoglobin pattern antibody HB PFIC progressive familial intrahepatic AST aspartate aminotransferase HC head circumference cholestasis BA biliary atresia Hct haematocrit PH partially hydrolyzed (fromula) BMI body mass index HD Hirschsprung’s disease Pi protease inhibitor BRIC benign recurrent intrahepatic HIV human immunodeficiency virus PN parenteral nutrition cholestasis HP Helicobacter pylori PPV positive predictive value Btl. bottle HPN home parenteral nutrition RAST radioallergosorbent test BUN blood urea nitrogen HSP Henoch–Schönlein purpura RDA recommended dietary allowances CD coeliac disease HUS haemolytic uraemic syndrome RDW red blood cell differentiation width CFU colony-forming units IBD inflammatory bowel disease RNA HCV hepatitis C virus RNA CK creatine kinase IBS irritable bowel syndrome SBS short bowel syndrome CM cow’s milk IF infant formula Sc scoop CMA cow’s milk allergy IDI intractable diarrhoea of infancy SE semi-elemental (formulas) CMV cytomegalovirus IGF-1 intestinal growth factor SGOT serum glutamic oxalacetic CNS central nervous system IL interleukin transaminase CPM caloric–protein malnutrition INSS International Neuroblastoma SGPT serum glutamic pyruvic CrD Crohn’s disease Staging System transaminase CT computed tomography IQ intelligence quotient SIOP Societé Internationale d´Oncologie CTT colonic transit time LA laparoscopic appendectomy Pédiatrique Da Dalton LDH lactate dehydrogenase STEP serial transverse enteroplasty DH dermatitis herpetiformis LF lactose-free (formula) TPN total parenteral nutrition DNA HBV hepatitis B virus DNA LKM liver/kidney microsomal TNF tumour necrosis factor EBV Epstein–Barr virus antibodies TS tricipital skinfold EC endoscopic capsule MAC middle arm circumference TSH thyroid stimulating hormone EF elemental formulas MCV mean cell volume UC ulcerative colitis EH extensively hydrolyzed (formula) MIBG meta-iodine-benzyl-guanidine UPDG galactose-1-phosphate-uridyl EIA enzyme immunoassay MRI magnetic resonance imaging transferase ERCP endoscopic retrograde NAFLD nonalcoholic fatty liver disease US ultrasonography cholangiopancreatography NASH nonalcoholic steatohepatitis WBC white blood count ESPGHAN European Society of NB neuroblastoma WD Wilson´s disease Pediatric Gastroenterology, NEC necrotizing enterocolitis WI Waterloo index Hepatology, and Nutrition NK natural killer cells WHO World Health Organization Chapter 1 1 Failure to thrive in infants and children José Manuel Moreno Villares, MD, and Antonio Monica Guerra, MD

Introduction

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

Inappropriate nutrient intake and growth parameters

FTT is a clinical label frequently used to describe infants and young children, generally under 3 years, who fail to grow as expected using established growth standards for age and gender along a period of time (usually longer than 3 months) (1.1). 1.1 Eleven-month-old boy, with growth faltering in the last Weight is a measure of the varying combination of height, 4–5 months, more severe in the last 2 weeks. Reduction body fat, and muscle bulk, which makes it a less in >2 major percentiles for weight. (Courtesy Fundación straightforward measure of growth than height. Orgebozo, Bilbao, Spain.) Nevertheless, because of its widespread availability and ease of measurement, it is the most usual tool when growth measure is considered. What constitutes a normal rate of not become pathological. Although the most commonly weight gain (Table 1.1)? It is often assumed that normal used definition of abnormality is that falling below a growth constitutes tracking along the birth centile. However, predetermined centile, usually the third (1.2), this would weight at birth is a reflection of the intrauterine environment include a number of constitutionally small children. An and is of limited prognostic value. Many children deviate alternative definition applies when a child has a weight curve from their earlier centile position, and this divergence may that has fallen more than two standard deviations or 2 Failure to thrive in infants and children

percentiles below a previously established rate of growth. Definition of FTT However, up to 30% of healthy term infants cross one percentile line and 23% cross two percentile lines (in either FTT describes an infant or child whose current weight or direction) by the age of 2 years. rate of weight gain is significantly below that expected of similar children of the same age and sex. Most paediatri cians diagnose FTT when a child’s weight for age falls below the fifth percentile of the standard growth charts or it crosses two Table 1.1 Normal weight gain and frequency of major percentile lines (1.3). One problem arises from the use monitoring of different growth charts; misinterpretation may occur if different genetic back ground are not considered. This problem may be overcome if universal growth references Normal weight gain could be used. The World Health Organization (WHO) has recently published charts resulting from the Multicenter Birth to 5 months 15–30 g/day Growth Reference Study, and are intended to substitute for 6 to 12 months 15 g/day the National Center for Health Stat istics/WHO 12 months to 2 years 6–8 g/day (NCHS/WHO) growth reference, which has been 2 years to 6 years 38 g/month recommended for international use since the late 1970s (www.who.int/childgrowth/standards/curvas_por_indicador Frequency of monitoring es/en/index.html) (1.4, 1.5). Monthly for the first two months, every other month FTT is not a final diagnosis but a description of a physical from 2 to 6 months; every 3rd month from state; therefore, a cause must always be sought. Because the 6 to 24 months, and yearly from 2 to 6 years old description itself is vague it has been proposed to use growth failure or undernutrition as a diagnostic replacement for FTT.

1.2 An 18-week-old female, with irritability and poor weight 1.3 Four-month-olld male. Loss of >2 major percentiles gain since birth. Weight below 3rd percentile. (Courtesy since birth. (Courtesy Fundación Orgebozo, Bilbao, Fundación Orgebozo, Bilbao, Spain.) Spain.) Failure to thrive in infants and children 3

A A

B B 1.4 WHO growth curves. Height/length for age (boys). 1.5 WHO growth charts. Length/height for age (girls).

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

FTT has been historically dichotomized as organic versus nonorganic (1.6). Organic FTT results from a major organ 1.6 Aetiology of FTT. system illness or dysfunction, while nonorganic FTT is generally a diagnosis of exclusion. A third category has been added, mixed FTT, to recognize the fact that many organic central to the development of the disorder. Family stressors, FTT often have a psychological component. This approach psychiatric disorders of parents, and disturbances in the is quite simplistic and inadequate for patient management. infant–parent relationship may interfere with the There is growing evidence that feeding difficulties are development of an adequate feeding relationship. 4 Failure to thrive in infants and children

It is important to note that an infant presenting with to be considered when making the diagnosis of FTT, for presumed FTT may have a normal variant of growth1. instance, infants with intrauterine growth retardation or Specific infant populations with growth variations also need premature infants.

Table 1.2 Normal variants of growth presenting as FTT

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. 3. Classification of FTT by pathological causes

Inadequate caloric intake Excessive loss of nutrients • Food not available • Vomiting – Type or volume of food not appropriate (e.g. too diluted – Gastro-oesophageal reflux formula) – Other causes of vomiting: central nervous system – Poverty and food shortages disorders, metabolic disease – Neglect • Malabsorption/diarrhoea – Feeding technique, parent–infant interaction problems – Inflammatory bowel disease • Lack of appetite – Short bowel syndrome – Chronic illness • Renal losses – Psychosocial disorder – Renal failure or tubular acidosis • Mechanical feeding difficulties, e.g. oral-motor – Diabetes mellitus or diabetes insipidus dysfunction or malformation Defective utilization Reduced absorption or digestion of nutrients • Chromosomal or genetic abnormality • Pancreatic insufficiency: cystic fibrosis • Metabolic disorder • Loss or damage to villous surface • Endocrine disorder – Coeliac disease • Congenital infections – Cow’s milk protein allergy – Vitamin or mineral deficiencies Increased metabolism • Cholestasis • Chronic infection or inflammation • Hypoxaemia (congenital heart disease, chronic lung disease) • Hyperthyroidism • Failure to thrive in infants and children 5

Within the group of normal variants of growth presenting Evaluation as FTT, four main patterns occur (Table 1.2)2. There are also growth curves available for syndromes with abnormal History and examination growth (e.g. Down syndrome, Noonan syndrome, The history is essential in defining the underlying cause of Prader–Willi syndrome) (1.7, 1.8). There are many reasons growth failure in children (1.9). The evaluation should why an infant does not take on adequate nutrition. A more include an assessment of the diet and eating behaviours, useful classification of FTT is then based on past and current medical, social, and family history, and pathophysiology, as shown in Table 1.3. should include a complete physical examination (Table

1.7 Patients with special conditions, e.g. Down syndrome, 1.8 Patient with a Silver–Russell syndrome. chromosomopathies and other genetic conditions, have their own growth rate and deserve specific growth curves.

1.9 Algorithm of management of FFT is suspected FTT in primary care. Most likely normal Clinical history Red flag signs variant of growth Physical examination Assessment of intake

Basic laboratory Hospital investigations

Organic failure Yes No Nonorganic failure Anomalous results? to thrive to thrive

Treatment – Success primary care Follow up Nutritional advice Psychological support Further work up/treatment – Lack of success hospital 6 Failure to thrive in infants and children

Table 1.4 Evaluation of medical history in FTT

Dietary history • Are they recurrent? • Amount of food and/or formula • Chronic medical conditions • Is the formula prepared correctly? • Past hospitalizations, injuries, accidents • Food patterns: types of foods, especially beverage • Vomiting? consumption (milk, juices, sodas) Social history Feeding history • Who lives in the home? • When does the child eat? Where? With whom? • Who are the caregivers? • Breastfed? • Who helps to support the family? • Positioning of the child • What is the child’s temperament? • Feeding battles • Any family problems? • Snacking Family history Past and current medical history • Medical conditions or FTT in siblings • Obstetric history • Growth pattern in other members of the family, • Birth history, including weight and height especially parents and siblings • Neonatal period • Mental illness • Recent acute illness especially upper airway infections, otitis, gastroenteritis

Table 1.5 Classification of undernutrition in children15, 16

Normal Mild risk Moderate risk High risk Weight for age (%) >90 75–89 60–74 <60% Weight for height (%) >90 80–90 70–79 70% Height for age (%) >95 95–90 89–85 <85%

1.4)3. A thorough psychosocial history is mandatory. An The severity of a child’s undernutrition can be classified accurate assessment of growth requires the evaluation of most easily using the Waterlow and Gomez criteria (Table current and past parameters including height or length, 1.5), as a percentage of the median for age. Further examina - weight, and head circumference. Occasionally further tion beyond growth should include physical examination assessments are performed such as mid-upper arm (1.10), including inspection of any physical sign of neglect or circumference, various skin fold thicknesses, body abuse, stigmas of underlying syndromes, dysmorphic proportions and, if indicated, puberal assessment. features, skin rashes, and observation of feeding if possible. Failure to thrive in infants and children 7

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

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

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

Table 1.6 Investigations in failure to thrive

Initial evaluation • Coeliac screen • Full blood examination/erythrocyte sedimentation rate • Thyroid function test or C-reactive protein • Bone age • Chemistry panel: urea, creatinine, lytes • Stool microscopy and culture • Iron status: iron, ferritin, transferrin, % saturation

• Blood glucose Third step (if clinically indicated or abnormal data from • Liver function tests: GGT, SGPT, SGOT, alkaline the initial investigations) phospatase, bilirubin • Metabolic screen (blood and urine for organic acids • Urinalysis and amino acids, ammonia, lactic/pyruvic acids, • Urine culture ketone bodies in urine) • Karyotype Second step • Allergy investigations • Acid–base balance • Sweat test • Immunoglobulins • pHmetry/endoscopy 8 Failure to thrive in infants and children

Treatment Dietary recommendations Children with FTT will need 150% of the recommended Medical intervention is dictated by the disease diagnosed. daily caloric intake, based on their expected, not actual, Addressing identified issues of attachment and other weight for height if tolerated5. As most of these children lack psychosocial issues is crucial and often requires input from the normal responses to internal hunger/satiation cues, high a multidisciplinary team. Most cases can be managed by energy snacks may improve their nutritional status6. In nutrition intervention or feeding behaviour modification. infants this increased caloric intake may be accomplished by Evaluation and treatment is generally accomplished in concentrating the infant formula or adding carbohydrates or outpatient settings rather than in the hospital. lipids to the formula or the puréed foods (1.11). Toddlers Nutritional rehabilitation by means of increased caloric can receive more calories by adding cheese, butter, and so intake is often best supervised with the advice of an on to common toddler foods. In toddlers and older children experienced dietician, allowing exact caloric requirements to we can also use high-calorie milk drinks, that provide be calculated. Asking the parent to write down the type of 1.0–1.5 kcal/ml. Vitamin and mineral supplementation is food and amounts a child eats over a 3-day period is one way also sometimes required. If all these attempts fail it may be of quantifying caloric intake. necessary to consider nasogastric tube feedings as a last resort (1.12)7. The advantages are ensuring adequate caloric intake and decreasing or eliminating some of the emotional stress and frustrations with feeding times. However, there are also disadvantages, including the suppression of appetite and sometimes the modification of feeding behaviour.

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

Concentrate formula to 15% Add maltodextrin 1 measure in 26 ml 88 kcal/100 ml (78 kcal/100 ml) 5 g/100 ml (20 kcal)

Concentrate formula to 17% Add MCT oil 1 measure in 23 ml 104 kcal/100 ml (89 kcal/100 ml) 2 ml/100 ml (16 kcal)

Concentrate formula to 20% Add maltodextrin 1 measure in 20 ml 124 kcal/100 ml (105 kcal/100 ml) 5 g/100 ml (20 kcal)

1.11 There are two ways to increase the caloric intake in an infant: to increase the strength of the regular formula or to add caloric modules (carbohydrates or lipids or both) to the regular formula. Failure to thrive in infants and children 9

Feeding or eating behaviours Parental anxiety about a child’s FTT can be helped by assessment on long-term results of FTT. Rudolph and reassurance. Paediatricians can intervene effectively in many Logan found only a small difference in intelligence quotient feeding problems, providing useful guidance for parents (IQ) (equivalent to 3 IQ points) in children with FTT (Table 1.7). Hospitalization is rarely required and may be compared to their peers13. This small difference is of counterproductive8. It may be necessary when the safety of questionable clinical significance. The height and weight a child is a concern, outpatient management has failed, or if differences in their analysis were larger, but few children the FTT is severe. were below the 3rd percentile at follow-up. In the light of these results, the aggressive approach to the identification and management of FTT needs reassessing13. Outcomes In addition, it is often difficult to disentangle the effects of FTT from those of the high-risk environments in which It is ascertained that children with FTT are at risk of adverse FTT often occurs (poverty, family stress, and poor parental outcomes such as short stature, behaviour problems, and coping skills). Nevertheless, to decrease the risk of adverse developmental delay9–12. However, there are only a limited effects, it is important to recognize and treat FTT promptly. number of outcome studies on children with FTT, with Sometimes this necessitates the intervention of community- different definitions and designs, so it is difficult to make an based resources14.

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

1 Make mealtimes pleasant 2 Avoid battles over eating. Encourage your child. Food should be used as nourishment, not as a reward or punishment 3 You are responsible for deciding what food your child is offered; your child decides how much to eat 4 Offer a variety of healthy and tasty foods 5 Establish a routine of meals and snacks and set 1.12 In some severe FTT cases, especially if an organic times condition is underlying, it is necessary to provide enteral 6 Recognize your child’s cues indicating hunger, nutrition through a nasogastric tube. This patient has satiety, and food preferences biliary atresia and FTT. 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 10 Failure to thrive in infants and children

Conclusion

It is common to confuse the description of poor growth with 10 Corbett SS, Drewett RF. To what extent is failure to a diagnosis. The term ‘failure to thrive’, although firmly thrive in infancy associated with poorer cognitive entrenched in the medical lexicon, adds little to our development? A review and meta-analysis. J C h il d understanding of this condition and does not guide our Psychol Psychiatr 2004;45:641–54. approach. Many have suggested it should be abandoned. It 11 Zenel JA. Failure to thrive: a general pediatrician’s represents a nonspecific description of symptoms rather perspective. Pediatr Rev 1997;18: 371–8. than a specific condition. Paediatricians and other 12 Drewett RF, Corbett SS. Cognitive and educational healthcare workers must come to a better understanding of attainments at school age of children who failked to thrive the complex dynamics of feeding normal children. When in infancy: a population-based study. J Child Psychol feeding and caloric issues have been ruled out, other Psychiatr 1999;4:551–61. considerations should be taken into account. It is not a 13 Rudolf MCJ, Logan S. What is the long-term outcome question of referring a child who is not growing well to the for children who fail to thrive? A systematic review. Arch feeding expert, the gastroenterologist, or the Dis Child 2005;90:925–31. endocrinologist, but rather the recognition that a rational, 14 Wright CM, Callum J, Birks E, Jarvis S. Effect of sequential approach needs to be followed, to allow for community based management in failure to thrive: investigation of all the possible explanations of why a child randomized controlled trial. BMJ 1998;317:571–4. is not growing. 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, References Chavez R, Vazquez J. Mortality in second and third degree malnutrition. J T r o p P ae d iat r 1956;2:77–83. 1 Krugman SD, Dubowitz H. Failure to thrive. Am Fam Phys 2003;68:879–84, 886. General reading 2 Bergman P, Graham J. An approach to ‘failure to thrive’. Aus Fam Phys 2005;34:725–9. Frank DA, Zeisel SH. Failure to thrive. Pediatr Clin North 3 McCann JB, Stein A, Fairburn CG, Dunger DB. Eating Am 1988;35:1187–1206. habits and attitudes of mothers of children with Jolley CD. Failure to thrive. Curr Probl Pediatr Adolesc nonorganic failure to thrive. Arch Dis Child 1994;70: Health Care 2003;33:183–205. 34–6. Gahagan S, Holmes R. A Stepwise approach to evaluation 4 Satter E. The feeding relationship: problems and of undernutrition and failure to thrive. Pediatr Clin North interventions. J P e d iat r 1990;117:S181–9. Am 1998;45:169–87. 5 Maggioni A, Lifshitz F. Nonorganic failure to thrive: an Kessler DB, Baker SS, Silverman LA. Growth assessment outpatient approach. Pediatr Clin North Am and growth failure. Consensus in Paediatr 2004;1:1–28. 1998;45:169–87. 6 Kasese-Hara M, Wright C, Drewett R. Energy compensation in young children who fail to thrive. J Child Psychol Psychiatr 2002;43:449–56. 7 Tolia V. Very early onset nonorganic failure to thrive in infants. J Pediatr Gastroenterol Nutr 1995;20:73–80. 8 Marcovitch H. Failure to thrive. BMJ 1994;308:35–8. 9 Dahl M, Kristiansson B. Early feeding problems in an affluent society. IV. Impact of growth up to two years of age. Acta Paediatr Scand 1987;76:881–8. Chapter 2 11 Vomiting José Manuel Moreno Villares, MD, and María José Galiano Sego via, MD

Introduction

Vomiting is a complex behaviour composed of three linked vomiting centres represent the integrated activity of the activities: nausea, retching, and expulsion of stomach paraventricular nuclei arrayed along the central neuraxis contents. The vomiting act is characterized by cycles of controlling a myriad of autonomic functions1. retching followed by forceful expulsion of gastric contents Vomiting may result from a variety of disorders affecting through the mouth. Although it was previously thought one paediatric patients (Table 2.1). History and physical or two anatomical vomiting centres existed in the central examination may help us to distinguish nonbilious from nervous system (CNS), it is now assumed that the central bilious causes, i.e. proximal or distal to the ampulla of Vater.

Table 2.1 Causes of vomiting and regurgitation

A. disorders • Superior mesenteric artery Other abdominal organs Oesophagus syndrome • Hepatitis • Achalasia • Gallstones • Gastro-oesophageal reflux (GER) Intestine and colon • Pancreatitis • Hiatal hernia • Atresia and stenosis • Congenital vascular or mucosal • Meconium ileus B. Extragastrointestinal tract rings • Malrotation, volvulus disorders • Stenosis • Duplication • Infections: sepsis, pneumonia, • Foreign body • Intussusception otitis, urinary tract infection, • Soy or cow’s milk protein meningitis Stomach intolerance • Intracranial hypertension: • Pyloric stenosis • Coeliac disease subdural effusion, hydrocephalus, • Diaphragmatic hernia • Food allergy brain tumour • Peptic disease • Hirschsprung’s disease • Intoxications or drugs • Antral web • Chronic intestinal pseudo- • Inborn errors of metabolism obstruction • Eating disorders Duodenum • Appendicitis • Cyclic vomiting syndrome • Annular • Inflammatory bowel disease • Duodenitis and ulcer • Gastroenteritis • Malrotation 12 Vomiting

Evaluation Gastro-oesophageal reflux and regurgitation Vomiting is a common symptom of many disease states. The differential diagnosis of the child with vomiting varies with This is defined as effortless expulsion of gastric contents by the age of the patient. Assessment of the child with vomiting the mouth and can be asymptomatic or symptomatic. should start with a complete history, physical examination, Gastro-oesophageal reflux disease (GERD) is defined as and description of the vomitus. Emesis of gastric contents is gastro-oesophageal reflux (GER) that occurs too frequently characteristic of gastric outlet obstruction, CNS masses or and damages the oesophageal mucosa leading to clinical infection, peptic disease, urinary tract infection, otitis, inborn symptoms. Spontaneous relaxation of the lower oesophageal error of metabolism, or psychogenic vomiting. The child who sphincter is the major mechanism by which GER occurs, vomits bile-stained material may have an intestinal with or without regurgitation2. GER is a physiological event obstruction and should be investigated urgently. The history that can be seen in a large num ber of infants: >50% of 2- and physical examination are essential starting points and month-old infants regurgitate twice a day. The highest should include duration of vomiting, presence of blood, prevalence is at 4 months, when two-thirds of infants abdominal pain, or fever. Pain located in the right lower regurgitate. By 1 year, <10% still present vomit ing daily. quadrant suggests appendicitis. Midline or diffuse abdominal GERD affects a much smaller proportion of infants (2.1). pain suggests pancreatitis or peritonitis. Abdominal distension suggests intestinal obstruction. Viral or bacterial Symptoms/examination gastroenteritis are usually accompanied by diarrhoea and The most common symptom is postprandial regurgitation of fever. The presence of mucus and blood in the stool may effortless spit-up. Severe GERD may present with failure to raise the suspicion of intussusception or bacterial or toxic thrive, oesophagitis with haematemesis, dysphagia, heart - colitis. The evaluation of bloody vomitus start with the burn or chest pain, anaemia, aspiration, chronic cough, and confirmation that the material vomited is blood. wheezing. Rumination is sometimes a symptom as well as Imaging may help to rule out anatomical causes or neck contortions (Sandifer’s syndrome). Apnoeic episodes intestinal obstruction. Further evaluation may include blood in neonates and very young infants can be caused by reflux. count, serum electrolytes, calcium, magnesium, blood urea GERD is common in neurologically impaired children. nitrogen, urinalysis, and culture, and stool examination for If not treated, GERD can lead to Barrett’s oesophagus. occult blood, leukocytes, and parasites. Specific indications This is a metaplasia of the oesophageal squamous from history and physical examination may result in epithelium that transforms to specialized columnar obtaining other tests including abdominal ultrasonography, epithelium; it is a premalignant condition associated with imaging of the head, test of liver function, serum amylase, dysplasia and . Peptic strictures can present toxicology screen, serum ammonia, urinary organic acids, in cases of severe but asymptomatic oesophagitis. and so on. If there is a bloody vomitus, the most productive test is upper intestinal endoscopy. Diagnosis GER is usually diagnosed by a thorough history and physical examination in infants under 6 months of age. It can be 70 diagnosed on barium swallow by observing regurgitation of >1 time/day 60 >4 times/day barium from stomach to oesophagus. Nevertheless, false-posi- Is a problem tive and false-negative tests are common. Nowadays, upper 50 gastrointestinal (GI) series only serve to rule out anatomical 40 problems. Ultrasonography is now used as a diagnostic tool to 30 confirm GER. A pH probe (prolonged monitoring of % positive 20 oesophageal pH) is the best test for GERD, but it will miss 10 cases of nonacid GER (2.2). Oesophageal and gastric scintigraphy is sometimes helpful in identifying pulmonary 0 0–3 4–6 7–9 10–12 aspiration. Endoscopy is not diagnostic, but evidence of Age (months) oesophagitis supports the diagnosis (2.3). Impedance studies 2.1 Reported regurgitation according to age. measure fluid movements rather than luminal pH changes3. Vomiting 13

2.2 A pH probe (prolonged S monitoring of oesophageal M M M H HH pH) is the best test for GER, 8 but it will miss cases of 6 nonacid GER. Top: normal pH probe; bottom: pH 4 pathological pH probe. 2 (C: chest pain; H: heartburn; M: meal; S: supine.). 0 11 am 3 pm 7 pm 11 pm 3 am 7 am 11 am

S MM M H H C C 8 7 6 pH 5 4 3 2 1 9 am 1 pm 5 pm 9 pm 1 am 5 am 9 am

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.

A B

C D 14 Vomiting

Treatment In 85–90% of patients, GER will disappear between 6 and 12 Table 2.2 Indications for antireflux surgery months with no treatment (2.4). Regurgitation is reduced by conservative measures such as small, frequent thickened feed- ings. H receptor antagonists (e.g. ranitidine, 5.0 mg/kg/d) and 2 1 Persistent vomiting with failure to thrive proton pump inhibitors (omeprazol 1 mg/kg/d) are effective in 2 Severe oesophagitis or oesophageal stricture controlling oesophagitis. Prokinetic agents such as meto - clopra mide (0.1 mg/kg/dose) or domperidone (0.2 3 Apnoeic spells or chronic pulmonary disease mg/kg/dose) may be used to hasten gastric emptying. Low unresponsive to medical therapy doses of erythromycin may also act as a promotility agent4. 4 Large hiatal hernias, if symptomatic Antireflux surgery (Nissen fundoplication) is indicated in selected cases (Table 2.2) but is associated with morbidity. Neurologically impaired children respond less well to medical therapy. Laparoscopic surgery has been associated with increased repeat operations, if compared with open surgery5.

Recurrent vomiting

History and physical examination

Yes Are there warning signals? Further evaluation

No Yes Are there signs of GERD? Further evaluation

No

Uncomplicated infantile GER ‘Happy spitter’

• No test • Consider • Education – Thickened formula • Consultation paediatric GI – Hypoallergenic formula • Review previous managment • Consider: – Endoscopy – Upper GI series – Oesophageal pH probe Yes No – Acid suppression ± prokinetic Well child Resolves by 18–24 hours?

2.4 Management of a vomiting infant. Vomiting 15

Hiatal hernia

Hiatal hernia is the protrusion of a portion of the stomach • Sliding, in which the gastro-oesophageal junction and a into the chest through an opening in the diaphragm (2.5). portion of the proximal stomach are herniated through Hiatal hernias are classified as: the oesophageal hiatus. Sliding hiatal hernia is common • Para-oesophageal, if the oesophagus and the gastro- in childhood. It may present accompanying GER, but oesophageal junction are normally placed but the gastric many cause no symptoms. cardia is herniated beside the oesophagus through the oesophageal hiatus (2.6). Hernias are treated surgically if medical treatment fails6.

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

A

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

A B 16 Vomiting

Infantile hypertrophic pyloric stenosis Diagnosis Laboratory tests demonstrate hypochloraemic, hypo- Infantile hypertrophic pyloric stenosis is a condition kalaemic metabolic alkalosis. Haemoconcentration is resulting from hypertrophy of the pylorus muscle in which reflected by elevated haemoglobin and haematocrit values. the lumen becomes obstructed by mucosa (2.7). It affects Ultrasound is the gold standard investigation and can 1.5–4.0 per 1,000 live births, and is more common in males reveal a thick pyloric muscle with a long pyloric channel and (4:1). There is a positive family history in 13%. The large pyloric diameter7. It shows a hypoechoic ring with a underlying mechanism is not understood. hyperdense centre, and thickness of circular muscle >4 mm in pyloric stenosis (2.8)8. A barium upper GI study reveals Symptoms/examination delay in gastric emptying and an elongated narrowed pyloric Vomiting usually begins between 2 and 4 weeks of age and channel with a double tract of barium (2.9). rapidly becomes projectile after every feeding. The vomitus is rarely bilious. Coffee-ground emesis may be seen as a Treatment and prognosis result of oesophagitis or gastritis. The infant is hungry and Pyloromyotomy is the treatment of choice and consists of nurses avidly. Infants do not generally appear ill unless incision down to the mucosa along the pyloric length undiagnosed for an extended period of time: constipation, (Ramstedt procedure) (2.10). Laparoscopic pyloromyotomy dehydration, weight loss, fretfulness, and finally apathy can is gaining acceptance9. Prior to surgery, it is imperative to occur. On examination, prominent gastric peristaltic waves may be seen after feeding. The pylorus may be palpable as a small, hard mass or as an ‘olive’ in the right upper abdomen.

A

B 2.7 Infantile hypertrophic pyloric stenosis is a condition 2.8 Ultrasound images in infantile hypertrophic pyloric resulting from hypertrophy of the pylorus muscle in which stenosis. A: Longitudinal view of the pylorus showing the lumen becomes obstructed by mucosa. Laparoscopic oval-shaped, enlarged pyloric muscle (dotted line). Pyloric view. muscle length >14 mm and thickness >3–4 mm are considered to be pyloric stenosis. B: Sagittal view of the pyloric olive. Vomiting 17

repair dehydration and electrolyte disturbances. of the duodenum. Treatment consists of decompression by The outlook is excellent following surgery. Sometimes a nasogastric tube and intravenous fluids. With improved vomiting may persist postoperatively for a few days if there nutrition symptoms usually resolve. Occasionally, it is is a long preoperative history. Mortality rates are low and necessary to perform surgery, such as realigning the usually associated with perforation or infection. duodenum or performing a duodenojejunostomy.

Cyclic vomiting syndrome Superior mesenteric artery syndrome The disorder is characterized by recurrent episodes of This syndrome is an unusual cause of recurrent vomiting. nausea and vomiting without an identifiable organic cause. The third part of the duodenum is obstructed as it passes The episodes are of rapid onset, often starting during sleep between the superior mesenteric artery anteriorly and the or early morning. It may persist for hours and days. The vertebral column posteriorly (2.11). Rapid linear growth episodes are separated by completely symptom-free without weight gain, weight loss, scoliosis, spinal surgery, intervals, lasting from several weeks to more than 1 year. confinement to bed, and use of a body cast may predispose They may end spontaneously, may cease after a period of to the condition10. It may present with unspecific symptoms sleep, or may progress to severe dehydration and electrolyte such as anorexia, nausea, and bilious vomiting. imbalance. Diagnosis is based on history and plain abdominal X-ray The pattern of inciting events and the characteristics of that shows a dilated stomach and proximal duodenum. the attack are usually similar in each individual. As the Upper GI series show a partial obstruction in the third part clinical picture mimics migraine attack and headaches may be present in up to 50% of patients, some authors consider cyclic vomiting as abdominal migraine. The diagnosis is based on the history, the normal physical examination, and a meticulous evaluation of other organic disease causing recurrent episodes of vomiting. Diagnostic evaluations should be focused on conditions suggested by the history. Symptomatic treatment should be started as early as possible after the onset of symptoms11, 12.

A B 2.9 Barium upper GI study. Narrowing of the pyloric 2.10 A: Surgical view of hypertrophic pyloric stenosis; channel with a double tract of barium (‘string sign’). B: pyloromyotomy. 18 Vomiting

2.11 Superior mesenteric artery syndrome. A: Compression of the third portion of the duodenum between the aorta and superior mesenteric artery; B: upper gastrointestinal 50° tract series shows dilatation of the second portion of the duodenum; 16° C: CT scan shows A narrowing between the superior mesenteric artery and aorta, with dilatation of the second portion of B the duodenum.

7 Stunden RJ, LeQuense GW, Little KET. The improved ultrasound diagnosis of pyloric stenosis. Pediatr Radiol 1986;16:200–5. 8 Hernanz-Schulman M. Infantile hypertrophic pyloric stenosis. Radiology 2003;227:319–31. 9 Aldrigde RD, Mac Kinley GA, Aldridge RB. Choice of C incision: the experience and evolution of surgical management of infantile hypertrophic pyloric stenosis. J Laparoendosc Adv Surg Tech A 2007;17:131–6. References 10 Lock G, Scholmerich J. Non-occlusive mesenteric ischemia. Hepatogastroenterology 1995;42:234–9. 1 Lawes IN. The origin of the vomiting response: a 11 Chow S, Golldman RD. Treating children’s cyclic neuroanatomical hypothesis. Can J Physiol Pharmacol vomiting. Can Fam Phys 2007;53:467–9. 1990;68:254–9. 12 Chepyala P, Svoboda RP, Orden KW. Treatment of 2 Kumar Y, Sarvananthan R. Gastro-oesophageal reflux in cyclic vomiting syndrome. Curr Treat Options children. Clin Evid 2005;14:349–55. Gastroenterol 2007;10:273–82. 3 Vandenplas Y, Salvatore S, Devrecker T, Hauser B. Gastro-oesophageal reflux disease: oesophageal impedance versus pH monitoring. Acta Paediatr Further reading 2007;96:956–62. 4 Keady S. Update of drugs for gastro-oesophageal reflux Hassall E. Step-up and step-down approaches to treatment disease. Arch Dis Child Educ Pract Ed 2007;92:ep of gastroesophageal reflux disease in children. Curr 114–8. Gastroenterol Rep 2008;10(3):324–31. 5 Hassal E. Outcomes of fundoplication: causes of concern, Li BU, Lefevre F, Chelimsky GG, et al. North American newer options. Arch Dis Child 2005;90:1047–52. Society for Pediatric Gastroenterology, Hepatology, and 6 Gottrand F. Gastro-oesophageal reflux in infants, Nutrition consensus statement on the diagnosis and children and adults. Hiatal hernia. Rev Pract management of cyclic vomiting syndrome. J P e d iat r 2007;57:95–8. Gastroenterol Nutr 2008;47(3):379–93. Chapter 3 19 Diarrhoea

ACUTE DIARRHOEA Enriqueta Román Riechmann, MD

Definition

Diarrhoea is a change in the individual bowel habit resulting enteric adenovirus (types 40 and 41), with some common in more frequent and/or looser stools. It expresses an acute features (Table 3.2)3. gastrointestinal inflammation (acute gastroenteritis). In Most common bacteria are Campylobacter spp. and childhood, gastrointestinal infection is the most common Salmonella spp., followed by Shigella, Yersinia and cause of acute diarrhoea worldwide1, 2. Escherichia coli. The major parasitic infections are Giardia and Cryptosporidium2.

Aetiology Epidemiology In industrialized countries the most clinically significant agents in infant acute diarrhoea are viruses (Table 3.1), Viral gastroenteritis is the second most common disease in mainly group A rotavirus (3.1A, B). Other viruses involved developed countries. The sporadic form affects all children are human calicivirus (norovirus and sapovirus, formerly in the first 5 years of life. Viruses are transmitted known as Norwalk and Sapporo virus), astrovirus and fundamentally by the faecal–oral route. There is faecal

Outer capsid: VP 4

Outer capsid:VP 7

Middle capsid: VP 6

Segmented genome A B 3.1 A: Electron microscopy of rotavirus particles from an infant with acute diarrhoea (courtesy Centers for Disease Prevention and Control, Atlanta, GA, USA); B: schematic of the complete rotavirus particle with structural proteins in the different shells. 20 Diarrhoea

Table 3.1 Main agents of infectious acute diarrhoea Table 3.2 Main features of viral agents

Viruses Bacteria • RNA viruses (except adenovirus) • Group A rotavirus • Salmonella • Nonlipoproteic envelope • Enteric adenovirus – S. typhi and paratyphi • Seasonal distribution • Astrovirus – Nontyphoidal Salmonella • Asymptomatic infection ⇔ severe disease • Human calicivirus S. enteritidis – Norovirus S. typhimurium • Frequent coinfections – Sapovirus • Shigella • Endemic, sporadic cases/epidemic, outbreaks – Shigella sonnei • Faecal–oral transmission • Campylobacter Parasites – C. jejuni Giardia lamblia • Yersinia Cryptosporidium – Y. enterocolítica parvum • Escherichia coli – Enteropathogenic E. coli Pathophysiology – Enterotoxigenic E. coli – Enteroinvasive E. coli Diarrhoea occurs when the volume of water and electrolytes – Enterohaemorrhagic E. coli present in the colon exceeds its capacity for absorption. This – Diffusely adherent E. coli can be mainly due to an increase in the secretion and/or a – Enteroaggregative E. coli decrease in the absorption level of the small intestine. • Aeromonas Decreased intestinal absorption occurs as a result of intestinal damage or inflammation (3.2). Viruses causing diarrhoea infect selectively mature enterocytes, causing cell lysis and producing a decrease in disaccharidase activity and excretion of viral particles in the days prior to clinical in mechanisms for active sodium and water absorption. The symptoms and continuing through to its resolution. consequence is a malabsorptive or osmotic diarrhoea. Rotavirus is a seasonal infection and in temperate climates Diarrhoea caused by bacterial infection is most frequently infections peak during the winter months3. In bacterial secretory. Bacteria can activate one of the intracellular enteric infection transmission can be through contaminated pathways leading to intestinal secretion through water or foodstuffs. enterotoxins.

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

A B Diarrhoea 21

Clinical features Assessment

Acute diarrhoea is a self-limiting process. Viral diarrhoea is In most cases, a complete clinical history and a careful typically acute in onset, watery-like, and the faeces do not physical examination is all that is necessary4–6. These should contain mucus, blood, or white cells. Diarrhoea can lead to rule out any life-threatening cause such as intussusception, dehydration, acidosis, and electrolyte imbalance. Vomiting surgical abdomen, and haemolityc–uraemic syndrome7. The appears at the beginning of the process. The most common severity of dehydration is assessed in terms of weight loss as age is 6–24 months and rotavirus infection is associated with a percentage of total body weight. An assessment of a more severe disease3. dehydration degree can be made by diverse scales of clinical In the secretory and osmotic diarrhoeas, faeces are watery (Table 3.4, 3.3). and profuse. The invasive diarrhoea is frequently Supplementary laboratory studies are usually unneces - characterized by mucus and macroscopic blood. sary. There are some recommendations on which patients Nevertheless, viral gastroenteritis cannot be distinguished should have blood tests (serum electrolytes, urea/creatinine, from that caused by bacteria through clinical history or bicarbonate) (Table 3.5) and on which patients should have physical examination, although some characteristics may faecal laboratory study (Table 3.6), as aetiology is irrelevant suggest bacterial diarrhoea (Table 3.3). for clinical management. Tests for specific pathogens

Table 3.3 Clinical features suggestive of bacterial diarrhoea

• Children older than 3 years • Hyperthermia • Increase in CRP • Acute onset • Bloody diarrhoea • Faecal white cells • No vomiting

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

Symptom Minimal or no Mild to moderate Severe dehydration dehydration dehydration Body weight loss <3% 3–9% >9% General condition Well, alert Restless, irritable Lethargic or unconscious: floppy Eyes Normal Slightly sunken Deeply sunken Tears Present Absent Absent Mouth and tongue Moist Dry Very dry Thirst Drinks normally, not thirsty Thirsty, eager to drink Drinks poorly, unable to drink Skin fold Instant recoil Recoil in <2 seconds Recoil in >2 seconds Fontanelle Normal Sunken Sunken Heart rate Normal Normal to increased Tachycardia, bradycardia in most severe cases Quality of pulses Normal Normal or slightly Moderately decreased decreased Extremities Normal capillary refill Delayed capillary refill Cool, mottled Urine output Slightly decreased <1 ml/kg/h <1 ml/kg/h 22 Diarrhoea

Sunken fontanelle Intestinal lumen Intestinal villous cell

Crying and Sunken eyes irritablility Substrate

Dry mouth Na+ Substrate Substrate Na+ D-hexoses D-glucose H O H O + Na+ D-galactose 2 2 L-amino acids Decreased skin turgor

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

Table 3.5 Recommendations on blood tests include stool cultures for bacteria and detection of faecal (adapted from AAP 1996)5, 8 viral antigen by enzyme immunoassay (EIA), agglutination with latex particles, or immuno chromatography.

• Severe dehydration • Moderate dehydration where clinical signs might Treatment indicate hypernatraemia • Moderate dehydrated patients whose histories or There is no specific treatment for acute gastroenteritis. The physical findings are inconsistent with straightforward main objective is to treat the dehydration and to lead to diarrhoeal episodes nutritional recovery. Treatment includes two phases, rehydration with quick replacement of fluid deficit, followed • History of excessive hypertonic or hypotonic fluid by maintenance in which rapid realimentation and ingestion maintenance fluids are indicated.

Rehydration The molecular process for cotransport of glucose and Table 3.6 Recommendations for faecal laboratory sodium was the basis for oral rehydration therapy (ORT) study development (3.4). ORT is recommended globally for the management of acute diarrhoea2, 6–8. The World Health Organization (WHO), the American • Immunocompromised Academy of Pediatrics (AAP), and the European Society of • Blood in the stool Pediatric Gastroenterology, Hepatology, and Nutrition • Uncertain diagnosis (ESPGHAN) recommend the use of ORT in the treatment • Severe or prolonged diarrhoea of gastroenteritis with mild to moderate dehydration (Table 3.7). Oral rehydration solution (ORS) is more physiological, • Hospitalization cost-effective and has fewer adverse effects that intravenous • Recent travel abroad therapy. Intravenous fluids should be reserved for patients with severe dehydration. Diarrhoea 23

Table 3.7 Oral rehydration solution composition

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 3.8 Contraindications for oral rehydration therapy

• Severe dehydration • Persistent vomiting • Potential surgical pathology – Shock • High ongoing faecal losses • ORT previous failure – Diminished consciousness (>10 ml/kg/h) • Significant psychosocial situation

A single hypo-osmolar ORS would be used for all years9. This has led the WHO and UNICEF to recommend diarrhoeal episodes (cholera and noncholera). These treatment with zinc in all children with diarrhoea in solutions should not be replaced by any other drinks such as developing countries10. clear fluids like water alone or homemade solutions, colas, sports drinks, or fruit juices. There are a few situations in Probiotics which ORT is contraindicated (Table 3.8). The schedule of The addition of probiotics to milk or infant formulas or to ORT should be to give small aliquots frequently (3.5). the rehydration solutions have shown a shortening in the duration of the diarrhoea. A moderate clinical benefit of Feeding some probiotics has been shown in the treatment of acute Early feeding may decrease the intestinal permeability watery diarrhoea, mainly by rotavirus in infants and young changes induced by infection, reduce illness duration, and children11. This effect seems to be: moderate in reducing improve nutritional recovery. The recommendations after diarrhoea by 17–30 hours; strain dependent with the period of rehydration are: Lactobacillus GG most effective; not effective in bacterial • Continuation of breastfeeding in all cases. invasive diarrhoea; effective in a dose >1010 CFUs and when • In formula-fed infants continuation of a nondiluted it is administered early in the disease to children in formula, without restriction of lactose intake. developed countries. • Resumption of full normal diet in older children, except for avoiding foods rich in simple sugars, due to its Drugs osmotic load. Antidiarrhoeal drugs, such as inhibitors of intestinal motility (loperamide and other opiates and anticholinergics), Micronutrients modifiers of the intestinal secretion (bismuth salts), and Zinc has been the main micronutrient implied in the adsorbent substances (cholesteramine, aluminum salts), are diarrhoeal process. Studies performed in developing not used in childhood as they have their effectiveness has not countries have shown its effectiveness in the treatment of been demonstrated and/or they have important adverse acute and persistent diarrhoea in children younger than 5 effects. 24 Diarrhoea

Acute diarrhoea/gastroenteritis

Other causes of diarrhoea and’/or vomiting excluded

Dehydration assessment

No dehydration Mild to moderate Severe

Risk factors? ORS (30–80 ml/kg) IV rehydration Infants <6 months over 4 hours and reassessment High frequency of watery stools or vomits

No Yes Rehydrated? Observation Discharge at least 24 hours Yes No

Consider nasogastric tube or IV rehydration

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

3.5 Management of acute diarrhoea.

Effectiveness and good oral tolerance of racecadotrile (an Prevention antihypersecretor with no effect on intestinal motility) has recently been described. Antiemetic drugs are unnecessary Since the main infectious route is faecal–oral, fundamental in the treatment of acute diarrhoea, although ondansetron to prevention is to reinforce environmental hygiene, with can sometimes be effective in diminishing vomiting and the appropriate hand cleaning and cleaning of the objects used necessity for hospitalization. The use of antibiotics would in the manipulation of children with diarrhoea. At present only be justified in: there are already two safe and effective vaccines against • Immunocompromised patients. severe disease by the most prevalent serotypes of rotavirus in • All cases of acute diarrhoea by Shigella, Vibrio cholerae, human pathology. Both are of oral administration in two and the majority of those produced by enteroinvasive and (monovalent human, Rotarix®) or three doses (pentavalent enteropathogenic E. coli and by Clostridium difficile. bovine–human, Rotateq®). These vaccines can be • Some cases of infection by Campylobacter, by Yersinia in administered with other regular childhood vaccines. cases of serious disease, by Salmonella in infants with In summary, the management of acute diarrhoea in bacteraemia, and in all patients younger than 3 months. children younger than 5 years should be: oral rehydration for 3–4 hours, followed by a fast reintroduction of usual feeding plus ORS for maintained losses (3.5, Table 3.9). Diarrhoea 25

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

Definition and pathophysiology Aetiology

Chronic diarrhoea is defined as a decrease of consistency or A wide variety of disorders including organ dysfunction, auto- increase in frequency or volume of stools lasting longer than immune diseases, and congenital alterations14 can account for 2 weeks12. Different mechanisms can be involved in chronic chronic diarrhoea in infancy as shown in Table 3.10. diarrhoea and usually a combination of more than one are responsible for this alteration13: Diagnosis • Osmotic diarrhoea: nonabsorbed substances in the distal bowel increases osmotic charge, pulling water along the A complete clinical history is mandatory. Some clinical signs intestinal lumen. and symptoms are relevant for a diagnostic approach14, • Secretory diarrhoea: increased secretion of water and including: electrolytes into the intestinal lumen, surpassing the • Nutritional repercussion. absorption capability. • Associated symptoms: fever, vomiting, abdominal pain, • Motility alterations: anorexia. – Hypermotility: unspecific chronic diarrhoea. • Stool characteristics: blood, mucous, nondigested – Hypomotility: intestinal bacterial overgrowth. substances, steatorrhoea. • Inflammatory: enterocyte injury with inflammatory • Physical examination: failure to thrive, abdominal response: humoral, cellular, and phagocytic, and with distension, visceromegaly, tenderness, presence of permeability alteration and decrease in disacaridases and abdominal masses. transporters. • Other organs affected, e.g. skin, respiratory system. – Infectious: bacteria, parasites. • Age of onset: according to the age of presentation, certain – Chronic inflammatory bowel disease (IBD) (Crohn’s disorders are more likely to occur (Table 3.11). disease and ulcerative colitis). • Digestion disorders (decreased enzymes, deconjugated bile salts).

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

l Use of oral rehydration solution (ORS) to correct estimated dehydration in 3–4 hours (fast rehydration) ll Use of hypo-osmolar solution (60 mmol/l sodium, 74–111 mmol/l glucose) lll Continuation of breast-feeding throughout lV Early refeeding: resumption of normal diet (without restriction of lactose intake) after 4 hours rehydration V Prevention of further dehydration by supplementing maintenance fluids with ORS (10 ml/kg/watery stool) Vl No unnecessary medication 26 Diarrhoea

Table 3.10 Aetiology of chronic diarrhoea

Pancreatic insufficiency Infectious • Cystic fibrosis • Prolonged viral enteritis • Schwachman syndrome • Salmonella • Campylobacter Hepatobiliary dysfunction • Yersinia • Deconjugated bile salts due to bacterial overgrowth • Giardia lamblia • Biliary atresia • Cryptosporidium • Cholestasis • Bowel bacterial overgrowth • Pseudomembranous colitis Congenital alterations in electrolyte transport • Congenital chlorated diarrhoea Anatomical or surgical disorder • Necrotizing enterocolitis Carbohydrate intolerance • Short bowel syndrome • Congenital alactasia • Blind loop syndrome • Secondary lactose intolerance • Hirschprung’s disease • Primary congenital racial intolerance • Intestinal lymphangiectasia • Glucose – galactose malabsorption Inflammatory Changes in mucosa • Crohn’s disease • Coeliac disease • Ulcerative colitis • Cow´s milk intolerance • Soy intolerance Other causes • Other food protein intolerance • Abetalipoproteinaemia • Congenital microvilli atrophy • Anderson disease • Autoimmune enteropathy • Enteropathic acrodermatitis • Immunodeficiency (congenital or acquired – HIV) Motility disorders • Postenteritis diarrhoea • Toddler´s diarrhoea • Protein-losing enteropathy • Hyperthyroidism • Bile acid malabsorption • Idiopathic bowel pseudo-obstruction • Irritable bowel syndrome

Table 3.11 Aetiology according to the age at presentation

<1 year 1–3 years >3 years Lactose intolerance Unspecific chronic diarrhoea Giardia lamblia Postenteritis diarrhoea Giardia lamblia Coeliac disease Food intolerance Coeliac disease Inflammatory bowel disease Cystic fibrosis Infectious diarrhoea Lactose intolerance Dietetic mistakes Postenteritis diarrhoea Diarrhoea 27

Laboratory studies – Exhaled hydrogen concentration test, mono/disac- • Stool analysis: faecal characteristics or faecal losses can charides tolerance test: carbohydrate malabsorption or point to specific syndromes (3.6). bacterial overgrowth. • Blood studies (3.7). – Pancreatic enzymes in duodenal fluid, immunoreactive • Other studies: trypsin, sweat chloride test: pancreatic insufficiency. • Enterocyte, smooth muscle, thyroid and islet cell serum antibodies: autoimmune enteropathy.

Macroscopic stool aspect: consistence, mucous or blood Imaging procedures Plain abdominal radiography may rule out anatomical disorders or surgical causes. An abdominal ultrasound may be useful in anatomical or surgical disorders, in infectious Presence of fat • Quantitative: different diarrhoea, or if IBD is suspected. The use of a barium upper • Fat malabsorption methods can be used • Pancreatic gastrointestinal (GI) study or a barium enema helps in the such as Van de Kamer, insufficiency steatocrit diagnosis of anatomical or surgical disorders. When IBD is • Qualitative: Sudan suspected an upper endoscopy or a should be performed and multiple biopsies taken.

• Protein-losing Proteins enteropathy • Alpha-1-antitrypsine • Pancreatic clearance insufficiency Haematology, • Quimiotrypsine • IBD biochemistry (including • Calprotectine • Pancreatic proteins, albumin), iron • Elastase Nutritional status insufficiency metabolism, vitamin levels, immunoglobulin levels

• Carbohydrate pH <5.5 malabsorption Protein-losing Reducing substances (glucose-galactose Total proteins, albumin malabsorption) enteropathy

• >280 mOsm/l – osmotic Coeliac autoantibodies diarrhoea (IgA antigliadin, specific Osmolarity Coeliac disease • <280 mOsm/l – tissue transglutaminase secretory diarrhoea antibodies)

Stool culture • Infectious diarrhoea IgE, prick test, food antigen RAST Food allergy/food Elimination and intolerance provocation tests Fresh view Parasites

Erythrocyte sedimentation • IBD rate, C-reactive protein • Infectious diarrhoea level, alpha-1- IBD Occult blood • Protein sensitivity glycoprotein, protein syndrome electrophoresis

3.6 Characteristics of stools may help to diagnose chronic 3.7 Biochemical analysis in blood that may help to diarrhoea. diagnose the aetiology of chronic diarrhoea. 28 Diarrhoea

3.8 The small bowel is an area of 3 the intestine not A accessible to 1 2 4 5 5 6 7 routine endoscopic 3 techniques. The recent development of the wireless 3.9 Schematic diagram of a video-capsule: 1, clear B endoscopic capsule optical dome; 2, lens; 3, illuminating LEDs; 4, CMOS (A) has allowed the imager; 5, battery; 6, ASIC transmitter; 7, antenna. possibility of Weight, 3.7 g. reaching these blind areas of the small bowel. Similar to a large antibiotic capsule, after being swallowed by the patient, the capsule C is propelled by peristalsis. Video images are transmitted (two images per second) from inside the body during 6–8 hours, to a sensor array secured to the patient’s abdomen (B, C). This is then connected to the recorder which stores the data.

The wireless endoscopic capsule The small bowel is an area of the intestine not accessible to routine endoscopic techniques. However, the recent development of the wireless endoscopic capsule (EC) (3.8) has revolutionized endoscopy15. Advances in miniaturiza - tion of electronic components have allowed the development of a new type of capsule endoscope (3.9, 3.10), enabling endoscopy of the whole GI tract15 with low A invasivity. Similar to a large antibiotic capsule, after being swallowed by the patient, the video-capsule is propelled by peristalsis and will transmit video images, 2 images per Video section second, from inside the body over 6–8 hours to a sensor array fixed to the patient’s abdomen and to a recorder. After Thumbnail the stored images are processed by a special software section (RAPID™ [Reporting And Processing of Images and Data] Comment Application Software), these can be stored as a high quality video. Individual frames and short videos can be also filed; Timebar moreover, digital data allow integration into reports which can be stored, printed, or sent by email. Video controls This device is therefore very useful for the diagnosis of B occult digestive bleeding and for the diagnosis, follow-up, and extension study of IBD16–18. 3.10 Video-capsule processor (A: workstation; Wireless EC shows great potential for the study of other B: main screen). Diarrhoea 29

Table 3.12 Advantages and drawbacks of the wireless EC system

Advantages Disadvantage • Noninvasive • Patient refusal or impossibility to swallow the • High-quality images of the entire small bowel capsule – the capsule can be introduced into the • Ambulatory examination stomach with a gastroscope • Imaging is possible even in the very frail patient • The capsule is retained in the stomach, i.e. no images of the small bowel are registered • Small bowel strictures can contraindicate the procedure

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

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.

A B disorders such as intestinal polyps, graft versus host disease, out a specific disorder or when other methods have failed to tumours, and so on (Table 3.12). Its optimal use in paediatric confirm a diagnosis, for instance Crohn’s disease restricted to patients has not yet been established. The only actual areas of the small intestine not accessible by conventional complication of the procedure is related to the presence of endoscopy (3.11)19. Small villous atrophy, characteristic of strictures that may cause the capsule to be retained, coeliac disease, may be patchy or present in distal jejunum necessitating removal by interventional or surgical procedures. making diagnosis extremely challenging by conventional In chronic diarrhoea, this procedure may be useful to rule methods (3.12). Although video-capsule endoscopy is not 30 Diarrhoea

currently a first step diagnostic procedure in chronic diarrhoea, overgrowth, and even genetic polymorphisms further technological improvements, such as a smaller size, (interleukin-10) have all been implicated. new capsule for large bowel, and the possibility of taking Treatment consists of reassuring parents and giving some biopsies, will surely widen the indications for this procedure. dietary advice: some patients may improve if they eliminate or restrict particular constituents of food such as lactose, fructose, sorbitol, flatulent vegetables, or fruits16. Dietetic Toddler’s diarrhoea restrictions are applicable only if there is an improvement following removal of the foodstuffs. In IBS with consti - Toddler’s diarrhoea usually occurs between 6 months and 3 pation, fibre intake can improve symptoms. Pharma- years of age, and is the most frequent cause of chronic cological treatment depends on the putative physio- diarrhoea in this age group. It usually occurs after an acute pathologic mechanisms. Different approaches can be used, beginning (infections, stress, antibiotic treatment). It usually but the efficacy of these treatments has not been established disappears at 2–4 years old, and evolves to recovery and an individual approach has to be considered (3.13)22. spontaneously. The main symptoms are 3–6 deposi tions/day, not formed, with more or less mucous and undigested food particles. Depositions do not occur nightly. Symptoms are Intractable diarrhoea of infancy (IDI) intermittent and self-limited20. There is no pain or abdominal distention and it does not affect weight or height. IDI is a severe life-threatening diarrhoea within the first 24 The physiopathology is not clear although it has been months of life, requiring parenteral nutrition. Persistent suggested that accelerated intestinal motility or an increase villous atrophy can be demonstrated in consecutive biopsies in bile salt elimination are responsible. Sometimes toddler’s and is resistant to the usual therapies (3.14). diarrhoea has been related to dietary mistakes: low fat and high carbohydrate diet, increased fruit juice intake, or increased water intake.

Intestinal motility Anticholinergics alteration Irritable bowel syndrome (IBS)

According to Roma III21 IBS is recurrent abdominal pain or Visceral 5-HT4 agonists discomfort for at least 3 days/month in the last 3 months, hypersensitivity Antidepressants 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 Deregulation central the stools. nervous system and 5HT agonists digestive tract interaction • The onset of pain starts with a change in the characteristics of the stools.

Low grade chronic Probiotics Usual symptoms are: deposition frequency range from intestinal inflammation fewer than three depositions in a week to more than three depositions a day; stools can be hard, pasty, or watery; stool evacuation with effort or urgency, with an incomplete Antibiotics evacuation feeling; mucous stools; abdominal distension Bacterial overgrowth Probiotics Diet impression; and nightly depositions. There is no clear physiopathology: intestinal motility alteration, visceral hypersensitivity, deregulation of the 3.13 The pharmacological treatment of irritable bowel central nervous system and digestive tract interaction, syndrome should be individually tailored to the most low-grade chronic intestinal inflammation, bacterial likely physiopathological cause. Diarrhoea 31

Mucous stools Microvillous inclusion disease

Neonatal

Choanal atresia Epithelial dysplasia Keratitis

Small for gestational age 1–3 months Facial dysmorphy Syndromatic diarrhoea (tufting) Abnormal hair

Extradigestive disease Autoimmune enteropathy Autoimmune, autoantibodies

3–12 months

Occasionally bloody stool Cow’s milk allergy and other immune-mediated disorders

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

Bacterial overgrowth syndrome Postenteritis syndrome

Bacterial overgrowth syndrome is due to malabsorption This presents as a protracted course of acute diarrhoea or resulting from poor enterocyte function and bacterial early relapse after improvement. It usually appears in infants transformation of nutrients into nonabsorbable and toxic and toddlers (6 months–3 years). Clinically, it presents as metabolites23. It most commonly present in infants younger watery stools with or without vomit, anorexia, and failure to than 2 years. It may be associated with anatomical damage, thrive. There are conditioning factors such as genetics, abnormal small bowel motility, and immunological medical conditions, the aetiology of infectious acute alterations. diarrhoea, nutritional status, and inadequate management If bacterial overgrowth is present, there is an alteration of of acute diarrhoea (indiscriminate use of antibiotics, the intraluminal metabolism of carbohydrates. Carbo- hypocaloric diet and excessive carbohydrate intake). hydrates are fermented into smaller osmotically active When diarrhoea is prolonged, the mucosa is damaged. molecules and organic acids by bacteria. Increased Enteropathy alters secretory and absorption function and osmolarity results in osmotic diarrhoea. Alteration of intestinal motility. The treatment consists of transient intraluminal metabolism of bile acids occurs, causing elimination of cow’s milk and lactose from the diet. If there deconjugation of the bile acids. These stimulate the colon to is a concomitant infectious cause of diarrhoea, aetiological secrete fluid (secretory diarrhoea) and inhibit the carbo - treatment is indicated. hydrate transporters and reduce intraluminal pH levels. Symptoms depend on the degree of mucosal damage, Transient food intolerance/allergy from abdominal pain or flatulence to severe diarrhoea with malabsorption. The diagnosis can be established by Transitory food allergy or intolerance is an adverse reaction duodenojejunal culture (≥106 UFC/ml) or exhaled hydrogen to foods. The term ‘food intolerance’ is usually preferred to concentration with an oral carbohydrate load. Treatment food allergy, in order to include pathological reactions consists of nonintestinal absorbable antibiotics. mediated by nonimmune mechanisms24. Cow’s milk 32 Diarrhoea

proteins are most frequently implicated as a cause of food intolerance during infancy. Soy protein is another common food antigen. From school age on, egg protein becomes Congenital: • Amylase deficiency: cystic fibrosis and more important. With increased consumption, sensitization Schwachman–Diamond syndrome from other sources becomes more frequent. • Congenital lactase deficiency • Glucose-galactose malabsorption It is known that gastrointestinal infections, decreased • Sucrose-isomaltase deficiency serum and secretory IgA, malnutrition, and atopic tendency • Adult-type hypolactasia are risk factors for increased intestinal permeability to food – Most common entity – From banal symptoms to established diarrhoea antigens. Oral tolerance does not develop and different – Onset age: 5–7 years immunological and inflammatory mechanisms occur with – Fluctuating prevalence: from 1–3% in North of Europe to 60% in southeast Africa epithelial damage (enteropathy). Clinical symptoms depend on different factors: age, site of food antigen exposure, different pathogenetic mechanisms, and degree of the enteropathy. Symptoms can be gastrointestinal (chronic Acquired: diarrhoea, failure to thrive), respiratory, or dermatological. • Lactose intolerance (secondary to a damage of the Diagnosis is established by elimination and challenge mucose that causes mucose atrophy such as viral tests. The test is positive for food intolerance when enteritis and coeliac disease) symptoms decline following dietary elimination of the suspected offending food and recur after a food challenge. A challenge should be performed with the suspected agent and 3.15 Carbohydrate intolerance is a common cause of with placebo. Immunological tests include: chronic diarrhoea in infancy. Several different medical • Skin prick test with the defined antigens. conditions can produce this clinical picture. • RAST: IgE class antibodies against specific food antigens. • IgG class antibodies against specific food antigens: interpretation of results will be done according clinical symptoms. • Total serum IgE. References

In addition, gastroenterological tests are available, such as 1 Casburn-Jones AC, Farthing MJG. Management of gastric biopsy, small bowel biopsy, and stool analysis infectious diarrhoea. Gut 2004;53:296–305. (eosinophils, blood). The definitive treatment of food 2 Davidson G, Barnes G, Bass D, et al. Infectious diarrhoea allergy is strict elimination of the offending food from the in children: Working Group Report of the First World diet. Food-induced intolerance is most often a temporary Congress of Pediatric Gastroenterology, Hepatology and disease. Most children can resume consumption of the Nutrition. J Pediatr Gastroenterol Nutr offending antigen after 1–4 years of an elimination diet. 2002;35:S143–50. 3 Wilhelmi I, Román E, Sánchez-Fauquier A. Viruses causing gastroenteritis. Clin Microbiol Infect Carbohydrate malabsorption 2003;9:247–62. 4 AAP. Provisional Committee on Quality Improvement, Carbohydrate malabsorption usually presents as watery and Subcommittee on Acute Gastroenteritis. Practice acid stools, abdominal distension and flatulence, perianal parameter: the management of acute gastroenteritis in area erythema, and failure to thrive (3.15)25. Treatment young children. Pediatrics 1996;97:424–33. consists of the elimination of all or specific dietary 5 Sandhu BK, for the European Society of Pediatric carbohydrates until the diarrhoea resolves. In congenital Gastroenterology, Hepatology and Nutrition Working disease, carbohydrates never will be introduced. Group on Acute Diarrhoea. Practical guidelines for the management of gastroenteritis in children. J P e d iat r Gastroenterol Nutr 2001;33:S36–9. Diarrhoea 33

6 King CK, Glass R, Bresee JS, Duggan C; Centers for 20 Fenton TR, Harries JT, Milla PJ. Disordered small Disease Control and Prevention. Managing acute intestinal motility: a rational basis for toddlers’ diarrhoea. gastroenteritis among children: oral rehydration, Gut 1983;24(10):897–903. maintenance, and nutritional therapy. MMWR Rec Rep 21 Sperber AD, Shvartzman P, Friger M, et al. A 2003;52(RR-16):1–16. comparative reappraisal of the Rome II and Rome III 7 Armon K, Stephenson T, Macfaul R, et al. An evidence diagnostic criteria: are we getting closer to the ‘true’ and consensus based guideline for acute diarrhoea prevalence of irritable bowel syndrome? Eur J management. Arch Dis Child 2001;85:132–42. Gastroenterol Hepatol 2007;19(6):441–7. 8 Rao MC. Oral rehydration therapy: new explanations for 22 Spiller R, Aziz Q, Creed F, et al. Guidelines for the an old remedy. Ann Rev Physiol 2004;66:385–417. management of irritable bowel syndrome. Gut 9 Hoque KM, Binder J. Zinc in the treatment of acute 2007;56:1770–98. diarrhoea: current status and assessment. 23 Gregg CR. Enteric bacterial flora and bacterial Gastroenterology 2006;130:2201–5. overgrowth syndrome. Semin Gastrointest Dis 10 WHO/UNICEF Joint Statement. Clinical management 2002;13(4):200–9. of acute diarrhoea. The United Nations Children´s 24 Assaad AH. Gastrointestinal food allergy and Fund/World Health Organization, 2004. intolerance. Pediatr Ann 2006;35(10):718–26. WHO/FCH/CAH/04.7. 25 Kneepkens CM, Hoekstra JH. Malabsorption of 11 Szajewska H, Setty M, Mrukowicz J, Guandalini S. carbohydrates. Nestle Nutr Workshop Ser Pediatr Probiotic in gastrointestinal diseases in children: hard and Program 2005;56:57–69; discussion 69–71. not so hard evidence of efficacy. J Pediatr Gastroenterol Nutr 2006;42:454–75. 12 Gibbons T, Fuchs GJ. Chronic enteropathy: clinical Further readings aspects. Nestle Nutr Workshop Ser Pediatr Program 2007;59:89–101; discussion 102–4. Kligler B, Hanaway P, Cohrssen A. Probiotics in children. 13 Booth IW, McNeish AS. Mechanisms of diarrhoea. Pediatr Clin North Am 2007;54:949–67. Ballières Clin Gastroenterol 1993;7:215–42. Guarino A, Albano F, Ashkenazi S, et al. European Society 14 Lee WS, Boey CC. Chronic diarrhoea in infants and for Paediatric Gastroenterology, Hepatology, and young children: causes, clinical features and outcome. J Nutrition/European Society for Paediatric Infectious Paediatr Child Health 1999;35(3):260–3. Diseases evidence-based guidelines for the management 15 Cave DR. Wireless video capsule endoscopy. Clin of acute gastroenteritis in children in Europe: executive Perspec Gastroenterol 2002;5:203–7. summary. J Pediatr Gastroenterol Nutr 2008;46:619–21. 16 Seidman EG, Sant´Anna AM, Dirks MH. Potencial European Society for Paediatric Gastroenterology, applications of wireless capsule endoscopy in the Hepatology, and Nutrition/European Society for pediatric age group. Gastrointest Endosc Clin N Am Paediatric Infectious Diseases. European Society for 2004;14(1):207–17. Paediatric Gastroenterology, Hepatology, and 17 Aabakken L, Scholz T, Ostensen AB, et al. Capsule Nutrition/European Society for Paediatric Infectious endoscopy is feasible in small children. Endoscopy Diseases evidence-based guidelines for the management 2003;35(9):798. of acute gastroenteritis in children in Europe. J P e d iat r 18 Argüelles-Arias F, Argüelles-Martín F, Caunedo A, et Gastroenterol Nutr 2008;46 suppl 2:S81–122. al. Utilidades de la cápsula endoscópica en gastroenterología pediátrica. Ann Pediatr 2003;59:586–9. 19 Argüelles-Arias F, Caunedo A, Romero J, et al. The value of capsule endoscopy in paediatric patients with a suspicion of Crohn´s disease. Endoscopy 2004;36(10):869–73. 34 Chapter 4 Constipation Carolina Gutiérrez, MD, and Jerónimo Gonzálvez, MD

Definition and aetiology Normal defecation and functional constipation Constipation can be defined as the delay or difficulty in defecation occurring for ≥2 weeks and causing significant Mechanisms of normal defecation and continence are distress to the patient. As a symptom, constipation can be summarized in figure 4.1. The term ‘functional caused by many different disorders (Table 4.1) but 90% of constipation’ (also called idiopathic or retentive constipation all constipated children have functional constipation, with or psychogenic megacolon) describes all children in whom no identifiable organic or anatomical cause. Constipation is constipation does not have an organic aetiology, and it is a common symptom in paediatric clinical practice, generally caused by a maladaptative response to defecation accounting for 3% of all general paediatric visits and (4.2). In functional constipation, fear of defecation after a between 10 and 25% of all cases in paediatric painful experience and repeated attempts of voluntary gastroenterology reference units. withholding of stools (vicious circle theory) lead to the

Table 4.1 Differential diagnosis of constipation

Functional constipation (90%) • Metabolic and endocrine disorders – Cow’s milk intolerance – Hypothyroidism • Abnormal abdominal musculature Organic constipation (10%) – Renal acidosis – Prune belly syndrome • Anatomical malformations – Diabetes insipidus – Gastroschisis – Anal stenosis – Hypercalcaemia – Down syndrome – Imperforatus anus – Hypokalaemia • Drugs – Anterior displaced anus • Intestinal nerve or muscle – Antacids – Pelvic mass (sacral teratoma) disorders – Codein • Neuromuscular disorders – Hirschsprung’s disease – Phenytoin – Cerebral palsy, hypotonia – Neuronal intestinal dysplasia – Opiates – Disorders of the spinal cord – Chronic intestinal pseudo- – Antidepressants – Myelomeningocoele obstruction – Anticholinergics – Spinal cord trauma • Gastrointestinal diseases – Iron – Spinal cord tumour – Coeliac disease – Muscular dystrophy – Cystic fibrosis Constipation 35

Sigmoid contraction Painful defecation

Fear of defecation A fecal mass accumulates in Stools in rectum Rectal distension

With-holding behaviour

• Temporary reflex relaxation of the IAE • Simultaneous • Functional megarectum (RAIR) mediated by the contraction of EAE • Loss of rectal sensitivity autonomic nervous giving time to decide if • Pelvic floor muscle fatigue system circumstances are • Anal sphincter incontinence • Stool in contact with appropriate for • Overflow incontinence sensitive receptors in defecation anal canal

4.2 Pathophysiology of functional constipation.

Defecation convenient Defecation inconvenient

formation of a functional megarectum with loss of rectal sensitivity and of the normal need to defecate. Progressive • Diaphragms and accumulation of feces in the rectum leads to pelvic floor abdominal muscle • Puborectalis muscle muscle fatigue and anal sphincter poor competence, causing contraction contraction • Increased intrarectal overflow incontinence and nonvoluntary expulsion of • EAE contraction pressure • Accommodation of faeces, or encopresis. Encopresis is the involuntary loss of • Puborectalis muscle rectum to its contents stool into the child’s underwear in a child with functional relaxation • Mediated by the • EAE relaxation constipation after the acquisition of the toilet skills that are voluntary nervous • Mediated by the system acquired by most children by the age of 4 years. voluntary nervous system Constitutional and inherited factors such as slow intrinsic motility and low fibre diet may contribute to constipation. Onset of functional constipation occurs in one of three periods: (1) in infants, often corresponding with the change Evacuation of stools Defecation postponed from breast milk to commercial formula or introduction of solids, (2) in toddlers acquiring toilet skills, and (3) in children as school starts. Table 4.2 summarizes the main 4.1 Normal mechanism of defecation and continence. In clinical symptoms and complications in children with newborn babies and very young infants, the role played functional constipation1. Diagnostic criteria for childhood by the cerebral cortex in these events is not yet functional gastrointestinal disorders, known as the Rome III developed; therefore, defecation occurs when the internal criteria have been recently reviewed2, 3. Functional disorders sphincter relaxes. IAE: internal anal sphincter; EAE: of defecation include infant dyschezia and functional external anal sphincter; RAIR: rectoanal inhibitory reflex. constipation in infants and children (Table 4.3). 36 Constipation

Table 4.2 Clinical symptoms and complications in children with functional constipation

• Retentive posturing: affected children are often • Urinary symptoms: described as standing on their toes, holding onto – Night-time urinary incontinence furniture, stiffening their legs and hiding in a corner – Daytime urinary incontinence • Infrequent and painful passage of huge stools – Urinary tract infection • Abdominal pain and irritability, anal or rectal pain – Less frequently: vesicoureteral reflux, urinary retention, • Anorexia megacystis, ureteral obstruction • Encopresis: sometimes is the first symptom and it is • Immediate resolution of symptoms after the passage of confused with chronic diarrhoea a huge stool • Anal fissures •

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

G6. Infant dyschezia Accompanying symptoms may include irritability, Must include both of the following in an infant younger decreased appetite and/or early satiety. The than 6 months of age: accompanying symptoms disappear immediately 1 At least 10 minutes of straining and crying before following passage of a large stool. successful passage of soft stools 2 No other health problems H3a. Functional constipation (child and adolescent) Must include 2 or more of the following in a child with a G7. Functional constipation (neonate and toddler) developmental age of at least 4 years*: Must include 1 month of at least 2 of the following in 1 Two or fewer defecations in the toilet per week infants up to 4 years of age 2 At least 1 episode per week of incontinence 1 Two or fewer defecations per week 3 History of retentive posturing or excessive volitional 2 At least 1 episode per week of incontinence after the stooling retention acquisition of toileting skills 4 History of painful or hard bowel movements 3 History of excessive stool retention 5 Presence of a large faecal mass in the rectum 4 History of painful or hard bowel movements 6 History of large diameter stools that may obstruct the 5 Presence of a large faecal mass in the rectum toilet 6 History of large-diameter stools that may obstruct the toilet *Criteria fulfilled at least once per week for at least 2 months before diagnosis

Infant dyschezia

Some otherwise healthy infants less than 6 months of age with pelvic floor relaxation. Parents need to be reassured appear to have significant discomfort and excessive straining that the phenomenon is part of the child’s learning process associated with passing soft stools. The symptoms resolve and that no intervention is necessary. Rectal stimulation spontaneously after a few weeks and are probably related to should be avoided to prevent artificial sensory experiences a failure to coordinate increased intra-abdominal pressure and laxatives are unnecessary. Constipation 37

Functional constipation

The definition of functional constipation takes into account with secondary intestinal ischaemia that contributes to not only the frequency of stools but also the passage of enterocolitis. The aganglionic segment begins in the internal painful bowel movements and stool retention with or anal sphincter and extends proximally, in 75% of cases to without encopresis. Normal stool frequency ranges from the rectosigmoid area, in 20% to the colon proximal to the four per day during the first week of life to two per day at 1 splenic flexure, in 3–5% there is total colonic aganglionosis year of age. The normal adult range of three per day to three and, even less frequently, there is total intestinal per week is attained by 4 years of age. Some breastfed babies aganglionosis. There is also a very rare form of the disease in have very infrequent stools of normal consistency without which there is an ultra-short segment involving only the very distress; these infants are usually perfectly healthy and distal 2–5 cm of the rectum. infrequent stools relate to almost complete absorption of Symptoms and signs of Hirschsprung’s disease are breast milk, leaving very little residue for stool formation. summarized in Table 4.4. Enterocolitis is the most serious complication and it could be the first manifestation of the disease. It is characterized by the abrupt onset of fever, Hirschsprung’s disease abdominal distention, and explosive and sometimes bloody diarrhoea, mainly in 2–3-month-old infants and is Hirschsprung’s disease, with an incidence of 1 in 5000 live associated with a mortality of 20%. Mortality is reduced births, is the most frequent cause of lower intestinal with early diagnosis of Hirschsprung’s disease. obstruction in newborns. It is found in about 3% of children and toddlers with severe refractory constipation referred to the paediatric gastroenterologist (4.3). Hirschsprung’s Table 4.4 Signs and symptoms suggestive of disease is characterized by the absence of ganglion cells in Hirschsprung’s disease (HD) in constipated children the myenteric and submucosal plexuses of the colon leading to sustained contraction of the aganglionic segment. The bowel proximal to the aganglionic segment becomes dilated Symptoms • Constipation beginning early in life • Delayed passage of meconium • Failure to thrive 4.3 Hirschsprung’s • Abdominal distention disease is • Absence of encopresis characterized by the • Fever, bloody diarrhoea (enterocolitis) absence of ganglion • Chronic constipation not responding to treatment cells in the myenteric and submucosal Signs plexuses of the colon • Passage of liquid stools and gas after rectal digital leading to sustained examination contraction of the • Empty rectal vault (although stool is palpable in the aganglionic segment abdomen) (A). The bowel • Increased anal tone proximal to the • Signs of syndromes associated with HD aganglionic segment – Down syndrome become dilated (B) – Multiple endocrine neoplasia IIA with secondary – Congenital deafness intestinal ischaemia – Waardenberg`s syndrome that contributes to – Neurofibromatosis enterocolitis. 38 Constipation

Diagnosis

A thorough history and physical examination (including the hypercalcaemia, hypothyroidism, and coeliac disease are perianal area, spine, reflexes in the distal extremities, and useful in selected cases. In constipated infants, and digital rectal examination) is generally sufficient to establish particularly if there is delayed passage of meconium, a sweat the diagnosis of functional constipation. The digital rectal test is recommended to exclude cystic fibrosis. examination is recommended to detect the faecal retention in the rectum typical of functional constipation. The Abdominal radiographs presence of symptoms or signs suggestive of organic disease Radiological studies are not indicated in uncomplicated or the persistence of symptoms after treatment should lead constipation. An abdominal radiograph can be useful in to further evaluation. determining the presence of faecal impaction in the child Constipation in early life is a special situation as it could who refuses a rectal examination, and in the obese child be the expression of a serious congenital disorder such as when abdominal and rectal examination are suboptimal Hirschsprung’s disease, meconium plugs, cystic fibrosis, (4.4). anal malformations, or spinal cord anomalies, but functional constipation is the main cause. Approximately 40% of Anorectal manometry children with functional constipation develop symptoms The main clinical role of anorectal manometry is in the during the first year of life4. evaluation of children with severe constipation not responding to treatment, or in those with signs or symptoms Laboratory tests suggestive of organic disease, in which the diagnosis of Occult blood testing in stool is recommended in infants with Hirschsprung`s disease needs to be excluded5. Different constipation and in children with associated abdominal probes for anorectal manometry are available (4.5). To pain, failure to thrive, and intermittent diarrhoea. A positive exclude Hirschsprung’s disease, an Arhan type anorectal occult blood test suggests enterocolitis or other causes of manometry probe connected to a pneumohydraulic capillary intestinal inflammation. Other laboratory tests to exclude infusion system is commonly used (4.6, 4.7).

4.5 A view of an anorectal manometry station. A manometry probe is connected to a polygraph with pneumohydraulic capillary infusion system and pressure transducers that transmit to a computer that generates a graphic pressure recording. The room must be 4.4 Abdominal X-ray showing severe faecal retention in comfortable; playing with familiar toys or watching the rectum of a child with functional constipation. cartoons on television help to reduce anxiety in the child. Constipation 39

4.6 A: Anorectal manometry probe formed by a plastic tube with four interior channels. One channel is connected to a latex balloon located in the distal segment able to distend with air (A). The second one is open to the rectal lumen (B). The third and fourth channels are covered by small latex balloons and located in the anal channel and the anal verge (C, D). B: A 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 B of the pressures of rectal ampulla (B), anal canal (C) and external anal sphincter (D). C

C D

B 4.7 A: The open-tipped perfusion manometer with 4–8 channels is the most accurate for recording resting and squeeze pressures of the anal canal and to define the vector volume. B: A soft catheter with 4–8 tiny openings around its circumference provides directional pressure measurements in four quadrants of the anal sphincter. Pressures are measured using a 1 cm station or a A continuous 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. 40 Constipation

An enema the night before the test is the recommended Barium enema study preparation, although some patients may need 2–3 days of A barium enema study is unnecessary in most children with enema administration to assure an empty rectal vault. Most constipation, and is less accurate than anorectal manometry infants and children can be tested without sedation, but and rectal biopsy in the diagnosis of Hirschsprung’s fasting for 4–6 hours is also prudent in case the child needs disease5. An unprepared barium enema is useful in children sedative medication or it is necessary to feed infants during with Hirschsprung’s disease to delineate the extent and the the test as a sedative manoeuvre. The procedure should be location of a transition zone between the tight aganglionic explained to the child and the parents to reduce anxiety and segment and the dilated proximal colon (4.11). promote cooperation. Technique and interpretation are summarized in figures 4.8–4.10.

4.8 A: The child lies comfortably in the left lateral decubitus position and the catheter is inserted into the rectum to simultaneously measure the pressures of the rectal ampulla, anal canal, and external anal sphincter. After a 10-minute stabilization period, the following A B parameters are recorded: mean rectal ampullar resting pressure, mean anal canal resting pressure, and mean external anal sphincter resting pressure. B: Posteriorly increasing volumes of air (5–50 ml) to inflate the rectal balloon are progressively introduced. This 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.

4.9 The RAIR is persistently absent in Hirschsprung`s disease because of the absence of ganglion cells that would transmit the distention reflex to the internal anal sphincter. The RAIR has been reported to be absent, atypical, or normal in patients with neuronal intestinal dysplasia. Barium enema and rectal biopsy to exclude Hirschsprung’s disease need to be performed in all patients with absent or atypical RAIR. Constipation 41

4.11 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 4.10 In chronic refractory constipation defecatory young infants a dynamics should also be assessed asking the child to transition zone expel the manometric balloon simulating defecation. may not be seen Normally, an increase in rectal pressure (Valsalva simply because there has not been enough time to manoeuvre with abdominal compression) with distend the ganglionic portion of the colon with stool. simultaneous drop in anal canal and external anal Patients with total aganglionosis may present with sphincter pressures (relaxation of the anal sphincter and microcolon or normal calibre colon. It is important not to perineal descent) is recorded. Paradoxical puborectalis cleanse the colon in order to accentuate the transition contraction of the external anal sphincter can be zone and the catheter should be inserted at the end of the demonstrated in children with chronic constipation and anal canal in order to avoid missing short-segment constitutes the manometric expression of the faecal disease. Barium enema should not be performed in retention behaviour. There is simultaneous increase in suspected enterocolitis as it can cause perforation. If the external anal sphincter, anal canal, and rectal pressures initial enema is not diagnostic a 24- and/or 48-hour follow- on attempted balloon expulsion. The presence of up abdominal radiograph including lateral projection could paradoxical anal contraction is correlated to severe be performed. Prolonged retention of barium suggest the constipation refractory to treatment. Biofeedback designed diagnosis of HD. to instruct patients on sphincter relaxation may help these patients.

Rectal biopsy Rectal biopsy stained for acetylcholinesterase activity is the Occasionally suction biopsies are not diagnostic and a full- best test to rule out Hirschsprung’s disease and should be thickness biopsy is necessary (4.12). Histopathological performed in infants and children with suggestive clinical absence of ganglion cells in the myenteric and submucosal data and absence or atypical RAIR in anorectal plexus and the presence of hypertrophied nerve fibres in the manometry5. The normal anus has a paucity or absence of lamina propria, muscularis mucosa, and submucosa are the ganglion cells at the level of the anal verge. To avoid missing hallmark of the disease (4.13). a rare case of ultra-short segment Hirschsprung`s disease, it is recommended to perform rectal biopsy 2–3 cm above the Colonic transit study mucocutaneous junction. The estimation of total and segmentary colonic transit time The biopsy can be obtained by suction at the bedside or is useful in two main situations: (1) to provide objective office, or a full-thickness biopsy can be performed. Biopsies information in children who report infrequent bowel should be deep enough to include adequate submucosa. movements, but who have no objective findings of 42 Constipation

2 112

1

A

2 1 1 2 4.12 In infants requiring laparotomy or in definitive 1 1 surgical procedure, serial, progressively proximal, full- thickness biopsies are obtained to determine the level at B which ganglionic bowel begins (levelling procedure). 4.13 A: Normal subject. Haematoxylin and eosin stain of colonic biopsy showing myenteric plexus with ganglionic cells (2) between the circular and longitudinal muscle layers (1). B: Hirschsprung`s disease (HD). Ganglion cells are absent in the intermuscular plexus with increase in nerve fibres. Acetylcholinesterase staining of colonic biopsy in HD shows an increased submucosal nerve plexus, as most of these nerve fibres are cholinergic. The histochemical staining for acetylcholinesterase requires only the lamina propria of the mucosa, which can be obtained by suction technique. 1: Muscle layers; 2: myenteric plexus (no ganglion cells).

A

abdominal radiograph to assess their progression through the colon is used to determine the colonic transit time (CTT) in patients with chronic constipation6 (4.14, 4.15). The presence of prolonged CTT in children with infrequent B bowel movements constitutes an objective sign of 4.14 A gelatin capsule with 10 polyurethane radiopaque constipation. The determination of segmental CTT is useful markers containing barium sulphate USP is administered in chronic refractory constipation (4.16, 4.17)6. 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 Management performed on day 7 (at 9:00 am). Most children with functional constipation with or without encopresis will benefit from a precise, well- organized plan including education, disimpaction, constipation on repeated physical examination, and (2) in maintenance treatment, follow-up, and treatment of children with chronic constipation refractory to recurrences4, 7 (Tables 4.5–4.7). The most common conventional treatment. reason for poor outcome is insufficient treatment, and Ingestion of radio-opaque markers followed by especially the reluctance of parents and physicians to the Constipation 43

4.15 To determine the 4.16 Constipation segmental transit with colonic inertia. time, three areas are (Total colonic transit delineated, tracing a time = 93.6 hours, line joining the spinal right colon = 26.4 processes of all the hours, left colon = vertebrae to L5. 26.4 hours, Using L5 as centre, rectosigmoid colon = lines are in turn 40.8 hours). A global traced to the left delay in colonic anterosuperior iliac transit may suggest spine and to the right the presence of a pelvic outlet, more generalized establishing areas alteration in colonic corresponding to the motility, amenable to right colon (caecum, treatment with ascending colon, prokinetic drugs. 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: 4.17 Constipation total colonic transit time and the segmental colonic transit with delayed left times for the right colon, the left colon, and the colonic and rectosigmoid colon. These transit times are estimated rectosigmoid using the following formula: colon transit time = (sum of transit. (Total the markers × [time between administration ÷ number of colonic transit time markers per capsule]) = sum of the markers × 2.4. = 120 hours, right colon = 14.4 hours, left colon = 45.6 use of laxatives for sufficient periods of time7, 8. hours, rectosigmoid Maintenance therapy may be necessary for many colon = 60 hours). months. Primary care providers and families should be A collection of aware that relapses are common and that difficulty with markers in the left bowel movements may continue into adolescence. In colon and children unresponsive to conventional management, rectosigmoid consideration may be given to a time-limited trial of a cow’s suggests outlet milk-free diet12, 13. Biofeedback consists of teaching to dysfunction such as recognize rectal distention, to contract and relax external paradoxical anal sphincter and puborectalis muscle, and to coordinate puborectalis contraction that could be demonstrated in these functions with the help of anorectal pressure anorectal manometry and may improve with various recording. It has been shown to be an effective short-term forms of biofeedback therapy. treatment of children with severe intractable constipation, especially those showing distal delay in CTT and paradoxical anal contraction in anorectal manometry14. For cooperative children, anorectal biofeedback training anal sphincter to produce evacuation and continence and it provides auditory and visual information about anal can help them to reduce the threshold volume for rectal sphincter pressure. Children learn to relax or contract the sensation (4.10). 44 Constipation

Table 4.5 Treatment of functional constipation

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

Disimpactation if faecal See Table 4.6 impaction detected

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

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

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

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

Table 4.6 Disimpactation treatment

Oral >2 years Polyethylene glycol with electrolytes 25 ml/kg/h up to 1000 ml/h until clear liquid stools (premedication with metoclopramide 5 mg, usually 12–20 hours are needed)

Polyethylene glycol without electrolytes 1.5 g/kg/day for 3 days

Mineral oil 3 ml/kg/twice day for 7 days

Lactulose or sorbitol 2 ml/kg/twice day for 7 days

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

Rectal Glycerin suppositories Physiological enema Contraindicated: soapsuds, tap water, or magnesium enemas Constipation 45

Table 4.7 Maintenance treatment

Osmotics Age Dose Magnesium 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

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

References

1 Loening-Baucke V. Urinary incontinence and urinary 12 Andiran F, Dayi S, Mete E. Cow’s milk consumption in tract infection and their resolution with treatment of constipation and anal fissure in infants and young chronic constipation of childhood. Paediatrics children. J Paediatr Child Health 2003;39(5):329–31. 1997;100(2 Pt 1):228–32. 13 Iacono G, Cavataio F, Montalto G, et al. Intolerance of 2 Hyman PE, Milla PJ, Benninga MA, et al. Childhood cow’s milk and chronic constipation in children. N Engl J functional gastrointestinal disorders: neonate/toddler. Med 1998;339(16):1100–4. Gastroenterology 2006;130(5):1519–26. 14 Heymen S, Jones KR, Scarlett Y, Whitehead WE. 3 Rasquin A, Di Lorenzo C, Forbes D, et al. Childhood Biofeedback treatment of constipation: a critical review. functional gastrointestinal disorders: child/adolescent. Dis Colon Rectum 2003;46(9):1208–17. Gastroenterology 2006;130(5):1527–37. 4 Youssef NN, Di Lorenzo C. Childhood constipation: Further reading evaluation and treatment. J Clin Gastroenterol 2001;33(3):199–205. Baker S, Liptak G, Colletti R, et al. Constipation in infants 5 de Lorijn F, Kremer LC, Reitsma JB, Benninga MA. and children: evaluation and treatment: a medical Diagnostic tests in Hirschsprung disease: a systematic position statement of the North American Society for review. J Pediatr Gastroenterol Nutr 2006;42(5):496–505. Pediatric Gastroenterology and Nutrition. J P e d iat r 6 Gutierrez C, Marco A, Nogales A, Tebar R. Total and Gastroenterol Nutr 1999;29:612–26. segmental colonic transit time and anorectal manometry Baker SS, Liptak GS, Colletti RB, et al. Evaluation and in children with chronic idiopathic constipation. J P e d iat r treatment of constipation in infants and children: Gastroenterol Nutr 2002;35(1):31–8. summary of updated recommendations of the North 7 Loening-Baucke V. Polyethylene glycol without American Society for Pediatric Gastroenterology, electrolytes for children with constipation and encopresis. Hepatology, and Nutrition. J Pediatr Gastroenterol Nutr J Pediatr Gastroenterol Nutr 2002;34(4):372–7. 2006;43:405–7. 8 Borowitz SM, Cox DJ, Kovatchev B, et al. Treatment of Loening-Baucke V. Anorectal manometry and Biofeedback childhood constipation by primary care physicians: training. In: Hyman PE, Di Lorenzo C (eds). Pediatric efficacy and predictors of outcome. Paediatrics Gastrointestinal Motility Disorders. Academy Professional 2005;115(4):873–7. Information Services, New York, 1994, pp. 231–52. 9 Marlett JA, McBurney MI, Slavin JL. Position of the Loening-Baucke V. Constipation and encopresis. In: Wyllie American Dietetic Association: health implications of R, Hyams JS (eds). Pediatric Gastrointestinal Disease: dietary fiber. J Am Diet Assoc 2002;102(7):993–1000. Pathophysiology, Diagnosis, Management. Saunders, 10 Nolan T, Debelle G, Oberklaid F, Coffey C. Philadelphia 2006, pp. 177–91. Randomized trial of laxatives in treatment of childhood Stallion A, Dough Kou T. Hirschsprung`s disease. In: encopresis. Lancet 1991;338(8766):523–7. Wyllie R, Hyams JS (eds). Pediatric Gastrointestinal 11 Sharif F, Crushell E, O’Driscoll K, Bourke B. Liquid Disease: Pathophysiology, Diagnosis, Management. paraffin: a reappraisal of its role in the treatment of Saunders, Philadelphia, 2006, pp. 735–48. constipation. Arch Dis Child 2001;85(2):121–4. 46 Chapter 5 Abdominal pain in childhood Iñaki X. Irasto rza Terradillo s, MD, and Juan C. Vito ria Co rm enzana, MD, PhD

Introduction

Abdominal pain is one of the most challenging symptoms in every pain perceived in the abdomen originates in the paediatric practice. Often imprecise, abdominal pain may abdomen, and not every pain originating in the abdomen is require, especially if acute, an intense diagnostic approach in perceived in the abdomen. Furthermore, characteristics of order to avoid misidentification of potentially underlying abdominal pain are very diverse; the specific pattern of medical or surgical problems. On the other hand, chronic abdominal pain sensation will help to establish the diagnosis. abdominal pain, most currently functional in origin, Specific types of pain receptors are located in the frequently generates a situation of familial and patient stress abdominal wall, in the mesentery, in the serosal surfaces, in due to the persistent recurrence of symptoms. The the hollow viscera wall, and in the mucosal surfaces. Main paediatrician can also be affected by this stress and can be receptors in each location will respond to specific stimuli ‘forced’ to prescribe multiple unnecessary medical types. Abdominal pain receptors can be triggered by investigations (5.1). mechanical and chemical stimuli (5.2). Mechanical stretch Understanding the neurophysiology of pain perception is and chemical stimuli are the main triggers involved in crucial to making an appropriate diagnostic approach. Not visceral nociceptor activation.

Traction Contraction Functional Bradykinin Histamine Functional PGs Torsion Mechanical Chemical Distension Organic Seratonin Stretch Organic Chloride Pain

Acute abdominal pain Chronic abdominal pain Culture Day/night Age

5.1 Aetiology of acute and chronic abdominal pain. Illness? Family School

5.2 Genesis and perception of abdominal pain. Abdominal pain in childhood 47

Pain of bilaterally innervated organs (i.e. small intestine) Table 5.1 Alarm symptoms, signs, and features in is perceived in the midline. Pain perceived on one side recurrent abdominal pain usually comes from nondigestive intra-abdominal organs (ovary, ureters, and kidneys), , ascending and descending colon, or abdominal wall which are mainly Pain distant from umbilicus (right upper or right lower ipsilaterally innervated. quadrant pain) Dysphagia Persistent vomiting Chronic abdominal pain Gastrointestinal blood loss Complaints of recurrent abdominal pain affect 10–40% of Nocturnal and/or severe diarrhoea children and its prevalence increases with age (5.3)1. Hepatomegaly, splenomegaly When recurrent abdominal pain was first described in Abdominal mass effect 19582, only 10% of patients had a definitive diagnosis; 90% Family history of inflammatory bowel disease, coeliac of patients remained undiagnosed or labelled as ‘suspected disease, or peptic ulcer disease functional abdominal pain’. New pathological entities such Arthritis as Helicobacter pylori infection or non-IgE mediated food allergies and the development of diagnostic techniques has Perirectal disease allowed diagnosis to improve to up to 50% of patients (5.4). Involuntary weight loss In order to avoid unnecessary tests a conservative Deceleration of linear growth approach is appropriate. Alarm symptoms, signs, and Delayed puberty features that should make the physician suspect that the Dysuria or haematuria pain has an organic background are listed in Table 5.1. In their absence, pain is very likely to have a functional origin Respiratory symptoms and therefore most tests will be unnecessary, leading only to Tenderness over the spine or at the costovertebral increase familial anxiety. angle Unexplained fever Pain that wakes up the child

Boys Organic Girls Organic

Functional Functional

0 2 4 6 8 10 12 14 1958 2000 Age (years)

5.3 Incidence of recurrent abdominal pain by age. 5.4 Aetiology of recurrent abdominal pain. 48 Abdominal pain in childhood

Functional gastrointestinal disorders

Functional gastrointestinal disorders (FGID) are defined as 5.4) it is therefore necessary to rule out organic diseases a variable combination of chronic or recurrent presenting with dyspepsia, such as gastro-oesophageal reflux gastrointestinal symptoms not explained by structural or disease (5.6, 5.7), Helicobacter pylori infection, eosinophilic biochemical abnormalities. A symptoms-based classifica - oesophagitis, and gastritis. tion, rather than a targeted organ-based one, has been set by the Rome III committee (Table 5.2) (5.5)3.

Functional dyspepsia Table 5.2 Functional gastrointestinal disorders Dyspepsia is pain or discomfort localized in the upper abdomen. Symptoms may vary including fullness, early satiety, bloating, nausea, retching, and vomiting. No signs or Vomiting and aerophagia symptoms reliably differentiate functional dyspepsia from Adolescent rumination syndrome 4 upper gastrointestinal organic disorders (Table 5.3) . Cyclic vomiting syndrome To establish the diagnosis of functional dyspepsia (Table Aerophagia

Abdominal pain-related FGID Functional dyspepsia* Irritable bowel syndrome* Functional Abdominal migraine* abdominal pain Functional abdominal pain Functional Functional abdominal pain Abdominal Constipation and incontinence dyspepsia syndrome migraine Functional constipation Nonretentive faecal incontinence Irritable bowel syndrome Although presented as independent categories, only a minority of patients shall be classified in any of the first three specific categories (*), while most will fall within the ‘Functional abdominal pain’ open-box category 5.5 Overview of abdominal pain-related functional gastrointestinal disease.

Table 5.3 Abdominal pain-related functional gastrointestinal disorders diagnostic approach

Suspected disorder Diagnostic tests Functional dyspepsia Always required 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 Abdominal pain in childhood 49

Table 5.4 Diagnostic criteria for functional dyspepsia

• Persistent or recurrent pain or discomfort centred in the upper abdomen (above the umbilicus) • Pain not relieved by defecation or associated with onset of a change in stool frequency or consistency • No evidence of inflammatory, anatomic, metabolic, or neoplastic process that explains subject’s symptoms

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

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

5.7 Gastric emptying scintigraphy. Same patient as in 5.6 after treatment with proton pump inhibitors, showing very slow gastric emptying with associated nonacid gastro-oesophageal reflux. 50 Abdominal pain in childhood

Irritable bowel syndrome investigations are required. Aetiology of IBS is multifactorial Irritable bowel syndrome (IBS) is characterized by episodes and not completely understood (5.8)5, 6. Available of recurrent abdominal pain temporally associated with therapeutic options are summarized in Table 5.6, although altered bowel habits: either constipation or diarrhoea (Table most of these patients’ symptoms improve if they manage to 5.5). If the child fulfils the diagnostic criteria no further reduce or dominate the stress intervening factors.

Table 5.5 Diagnostic criteria for IBS

• Abdominal discomfort or pain associated with 2 or more of the following at least 25% of the time: – Improvement with defecation – Onset associated with a change in frequency of stool – Onset associated with a change in consistency of stool • No evidence of inflammatory, anatomic, metabolic, or neoplastic process that explains subject’s symptoms

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

Table 5.6 Treatment of abdominal pain-related FIGD

Functional dyspepsia Abdominal migraine • Avoidance of nonsteroidal anti-inflammatory drugs • Avoidance of foods containing: • Avoidance of foods that aggravate symptoms: – Caffeine – Nitrites – Caffeine – Spicy foods – Amines – Fruit juices – Fatty foods • Behavioural intervention • H2 blockers • Drugs: • Proton pump inhibitors – Pizotifen – Propanolol • Prokinetic drugs: – Cyproheptadine – Sumatriptan – Domperidone – Erythromycin Functional abdominal pain – Cisapride • Psychosocial intervention • Psychological behavioural intervention • Tricyclic antidepressants Irritable bowel syndrome • Peppermint oil • Psychological behavioural intervention

5.8 Aetiology of IBS. Visceral hypersensitivity, • Anxiety • Infection • Depression • Inflammation often appearing after an • Trauma • Social learning of illness enteral aggression behaviour • Allergy Genetic predisposition event in genetically Psychological predisposed patients, Visceral hypersensitivity may lead under stressing circumstances Irritable bowel syndrome to IBS. Abdominal pain in childhood 51

Other disorders lactose intolerance (5.9), coeliac disease (5.10), food Other prevalent disorders that usually present with chronic allergies (5.11), inflammatory bowel disease, and giardiasis abdominal pain and diarrhoea or constipation include: (5.12).

5.9 Lactose intolerance. A: Lactose breath hydrogen test is is a noninvasive test that Liquid measures lactose faeces nonabsorption. B: Faecal reducing 2/3 water 15 drops Clinitest substances: arrival of 1/3 faeces Ames tablet undigested lactose to the large bowel leads to the -ve Trace + ++ +++ +++ presence of reducing +++ 0% 1/4% 1/2% 3/4% 1% 2% sugars in the faeces. Negative? Positive A B

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

A

B 5.10 Coeliac disease. A: Upper gastrointestinal endoscopy in a patient with recurrent abdominal pain and 5.12 Intestinal biopsy showing multiple Giardia lamblia positive coeliac serological markers. B: Duodenal biopsy trophozoites (inset). with villous atrophy, intraepithelial lymphocytes, and crypt . 52 Abdominal pain in childhood

Abdominal migraine Abdominal migraine is characterized by recurrent Familial aggregation and response to antimigraine drugs, paroxysmal episodes of acute, periumbilical and noncolicky although not included in the diagnostic criteria, support the pain associated with anorexia, nausea, vomiting, headache, diagnosis. Treatment options are listed in Table 5.6. and pallor (Table 5.7). The origin of abdominal migraine is A number of digestive and extradigestive conditions linked to other functional disorders like migraine headache including renal colic, recurrent pancreatitis (5.13), and cyclic vomiting syndrome, and patients often progress choledocholithiasis, familial Mediterranean fever, Crohn’s from one to another. Abdominal migraine is one of the disease (5.14), and porphyria, must be ruled out before functional disorders that present more familial aggregation. establishing the diagnosis of abdominal migraine.

Table 5.7 Diagnostic criteria for abdominal migraine

• Paroxysmal episodes of intense, acute periumbilical pain that last for 1 hour or more • Intervening periods of usual health lasting weeks to months • Pain interferes with normal activities • Pain is associated with two or more of the following: – Anorexia – Nausea – Vomiting – Headache – Photophobia – Pallor • No evidence of inflammatory, anatomic, metabolic, or neoplastic process that explains subject’s symptoms

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

5.13 An abdominal X-ray during an endoscopic retrograde cholangiopancreatography (ERCP) shows gallstones in bile ducts in a patient with recurrent pancreatitis. 5.14 Barium follow-through in a patient with stenosing Crohn’s disease. Abdominal pain in childhood 53

Childhood functional abdominal pain Children with recurrent abdominal pain episodes that do reasonable to decide the laboratory and radiological tests to not fulfil the previous categories but in whom organic perform or decide if the patient requires an endoscopy. pathology has been reasonably excluded fall within this A pychosocial approach in patients with functional category (Table 5.8). They represent the vast majority of abdominal pain is particularly indicated because the patients consulting for recurrent abdominal pain in primary symptoms are often associated with varying degrees of paediatric care. anxiety, depression, or manipulative behaviour. Behavioural Functional abdominal pain syndrome has been described intervention associated or not with antidepressant drugs is for a subgroup of patients with functional abdominal pain indicated in these patients7. with more persistent abdominal symptoms associated with Differential diagnosis include a wide range of digestive other somatic symptoms (Table 5.9). Functional abdominal and nondigestive diseases such as coeliac disease (5.15), pain diagnosis can be difficult to establish as there are no inflammatory bowel disease (5.16), food intolerances, specific criteria as there are for other abdominal pain-related Helicobacter pylori infection, eosinophilic enteritis, chronic FGID. It is therefore sensible to perform some basic pyelonephritis, and parasite infestation. However, it is investigations (Table 5.10) in order to exclude an organic important to remember that in most cases there will be no origin of the symptoms. Routine investigations are not organic underlying disease and that not every endoscopic or required in every patient. Depending on the signs, radiological finding will prove an organic aetiology (5.17). symptoms, age, and gender of the patient it will be

Table 5.8 Diagnostic criteria for functional Table 5.10 Investigations in patients with abdominal pain suspected functional abdominal pain

• Episodic or continuous abdominal pain • Full blood count • Insufficient criteria for other FGID • C-reactive protein • No evidence of inflammatory, anatomic, metabolic, or • Erythrocyte sedimentation rate neoplastic process that explains the subject’s • Amylase symptoms • Sugars breath hydrogen test All three criteria must be fulfilled at least once per week • Helicobacter pylori test for at least 2 months • Stool culture and examination for ova and parasites • Urinalysis and urine culture • Pregnancy test Table 5.9 Diagnostic criteria for functional • Barium swallow abdominal pain syndrome • Barium follow-through • Abdominal ultrasound scan • Functional abdominal pain at least 25% of the time and at least one of the following: • CT scan – Some loss of daily activity • MRI – Additional somatic symptoms: headache, limb pain, or • Endoscopy difficulty sleeping

Criteria must be fulfilled at least once per week for at least 2 months. 54 Abdominal pain in childhood

A B C 5.15 Trichobezoar removed from the stomach of a girl 5.16 Same findings in barium enema (A), abdominal MRI with recurrent abdominal pain and undiagnosed coeliac (B) and HMPAO-Tc99m leukocytes scintigraphy (C) in a disease. patient with ascending colon stenosing Crohn’s disease.

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

Infant colic

Although it has not been proven that infant colic has a Rhythmic rocking and a car ride are efficient manoeuvres to digestive or even abdominal origin, many infants with calm the infant. It has been reported that milk intolerance or recurrent paroxysms of irritability, fussing, and crying8 oesophagitis might be the cause of excessive crying. A episodes are referred to paediatric gastroenterologists therapeutic trial with a hydrolysed protein formula or (Tables 5.11, 5.12). The most important point is to reassure medication to suppress gastric acid secretion would be a parents, to make sure they understand that colic is reasonable approach10, 11. ‘something infants do, rather than a condition they have’9. Abdominal pain in childhood 55

Table 5.11 Diagnostic criteria and supporting Table 5.12 Treatment of infant colic features for infant colic

• Parent reassurance Diagnostic criteria • Rhythmic rocking and patting 2–3 times per second • Paroxysms of irritability, fussing, or crying in a quiet environment • Episodes lasting 3 or more hours per day and occurring at least 3 days per week for at least • Car ride 1 week • Time-limited therapeutic trial: • No failure to thrive – Hydrolyzed protein formula All the criteria must be fulfilled in infants from birth – Medication to suppress gastric acid secretion to 4 months of age Relief of symptoms should be apparent within 48 hours Supporting features • Starts and stops suddenly • Occurs late in the day • Prolonged, inconsolable crying • Crying after feedings • Facial grimace • Abdominal distension 8 Wessel MA, Cobb IC, Jackson EB, et al. Paroxysmal • Increased gas fussing in infancy, sometimes called colic. Pediatrics • Flushing 1954;14:421–34. • Legs flexed over the abdomen 9 Barr RG. ‘Colic’ is something infants do, rather than a • Rhythmic rocking and patting quietens the baby condition they ‘have’: a developmental approach to crying • Car riding stops the crying phenomena, patterns, pacification, and (patho)genesis. In: Barr RG, St James-Roberts I, Keefe MR (eds). New Evidence on Unexplained Early Crying: its Origins, Nature, and Management. Johnson & Johnson Pediatric References Institute, Cincinnati, 2001, pp. 87–104. 10 Lothe L, Lindberg T. Cow’s milk whey protein elicits 1 Oster J. Recurrent abdominal pain, headache, and limb symptoms of infant colic in colicky formula-fed infants: a pains in children and adolescents. Pediatrics 1972;50:429. double blind crossover study. Pediatrics 1989;83:262–6. 2 Apley J, Naish N. Recurrent abdominal pains: a field survey 11 Hyman PE, Milla PJ, Benninga MA, et al. Childhood of 1,000 school children. Arch Dis Child 1958;33:165–70. functional gastrointestinal disorders: neonate/toddler. 3 Rasquin A, Di Lorenzo C, Forbes D, et al. Functional Gastroenterology 2006;130:1519–26. gastrointestinal disorders: child/adolescent. Gastroenterology 2006;130(5):1527–37. 4 Boyle JT. Recurrent abdominal pain: an update. Pediatr Further reading Rev 1997;18:310. 5 Mayer EA, Collins SM. Evolving pathophysiologic Barad AV, Saps M. Factors influencing functional models of functional gastrointestinal disorders. abdominal pain in children. Curr Gastroenterol Rep Gastroenterology 2002;122:2032–48. 2008;10:294–301. 6 Morris-Yates A, Talley NJ, Boyce PM, et al. Evidence of a McOmber MA, Shulman RJ. Pediatric functional genetic contribution to func tional bowel disorder. Am J gstrointestinal disorders. Nutr Clin Pract Gastroenterol 1998;93:1311–17. 2008;23:268–74. 7 Campo JV, Bridge J, Ehmann M, et al. Recurrent Perez ME, Youssef NW. Dyspepsia in childhood and abdominal pain, anxiety, and depression in primary care. adolescence: insights and treatment conditions. Curr Pediatrics 2004;113:817–24. Gastroenterol Rep 2007;9;447–55. 56 Chapter 6 Gastrointestinal bleeding George Gershman, MD, PhD

Introduction Haematemesis Haematemesis is the vomiting of bright-red ‘fresh’ blood, or Bleeding from the gastrointestinal (GI) tract in infants and ‘coffee ground’ emesis of dark-brown ‘old’ blood with children is always stressful and frightening for patients and haemoglobin (Hb) converted to haematin in the stomach by their parents and challenging for a physician, especially if hydrochloric acid. Usually, haematemesis reflects acute bleeding is severe. The attending paediatrician should act bleeding from the oesophagus, stomach, or proximal promptly and adequately to the degree of haemodynamic duodenum. Swallowing of maternal blood in neonates, and instability and initiate a diagnostic work-up according to the epistaxis in older children, should be ruled out. mode of presentation and common age-specific causes of GI haemorrhage. Melena Melena implies liquid, coal black, shiny, sticky, tarry, and foul-smelling stool. It suggests bleeding from the upper GI Epidemiology tract. Occasionally, the site of bleeding can be found in the ileum or right colon. However, in this case stool is black but The incidence of upper GI bleeding among infants and not tarry. Melena suggests a minimum loss of 50–100 ml5 or children is unknown. Epidemiological data from the UK 2% of blood volume6. Stool may remain black or tarry for a and USA indicate that the incidence of upper GI bleeding in few days after massive haemorrhage, even though active adults younger than 29 is approximately 18–23 per 100,000 bleeding has ceased. adults per year, which is almost 4 to 5 times less than among older groups1. It is reasonable to assume that the incidence Occult gastrointestinal bleeding of upper GI bleeding in infants and children is even lower. Occult GI bleeding is the presence of an invisible quantity of However, the risk of upper GI bleeding is higher (between blood in stool detected by a special technique. It is a 6.2 and 10.2%) in infants and children admitted to synonym of chronic, recurrent losses of small amounts of paediatric intensive care units2, 3. blood, which often lead to severe microcytic anaemia. Although rectal bleeding is quite common in paediatric practice, the epidemiology of this problem is not well Haematochezia established. According to published data, rectal bleeding Haematochezia is the passage of bright red or maroon blood was a chief complaint of 0.3% of all visits to a tertiary from the rectum. This may be pure blood, bloody diarrhoea emergency department during a 10-month period4. or blood mixed with stool. As a rule, it is a sign of lower GI bleeding from the colon or distal ileum.

Definitions Assessment

There are four presentations of blood loss from the GI tract: Initial assessment of the child with suspected GI bleeding haematemesis, melena, occult bleeding, and haematochezia. should be focused on haemodynamic stability and clues for Gastrointestinal bleeding 57

the aetiology of bleeding. A prompt assessment of estimated tomatoes, sweets, amoxicillin, phenytoin, and rifampin can blood loss and the degree of haemodynamic instability colour stool and emesis to red or burgundy. Bismuth should be done using objective criteria, such as mental preparations, activated charcoal, iron, spinach, blueberries, status, skin colour, capillary refill, pulse, blood pressure, and liquorice can simulate bleeding by black staining of emesis orthostatic manoeuvres (Table 6.1). Special attention and stool. An appropriate history, a normal physical exam- should be focused on tachycardia and narrowed pulse ination, guaiac-negative stool, and/or gastroccult-negative pressure, which are the earliest signs of impending shock. vomitus are sufficient to rule out a true bleeding episode. Hypotension usually occurs in the late phase of shock in It is important to remember that haematemesis and/or children, and is an ominous finding. The value of the initial melena can be secondary to epistaxis. History of recent haematocrit (Hct) may not accurately reflect the severity of tonsillectomy and adenoidectomy or picking nose habits blood loss. Firstly, the Hct does not fall immediately with increases the probability of epistaxis. Thorough examination haemorrhage due to proportionate reductions of plasma and of the nose and oropharynx can help to establish the right red cell volumes. Secondly, it begins to fall due to diagnosis. compensatory restoration of the intravascular volume by the Detailed history and physical examination can help to shift of extravascular fluids into the vascular bed. This narrow the diagnostic work-up. For example, treatment process begins shortly after the onset of bleeding. However, with nonsteroidal anti-inflammatory drugs (NSAIDs) is a it is not complete for 24–72 hours. At this point, plasma risk factor for acute gastric ulcers and bleeding from the volume is larger than normal and the Hct reaches its true stomach. Jaundice, hepatomegaly, spider haemangiomata, nadir assuming that bleeding has stopped. prominent vessels of the abdominal wall, or ascites are signs of chronic liver disease and suggestive of portal Diagnosis hypertension. Alternatively, GI bleeding in an acutely ill, febrile child with jaundice could be secondary to Red food and some medications can stain stool or emesis. coagulopathy or the acute ulceration of the stomach or the Cranberries, cranberry juice, cherries, strawberries, beets, duodenum due to sepsis. Careful assessment of the

Table 6.1 Manifestations of different degrees of GI blood loss

Symptoms and signs Blood loss <15% Blood loss <30% Blood loss >30% Normal appearance + – – Some anxiety ± + + Disorientation – – + Lethargy – ± + Tachycardia ±* ++ + Pallor – + ++ Livedo reticularis – + ++ Cold extremities – + + Capillary refill <2 sec – + + Hypotension – ± ++ Narrowed pulse pressure – + + Elevated diastolic pressure – + – Low diastolic pressure – – +

*Tachycardia could be due to agitation or anxiety in children with mild blood loss 58 Gastrointestinal bleeding

perineum can reveal fissures, fistulas, or perianal induration. The results of blood test can give some clues to the nature If the source of bleeding is not obvious, the placement of a of bleeding. Low Hb and Hct with normal mean cell volume nasogastric tube is very useful. The largest bore tolerable tube (MCV) are typical for recent blood loss. An elevated blood should be placed for adequate gastric lavage: a 10 to 12 Fr urea nitrogen (BUN) suggests volume depletion and sump tube is a reasonable choice for small children and 14 to absorption of the blood proteins in the small intestine, 16 Fr for older patients. Room temperature saline is the which support the diagnosis of upper GI bleeding. Very low optimal fluid for this procedure. Iced saline lavage is no longer Hb, Hct, and MCV in haemodynamically stable patients, is recommended because it compromises platelet function at the consistent with chronic GI blood loss. Knowledge of bleeding site and may induce hypothermia (especially in common causes of GI bleeding in age-specific groups of infants) and subsequent clinically significant arrhythmia. A children helps with the diagnostic strategy (Table 6.2). bloody or coffee ground aspirate indicates upper GI bleeding, Endoscopy is the method of choice for diagnosis of the if epistaxis was ruled out. The absence of blood in the specific causes of acute and chronic GI bleeding related to stomach does not exclude upper GI bleeding, since the source mucosal and submucosal lesions of GI tract. A tagged red of haemorrhage can be in the duodenum. The presence of blood cell scan and angiography are alternative methods coffee ground fluid in gastric aspirate, which promptly clears used to diagnose children with active GI bleeding of obscure by gastric lavage, suggests that bleeding has stopped. origin, especially when vascular anomalies or haemobilia are Ineffective gastric lavage indicates ongoing bleeding. suspected.

Table 6.2 Common causes of GI bleeding in children

Age Upper GI Bleeding Low GI bleeding

Neonates (0–30 days) Swallowed maternal blood 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 Gastrointestinal bleeding 59

Age-associated aetiologies Intermittent rectal bleeding with streaks of frank blood mixed with normal appearing stool could be secondary to Neonates nodular lymphoid hyperplasia of the colon or terminal ileum. In the first few days of life, coffee ground emesis or bloody During endoscopy, multiple hemispheric smooth nodules less stools in an otherwise healthy and haemodynamically stable than 4 mm can be found in clusters or diffusely throughout the neonate are most likely caused by swallowed maternal blood GI tract (6.1). It is considered to be an excessive reaction of either during delivery or breast-feeding. In such cases, the the GI tract lymphatic tissue (lymphoid follicles and Peyer’s Apt-Downey test should be performed to differentiate patches) to food-related or other antigens. Spontaneous between maternal and infant blood. Acute gastric or regres sion of lymphoid follicles is quite common. In addition duodenal ulcers should be suspected in sick premature or to parental reassurance, an elimination diet for nursing full-term asphyxiated or septic newborns or patients with mothers is a reasonable initial treatment. Feeding with exten - intracerebral bleeding, raised intracranial pressure, sively hydrolyzed protein formula is the next step of therapy. congenital heart disease, respiratory failure, or hypo - Corticosteroid therapy is restricted to infants with a severe glycaemia. The typical scenario includes sudden onset of form of this disease, with recurrent abdominal pain, signifi cant haematemesis or melena and signs of haemodynamic anaemia, persistent rectal bleeding, diarrhoea, and failure to instability. Occasionally, severe upper GI bleeding can occur thrive. In such cases, immunodeficiency has to be excluded. in healthy full-term neonates within the first few days of life7. Oesophagitis should be suspected as a cause of bleeding GI bleeding is a common manifestation of necrotizing in infants with a history of recurrent emesis and interrupted enterocolitis (NEC). Rare causes of GI bleeding in the first feeding patterns associated with crying, irritability, or month of life include Hirschsprung enterocolitis, midgut arching (6.2). The patients with repaired oesophageal volvulus, duplication cyst, vascular malformation, and atresia with or without tracheaoesophageal fistula are at haemorrhagic disease of the newborn, particularly in breast- higher risk of severe reflux disease and oesophagitis. feeding neonates, who did not receive vitamin K. Bleeding induced by oesophagitis is usually recurrent and not intensive. The patients may have haematemesis with Infants up to 6 months of age streaks of blood or guaiac-positive stool. One of the leading causes of GI bleeding in infants less than Infants or older children can develop minor bleeding due 6 months of age is cow’s milk or soy protein allergy. The to prolapse of gastric mucosa into the oesophagus through spectrum of symptoms includes recurrent vomiting, the gastro-oesophageal junction (prolapse gastropathy) haematemesis, failure to thrive, and diarrhoea with guaiac- (6.3). This condition is manifested by recurrent emesis with positive stools or haematochezia. Exclusively breast-fed food, and appearance of brown flecks of denaturated blood infants may develop similar symptoms on rare occasions. An at the end of vomiting. The presence of frank blood or clots anal fissure is another common cause of bleeding in infants. at the end of recurrent emesis suggests a more serious The diagnosis is made by careful examination of the anus. problem such as a Mallory–Weiss tear.

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).

A B 60 Gastrointestinal bleeding

Infants and children less than 7 years of age Intussusception Portal hypertension Intussusception, which is common in the first 2 years of life, The signs and symptoms of portal hypertension are a large is strongly considered in infants and children with sudden volume haematemesis, history of omphalitis secondary to onset of severe cramping abdominal pain intercepted with catheterization of umbilical vein, presence of splenomegaly or pain-free episodes and currant jelly stools. A lead point is hepatosplenomegaly, and other stigmata of chronic liver often present in children older than 2 years of age. Diagnosis disease such as jaundice, spider angiomas, caput medusa, and is confirmed by ultrasonography demonstrating positive ascitis. Oesophageal varices are the most common site of ‘concentric circles’ or the ‘target-shaped’ sign, or barium bleeding in children with intrahepatic-sinusoidal and enema. Hydrostatic reduction of intussusceptions is extrahepatic-presinusoidal forms of portal hypertension (6.4). successful in more than 90% of children. Two-thirds of children with portal hypertension will bleed before 5 years of age. The diagnosis is made based on the Meckel’s diverticulum presence of oesophageal or gastric varices (6.5) or hypertensive Meckel’s diverticulum is the most common congenital gastropathy (6.6) during an upper GI endoscopy. anomaly in children. It is estimated that approximately 2% of infants have a remnant of the omphalomesenteric duct.

6.2 Oesophagitis: prominent oedema, erythema and 6.3 Prolapse gastropathy. Multiple mucosal haemorrhages erosions in the distal oesophagus. in the gastric cardia due to recurrent prolapse of the affected area through the diaphragm into the oesophagus.

6.4 Oesophageal varices: enlarged tortuous veins of the 6.5 Gastric varices: multiple varices of the gastric cardia. distal oesophagus. Gastrointestinal bleeding 61

6.6 Hypertensive gastropathy: oedematous gastric 6.7 A juvenile polyp of sigmoid colon: a small amount of mucosa with focal erythema and multiple small mucosal blood is present on the head of the polyp. The adjacent haemorrhages. area is slightly pale and has multiple small grooves, so- called ‘goose-skin’ sign.

However, less than 5% of children will develop composed of normal and cystically dilated crypts embedded complications, including GI bleeding. Half of them become in an abundant lamina propria. Colonoscopy is indicated symptomatic in the first 2 years of life. The predominant due to high incidence (almost 50%) of coexisting polyps in location of Meckel’s diverticulum is the distal ileum (40–60 the descending and more proximal portions of the colon. cm above the ileocaecal valve). Ectopic tissue is present in Endoscopic polypectomy is the treatment of choice. There up to 80% of symptomatic patients. The gastric mucosa is is a general consensus that a single juvenile polyp is not a the most common type of ectopia. The cause of bleeding is premalignant condition. Therefore, removal of a solid juvenile peptic ulceration at the junction of the ectopic gastric polyp is curative. Surveillance colonoscopy is not indicated mucosa and normal ileum, the so-called marginal ulcer. The unless the child develops a new episode of rectal bleeding. bleeding can be massive, but it may cease spontaneously secondary to contraction of the splanchnic vessels in Haemolytic uraemic syndrome response to hypovolemia. This phenomenon explains an Haemolytic uraemic syndrome (HUS) should be always intermittent nature of bleeding from Meckel’s diverticulum. suspected in infants and toddlers with bloody diarrhoea, Bleeding is usually painless, but sometimes coincides with which is present in three-quarters of children with epidemic recurrent abdominal pain. The diagnostic procedure of HUS. In two-thirds of these children, Escherichia coli choice is a 99mTc pertechnetate scan, which has sensitivity of 0157:H7 can be isolated. The cause of bloody diarrhoea in 85% and specificity of 95%. HUS is haemorrhagic colitis due to endothelial damage produced by verotoxin and chiga toxin and submucosal Juvenile polyps haemorrhages. Tenesmus is common. Diffuse, severe Juvenile polyps may occur in as many as 1% of children, with abdominal pain with peritoneal signs can occur. peak incidence from 2 to 5 years of age. The common clinical The presence of the so-called a ‘thumb printing’ sign on a presentation is recurrent, painless bleeding with a small barium enema or a CT scan reflects a submucosal haemorr- amount of blood on formed stool. Diarrhoea and tenesmus hage of the colon. Colitis-related symptoms last no longer can occur when the polyp is large and located in the left colon. than a week, followed by signs of haemolytic anaemia and Typical juvenile polyps are smooth, rounded, and red. oliguria. Known GI complications of HUS are intussuscep - Polyps less than 1 cm are usually sessile (6.7); polyps larger tion, pancreatitis, and intestinal obstruction. The small or than 1 cm have short or long stalks. Juvenile polyps are large bowel perforation may occur during peritoneal dialysis. 62 Gastrointestinal bleeding

6.8 Henoch–Schönlein purpura: multiple submucosal 6.9 Helicobacter pylori gastritis: nodular appearance of haemorrhages and secondary oedema are common the antral mucosa is a commom finding in children with findings in the colon. HP gastritis.

Henoch–Schönlein purpura Although peptic ulcer disease is relatively rare in Henoch–Schönlein purpura (HSP) is most common in paediatric patients, it comprises at least one-third of the children less than 7 years old. The median age is 4 years. cases of upper GI bleeding in school age children. The HSP should be suspected in children with sudden onset of majority of bleeding ulcers are located in the duodenal bulb severe diffuse abdominal pain, vomiting, and haemato - (6.10). At least 80% of bleeding episodes from duodenal chezia, especially if this happens after viral illness in winter ulcers cease spontaneously. However, if the bleeding is and early spring and about a week after purpuric-type skin arterial, it may recur and become life threatening. Urgent lesions appear on the buttocks or low extremities. On rare endoscopy is necessary as soon as the patient becomes more occasions, GI manifestations may precede skin rash. Severe stable after fluid resuscitation. anaemia is uncommon. The small and/or large bowel has The risk factors for recurrent bleeding are: large ulcer different degree of haemorrhagic lesions (6.8). These may (more than 2 cm), location of the ulcer on posteroinferior be apparent on a small bowel X-ray series or barium enema wall of the duodenal bulb, blood spurting from the base of with coarsening of folds and thumb printing. Abdominal the ulcer, a visible vessel, or an adherent clot. These high-risk pain and haematochezia is self-limited. Treatment with patients require a second-look endoscopy 24 hours after the corticosteroids is controversial, although it may shorten the index endoscopy, and careful observation in the intensive course of GI symptoms of abdominal pain by 1 or 2 days. care unit. The most critical time for rebleeding is the first 3 days following the initial haemostasis. Haemodynamically Children aged 7 years and older stable children without the endoscopic risk factors for Drug-induced gastritis or acute ulcer should be strongly recurrent bleeding do not require endoscopic haemostasis suspected in children who received treatment with NSAIDs and can be managed safely on an outpatient basis. or oral steroids. The degree of bleeding varies between mild Colitis is the most common cause of rectal bleeding in to moderate. The usual clinical presentation is the sudden older children and teenagers. Infectious colitis is more onset of abdominal discomfort followed by haematemesis or common by far than inflammatory bowel disease. In melena. Haemorrhage usually originates from the stomach. general, bacterial colitis is an acute, self-limited disorder The incidence of NSAID-related GI bleeding is much manifested by sudden onset of fever, tenesmus, and bloody higher in patients with Helicobacter pylori (HP) gastritis diarrhoea lasting from 5 to 7 days. Chronic diarrhoea (6.9). Therefore, eradication of HP infection is (lasting 2 weeks or more) is usually associated with chronic recommended before long-term therapy with NSAIDs. inflammatory bowel disease. Ulcerative colitis (6.11) usually Gastrointestinal bleeding 63

6.10 Duodenal ulcer, with active bleeding. 6.11 Ulcerative colitis: diffuse erythema, oedema, loss of vascular pattern, and exudates are seen.

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

Treatment clotting factors. Oxygen supplementation and bolus of saline targets tissue oxygenation and restoration of circulation. The It is imperative to initiate resuscitation of a haemodynamically volume of isotonic solution should be sufficient to reverse unstable patient almost immediately before any diagnostic tachycardia and postural hypotension. Blood transfusion is procedure is considered. Two large-bore peripheral indicated for patients with persistent orthostatic hypotension intravenous lines or a central line should be placed and after replacement of 15–20% of blood volume with isotonic secured. Blood has to be typed and cross-matched and sent for solution, children with acute haemorrhage and initial Hct of baseline laboratory assessment including liver enzymes and less than 20%, and children with haemorrhagic shock. Packed 64 Gastrointestinal bleeding

red cell transfusion is the product of choice for replacement of References blood loss. Matched whole blood is preferred for patients with massive bleeding. Fresh-frozen plasma is indicated for children 1 Rockall TA, Logan RFA, Devlin HB, et al. Incidence of with suspected or documented clotting factor deficiency, such and mortality from acute upper gastrointestinal as children with acute or chronic liver disease. Platelet haemorrhage in the United Kingdom. BMJ transfusion is indicated in rare cases of severe bleeding with 1995;311:222–6. estimated blood loss of more than 50% of the patient’s blood 2 Lacroix J, Nadeau D, Laberge S, et al. Frequency of upper volume or children with active haemorrhage and platelet count gastrointestinal bleeding in a pediatric intensive care unit. less than 50,000/mm3. Early blood transfusion is reasonable Crit Care Med 1992;20:35–42. for children with active bleeding and known chronic heart or 3 Chaibou M, Tucci M, Dugas MA, et al. Clinically lung diseases. Monitoring of vital signs is a more accurate way significant upper gastrointestinal bleeding acquired in a to assess the effect of blood transfusion than monitoring of the pediatric intensive care unit: a prospective study. Hct soon after transfusion. It is reasonable to wait 6 hours Pediatrics 1998;102:933–8. before checking posttransfusion Hct. 4 Teach SJ, Fleisher GR. Rectal bleeding in the pediatric Octreotide (a synthetic somatostatin analogue) is effective emergency department. Ann Emerg Med adjuvant medical therapy for severe bleeding from 1994;23:1252–8. oesophageal or gastric varices8. It should be given to the 5 Gilger MA. Upper gastrointestinal bleeding. In: Walker child with active haemorrhage and any evidence of chronic WA, Goulet OJ, Kleinman RE, et al. (eds). Pediatric liver disease or previously diagnosed portal hypertension. Gastrointestinal Disease: Pathophysiology, Diagnosis and The initial bolus of 1 µg/kg of intravenous octreotide is Management, 4th edn. BC Decker, Hamilton, 2004, pp. followed by continues infusion of octreotide 1 µg/kg/h. The 258–65. dose can be increased every 6 hours up to 5 µg/kg/h. 6 Ament ME. Diagnosis and management of upper gastrointestinal tract bleeding in the pediatric patient. Pediatr Rev 1990;12:107–16. Endoscopic haemostasis of nonvariceal 7 Goyal A, Treem WR, Hyams JS. Severe upper and variceal bleeding gastrointestinal bleeding in healthy full-term neonates. Am J Gastr 1994;89:613–6. Indications for endoscopic haemostasis of nonvariceal 8 Eroglu Y, Emerick KM, Whitingon PF, et al. Octreotide bleeding include: therapy for control of acute gastrointestinal bleeding in • Active bleeding from the gastric or duodenal ulcer. children. JP G N 2004;38:41–7. • Stigmata of recent bleeding: a nonbleeding visible vessel in the ulcer base and a densely adherent clot. • Bleeding arteriovenous malformation. Further reading • Bleeding after polypectomy. Boyle JT. Gastrointestinal bleeding in infants and children. Three methods are routinely used for endoscopic Pediatr Rev 2008;29:39–52. haemostasis of nonvariceal bleeding: injection of Gershman G, Ament M. Practical Pediatric Gastrointestinal vasoconstrictive agent, thermal coagulation, and metal clips. Endoscopy. Blackwell Publishing, Massachusetts, 2007. Indications for endoscopic haemostasis of variceal Kay MH, Wyllie R. Therapeutic endoscopy for nonvariceal bleeding include: gastrointestinal bleeding. J Pediatr Gastroenterol Nutr • Active bleeding from oesophageal or gastric varices. 2007;45:157–71. • History of bleeding secondary to portal hypertension. Murphy MS. Management of bloody diarrhea in children in • Failed surgical shunting procedure. primary care. BMJ 2008;336:1010–15. Shamir R, Eliakim R. Capsule endoscopy in pediatric Two different techniques are currently used for patients. World J Gastroenterol 2008;14:4152–5. haemostasis of variceal bleeding, sclerotherapy and endoscopic variceal ligation. Chapter 7 65 Cow’s milk allergy Antonio Nieto, MD, PhD, and Angel Mazón, MD

Introduction they are denominated allergic: the classic allergic reactions are termed IgE mediated (7.1), and the classic intolerance to Allergy to cow’s milk (CM) proteins appears mainly in CM proteins is now termed non-IgE-mediated allergy (7.2). infants and persists for several months or years, or may even The nontoxic reactions, which are not mediated by an be lifelong. Allergic reactions to CM are frequent (1–2% of immunological mechanism, are now termed intolerance. infants)1–4. Cow’s milk allergy (CMA) constitutes a Proteins are the agents that cause allergic reactions. The challenge for paediatricians, who must be aware of the basic units of proteins are amino acids. The molecular condition, and know how to initiate diagnostic and weight of amino acids ranges from 89 to 204 Da. The therapeutic approaches. primary structure of proteins is a chain of amino acids bound to each other through their acid (-COOH) and Adverse reactions to foods amino (-NH2) terminals. The amino acids can occur in short chains of 6–9 amino acids (called peptides) or long The European Academy of Allergy and Clinical chains of hundreds of amino acids. It is important to notice Immunology divides adverse reactions to foods into toxic the molecular weight to estimate the number of amino acids and nontoxic. If an immunological mechanism is involved that can be found in a peptide or a protein.

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

Mastocyte

Release of mediators 66 Cow’s milk allergy

Mast cell Table 7.1 Cow’s milk proteins Milk IL-4 IL-13 IgE Th2 B Casein Caseins* 21 kD Histamine triptase Whey α-lactoalbumin* 15 kD IgG β-lactoglobulin* 36 kD APC Th0 Bas ECP Eos Seroalbumin 68 kD IL-12 Neu MPO IFN-γ Lactoferrin 87 kD Th1 IgG1 160 kD IgG2 160 kD IgM 900 kD IgA 400 kD 7.2 Non-IgE immune responses to foods. There is no Other definite known intermediary pathogenic mechanism: probably cell-mediated responses are involved, or mixed *Synthesized in the mammary gland 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, disappear when the offending food is withdrawn, and and they need a relatively large amount of protein. The reappear when the patient is challenged with it. The classical interval between exposure and symptoms is longer than symptoms appear immediately after ingestion or contact with for IgE responses. the allergen. They can show as urticaria-angioedema involv- ing skin and mucosa; digestive symptoms such as vomit ing, There are several casein proteins, whose molecular abdominal pains or cramps, and diarrhoea, or respiratory weight is around 21 kD, and which comprise around 200 symptoms including wheezing, difficult breath ing, and amino acids. Although the absolute amount of whey rhinoconjunctivitis. The most severe disorder is anaphylaxis. proteins is lower, the number of different proteins is greater Group B includes patients who often have a sensitization to as are their molecular weights (Table 7.1). A patient can be foods. Some patients have an IgE sensitization, and respond to sensitized to only one or more than one protein. avoiding/challenging with the food in the same way that group The human breast does not synthesize β-lactoglobulin. A does. Nevertheless, other patients who are also sensitized Thus, any content in human milk comes from the dietary have no clinical response to diet, and the course remains intake. A regular infant formula contains about 300 mg of irrespective of diet. The group B includes mainly atopic β-lactoglobulin per 100 ml. Human milk contains around dermatitis. In cases of a complete or partial response to 0.42 μg%. A few drops of formula contain as much lacto - avoiding and challenging, it is usually not immediate, but takes globulin as 100 litres of human milk. These few drops con - several hours or even days to be evident. Pathogenic tain as much lactoglobulin as the amount present in human mechanisms not mediated by IgE may be involved. Some milk that a lactating mother gives in 3 or more months. No infants with CMA have isolated haematochezia and are wonder that a child who is sensitized to CM but has no otherwise healthy. Eosinophilic infiltration of one or several symptoms while being breast-fed develops overt severe portions of the digestive tract can appear in children with symptoms the first time that he is given a bottle of formula. CMA: it is diag nosed by the eosinophilic count in biopsy samples. Depending on the affected portion it causes dysphagia, nausea, vomiting, gastro-oesophageal reflux, Clinical picture abdominal pain or cramps, diarrhoea of variable severity, occult or overt blood in stools. Group A comprises signs and symptoms associated with a Group C includes diseases in which no IgE mechanism is demonstrated IgE sensitization to foods. These symptoms identified. They have a good clinical response to the Cow’s milk allergy 67

elimination of the offending food. The most frequent Table 7.2 Clinical history disorder in group C is what was formerly called intolerance to CM proteins. When diarrhoea is present, malabsorption can appear and lead to failure to thrive or to specific • Antecedents of allergy nutritional deficits. • Feeding: breast/mixed/formula All the symptoms are very common and they are not • Age at onset of symptoms always caused by CMA. Indications for an allergologic • Chronology and type of symptoms work-up would be those in whom the clinical history is • Amount of milk which causes symptoms suggestive of CMA.

Table 7.3 Allergologic evaluation Diagnostic approach

When first facing a child with a clinical picture suspicious of Prick tests (>3 mm diameter) CMA, the initial approach is based on a good clinical history Sensitivity 70% (Table 7.2). The three first issues may orientate the physician Specificity 83% towards a higher or lower probability of allergy, but their Positive likelihood ratio 4.12 usefulness is very limited. The two last issues are much more Serum specific IgE informative about the suspect mechanism of reaction. Sensitivity 0.63 It is important to try to identify if the patient has an IgE or Specificity 0.83 non-IgE reaction. The allergologic tests try to identify if there Positive likelihood ratio 3.71 is specific IgE against CM proteins5. This is accomplished with the use of skin prick tests, and the quantification of Tests with other allergens specific IgE in serum. Both tests have a good specificity but a more modest sensitivity (Table 7.3). As some patients have discordant responses in the tests, performing both gives the Table 7.4 Allergologic evaluation: double blind best yield, but even so some patients will be misclassified as placebo controlled challenge test non-IgE responders. The positivity of any of the tests proves that there is a sensitization to CM; the relationship of Open challenge test acceptable in infants sensitization with clinical symptoms must be clarified through the interpretation of the clinical history or Perform if: performing challenge tests. Sensitization to other allergens • Adequate clinical condition must be assessed: it is not surprising to find out that the • No symptoms patient is sensitized to other allergens, especially hen’s eggs. • Symptom-free interval The gold standard for the diagnosis of food allergy is the • Under strict medical control double-blind placebo-controlled challenge test. This is often required for investigational studies, but in the routine clinical • No anaphylactic reactions practice an open challenge is acceptable (Table 7.4). The protocol must be adapted to every child, taking into account the clinical history, previous reactions, and results of tests without symptoms. However, between these extremes are (Table 7.5). More caution must be taken for those with posi - found a range of responses that are difficult to interpret. Thus, tive IgE tests, while those with negative tests usually tolerate repeated challenges are sometimes needed until a clear greater amounts, and the protocol can be performed more interpretation can be reached. The positive response to the rapidly. Several days must elapse until a negative response can challenge test permits a diagnosis of allergy, but it cannot be ascertained. The test is easily interpreted as positive when identify which mechanism is involved. The allergologic immediately evident typical reactions appear, and easily evaluation is complete when IgE tests and the challenge are interpreted as negative when there is a long follow-up time performed (7.3). 68 Cow’s milk allergy

Table 7.5 Allergologic evaluation: challenge test and interpretation

Challenge test Interpretation • Increasing amounts (from 1 drop) • Subjective criteria • 15–30 minute intervals • Difficult in delayed responses • Assess clinical response • May have to be repeated • May take several days • Identifies allergy, but not the mechanism

Allergy tests Suspect symptoms Prick/serum IgE

+ –

Challenge Challenge

+ – + –

IgE mediated Asymptomatic Non-IgE mediated Current CM allergy sensitization CM allergy tolerance

7.3 Algorithm of the allergologic evaluation.

Treatment

Treatment is based on a diet free of CM proteins. Breast- also eliminating peptides of large molecular weight. feeding must be encouraged. The lactating mother has to When proteins are heated, their tertiary structure is avoid CM proteins. If the mother has a varied diet, there is damaged. The chemical bonds are ‘broken’ and the protein no risk of nutritional deficits, except for calcium. If breast- is unfolded. This separates the portions which form the feeding is not possible, an alternative feeding regimen must conformational epitopes, which lose their allergenic ability, be chosen. The two approaches are based on the and are unable to bind the specific IgE. Enzymes are able to modification of native CM proteins and on the use of break the bonds between the amino and the acid terminals proteins of another, not related to CM, source6, 7. of amino acids and split the proteins into smaller fragments. To modify the CM proteins three steps are commonly These resulting fragments, depending on their size, can hold used. The action of heat and hydrolysis pretends to suppress one to several dozen amino acids. The breakage of the or lower the allergenicity of proteins through changes in protein can result in fragments that keep whole undamaged their structure. Ultrafiltration is directed at eliminating epitopes, able to bind to the specific IgE. A fragment can be enzymatic products used in the process of hydrolysis and large enough to keep two or more epitopes, able to bind Cow’s milk allergy 69

simultaneously to molecules of IgE and trigger the allergic Table 7.6 Molecular weight of small peptides reaction. This is called residual allergenicity, and is more present in hydrolyzed milk formulas probable when the molecular weight of the fragments is larger8. In elemental formulas, in which there are no peptides but only amino acids, the ability to bind IgE is nil. Molecular weight Number of amino acids The first choice for IgE-mediated allergy to CM seems to 500 Da 4 be soy formula, due to the absence of allergenicity, and also 1000 Da 7 the lower price. Some physicians are reluctant to use soy 1500 Da 11 formula in children under 6 months of age. When choosing an extensively hydrolyzed formula, some requirements must 3000 Da 22 be met and others are advisable. All peptides must have a 5000 Da 36 molecular weight under 5,000 Da, and the formula must 9000 Da 65 have been tested and prove to have negative results in >90% 12,000 Da 88 of children with CMA. The maximal admitted weight of the peptides is 5 kD, but if the distribution of molecular weight is provided the chances that residual allergenicity is present can be estimated: the higher the percentage of very small peptides, the lower the probability of residual allergenicity acids. Soy formulas have modified carbohydrates and lipids, (Table 7.6). Table 7.7 shows the types of milk formulas used and the proteins are purified soy proteins. for the feeding of infants, classified according to their We would recommend the following treatment algorithm constituents. The regular formula used for feeding healthy for children with CMA (7.4). The first choice for those with infants is infant formula (IF). If lactose intolerance is IgE-mediated allergy would be soy formula, and for those present a lactose-free formula (LF) should be used; no with non-IgE-mediated allergy would be extensively change in proteins is required, so native whole proteins are hydrolyzed (EH) formula. The response, with used. When these proteins undergo a low degree hydrolysis disappearance of symptoms, must be fast, usually within a partially hydrolyzed (PH) formula is obtained, also known 24–48 hours. If there is no such good response in 7 days, a as hypoallergenic formulas. In extensively hydrolyzed (EH) second choice formula should be tried. In those cases who formulas, proteins undergo a high degree hydrolysis. Semi- do not respond well to the first choice, the diagnosis should elemental (SE) formulas have extensively hydrolyzed be reconsidered: the second choice should be EH formula proteins and also a modification in carbohydrates and lipids. for IgE-mediated and soy formula for non-IgE-mediated The elemental formulas (EF) have modified carbohydrates allergy. If there is a lack of response to this second choice, and lipids and no proteins or peptides, substituted by amino an elemental formula should be used. Whenever the patient

Table 7.7 Types of formulas classified according to their constituents

Carbohydrate Lipid Protein Cow Soy/pork AA Soy Whole 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 70 Cow’s milk allergy

IgE allergy Non-IgE allergy

Soy formula EH formula

Yes Yes Good response Good response

No No

EH formula Soy formula

No No Yes Good response Good response

Elemental formula Yes

No Yes Reconsider diagnosis Good response

Maintain and follow

7.4 Algorithm of treatment in cow’s milk allergy.

does not respond to the selected treatment, the diagnosis could be postponed. The indication of the challenge test can should be reconsidered, especially if the child does not be guided by results of IgE tests, but in the case of non-IgE improve with an elemental formula. allergy these tests have no value, so its indication must be In children who have been diagnosed and are being treated based on clinical grounds, with challenge tests every 6 months. for CMA a follow-up is recommended (Table 7.8) to check In IgE-mediated allergy, the presence of specific IgE does not that the symptoms have disappeared. Care must be paid to the always mean that the challenge test must be postponed. Some appearance of new symptoms that could be due to the initial children who have had clear allergic reactions may outgrow allergy or to allergy to other allergens. A physical examination their symptoms and have a good tolerance to CM even if must be performed to rule out signs that could have passed specific IgE persists for months or years after achieving unnoticed, as well as an assessment of the current diet and tolerance. The indication can be guided by IgE tests, but must nutritional status to avoid too restrictive, unnecessary diets, be decided by the age and the clinical symptoms of the patient, which could lead to specific deficits9–13. According to an and by the experience of the physician. individual’s evolution of symptoms, an allergologic study and The prognosis of CMA is globally good. Most children a challenge test might be indicated. If the patient has had will outgrow their allergy and reach good tolerance to CM, recent symptoms related to contact or ingestion of CM, they specially those with non-IgE allergy, in whom persistence of Cow’s milk allergy 71

Table 7.8 Follow-up of allergy to cow’s milk protein Clin Exp Allergy 1996;26:254–61. 6 Host A, Koletzko B, Dreborg S, et al. Dietary products used in infants for treatment and prevention of food Schedule of follow-up visits allergy. Arch Dis Child 1999;81:80–4. • 3 months later 7 American Academy of Pediatrics. Committee on • 6 months later Nutrition. Hypoallergenic infant formulas. Pediatrics • At 18 months of age 2000;106:346–9. 8 Caffarelli C, Pleban A, Poiesi C, et al. Determination of • At 2 years of age allergenicity to three cow’s milk hydrolysates and an • Yearly amino acid-derived formula in children with cow’s milk allergy. Clin Exp Allergy 2002:32:74–9. 9 Paganus A, Juntunen-Backman K, Savilahti E. Follow-up the allergy is exceptional14. Many of those who have not nutritional status and dietary survey in children with reached tolerance by the age of 5 years will have lifelong cow’s milk allergy. Acta Paediatr 1992;81:518–21. allergy. Risk factors for the persistence of IgE allergy are 10 Isolauri E, Sütas Y, Salo M, et al. Elimination diet in high levels of serum total IgE, and high levels of serum cow’s milk allergy: risk for impaired growth in young specific IgE against CM proteins. children. J P e d iat r 1998;132:1004–9. A treatment that is increasingly gaining acceptance is 11 Christie L, Hine J, Parker JG, Burks W. Food allergies desensitization. The usual treatment is avoidance of CM in children affect nutrient intake and growth. J Am D ie t until the patient develops spontaneous tolerance. As some Assoc 2002;102:1648–51. children do not spontaneously reach tolerance, 12 Black RE, Williams SM, Jones IE, et al. Children who desensitization is becoming an alternative. The patient is avoid drinking cow milk have low dietary calcium intakes given gradually increasing amounts of CM, until a usual and poor bone health. Am J Clin Nutr 2002;76:675–80. daily dose is reached, and the child then continues having 13 Seppo L, Korpela R, Lönnerdal B, et al. A follow-up that amount of CM every day. The rationale is based on the study of nutrient intake, nutritional status, and growth in fact that very small amounts of CM are not able to trigger infants with cow milk allergy fed either a soy formula or symptoms or, if symptoms appear, they will not be severe an extensively hydrolysed whey formula. Am J Clin Nutr and can be treated with no risk for the patient. 2005;82:140–5. 14 Vanto T, Helppilä S, Juntunen-Backman K, et al. Prediction of the development of tolerance to milk in References children with cow’s milk hypersensivity. J P e d iat r 2004;144:218–22. 1 Martín Esteban M, Bone Calvo J, Martorell Aragonés A, et al. Adverse reactions to cow’s milk proteins. Allergol et Immunopathol 1998;26:171–94. Further reading 2 Dean T. Prevalence of allergic disorders in early childhood. Pediatr Allergy Immunol 1997;8:27–31. Hill DJ, Murch SH, Rafferty K, et al. The efficacy of amino 3 Sanz Ortega J, Martorell Aragonés A, Michavila Gómez acid-based formulas in relieving the symptons of cow’s A, Nieto García A y Grupo de Trabajo para el estudio de milk allrgy: a systematic review. Clin Exp Allergy la Alergia Alimentaria. Estudio de la incidencia de alergia 2007;37:808–22. mediada por IgE frente a la proteína de la leche de vaca Meyer R. New guidelines for managing cow’s milk allergy in en el primer año de vida. An Esp Pediatr 2001;54:536–9. infants. J F am H e al t h C ar e 2008;18:27–30. 4 Crespo JF, Pascual C, Burks AW, et al. Frequency of food Niggemann B, Beyer K. Diagnosis of food allergy in allergy in a pediatric population from Spain. Pediatr children: toward a standarization of food challenge. J Allergy Immunol 1995;6:39–43. Pediatr Gastroenterol Nutr 2007;45:399–404. 5 Baehler P, Chad Z, Gurbindo C, et al. Distinct patterns Vandenplas Y, Koletzo S, Isolauri E, et al. Guidelines for the of cow’s milk allergy in infancy defined by prolonged, two diagnosis and management of cow’s milk protein allergy stage double-blind, placebo-controlled food challenges. in infants. Arch Dis Child 2007;92:902–8. 72 Chapter 8 Abdominal masses Juan A. To var, MD, PhD

Masses of gastrointestinal origin

Tumours and of the liver is fusiform, in which the entire extrahepatic-biliary tract is The liver is accessible to palpation when enlarged and enlarged (8.1). If not detected prenatally, this condition may therefore masses in the liver are easily detected. become symptomatic later on as a painful mass occasionally accompanied by jaundice. CT scan and bilio-pancreatic Hydatic cysts magnetic resonance imaging (MRI) allow preoperative These are the result of accidental ingestion of scolices of depiction of the anatomy of the cyst. Treatment is surgical and Echinoccocus granulosus, a worm that parasitizes the consists of the excision of the choledocal duct together with the intestine of the dog. When the scolices are ingested by lambs gallbladder, the cystic and common hepatic duct, and of the or humans, they pass the intestinal barrier and are replacement of the biliary tract by a Roux-en-Y hepatic- transported by the blood stream to the first or second jejunostomy performed in an open or laparoscopic operation1. tissular filters, respectively the liver and the lung, where a form of resistance develops forming a cyst that grows slowly. Vascular tumours of the liver (haemangioma) The inside of the cyst contains a white gelatinous membrane These are the most frequent benign liver tumours in the lined by a fertile proligerous layer that frees live scolices into newborn. They may be focal, multifocal, or diffuse and each the clear hydatic fluid. The surrounding liver parenchyma one has a different pathologic pattern2. The focal variety is undergoes an inflammatory and fibrotic reaction (pericystic layer). Hydatic cysts are often scarcely symptomatic in children, except when they fissure causing anaphylactic reactions. They are detected by abdominal palpation and the diagnosis is confirmed by ultrasound or computed tomography (CT) scan. Specific antigenic and blood tests help to confirm the diagnosis. Treatment consists of albendazol and surgical emptying, sterilization and removal of the membrane of the cyst/s, accompanied by partial resection of the pericystic layer. Surgical removal may be performed laparoscopically.

Choledocal cysts These usually originate in a defective bilio-pancreatic junction in which both ducts are confluent within the pancreas, 8.1 Choledocal cyst occupying the entire right upper allowing the bile and the pancreatic juice to mix and quadrant of the abdomen in a 3-month-old female with subsequently damage the choledocal wall. There are several palpable mass and mild icterus. She is doing well anatomical varieties of choledocal cysts, but the most common 14 years after Roux-en-Y hepatic-jejunostomy. Abdominal masses 73

a rapidly involuting congenital haemangioma and, as well as asymptomatic except when they enlarge and are detected as multifocal, often creates cardiovascular compromise due to liver masses. Modern imaging allows accurate preoperative large intratumoural arteriovenous shunts. Platelet trapping assessment that is helped by the near-normal levels of and consequently coagulation disorders may occur. In tumoural markers. Treatment is always surgical (8.3). When contrast, the most clinically relevant feature of diffuse removal is complete, there is no risk of recurrence3. tumours is their large volume that creates a compartment syndrome and eventually liver failure. Hepatoblastoma Ultrasonography and MRI help to delimitate the extent. Although it is the more frequent malignant liver tumour in Biopsy is sometimes necessary particularly in cases with children, hepatoblastoma remains rare. It grows rapidly and unusual features. Treatment is based on the awareness of is occasionally multicentric. It can invade the vessels and the potential regression and of their responsiveness to also metastasize in the regional lymph nodes or, through the corticosteroids and interferon (8.2). Most of these patients, liver outflow, to the lungs and elsewhere. Most cases except those in whom heart failure cannot be managed, manifest as abdominal masses detected upon palpation. improve over a few months and have their tumours reduced Alpha-fetoprotein (AFP) is a useful marker for diagnosis to residual, partially calcified masses. Surgical removal is and follow-up. seldom indicated and in some rare instances of diffuse CT scan and MRI are the cornerstones of pretreatment tumours, liver transplantation is unavoidable. staging that allows selection of management protocols. We adhere to the staging of the Societé Internationale Mesenchymal of the liver d´Oncologie Pédiatrique (SIOP). The liver is divided into These are usually multicystic with solid mesenchymal two lobes by the falciform ligament and both lobes are components and may locate anywhere in the organ. They are subdivided in turn into two, to yield four segments. When

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 A B treated with corticosteroids and interferon. Two years later (C, D), only residual vascular areas are visible and the child is healthy.

C D 74 Abdominal masses

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

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

B

A

C 8.3 A 1-year-old female with a palpable mass in the right hypochondrium and normal liver function and AFP. MRI B showed a fluid-filled mass originating between the gallbladder and the falciform ligament (A). Surgical 8.4 Hepatoblastoma (HB) located in the lateral segment of removal could be performed removing the gallbladder and the left liver lobe in a 6-month-old female (SIOP Stage 1). a rim of liver tissue, but respecting the main vascular and The tumour could be readily removed and the patient is biliary conduits (B, C). alive and well 14 years later. Abdominal masses 75

children and adolescents. The tumour is often multicentric proximal small bowel are filled with this material, interfering and secretes AFP. It metastasizes early, often to the lungs, with normal feeds. The bezoar is palpable as an epigastric and responds poorly to chemotherapy. This tumour has mass. Diagnosis is confirmed by ultrasonography and limited surgical possibilities and the prognosis is therefore sometimes by other imaging procedures. poor except in patients with metabolic cirrhosis, in whom The bezoar has to be surgically removed and the patient liver transplantation for the original disease allows total should be provided with adequate psychological support. removal before metastases develop6. Gastric tumours and cysts Gastric tumours and masses Duplications of this part of the gastrointestinal tract may Bezoars produce palpable epigastric masses. Leiomyosarcomas, This condition always involves a psychopathological rhabdomyosarcomas, teratomas, or gastrointestinal stromal background. These children swallow either indigestible tumours (GIST) formed by C-Kit-positive cells (interstitial material (seeds, vegetal fibres that produce phytobezoar) or Cajal cells) may be occasionally observed at this level where hair (trichobezoar). The entire gastric lumen and sometimes they cause ulceration and haemorrhage7.

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. 76 Abdominal masses

Duodenopancreatic tumours patients have other symptoms in addition to the mass. When Pancreatic cysts the child is operated on for one of the above-mentioned The most frequent pancreatic cystic masses are pseudocysts acute conditions, he/she may benefit from surgical removal caused by pancreatitis of traumatic or other origins. When of the tumour when it is localized. However, in most cases the pancreatic ducts are disrupted by trauma or the operation serves only for obtaining enough biopsy inflammation, the enzymes are spilled into the parenchyma material. US, CT, and MRI, together with bone marrow causing a severe pancreatitis. Secondarily, areas of necrosis aspiration and eventually contrast studies, allow diagnosis. and eventually cysts filled with pancreatic juice may appear Fine needle aspiration may be a rapid method of histo - and occupy the retrogastric space and even extend into the pathologic diagnosis. The mainstay of treatment is thorax through the diaphragm. A palpable mass can be chemotherapy9, 10. The current results are rapidly improv - detected and diagnosis can be ascertained by increased ing and a high proportion of these children survive. enzyme levels in blood and fluid and by imaging procedures. Pancreatoblastomas and cystic and solid tumours (Frantz’s tumours) are exceedingly rare. Masses of genitourinary origin

Tumours of the jejunum, ileum, and colon Malformations, tumours, and cysts of the kidney Cystic lymphangioma Cystic kidneys Cystic lymphangiomas originate at the major lymphatic Familial polycystic kidneys may appear in an infantile form, confluences. In the abdomen the more frequent location is autosomal recessive pattern (mutation of PKHD1 gene in the mesentery. These lymphangiomas are uni- or 6p), or an adult variety in which the pattern is autosomal multiloculated. They occupy the space between both dominant (mutation of PKD1 gene in chromosome 16). In mesenteric layers and compress the bowel from the ante- the infantile form most patients die early after birth because mesenteric border. They may be voluminous and are formed of renal failure. The kidneys are enlarged and the by yellowish or milky fluid-filled cysts of various dimensions parenchyma is replaced by multiple small cysts (8.9). This (8.7). They rarely cause major symptoms except those form may be accompanied in long-term survivors by derived from intermittent torsion or bowel distension. progressive liver fibrosis leading to portal hypertension. They may be diagnosed before birth or detected Multicystic kidneys appear as malformations of one or incidentally for other reasons. Ultrasonography (US) depicts the cystic nature and may help to locate them. MRI is the best procedure for imaging and it can depict the nature of the contents, the presence of calcification, and the eventual association with venous or arterial components. The risks of torsion and volvulus justify prompt removal after detection. This usually entails limited bowel resection. Occasionally these tumours can be enucleated8.

Lymphoma Most intraabdominal lymphomas are non-Hodgkin, B-type tumours located near the ileocaecal valve, where the density of gut-associated lymphoid tissue is higher. Epstein–Barr virus is sometimes an aetiological factor, particularly in immunosuppressed patients. The mass/masses develop rapidly, sometimes within the lumen of the terminal ileum or caecum (8.8) but more often in the mesenteric lymph nodes. 8.7 Cystic lymphangioma of the mesentery in a 3-year-old Occasionally these lymphomas manifest as intussusception male. The jejunal mesentery contains a huge grape of or acute abdominal pain suggesting appendicitis. cysts filled with milky lymph. The jejunum is laminated on Abdominal lymphoma is a systemic disease and most the surface of the tumour. Limited resection led to cure. Abdominal masses 77

both organs. The diseased parenchyma is devoid of normal ones may be detected upon fetal ultrasonography or palpated nephrons and consists of a group of cysts that form a ‘grape during infancy. There is associated pathology (reflux, cluster’, and do not communicate with the ureter (8.10). hydronephrosis) in the contralateral kidney. The need for Bilateral cases are incompatible with life whereas unilateral removal of these dysplastic masses is controversial11. It is

A 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.

8.10 Nephrectomy specimen in a A B case of multicystic kidney. The 8.9 Autopsy of a newborn female with infantile recessive polycystic disease, parenchyme is replaced by a grape who died of renal failure. All organs except the kidneys were removed (A). cluster of fluid-filled cysts. The Section of one of the kidneys shows that the renal parenchyme is replaced by ureter is in apparent continuity with multiple honeycomb cysts (B). the kidney. 78 Abdominal masses

justified in cases in which the volume is large. In all other Tumours of the kidney cases laparoscopic or retroperitoneoscopic removal is an Nephroblastoma or Wilms’ tumour is a malignant neoplasia option, but the dysplastic organ can be left in place because derived from the original blastema of the kidney. It appears it tends to decrease in size over time and does not cause more often in patients with some conditions such as aniridia, symptoms. There is a remote risk of malignancy on these hemihypertrophy, Denys–Drash or Wiedeman Beckwith dysplastic tissues, supporting the indication for removal. syndromes. It is usually unilateral, but 5% are bilateral. Some structures recalling glomeruli or tubuli may be found Hydronephrosis within the mass together with frankly malignant cells and Stenosis of the uretero-pyelic junction leads to a dilated areas of necrosis or haemorrhage. The tumour grows rapidly renal pelvis. The ureter is thin and the pelvis dilates within the parenchyma and may invade the excretory system progressively, laminating the renal parenchyma. and/or the vessels. It metastasizes to the regional lymph Hydronephrosis is often detected prenatally by nodes and to the lungs by the haematogenous route (8.12). ultrasonography. Half these babies undergo regression of the Wilms’ tumour is generally palpated by paediatricians or dilatation, whereas in the remaining ones it persists and parents in otherwise healthy children. Haematuria may becomes a palpable mass with or without pain and infection. appear rarely when the excretory system is invaded. US, CT, US depicts the dilated pelvis, pyelography may give some and MRI depict the mass which grows within the more information, but the crucial test is isotopic excretion parenchyma displacing the pelvis and calices. scintigraphy (MAG3) with furosemide that provides a Treatment is always surgical but it is usually performed in functional idea of the retention of urine in the pelvis and Europe after reducing the size of the tumour and controlling allows differentiation between simple dilatation and real its eventual extensions with chemotherapy. In other obstruction. Surgical repair consists of resection of the countries surgery is performed first but although this obstructed junction and reduction of the dilated pelvis attitude has the theoretical advantage of allowing better (8.11). The potential for parenchymal recovery is directly histological staging, it involves increased risks of tumour related to the duration and the severity of the obstruction. rupture or surgical complications. The results are similarly

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).

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

A B

good with both types of protocol12, 13. When metastases are Bladder tumours present, they are treated with chemotherapy and/or Genitourinary rhabdomyosarcomas may cause hypogastric radiotherapy and they can be removed surgically if limited. masses. Other tumours of the bladder, such as malignant Mesoblastic nephroma is a benign counterpart of Schwannoma (neurofibrosarcoma), may arise in patients nephroblastoma seen in fetuses or newborns. It is grossly with neurofibromatosis. identical to Wilms’ tumour except for its purely mesenchymal nature. Upon section, it has a surface that Ovarian tumours resembles uterine myoma and only rarely metastasizes. Ovarian cysts are easily diagnosed by fetal ultrasound. Most Removal of the kidney with the tumour is the usual are the result of follicular stimulation by maternal chorionic treatment (8.13). gonadotrophins and, except when they are twisted and 80 Abdominal masses

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.

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.

A B

devitalized, they tend to regress. Even in cases in which the secretory and cause respectively isosexual and heretosexual blood supply is interrupted by torsion (8.14), there is a precocious puberty. Finally, tumours derived from the tendency to spontaneous resolution. The current attitude is epithelial cells are cystadenomas that may be serous or to follow them ultrasonographically and to remove them mucinous and are the equivalent of ovarian carcinomas in only when they are large or ‘complex’14. adult women. When germ cells are not differentiated they may cause Ovarian tumours are more often detected as lower dysgerminoma. When they differentiate into embryonal abdominal masses since only 10% are secreting. An tissues they cause teratomas (8.15) and when they increased secretion of hormones with normal differentiate into extraembryonal tissues they cause yolk sac gonadotrophins is suggestive of ovarian tumour. AFP is (endodermal sinus) tumours and choriocarcinomas. increased in malignant teratoma and in yolk sac tumours. Tumours derived from the sex cords are granulosa-theca The treatment is surgical; conservation of some ovarian cell tumours and Sertoli-Leydig cell tumours. Both may be tissue is advocated when possible and safe15, 16. Abdominal masses 81

Masses from other retroperitoneal organs

Neuroblastoma-ganglioneuroma tumour and its metastases, and detection of increased levels Tumours of neural crest origin are the second most frequent of catecholamines or its metabolites in serum and urine. The solid neoplasias in children after brain tumours. They may cellular and molecular predictors of malignity are tested on originate at any point in the wide variety of tissues and tissue samples and therefore, biopsy is advisable before organs receiving the migrating neuroblasts from the neural starting treatment. crest, but they involve more often the adrenal medulla, the Therapeutic protocols are currently based on postsurgical paraspinal sympathetic chains, and the nervous plexuses International Neuroblastoma Staging System (INSS). Stage 1 that surround the aorta and its main abdominal branches. tumours are limited to the organ of origin and are completely These tumours range from the malignant neuroblastoma removed. Stage 2 tumours are extended to regional lymph (NB) in which neuroblasts predominate and sometimes nodes but are removed as well. Stage 3 tumours are usually group in pseudo-rosettes, and the benign ganglioneuroma extended on both sides of the midline and cannot be removed (GN) in which the neural cells are mature neurones at the first operation (8.16), Stage 4 are those with distant embedded into a fibrilar supporting stroma. Most NB retain metastases. Both Stages 3 and 4 require aggressive chemo - the secreting properties of the adrenal medulla and take up therapy before complete removal of the primary is attempted. amine precursors while secreting catecholamines. For this Chemotherapy is continued after surgery and in Stage 4 reason, they may be imaged by isotope-tagged meta-iodine- megatherapy and bone marrow transplantation are indicated. benzyl-guanidine (MIBG) and they can be detected by There is another Stage 4s corresponding to metastatic disease increased urinary excretion of catecholamine metabolites. that does not involve the bone, in babies younger than 6 NB develops within the organ of origin, has no real months who have their tumour detected upon palpation of a capsule, spreads to the regional lymph nodes, and massive liver enlargement that may eventually threaten metastasizes by the haematogenous route to other structures survival by creating a compartment syndrome with respiratory such as the skin, bone marrow, liver, or bone. The primary and cardiovascular embarrassment (8.17). The current may grow rather rapidly undergoing necrosis, haemorrhage, approach to this particular stage is rather conservative. The and calcification. Due to the secretion of amines, these primary may or may not be removed and supportive measures patients often have symptoms like diarrhoea, hypertension, are provided to allow for regression of the liver enlargement. pallor and appear sick and pained, particularly when they The results are very good in Stages 1 and 2, they are have bone metastases. improving in Stage 3 and remain poor in Stage 4. The The diagnosis is based upon CT scan and MRI imaging, prognosis for Stage 4s tumours ranges between those of bone marrow aspiration, positive uptake of MIBG by the Stages 2 and 317–19.

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

A B 82 Abdominal masses

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

C

Adrenal tumours Adrenocortical carcinoma and phaeochromocytoma are externally, internally, or on both spaces. They are rarely very rare neoplasias in children. Teratomas are germ cell retroperitoneal at any point in this body space. neoplasias that differentiated towards embryonal tissues. At birth they are generally benign although they may have They consist of tissues derived from the three blastodermic immature areas. After 6 months of age, a high proportion of layers that may adopt an organoid pattern and mix in them become malignant and may contain areas of yolk sac amazing patterns. These tumours can be cystic and also (endodermal sinus) tumour and secrete AFP that is a useful contain bone, cartilage, or calcifications. When they have a marker for follow-up. human-like structure they are considered as a rare form of Treatment is surgical and may be difficult. In malignant parasitic twin or ‘fetus in feto’. They are generally located in cases chemotherapy is required before and after surgery. The the midline in the sacrocoxigeal area where they can develop current results are quite good even in malignant cases20. Abdominal masses 83

References

1 Miyano T, Yamataka A, Kato Y, et al. Hepatico - 11 Okada T, Yoshida H, Matsunaga T, et al. Multicystic enterostomy after excision of choledochal cyst in dysplastic kidney detected by prenatal ultrasonography: children: a 30-year experience with 180 cases. J P e d iat r natural history and conservative management. Pediatr Surg 1996;31(10):1417–21. Surg Int 2003;19(3):207–10. 2 Christison-Lagay ER, Burrows PE, Alomari A, et al. 12 Neville HL, Ritchey ML. Wilms’ tumour. Overview of Hepatic hemangiomas: subtype classification and National Wilms’ Tumour Study Group results. Urol Clin development of a clinical practice algorithm and registry. North Am 2000;27(3):435–42. J Pediatr Surg 2007;42(1):62–7. 13 Reinhard H, Semler O, Burger D, et al. Results of the 3 Stringer MD, Alizai NK. Mesenchymal of SIOP 93-01/GPOH trial and study for the treatment of the liver: a systematic review. J Pediatr Surg patients with unilateral nonmetastatic Wilms tumour. 2005;40(11):1681–90. Klin Padiatr 2004;216(3):132–40. 4 Czauderna P, Otte JB, Aronson DC, et al. Guidelines for 14 Sapin E, Bargy F, Lewin F, et al. Management of surgical treatment of hepatoblastoma in the modern era: ovarian cyst detected by prenatal ultrasounds. Eur J recommendations from the Childhood Liver Tumour Pediatr Surg 1994;4(3):137–40. Strategy Group of the International Society of Paediatric 15 De Backer A, Madern GC, Oosterhuis JW, et al. Oncology (SIOPEL). Eur J Cancer 2005;41(7):1031–6. Ovarian germ cell tumours in children: a clinical study of 5 Otte JB, Pritchard J, Aronson DC, et al. Liver 66 patients. Pediatr Blood Cancer 2006;46(4):459–64. transplantation for hepatoblastoma: results from the 16 Cass DL, Hawkins E, Brandt ML, et al. Surgery for International Society of Pediatric Oncology (SIOP) study ovarian masses in infants, children, and adolescents: 102 SIOPEL-1 and review of the world experience. Pediatr consecutive patients treated in a 15-year period. J P e d iat r Blood Cancer 2004;42(1):74–83. Surg 2001;36(5):693–9. 6 Czauderna P. Adult type vs. childhood hepatocellular 17 Navarro S, Amann G, Beiske K, et al. Prognostic value carcinoma: are they the same or different lesions? Biology, of International Neuroblastoma Pathology Classification natural history, prognosis, and treatment. Med Pediatr in localized resectable peripheral neuroblastic tumours: a Oncol 2002;39(5):519–23. histopathologic study of localized neuroblastoma 7 El Behery MM, Soliman HA. Primary gastric tumours in European Study Group 94.01 Trial and Protocol. J C l in infancy and childhood. Saudi Med J 2003;24(5 Oncol 2006;24(4):695–9. Suppl):S41. 18 La Quaglia MP, Kushner BH, Su W, et al. The impact 8 Steyaert H, Guitard J, Moscovici J, et al. Abdominal of gross total resection on local control and survival in cystic lymphangioma in children: benign lesions that can high-risk neuroblastoma. J Pediatr Surg have a proliferative course. J Pediatr Surg 2004;39(3):412–7. 1996;31(5):677–80. 19 Castel V, Tovar JA, Costa E, et al. The role of surgery 9 Wright D, McKeever P, Carter R. Childhood non- in stage IV neuroblastoma. J Pediatr Surg Hodgkin lymphomas in the United Kingdom: findings 2002;37(11):1574–8. from the UK Children’s Cancer Study Group. J C l in 20 Luo CC, Huang CS, Chu SM, et al. Retroperitoneal Pathol 1997;50(2):128–34. teratomas in infancy and childhood. Pediatr Surg Int 10 Mann G, Attarbaschi A, Steiner M, et al. Early and 2005;21(7):536–40. reliable diagnosis of non-Hodgkin lymphoma in childhood and adolescence: contribution of cytomorphology and flow cytometric immuno pheno - typing. Pediatr Hematol Oncol 2006;23(3):167–76. 84 Chapter 9 Liver disorders

CHOLESTASIS Pio tr So cha, MD, Joanna Pawło wska, MD, and Anil Dhawan, MD, FRCPCH

Jaundice and cholestasis

Jaundice results from the deposition of unconjugated or account. Infectious diseases may also cause cholestasis, thus conjugated bilirubin pigment in the skin and mucous urinary tract infections as well as cytomegalovirus (CMV) membranes. Cholestasis is defined as conjugated and toxoplasmosis should be excluded. The role of CMV as hyperbilirubinaemia. Liver disease may present as the causative factor of cholestasis is still under debate, as cholestasis alone, cholestasis that accompanies liver cirrhosis congenital CMV infections may present with liver damage or severe liver disease with liver insufficiency. Ascites, and cholestasis. It is very important to assess stool colour to peripheral oedema, bruises and so on can be present which make a timely diagnosis of biliary atresia (BA). BA is a indicate severe liver damage. A jaundiced child with liver relatively uncommon disease characterized by a biliary insufficiency requires immediate hospitalization with obstruction of unknown origin that presents in the neonatal prompt diagnosis to find the underlying liver disease. period2. However, it is the most important surgically Prothrombin time can be solely regarded as an indicator of correctable cause of cholestatic jaundice in this age group acute liver failure. and is the most common indication for liver transplantation in children. Untreated, BA leads to cirrhosis and death Infancy within the first years of life. Surgical treatment usually Cholestasis should be diagnosed quickly in infancy as involves an initial attempt to restore bile flow: the Kasai various diseases require immediate therapy. Numerous portoenterostomy3 which is performed as soon after aetiologies make diagnosis difficult. The American Academy diagnosis as possible. Prognosis of the disease seems to be of Pediatrics has elaborated practical guidelines for the better in infants operated on before 90 days of age4. Other management of hyperbilirubinaemia in newborn infants, causes of cholestasis with pale stools are: Alagille syndrome, mainly concentrating on indirect hyperbilirubinemia1. The progressive familial intrahepatic cholestasis (PFIC), alpha- guidelines emphasise the importance of measuring direct 1-antitrypsin deficiency (α1-ATD), and cystic fibrosis. bilirubin in sick infants and in those who are jaundiced at or Neonatal haemochromatosis, Zellweger syndrome, beyond 3 weeks. If the direct or conjugated bilirubin level is Niemann–Pick disease type C, and glycogen storage disease elevated, additional assessment for the causes of cholestasis type IV should also be considered in the differential is recommended. For instance, hypothyroidism, diagnosis of infantile cholestasis (Tables 9.1, 9.2). galactosaemia, and tyrosinaemia should be taken into Liver disorders 85

Table 9.1 Differential diagnosis of cholestatic liver disease of infancy

Extrahepatic cholestasis Cystic fibrosis • Biliary atresia Bile acid metabolism disturbances • Choledochal cyst Peroxisomal disorders • Choledocholithiasis Zellweger syndrome Congenital defects of glycosylation Intrahepatic cholestasis Infectious diseases Familial cholestatic diseases TORCH (Toxoplasmosis, Others, Rubeolla, Idiopathic neonatal hepatitis Cytomegaloviral infection, Herpes) Progressive familial intrahepatic cholestasis Other viral infections Alagille syndrome Reo Nonsyndromatic paucity of bile ducts Echo Recurrent intrahepatic cholestasis Parvovirus Benign-familiar Listeria With lymphatic oedema (Aageneas syndrome) Sepsis Urinary tract infection Anatomical changes Tuberculosis Caroli disease HIV Multicystic liver and kidney disease

Metabolic diseases Chromosomal diseases α1-antytrypsin deficiency Down syndrome Carbohydrate metabolism disturbances Galactosaemia Other causes Fructosaemia Hypothyroidism Glycogenosis: type IV Histiocytosis X Amino acid metabolism disturbances Necrotizing enterocolitis Tyrosinaemia Parenteral nutrition-associated cholestasis Lipid metabolism disturbances Drug-induced cholestasis Niemann–Pick disease Cholesterol ester storage disease Wolman disease

Table 9.2 Diagnostic approach to cholestasis of infancy

Urgent diagnosis indicated Elective diagnosis performed Biliary atresia PFIC Galactosaemia Alagille syndrome Hypothyroidism Cystic fibrosis Tyrosinaemia Choledochal cyst (if not accompanied by cholangitis) Neonatal haemochromatosis α1-ATD Zellweger syndrome Niemann–Pick disease type C Infections (sepsis, urinary tract infection, CMV, Toxo) Glycogen storage disease type IV 86 Liver disorders

Childhood Clinical characteristic and laboratory Jaundice is uncommon in children. However, indirect findings hyperbilirubinaemia can be the presentation of a benign, inherited condition, Gilbert syndrome, which affects about Alagille syndrome 6% of the adult population. Mutations in hepatic enzyme Alagille syndrome can present with very early cholestasis of isoform (1A1) belonging to the urine diphosphoglucuronate infancy but it may also be asymptomatic for a very long time. glucuronosyltransferase (UGT) family of enzymes are Liver damage may progress quickly in some patients with responsible for this condition5. Gilbert syndrome can be portal hypertension, recurrent cholangitis, and malnutrition6. confirmed by molecular diagnosis but it should be suspected Diagnosis of Alagille syndrome is aided by the presence of in an otherwise asymptomatic child whose other liver tests syndromic features, including paucity on liver are normal and there are no signs of haemolysis. histology, chronic cholestasis, cardiac murmur, vertebral Several liver diseases may present with jaundice such as abnormalities, peculiar facies, eye findings, renal disease, and infection with hepatitis B, hepatitis A, and hepatitis C virus, xantomas7. Usually differential diagnosis is performed in early autoimmune hepatitis, Wilson disease, and α1-ATD. infancy when biliary atresia must be excluded. Cholecystitis is a rare condition in children and acute Typical facial features are a prominent forehead, pointed clinical symptoms with jaundice and fever are very unusual. chin, deep set eyes, moderate hypertelorism, and a saddle or Choledocholithiasis is also infrequent in childhood. straight nose with a bulbous tip (9.1), but these features are Familial cholestatic diseases (Alagille syndrome, PFIC) not very typical in early infancy. The parents may also have and postoperative biliary atresia may present with episodes the typical appearance (9.2) which may indicate the need to of increased hyperbilirubinaemia or symptoms of liver diagnose this disease. Pulmonary artery stenosis is a typical insufficiency. That is why it is important to follow these finding which may also cause a serious heart disease (9.3, patients carefully and the primary care physicians have to be 9.4). Embryotoxon posterior observed in a slit lamp is one aware of possible exacerbation of symptoms. Cholangitis of the most common features of the Alagille syndrome. episodes in postoperative biliary atresia require rapid Butterfly vertebrae observed in late infancy are also a diagnosis and treatment. Septic and hypoxic damage to the characteristic feature (9.5). Liver biopsy is helpful to liver can cause cholestasis, and septicaemia seems to be a establish the diagnosis (9.6). Liver disease may slowly common reason for referral of a jaundiced child to liver progress to liver insufficiency and liver transplantation may clinics. be needed. However, in most of the patients liver disease remains stable for a long time.

9.1 Typical facial 9.2 The parent appearance in a of the child child with Alagille usually presents syndrome. also with very typical facial appearance. Liver disorders 87

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).

9.5 Butterfly vertebrae in Alagille syndrome.

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.) 88 Liver disorders

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

9.7 Pruritus as a presenting symptom of PFIC.

A

B

Table 9.3 Genetic background of cholestastic diseases

PFIC 1 PFIC 2 PFIC 3 Alagille syndrome

Genetics Autosomal recessive Autosomal recessive Autosomal recessive Autosomal dominant with highly variable expression

Gene FIC 1 BSEP MDR 3 JAG 1

Mutation on 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 Liver disorders 89

Progressive familial intrahepatic cholestasis Benign recurrent intrahepatic cholestasis PFIC is an inherited disorder where bile acid excretion is Benign recurrent intrahepatic cholestasis (BRIC) is impaired (Table 9.3). This diagnosis should always be characterized by intermittent episodes of cholestasis without suspected in patients with high serum bile acid concentra - progression to cirrhosis. The onset of the disease usually tion, low/normal or elevated gamma glutamyl trans- occurs before the second decade of life. The attacks of peptidase (GGT), and pruritus. cholestasis vary in severity and duration (from 1 to 18 Pruritus is usually the predominant symptom and skin months) and may be preceded by a preicteric phase with excoriations due to itching may be observed (9.7). Short malaise, anorexia, and pruritus. Biochemically it is stature is a typical feature in later age (9.8). Liver histology characterized by increased concentrations of bilirubin, may reveal giant cell transformation, ductular proliferation, serum bile acid, and alkaline phosphatase; GGT remains and fibrosis (9.9). The disease may progress to end-stage liver low. There are no pathological changes in the liver on biopsy disease. Some experience from centres in the USA and Poland besides some hepatocellular cholestasis. In between points to a successful therapy with partial external biliary episodes patients are totally asymptomatic both clinically diversion (9.10) when performed early in the course of the and biochemically. Treatment is symptomatic. disease8. PFIC also seems to be a risk factor for hepato cellular carcinoma9. In general, diagnosis of PFIC is not very urgent but doctors should be aware of the potential health effects.

A

B 9.8 Short stature in a 9.9 Liver histology in PFIC. A: Missing bile duct in a portal 9.10 Partial biliary 14-year-old girl with space (arrow, artery; arrowhead, portal truct); diversion in a child with PFIC. B: enlargement of the portal truct with septal fibrosis PFIC. Catch up growth is (brace). observed since the procedure was performed. 90 Liver disorders

Biliary atresia exceeding 2 mg/dl (34 μmol/l) over 2 weeks of age be BA presents with cholestasis in early infancy (1–2 months of referred to liver centres for further work-up to avoid wasting age) in an otherwise healthy child, thus diagnosis may be valuable time in making the diagnosis. BA may progress delayed. The most common clinical features are: jaundice quickly to cirrhosis with ascites (9.14) and oesophageal with conjugated bilirubin beyond 2 weeks of life (9.11), varices as a consequence of portal hypertension. white stools and dark urine as well as hepatomegaly, which may not always be evident. Usually a complete work-up of Alpha-1-antytripsin deficiency cholestatic diseases is performed to confirm the diagnosis α1-ATD is inherited as an autosomal codominant disorder. and to exclude other liver diseases with early presentation. The most frequent and severe mutation that causes severe The gall bladder may not be visible on ultrasound in many α1-ATD arises in the SERPINA1 gene (formerly known as patients with biliary atresia, dynamic scintigraphy (HIDA) PI) and gives rise to the Z allele. Determination of α-1- does not show any bile passage to the gut (9.12), and liver antitrypsin phenotype but not measurement of α-1- histology may present ductal plate malformation with bile antitrypsin concentration is the way to make the final duct proliferation and fibrosis (9.13), which is regarded as a diagnosis. During the first year of life, infants with the typical feature that confirms the diagnosis. It is homozygous Pi ZZ phenotype may temporarily show recommended that infants with direct hyperbilirubinaemia elevated levels of liver enzymes and cholestasis and

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

B

A B C

D E F 9.12 Dynamic scintigraphy of the 9.13 Histological evaluation of biliary atresia. A: Intracellular cholestasis liver in BA does not show any bile (arrow); B: giant cell transformation (arrow); C: septal fibrosis (arrow); passage to the gut after 24 hours. D–F: ductal plate malformation (arrows). Liver disorders 91

(UDPG)10. It is important to know that the diagnosis of galactosaemia may lead to a false result if the infant has received a blood transfusion in the preceeding 3 months as the UDPG test does not differentiate between donor or recipient enzyme levels. If the diagnosis of galactosaemia is suspected, galactose-containing feedings should be discontinued immediately and replaced by a lactose-free formula pending the results of an appropriate enzyme assay on erythrocytes to confirm the diagnosis. Hereditary tyrosinaemia may also present with jaundice and clotting disturbances. Determination of succinylacetone in the urine is a helpful diagnostic test for this disorder11. Neonatal haemochromatosis may also present acutely with liver failure and must be diagnosed very quickly. Other metabolic disorders like Niemann–Pick disease type C or 9.14 Ascites in a small child with biliary atresia. glycogen storage disease type IV do not progress so rapidly and diagnosis is not so urgent. Another neonatal liver disease presenting with typical differential diagnosis with BA should be performed. In a features and cholestasis is Zellweger’s syndrome (9.15), a small percentage of patients the disease may progress to liver generalized peroxisomal biogenesis disorder which is insufficiency and liver transplantation should be considered. characterized by a wild spectrum of abnormalities including in the nervous system and kidneys. Patients have Other aetiologies of cholestasis characteristic craniofacial abnormalities with wide Galactosaemia and tyrosinaemia should be diagnosed very fontanelle, prominent forehead, anteverted nostrils, and quickly, as they can be managed with a special diet and the narrow upper lip. Hepatic involvement includes disease may progress very rapidly. Galactosaemia is a rare hepatomegaly and conjugated hyperbilirubinaemia due to disease usually presenting with prolonged prothrombin abnormal bile acid synthesis. In some cases cirrhosis and time, but most developed countries carry out newborn portal hypertension has been reported in the first year of life. screening. The definitive diagnosis is done by enzymatic The administration of primary bile acids (cholic acid and testing for galactose-1-phosphate-uridyltransferase activity chenodeoxycholic acid) may improve liver function.

9.15 Zellweger syndrome (skeletal features). 92 Liver disorders

HYPERTRANSAMINASAEMIA IN CHILDHOOD Luís Peña-Quintana, MD, and Daniel González-Santana, MD

Introduction Table 9.4 Characteristics of aminotransferases (normal levels ≤40 U/l) Hypertransaminasaemia in childhood is a common finding which requires a staggered study depending on the clinical AST features and the severity of the disease, in order to obtain a • Mitochondrial and cytosolic 12 correct diagnosis . Investigation of the liver function relies • Half-life: 48 h on four major signs, markers of: • Liver, heart, brain, pancreas, muscle, kidney, lung, • Cytolysis (ALT/GPT; AST/GOT; GGT, and LDH). leukocytes and erythrocytes • Cholestasis (alkaline phosphatase; GGT; direct bilirubin; • More unspecific bile acids, cholesterol, and 5´ nucleotidase). • Synthetic liver function (albumin, prothrombin time, and ALT cholinesterase). • Cytosolic • Chronicity (immunoglobulin G and other immuno - • Half-life: 18 h globulins). • Liver. Minimal amounts in other tissues (mainly in muscles) Aminotransferases represent the integrity of liver cells. The • AST/ALT ≤1 quotient AST/ALT is normally less than 1. When it is higher • More specific than 1, it may mean that a more severe liver damage is present Released into plasma during hepatocyte necrosis (Table 9.4). GGT and alkaline phosphatase increase if there is an obstruction or a damage in hepatic canaliculae (Tables 9.5, 9.6). Prothrombin time is an excellent marker of liver synthetic Table 9.5 Characteristics of GGT function, as most coagulation factors are synthesized in the liver. Prothrombin time is a measure of the extrinsic and • Synthesized by hepatocytes and bile duct epitelium common pathway of coagulation. Prolonged prothrombin • Cytolysis and cholestasis enzyme time is a sign of an important hepatocellular dysfunction. • Location: kidney, heart, pancreas, brain, spleen • It only increases in liver disease • Greater in cholestasis and toxic hepatitis Symptomatology • It is stimulated by: phenobarbital, phenytoin, alcohol • Higher levels in plasma in prematures, newborns, and Patients with a liver disease do not present any specific babies younger than 2 months of age symptom. Most patients are asymptomatic. An underlying liver disease can be discovered due to hyper trans- aminasaemia found in an ordinary blood test. Other patients nonhepatic disorders causing acute or chronic elevation of may present any of the symptoms listed in Table 9.7. transaminases (e.g. rotavirus infection or coeliac disease).

Viruses Specific causes of liver disease Hepatotropic virus A, B, C, D, E, and probably G, Epstein–Barr virus (EBV), cytomegalovirus (CMV), and Viral infections and drug toxicity are the main causes of other viruses (herpesvirus, adenovirus, parvovirus) may acute liver disease (Table 9.8), while the list of causes of produce acute hepatitis. Patients may be asymptomatic or chronic disease is broader (Table 9.9). There are also some paucisymptomatic. The classic presentation with three Liver disorders 93

Table 9.6 Characteristics of LDH and alkaline Table 9.7 Symptomatology phosphatase

Symptoms Signs • Astenia • Hepatomegaly: LDH • Anorexia – Firm: congestive • ↑ in hepatic and extrahepatic damage • Abdominal pain – Nodular: cirrhosis • Less specific • Jaundice – Rounded and painful: • Fraction 5: more liver specific • Choluria acute hepatitis • Acholia Alkaline phosphatase • Pruritus • Synthesis in bile canaliculi membranes • ↑Abdominal perimeter • Bone, kidney and small intestine • Haematomas • If there is no GGT rise, hepatopathy is not probable • Peripheral oedema

Table 9.8 Causes of acute liver disease Table 9.9 Causes of chronic liver disease

• Viral hepatitis by A, B, C, D, E, G virus • Viral chronic liver disease • Viral hepatitis by CMV, EBV • Wilson’s disease • Drug-induced hepatitis, alcohol • α-1-antitrypsin deficiency • Ischaemic hepatitis (heart failure, hypotension, • Autoimmune hepatitis sepsis, Budd–Chiari) • Drug/alcohol-induced hepatitis • Cholangitis • Nonalcoholic fatty liver disease • Wilson’s disease • Haemochromatosis • Autoimmune hepatitis • Porphyrias • Other rare infectious agents • Cystic fibrosis

phases (preicteric, icteric, and posticteric or convalescent Table 9.10 Hepatotoxic drugs phase) is less frequent. Some patients may present prolonged abnormal liver function tests or fulminant liver failure. Only hepatitis due to B, C, D, E and G viruses can • Amiodarone • Phenobarbital lead to chronic liver disease. • Anti-neoplastic drugs • Haloperidol • Azatioprine • Valproate Toxic hepatitis • Carbamazepine • Paracetamol Toxic hepatitis is less frequent in children than in adults • Cocaine • Acetylsalicylic acid (Table 9.10). Most patients remain asymptomatic, and it is • Ciclosporin • Ketoconazole often casually discovered by elevation of transaminases. In • Ecstasy • Isoniazid 13 other cases, there are unspecific symptoms or cholestasis . • Erythromycin • Methyldopa There is no specific test to diagnose toxic hepatitis. • Strogens • Sulphonamide • Halothane • NSAIDs Wilson’s disease • Methotrexato • Verapamil Wilson´s disease (WD) is an autosomic recessive genetic • Minocycline, penicillins • Pemoline 14 disorder affecting gene ATP7B in chromosome 13q14.3. • Alcohol • Retinoids It codes for transmembrane copper transporter in hepatocytes and for excretion into the bile canaliculus as 94 Liver disorders

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

well as for joining copper to coeruloplasmin. As a result, such as anti-soluble liver antigen, anti-liver cytosol, anti- there is an abnormal accumulation of copper in liver, brain, liver–pancreas antigen, or anti-asialoglycoprotein receptor. kidney, and other organs, mitochondrial damage, and low Anti-actine and antineutrophil cytoplasmic autoantibodies levels of bile copper and coeruloplasmin. may also be useful in the diagnosis. Patients may present Prevalence in Europe is 1/30,000, with 1/100 with acute hepatitis or as chronic hepatitis with insidious heterozygous. In the Canary Islands, the incidence is symptomatology. In other cases, it is an incidental finding. 1/2,60015. It may present as asymptomatic hypertrans- The increase in transaminases has no relationship with aminasaemia or as chronic hepatitis, cirrhosis, or acute liver the degree of hepatic necrosis. Polyclonal hypergamma - failure in childhood. In older children and adults, globulinaemia (IgG) is often found (2–6 g/l). If the levels of extrapyramidal neurological symptoms (dysarthria, IgG are low it is a sign of good response to therapy. dystonia, ataxia, tremor, dysphagia), psychiatric manifesta - Although the detection of autoantibodies is very useful for tions, Kayser–Fleischer ring (due to copper deposits in the diagnosis, they are not specific. Therefore, autoimmune Descemet corneal membrane, very specific but not hepatitis is not excluded in the presence of low serum pathognomonic of WD), and renal tubulopathies (with autoantibody titres. Liver biopsy is fundamental for aminoaciduria and phosphaturia) are more frequent16. diagnosis, and the findings vary from hepatitis with It is typical to find low plasma coeruloplasmin, although moderate or severe activity to cirrhosis, which is present in in 5–10% of patients it may be normal (>20 mg/dl), and almost 50% of the children at diagnosis (piecemeal necrosis decreased serum copper levels. A raised urine copper after (9.16), lobular hepatitis [not constant], central–portal penicillamine (higher than 100 μg/day) and an elevated liver bridging necrosis) (9.17). copper concentration (higher than 250 μg/g of dry liver tissue) are helpful in diagnosis. Liver biopsy shows the stage Alpha-1-antitrypsin deficiency (α1-ATD) of the disease. Genetic tests (>150 mutations) may help. In this autosomal recessive disease there is a chromosome 14 mutation18 that leads to the production of abnormal and Autoimmune hepatitis hepatotoxic α1-AT that is retained in the endoplasmic Autoimmune hepatitis (AIH) is a chronic inflammatory reticulum (9.18). Frequency is 1:2000 newborns. disorder affecting the liver, with unknown aetiology. It may α1-AT glycoprotein may present as 100 variants, with cause severe progressive liver disease and, eventually, lead to codominant inheritance, which are classified according to cirrhosis and liver failure. It is classified in three types17: the protease inhibitor (Pi) phenotype system based on their Type 1, with positive anti-nuclear and/or anti-smooth electrophoretic moiety: Pi MM variant (with normal serum muscle antibodies; Type 2, with positive anti-liver–kidney concentration and normal activity), Pi null-null variant microsomal antibodies; and Type 3, with other antibodies, (absence of α1-AT associated with lung disease), defective Liver disorders 95

9.18 Liver biopsy in a patient with alpha-1-antitrypsine 9.19 Diagnosis of alpha-1-antitrypsine deficiency is based deficiency. on a decrease in the α1 band (arrow) (readout from electrophoretic gel). variants (such as Pi Z and Pi S, with low serum concentration and lung and liver disease). MM phenotype is Microvesicular accumulation of fat in hepatocytes found in healthy individuals; ZZ phenotype causes the most (>5%) without excessive aclcohol consumption severe deficiency and it represents 95% of patients. SZ phenotype may cause liver disease (neonatal cholestasis, mild dysfunction, chronic hepatitis, liver failure, cirrhosis, The main cause of chronic liver disease in ), while MS/MZ phenotypes do pre-adolescents and adolescents not produce liver disease in children but do in adults. Diagnosis is based on a decrease in the α1 band (electrophoretic gel) (9.19), a decrease in α1-AT in blood Simple steatosis Steatohepatitis (NASH) and Pi phenotype. On the liver biopsy, an abnormal accumulation of α1-AT in liver is present.

Nonalcoholic fatty liver disease Nonalcoholic fatty liver disease (NAFLD) includes simple fatty liver (steatosis), nonalcoholic steatohepatitis (NASH) and cirrhosis19 (9.20). Most patients with NAFLD present with obesity, mainly central adiposity20, as part of the metabolic syndrome21 (9.21). The pathology of the NAFLD in children includes: Type Cirrhosis 1, characterized by steatosis, hepatocyte balloonization, and perisinusoidal fibrosis (similar to NAFLD in adults and more frequent in white children in both sexes), and Type 2 9.20 Nonalcoholic fatty liver disease. (infantile), characterized by steatosis, portal inflammation, and portal fibrosis (9.22) (more common in male and children of Asian, Native American, and Hispanic acanthosis nigricans (9.23), and absence of symptoms ethnicity)22. (when the disease has been diagnosed by screening tests Clinical experience in children with NAFLD is limited. and/or abdominal ultrasonography). Although most patients NAFLD in childhood and adolescence used to occur in the remain asymptomatic, other individuals may present with a male obese patient, with AST>ALT (when variety of symptoms: hypertension, dyslipidaemia, insulin hypertransaminasaemia is present), hypertriglyceridaemia, resistance, type 2 diabetes, and central obesity23. 96 Liver disorders

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

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

9.23 Acanthosis nigricans.

simple esteatosis and NASH is liver biopsy (Table 9.11)26. It confirms diagnosis, assesses esteatosis severity, and serves as a prognostic marker. Patients with simple esteatosis have a benign course without histological progression, but 9.24 Ultrasonography showing increased ecogenicity due patients with NAFLD may progress to cirrhosis or to fat infiltration. hepatocarcinoma (described just in adults)27.

Transaminases can be normal or mildly elevated, Practical issues in a patient with persistently or intermittently (usually AST/ALT <1). In increased transaminases 25% of cases, patients show an increase in GGT24, 25. Imaging techniques such as ultrasonography (9.24), In the differential diagnosis of hypertransaminasaemia, computed tomography, and nuclear magnetic resonance coeliac disease should be considered, even when there are imaging do not distinguish between simple esteatosis and no other symptoms28. The baseline investigations may be NASH. The gold standard test to distinguish between found in Table 9.12. If these are not enough to lead to the Liver disorders 97

Table 9.11 Histopathological findings in nonalcoholic liver disease

Children Adults Steatosis Marked Portal Lobular Ballonization Rare Frequent Fibrosis >Portal Lobular 9.25 Evolution to cirrhosis in a child with a severe Cirrhosis Rare >Frequent congenital heart disease.

Table 9.12 Investigations to be performed in diagnosis, second-line investigations should be performed29. patients with increased transaminases In acute hepatitis, liver biopsy should be indicated if there is unknown aetiology, prolonged hepatitis or several relapses, Transaminases < twice normal: repeat suspicion of underlying chronic disease, or cholestasis probable normalization associated with acute cytolysis30. In chronic hepatitis, liver biopsy is essential and is Baseline indicated to investigate the aetiology, for histological • Coagulation test diagnosis, for the prognosis based on inflammation intensity • Iron, ferritin, transferrin (grade) and fibrosis (stadium), and to evaluate anti-viral • Immunoglobulins therapy response. Some practical considerations are: • Electrophoretic gel • ↑ AST isolated: macrotransaminasaemia (AST–immu no - • Copper and coeruloplasmin globulin complex, without liver damage). Second line • The degree of transaminases elevation does not correlate • CK, aldolase with prognosis. • RNA HCV; DNA HBV • The most frequent causes of gross elevation in • Serology: CMV, EBV, herpesvirus transaminases in acute hypertransaminasaemia (AST- • Autoimmunity (ANA, ASMA, LKM, citosol, AMA) ALT >1000) are: viral hepatitis, drug and alcohol- • α-1-antitrypsin levels and phenotype Pi induced hepatitis, and ischaemic hepatitis (heart failure, • IgA-antigliadin; IgA- antitransglutaminase hypotension, sepsis, Budd–Chiari). • T3-T4-TSH • In chronic hepatitis, the inversion of the quotient AST/ALT (>1), indicates a deeper damage (mito - Liver biopsy chondrial) and evolution to fibrosis-cirrhosis (9.25). • Liver transplantation is indicated if there is reduced transaminases with increased bilirrubin and decreased 2 Alagille D. Extrahepatic biliary atresia. Hepatology prothrombin time. These are signs of submassive liver 1984;4:7S–10S. necrosis and consequent hepatocellular failure. Grade 3 Kasai M, Kimura S, Asakura Y, et al. Surgical treatment III/IV encephalopathy and/or factor V <25% are clear of biliary atresia. J Pediatr Surg 1968;3:665–75. indications for liver transplantation. 4 Altman RP, Lilly JR, Greenfeld J, et al. A multivariable risk factor analysis of the portoenterostomy (Kasai) procedure for biliary atresia: twenty-five years of References experience from two centers. Ann Surg 1997;226:348–55. 1 American Academy of Pediatrics. Management of 5 Kaplan M, Hammerman C, Maisels MJ. Bilirubin genetics hyperbilirubinemia in the newborn infant 35 or more for the nongeneticist: hereditary defects of neonatal weeks of gestation. Pediatrics 2004;114:297–316. bilirubin conjugation. Pediatrics 2003;111:886–93. 98 Liver disorders

6 Quiros-Tejera R, Ament ME, Heyman MB, et al. 21 Marchesini G, Brizi M, Bianchi G, et al. Nonalcoholic Variable morbidity in Alagille syndrome: a review of 43 fatty liver disease: a feature of the metabolic syndrome. cases. J Pediatr Gastroenterol Nutr 1999;29:431–37. Diabetes 2001;50:1844–50. 7 Emerick KM, Rand EB, Goldmuntz E, et al. Features of 22 Schwimmer JB, Behling C, Newbury R, et al. Alagille syndrome in 92 patients: frequency and relation Histopathology of pediatric nonalcoholic fatty liver to prognosis. Hepatology 1999;29:822–29. disease. Hepatology 2005;42:641–9. 8 Whitington PF, Whitington GL. Partial external 23 Peña-Quintana L, Colino E, Montedeoca N, et al. diversion of bile for the treatment of intractable pruritus Obesity and nonalcoholic fatty liver disease. J P e d iat r associated with intrahepatic cholestasis. Gastroenterology Gastroenterol Nutr 2005;40:686–7. 1988;95:130–36. 24 Fishbein MH, Mogren C, Gleason T, et al. Relationship 9 Knisely AS, Strautnieks SS, Meier Y, et al. Hepatocellular of hepatic steatosis to adipose tissue distribution in carcinoma in 10 children under 5 years of age with bile salt pediatric nonalcoholic fatty liver disease. J P e d iat r export pump deficiency. Hepatology 2006;44:478–86. Gastroenterol Nutr 2006;42:83–8. 10 Schweitzer-Krantz S. Early diagnosis of inherited 25 Festi D, Colecchia A, Sacco T, et al. Hepatic steatosis in metabolic disorders towards improving outcome: the obese patients: clinical aspects and prognostic controversial issue of galactosaemia. Eur J Pediatr significance. Obesity Reviews 2004;5:27–42. 2003;162:S50–S53. 26 Joy D, Thava VR, Scott BB. Diagnosis of fatty liver 11 Burton BK. Inborn errors of metabolism in infancy: a disease: is biopsy necessary? Eur J Gastroenterol Hepatol guide to diagnosis. Pediatrics 1998;102:1–9. 2003;15:539–43. 12 Suchy FJ, Sokol R, Balistreri W (eds). Liver Disease in 27 Molleston JP, White F, Teckman J, et al. Obese children Children, 3rd edn. Cambridge University Press, New with steatohepatitis can develop cirrhosis in childhood. York, 2007. Am J Gastroenterol 2002;97:2460–2. 13 Impicciatore P, Choonara I, Clarkson A, et al. Incidence 28 Abdo A, Meddings J, Swain M. Liver abnormalities in of adverse drug reactions in paediatric in/out-patients: a celiac disease. Clin Gastroenterol Hepatol systematic review and meta-analysis of prospective 2004;2:107–12. studies. Br J Clin Pharmacol 2001;52:77–83. 29 Pratt DS, Kaplan MM. Evaluation of abnormal liver- 14 Roberts EA, Schilsky ML. A practice guideline on enzyme results in asymptomatic patients. N Engl J Med Wilson disease. Hepatology 2003; 37:1475–92. 2000;342:1266–71. 15 Garcia-Villarreal L, Daniels S, Shaw SH, et al. High 30 Kelly DA. Diseases o f the Liver and Biliary System in prevalence of the very rare Wilson disease gene mutation Children, 2nd edn. Blackwell Science, Oxford, 2003. Leu708Pro in the Island of Gran Canaria (Canary Islands, Spain): a genetic and clinical study. Hepatology 2000;32:1329–36. Further reading 16 Ferenci P, Caca K, Loudianos G, et al. Diagnosis and phenotypic classification of Wilson disease. Liver Int Fregonese L, Stolk J. Hereditary alpha-1-antitrypsine 2003;23:139–42. deficiency and its clinical consequences. Orphanet J Rare 17 Czaja AJ, Freese D. Diagnosis and treatment of Dis 2008;19(3):16. autoimmune hepatitis. Hepatology 2002;36:479–97. Harb R, Thomas DW. Conjugated hyperbilirubinemia: 18 Primhak RA, Tanner MS. Alpha-1 antitrypsin screening and treatment in older infants and children. deficiency. Arch Dis Child 2001;85:2–5. Pediatr Rev 2007;28:83–91. 19 Patton HM, Sirlin C, Behling C, et al. Pediatric Kelly DA, Devenport M. Current management of biliary nonalcoholic fatty liver disease: a critical appraisal of atresia. Arch Dis Child 2007;92:1132–5. current data and implications for future research. J Moerschel SK, Cianciaruso LB, Tracy LR. A practical Pediatr Gastroenterol Nutr 2006;43:413–27. approach to neonatla jaundice. Am Fam Physician 20 Fishbein MH, Miner M, Mogren C, et al. The spectrum 2008;77:1255–62. of fatty liver in obese children and the relation-ship of serum aminotransferases to severity of steatosis. J P e d iat r Gastroenterol Nutr 2003;36:54–61. Chapter 10 99 Coeliac disease Isabel Polanco MD, PhD

Definition

Coeliac disease (CD) is an immunologically mediated administration of extra-gluten to HLA-identical siblings of enteropathy of the small intestine, characterized by lifelong coeliac patients does not always result in pathological intolerance to the gliadin and related prolamines from wheat changes to the intestine. The HLA-DQ dimmer is also and other cereals that occurs in genetically predisposed strongly linked to HLA-DR status8. individuals1. Symptoms result from structural damage to the mucosa of the small intestine, which may cause malabsorption. Normal mucosal architecture is restored Pathology after commencing a gluten-free diet (GFD); villous atrophy reappears when gluten is reintroduced into the diet (gluten The proximal mucosa of the small intestine in patients with challenge)1–3. CD becomes abnormal on gluten ingestion and small bowel biopsy is essential to confirm the diagnosis (10.1). The abnormality is characterized by stunted or even absent villi Epidemiology associated with an increase in crypt length and cell numbers, the so-called ‘flat mucosa’ (10.2). The flat gut lesion is The true incidence of CD in susceptible populations characteristic, but nonspecific of CD (Table 10.1)9. may be dramatically higher than has been previously All structural damage resolves on gluten withdrawal, but recognized1, 3, 4 and most cases remain undiagnosed, unless recurs if gluten is reintroduced to the diet. Similar intestinal actively identified through mass serological screening. CD changes are frequently found in dermatitis herpetiformis affects females more than males (ratio 2:1). (DH), an intensely itchy, chronic papulovesicular skin A relationship between various factors and the diagnosis of CD has been described, including genetic background, quality and quantity of gluten, age at gluten introduction, and breast-feeding5–7.

Genetic factors

The primary association of CD is the HLA-DQ dimer DQA1*0501/DQB1*0201. The majority of patients and first-degree relatives (and up to 20% of normal controls in susceptible populations) may express this dimer on antigen- presenting cells. The possession of this haplotype is not 10.1 Histological section of a flat mucosa in untreated enough to cause gluten-induced changes, and the coeliac disease. 100 Coeliac disease

10.2. Histological features. (From Horvath K. Recent Advances in Pediatrics, 2002.)

Normal 0 Infiltrative 1 Hyperplastic 2

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

Table 10.1 Causes other than coeliac disease that Clinical features may produce a flattened jejunal mucosa CD can appear with different clinical manifestations. In general, the first symptoms appear in the months following Children the introduction of gluten in the diet (10.3, 10.4). The • Transient gluten intolerance earlier gluten is introduced, the shorter the interval between • Soy and cow’s protein enteropathy introduction and occurrence of the first symptoms. The first • Autoimmune enteropathy symptoms of CD, therefore, traditionally occur between 12 • Acute viral enteritis months and 3 years of age (Table 10.2). • Giardiasis In a minority of children, diagnosis is not made by the age • Prolonged malnutrition of 5 years. CD can therefore be diagnosed at any time up to adulthood, because symptoms have been either ignored or Adults misinterpretated (e.g. short stature), because the disease is • Zollinger–Ellison syndrome truly symptomless or when some other autoimmune disease • Tropical sprue occurs (Tables 10.3, 10.4). • Giardiasis • Oral contraceptives • Others Latent coeliac disease

Coeliac subjects may present with a severe or mild enteropathy at different times of their life. There are in fact subjects who had a normal jejunal biopsy while taking a disorder, caused by granular subepithelial IgA deposits in normal diet, and, at some other time, have had a flat jejunal the upper dermis. Both the cutaneous and intestinal lesions biopsy which recovered on a GFD. For such subjects the regress with a GFD. DH is now considered as a specific skin definition of latent coeliac disease has been proposed. This manifestation of CD. definition can also be applied to ‘late relapsers’10–12. Coeliac disease 101

10.3 An untreated coeliac girl. Table 10.2 Clinical presentation according to the She is pale and looks miserable age of onset of symptoms in CD and depressed.

Symptoms Signs Classic presentation Chronic 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 age Asymptomatic 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 adulthoood Anxiety/depression Glossitis, aphthous ulcers Chronic diarrhoea Malnutrition Anorexia Spontaneous haemorrhage Abdominal pain Peripheral oedema Infertility Isolated megaloblastic Paraesthesias anaemia Nocturnal diuresis Cramps/tetany A B Bone pain Digital clubbing Cerebrospinal Proximal myopathy 10.4 A, B: A typical 3-year-old coeliac boy with active degeneration Peripheral neuropathy disease. Note his distended and prominent abdomen, Variety of rashes muscle wasting, and severe malnutrition. Subcutaneus fat Hyposplenism disappears. Muscle wasting, affecting mostly the buttocks, thighs, and shoulders, contrasts markedly with the prominent abdominal distension. 102 Coeliac disease

Table 10.3 Associated disorders found in Table 10.4 Mode of presentation in 1010 coeliac 1010 coeliac children at the Hospital Infantil Children at the Hospital Infantil Universitario Universitario La Paz Madrid (Spain) La Paz, Madrid (Spain)

Selective IgA deficiency 37 Classic presentation: 580 cases (57.4%) Dermatitis herpetiformis 36 • Chronic diarrhoea, abdominal distention, failure to Diabetes mellitus 32 thrive, anorexia, etc. Bronchial asthma 6 Psoriasis 6 Atypical presentation: 430 cases (42.6%) Chronic active hepatitis 6 • Retarded growth 90 Epilepsy 6 • Anaemia 79 Vitiligo 4 • Constipation 72 Down syndrome 3 • Abdominal pain 57 Cardiac disease 3 • Abdominal distension 46 Thyroid disorders 3 • Muscular hypotony 25 Cystic fibrosis 1 • Bleeding 23 Fibrosing alveolitis 1 • Oedema 20 Renal tubular acidosis 1 • Aphthous stomatitis 8 Spino-cerebellar degeneration 1 • Epilepsia 6 Total 146 • Ataxia 4

Diagnosis

The diagnosis of coeliac disease requires both a jejuno- screening for coeliac disease (Table 10.5). The titres of duodenal biopsy that shows the characteristic findings of endomysial antibodies and anti-tissue transglutaminase intraepithelial lymphocytosis, crypt hyperplasia, and villous antibodies correlate with the degree of mucosal damage; as atrophy (10.1) and a positive response to a GFD. The a result, the sensitivity of these antibody tests declines when diagnostic criteria developed by the European Society for a greater number of patients with lesser degrees of villous Paediatric Gastroenterology and Nutrition2 require only atrophy are included in studies. The various commercially clinical improvement with the diet, although histological available assays for anti-tissue transglutaminase antibodies improvement on a GFD is frequently sought and is have different characteristics and resultant sensitivities and recommended in adults because villous atrophy may persist specificities. despite a clinical response to the diet. In most patients, the diagnosis is easily established. However, roughly 10% of cases are difficult to diagnose because of a lack of Treatment concordance among serologic, clinical, and histological findings1–3. A strict GFD with exclusion of gluten from wheat, rye, The most sensitive antibody tests for the diagnosis of barley, and oats must be recommended lifelong in both coeliac disease are of the IgA class. The recognition that the symptomatic and asymptomatic individuals. Lifelong enzyme tissue transglutaminase is the autoantigen for the adherence to a strict GFD should be advised to all coeliac development of endomysial antibodies allowed development children in order to avoid the late complications of the of automated enzyme-linked immunoassays that are less disease13. Adherence to a strict GFD is essential but not expensive than the endomysial antibody test. Overall, the easy and a follow-up control by a gastroenterologist about sensitivity of the tests for both endomysial antibodies and once a year seems to be advisable. The Coeliac Patients anti-tissue transglutaminase antibodies is greater than 90%, Associations help patients to adhere to a GFD and to and a test for either marker is considered the best means of understand their disease better. Coeliac disease 103

Table 10.5 Serological tests for coeliac disease9

Test Sensitivity (%) Specificity (%) PPV NPD AGA IgG 57–100 42–98 20–95 41–88 AGA IgA 53–100 65–100 s28–100 65–100 AEA IgA 75–98 96–100 98–100 80–95 Guinea pig tTG 90.2 95 Human tTG 98.5 98

PPV: positive predictive value; NPD: negative predictive value

References

1 Green P, Cellier C. Celiac disease. N Engl J Med 10 Polanco I, Larrauri J. Does transient gluten intolerance 2007;357:1731–43. exist? In: Kumar PJ, Walker-Smith JA (eds). Coeliac 2 Walker-Smith JA, Guandalini S, Schmitz J, et al. Revised Disease: One Hundred Years. Leeds University Press, criteria for the diagnosis of coeliac disease. Report of Middlesex, 1990, pp. 226–30. working group of ESPGHAN. Arch Dis Child 11 Kaukinen K, Collin P, Mäki M. Latent coeliac disease 1990;65:909–11. or coeliac disease beyond villous atrophy? Gut 3 Troncone R, Auricchio R. Celiac disease. In: Wyllie R, 2007;56:1339–40. Hyams JS (eds). Pediatric Gastro intestinal and Liver 12 Polanco I, Larrauri J, Prieto G, et al. Severe villous Disease, 3rd edn. Saunders Elsevier, The Netherlands, atrophy appearing at different ages in two coelias siblings 2006, pp. 517–27. with identical HLA haplotypes. Acta Paediatr Belg 4 Polanco I, De Rosa S, Jasinski C. Coeliac disease in Latin 1980;33:276. America. In: Auricchio S, Visakorpi JK (eds). Common 13 Holmes GKT. Long-term health risks for unrecognized Food Intolerance I: Epidemiology of Coeliac Disease. coeliac patients. Dyn Nutr Res 1992;2:105–18. Dynamic Nutrition Research (series). Karger, Basel, 1992:2:10–29. 5 Polanco I, Vázquez C. The influence of breast feeding in Further reading coeliac disease. Paediat Res 1981;75:1193. 6 Polanco I, Biemond I, van Leeuwen A, et al. Gluten- Baldassarre M, Lanene AM, Grosso R, et al. Celiac disease: sensitive enteropathy in Spain: genetic and environmental pathogenesis and novel therapeutic strategies. Endocr factors. In: McConnell RB (ed). The Genetics of Coeliac Metab Immune Disrd Drug Targets 2008;8:152–8. Disease. MTP Press, Lancaster, 1981, pp. 211–34. Barton SH, Murray JA. Celiac disease and autoimmunity in 7 Mearin ML, Biemond I, Peña AS, et al. HLA-DR the gut and elsewhere. Gastroenterol Clin North Am phenotypes in spanish coeliac children: their contribution 2008;37:411–28. to the understanding of the genetics of the disease. Gut Fasano A, Troncone R, Branski D. Frontiers in Celiac 1983;24:532–37. Disease. In: Pediatric and Adolescent Medicine, vol 12. 8 Polanco I, Mearin ML, Larrauri J, et al. The effect of Branski D, Kiess W (eds). Karger, Basel, 2008. gluten supplementation in healthy siblings of children Polanco I. Celiac Disease. J Pediatr Gastroenterol Nutr with celiac disease. Gastroenterology 1987;92:678–81. 2008;47(suppl 1):S3–6. 9 Marsh MN. Gluten, major histocompatibility complex, Setty M, Harmaza L, Guandalini S. Celiac disease: risk and the small intestine. A molecular and immunologic assessment, diagnosis, and monitoring. Mol Diagn Ther approach to the spectrum of gluten sensitivity (celiac 2008;15:289–98. sprue). Gastroenterology 1992;102:330–54. 104 Chapter 11 Ulcerative colitis Carlos Sierra Salinas, MD, and Javier Blasco Alo nso , MD

Introduction Pathogenesis

Ulcerative colitis (UC) is a relapsing and remitting disease The pathogenesis remains unknown. Recent literature characterized by acute non-infectious inflammation of the reports an intensive search for the antigens that trigger the colorectal mucosa. Crohn’s disease (CrD) and UC are the immune response in inflammatory bowel disease. One two main types of inflammatory bowel disease (IBD). While hypothesis is that these triggers are microbial pathogens, as children and adults develop similar symptoms, children yet unidentified with an appropriate but ineffective immune often present with more extensive disease. response to these pathogens. Another hypothesis affirms that there are some common dietary antigens or nonpathogenic microbial agents to which the patient Epidemiology mounts an abnormal immune response. The autoimmune theory postulates that an antigen is expressed on the UC may appear at any age. Most of the children are patient’s own intestinal epithelial cells and there is an between 10 and 18 years. The incidence of UC in children immune response to antigen and own epithelium which are and adolescents per 100,000 children per year varies thus destroyed by immune mechanisms. between 0.5 (France) and 4.3 (Norway). The incidence of UC in children has remained relatively stable. Multiple genes may contribute to the pathogenesis of UC; essential is Clinical features the interaction with the environment. Among others factors, several authors have suggested the correlation with exposure The presentation may vary depending upon the extent of to infections in the perinatal period or early life, the inverse colonic involvement and the severity of inflammation. relationship with breast-feeding, the administration of According to the extent of the disease, three subgroups have nonsteroidal anti-inflammatory drugs, and the inverse been established (11.1): relationship with appendectomy before the age of 20 years. • Proctitis (25%): disease limited to the rectum. Evidence of higher rates of UC in urban areas raises the • Left-sided colitis (30%): involving the descending colon issue of a transmissible agent that may be responsible for the up to the splenic flexure. disease expression or increased susceptibility. However, no • Pancolitis (45%): involvement proximal to the splenic specific infectious agent has been associated with the flexure, usually up to the caecum. development of the disease. Ulcerative colitis 105

Table 11.1 Symptoms of ulcerative colitis

Colonic • Rectal bleeding • Diarrhoea • Tenesmus • Incontinence • Lower abdominal cramps and pain with defecation Proctitis Left-sided colitis Pancolitis Systemic 11.1 Extent of bowel involvement in different ulcerative • Tiredness colitis. • Weight loss • Fever

The predominant symptom is diarrhoea, which can be Extraintestinal associated with frank blood in the stool. The patient has • Related to activity of colitis: frequent bowel movements, which may be small in volume, – Peripheral arthritis as a result of irritability of the inflamed rectum. Other – Erythema nodosum symptoms include abdominal or rectal pain related to – Iritis, uveitis defecation, fever, and weight loss (Table 11.1). • Unrelated to activity of colitis: Proctitis may present with tenesmus, urgency, and the – Sclerosing cholangitis passage of semi-formed stool with blood and mucus. In – Autoimmune hepatitis contrast, left-sided colitis or pancolitis may present with – Sacroileitis bloody diarrhoea and significant abdominal pain. The majority of patients will present with a history of symptoms for several weeks. For this reason growth failure is much less Table 11.2 Disease severity at presentation frequent than in children with CrD. The extent of colonic mucosal involvement and severity of disease correlate with the clinical manifestations of UC (Table 11.2) Mild • Up to 4 stools per day • Presence of blood in the stool less than daily Differential diagnosis • No systemic symptoms

The most difficult decision may be to establish whether the Moderate/severe diagnosis is UC or CrD (Table 11.3). The infectious • ≥5 stools per day aetiologies should be investigated with stool cultures and • Daily presence of blood in the stool stool test for Clostridium difficile toxins A and B. • With or without systemic symptoms Identification of a pathogen, however, does not necessarily exclude a diagnosis of UC, as a first episode of UC may Fulminant present after documented enteric infection (Table 11.4). In • ≥ Grossly bloody stools per day infancy it is important to exclude other causes of bloody • Fever >38°C diarrhoea such as allergic colitis and Hirschsprung´s colitis. • Tachycardia Physical examination is notably less informative than in • Haemoglobin ≤8 g/dl CrD, except for the demonstrations of extraintestinal • Serum albumin ≤3.0 g/dl manifestations that may be associated with UC. 106 Ulcerative colitis

Table 11.3 Differences between UC and CrD-colitis

UC CrD Long latent period No Yes Osteopaenia at diagnosis No Yes Growth failure No Yes Oral and perianal disease No Yes Cytokines ↑ interleukin 4, 5; Normal interleukin 4, 5; normal γ interferon and ↑ γ interferon and interleukin 12 interleukin 12 Granuloma No Yes Transmural inflammation No Yes

Table 11.4 Infectious colitis Initial assessment

The first steps in the diagnostic work-up of children with Viral suspected UC should include blood tests, stool • Cytomegalovirus examination, and bowel wall ultrasonography • HIV measurement1. There is a low diagnostic accuracy of the • HIV-related opportunistic infections common laboratory parameters of inflammation such as platelet count, erythrocyte sedimentation rate, and C- Bacterial reactive protein. Experience with faecal calprotectin in • Campylobacter children with suspected IBD has been encouraging and • Salmonella suggests that this protein is a reliable diagnostic predictor for • Shigella intestinal activity, with greater sensitivity and negative • Yersinia predictive value compared with those of other common • Escherichia coli 0157:H7 and other laboratory parameters of inflammation. However, faecal enterohaemorrhagic E. coli calprotectin is not disease-specific, being elevated in all • Clostridium difficile kinds of intestinal inflammation such as infectious • Tuberculosis enterocolitis. The serological immune markers anti- Saccharomyces cerevisiae antibodies (ASCA) and anti- Parasitic neutrophil cytoplasmic antibody with perinuclear staining • Entamoeba histolytica pattern (pANCA) are associated with CrD and UC, • Giardia lamblia respectively, and they are rarely found in healthy controls. The ultrasonographic evaluation of the intestinal thickness has gained importance as a reliable, noninvasive imaging modality for the diagnostic and clinical follow-up of IBD patients. The combined use of faecal calprotectin, ASCA/pANCA, and bowel wall ultrasonography measurement is a useful clinical decision-making strategy. If these test results are positive, the patient would then undergo a complete evaluation2. Ulcerative colitis 107

Radiographic and endoscopic evaluation

In the early phase, the oedema and inflammatory infiltration Table 11.5 Endoscopic staging of ulcerative colitis cause a flattening of the haustras. In the active stage there is a disseminated ulceration and loss of haustra (11.2). Deeper ulcers may undermine the mucosa, which leads to Stage 0 Vessels slightly kinked, pale mucosa development of the characteristic collar-button ulcerations. Stage 1 Erythema, slight granularity Evaluation with colonoscopy should be performed to Stage 2 Individual ulcerations, no vessels visible, diagnose UC and to determine the extent and severity of spontaneous bleeding UC presentation (Table 11.5) (11.3). Stage 3 Larger ulcerations, spontaneous bleeding, oedematous mucosa Histopathological findings

UC is defined histologically by diffuse chronic depletion) (11.4B) and crypt abscesses (11.4C). inflammation limited to the mucosa with severe crypt cell Inflammation is diffuse and solely mucosal. Vascularity is distortion (11.4A), diffuse goblet cell depletion (mucous increased.

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

A B

C D 108 Ulcerative colitis

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 A B nonconfluents superficial ulcers; D: rectum with loss of vascular pattern, oedematous mucosa, and small ulcers.

C D

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

A B

C Ulcerative colitis 109

Management References

For children with distal disease, local steroids as 1 Canani RB, Tanturri de Horatio L, Terrin G, et al. hydrocortisone or budesonide may be successful but rectal 5- Combined use of noninvasive tests is useful in the initial ASA derivatives may also be tried. For mild colitis oral diagnostic approach to a child with suspected mesalamine (50–70 g/kg/day) or sulfasalazine inflammatory bowel disease. J Pediatr Gastroenterol Nutr (50–70 mg/kg/day) are recommended. For moderate colitis, 2006;42(1):9–15. treatment with oral steroids in a dose of 1–2 mg/kg/day up to 2 IBD Working Group of the ESPGHAN. Inflammatory 60 mg/day is recommended associated with mesalamine. bowel disease in children and adolescents: This dose should be continued for 1–2 weeks depending recommendations for diagnosis: the Porto Criteria. J upon the response. It is then tapered over the next 3 months, Pediatr Gastroenterol Nutr 2005;41(1):1–7. at first by weekly reductions by 5 mg/week and then a more 3 Mamula P, Markowitz JE, Cohen LJ, et al. Infliximab in gradual taper on alternate days and cessation if clinical pediatric ulcerative colitis: two year follow-up. J P e d iat r remission is maintained. The immunomodulatory drugs Gastroenterol Nutr 2004;38(3):298–301. azathioprine (1.5–2.5 mg/kg/day) and its metabolite 6- mercaptopurine (1.5 mg/kg/day) can reduce the disease activity and allow the withdrawal of steroid therapy in Further reading children with steroid-dependent UC. Children with severe colitis are a medical emergency and require urgent treatment Higuchi LM, Bousvaros A. Ulcerative colitis. In: with intravenous fluids, antibiotics, and intravenous steroids Guandalini S (ed). Texbook of Paediatric for 7–10 days. If the child has not responded, then intensive Gastroenterology and Nutrition. Taylor & Francis, immunosuppression should be started with oral tacrolimus London 2004, pp. 385–418. (0.12 mg/kg/day) or intravenous or oral cyclosporine (2–4 McGinnis JK, Murray KF. Infliximab for ulcerative colitis in mg/kg/day). Most of children achieve clinical remission children and adolescents. J Clin Gastroenterol 2008;42: within 3–9 days. However, even if they respond to the 875–9. immunosuppression the majority of patients will require Oliva-Hemker M, Escher JC, Moore D, et al. Refractory colectomy a few months or years later (Table 11.6). inflammatory bowel disease in children. J P e d iat r The role of infliximab in treating paediatric UC is not Gastroenterol Nutr 2008;47:266–72. well defined. In recent papers, infliximab (5 mg/kg/day) is Van Limberger J, Russell RK, Drummond HE, et al. associated with short- and long-term clinical improvement Definition of phenotypic characteristics of childhood- in children and adolescents with moderate to severe UC and onset inflammatory bowel disease. Gastroenterology less effective in steroid-dependent patients3. 2008;135:1114–22.

Table 11.6 Indications for colectomy in ulcerative colitis

• Fulminant colitis • Medical therapy failure • Steroid dependency • Colonic dysplasia 110 Chapter 12 Crohn’s disease David Ziring, MD, and Jorge Vargas, MD

Prevalence and incidence

Crohn’s disease (CrD) is a chronic, immune-mediated consortia have pinpointed distinct genes that are associated gastrointestinal (GI) disease and one of the inflammatory with the development of CrD. These include genes for bowel diseases (IBD) (including ulcerative colitis [UC] and proteins that sense bacterial products, like the indeterminate colitis). IBD currently affects nearly 1 million NOD2/CARD15 gene. 40% of patients with CrD have a patients in the United States, 25% of whom are children1–3. ‘gain of function’ mutation in NOD29, 10. These patients are Nearly 30 patients of every 100,000 in the population are more likely to have ileal disease with stricture formation11. diagnosed each year, and the incidence is increasing4, 5. The Similarly, a genetic polymorphism has been identified in prevalence of IBD is higher in industrialized nations, the protein encoded by the organic cation transporter gene especially in northern latitudes4. The number of patients (OCTN)12. Most recently, researchers have identified a affected with CrD outnumbers those with UC nearly two- polymorphism in the interleukin-23 (IL-23) receptor gene. fold2. This polymorphism provides protection against the development of CrD13. The IL-23 receptor is expressed by a pathogenic subset of T cells thought to be the effectors Aetiology responsible for intestinal inflammation.

This disease entity stems from an abnormal host immune Environment response to normally occurring gut constituents. Three The rate of new diagnoses of IBD has increased 10-fold unifying forces underlie the pathogenesis of IBD. First, at since the 1940s. Many believe that this increase is associated risk patients have a genetic predisposition. Next, there is an with our improved hygiene5. The ‘hygiene hypothesis’ posits environmental trigger (or triggers, in the case of antigens that autoimmune disease is on the rise because regulatory borne by intestinal bacteria). Lastly, there is a dysregulation cells of the developing immune systems are not educated by of the normal homeostasis of the intestinal immune system. the normal complement of environmental bacteria.

Genetics Immunology CrD is a polygenic disease, i.e. several genes contribute to The intestinal immune system is incredibly complex. the pathogenic immune phenotype. The role that genetic Several different cell types protect the mucosa from invasion susceptibility plays in developing IBD is illustrated by its by neighbouring bacteria. This ‘innate immune system’ is prevalence in monozygotic twins. Between 36 and 58% of comprised of dendritic cells, macrophages, natural killer affected twins have an identical twin with CrD, while (NK) cells, and natural killer T (NKT) cells14. It is the first nonidentical siblings have only a 4% concordance rate6–8. line of defence and provides the quickest response to antigen Many genetic susceptibility loci have been identified in without the need for immune memory. Intestinal epithelial patients, but over the last several years, large genetic cells have receptors for bacterial products. Paneth cells Crohn’s disease 111

reside in the crypts and produce antibacterial proteins. well as symptoms lasting in excess of 2 weeks. Also, a careful Specialized dendritic cells are able to stick their processes in clinician will elicit any use of nonsteroidal anti-inflammatory between intestinal epithelial cells and ‘sample’ gut drugs (NSAIDs) in the recent past, as NSAID enteropathy bacteria15. The chronic inflammation of IBD is due to a loss may mimic CrD. of tolerance to these antigens. Defects have been identified Physical examination of a patient with CrD may reveal a in special immune suppressor cells, normally responsible for left lower quadrant mass with tenderness, or the presence of toning down the inflammatory response16, 17. perianal findings such as skin tags or fistulae (12.1, 12.2). The effector cells, those cells responsible for coordinating Patients with CrD may also have associated skin rashes, the damaging inflammation in CrD, are a special set of such as erythema nodosum, or less commonly, pyoderma CD4+ T helper cells. These cells produce large amounts of gangrenosum (12.3, 12.4). Ophthalmological findings proinflammatory cytokines such as tumour necrosis factor include episcleritis or uveitis. Besides typical aphthous (TNF), IL-6, and IL-17. ulcers appearing in the mouth, patients may have cheilitis, or inflammation evidenced as a red, scaly rash at the corners of the mouth. Seronegative joint pains, or arthropathies are Diagnosis not uncommon (12.5, 12.6). These include pauciarticular large joint arthropathy and polyarticular small joint The diagnosis of CrD depends on several medical arthropathy. modalities, including a proper history and physical examination, radiological imaging, stool testing and blood Radiology testing for indicators of inflammation, gross inspection on Several radiological diagnostic studies contribute endoscopy, and careful analysis of the intestinal tissue information to diagnosing IBD. These include the barium biopsies obtained during endoscopy. contrast series and computed tomography (CT) scan (12.7, 12.8). Barium radiograph (or ‘small bowel follow through’) History and physical examination studies help in the diagnosis of CrD when the presence of Patients with CrD and UC typically have quite different narrowing (stenosis) or ulceration is present in the small presentations. CrD often presents with abdominal pain, bowel (12.9, 12.10). Stenosis, most often seen in the weight loss, unexplained fevers, and/or a dampened growth terminal ileum of patients with CrD, has been given the velocity. On the other hand, patients with UC typically moniker ‘string sign’ (12.11, 12.12). Bowel oedema can be present with bloody diarrhoea. Differentiating acute seen as ‘thumbprinting’ or exaggerated swollen mucosal infectious diarrhoea from CrD relies on negative cultures as folding. Abnormal communication between loops of bowel

12.1 Presence of perianal findings: fistulae in a young 12.2 Presence of perianal findings: skin tags in a young patient with Crohn’s disease (arrow). patient with Crohn’s disease (arrow). 112 Crohn’s disease

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. Crohn’s disease 113

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).

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

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

that stem from chronic transmural inflammation are called detected in the stool as alpha-1-antitrypsin. Other more fistulae, and can also be noted on these barium radiographs. sensitive and specific markers of inflammation that can be Some experienced groups use ultrasound as a first approach detected in the stool include faecal calprotectin and in imaging for diagnosis of CrD (12.13, 12.14). S100A12. Several progressive European centres utilize magnetic resonance imaging (MRI) enterography. Cases difficult to Blood testing diagnose may employ the use of radiolabeled markers, such There are several sensitive indicators of bowel inflammation as technetium, to tag white blood cells and localize the that can be examined in the blood. These include the white intestinal site of inflammation. blood cell count, platelet number, erythrocyte sedimentation rate, and C-reactive protein. Iron deficiency Stool testing anaemia as evidenced by a microcytic anaemia with an Patients with CrD often have inflammation that causes the elevated red blood cell differentiation width (RDW) may lining of the intestine to leak protein. This protein is arise as a result of decreased oral intake, blood loss from the 114 Crohn’s disease

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

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

A B

GI tract, or poor iron absorption. Decreased serum albumin Endoscopy may similarly result from poor oral intake or protein loss Colonoscopy and upper endoscopy allow the clinician to from the gut. Patients may also have a decreased obtain biopsies for histological diagnosis. Inflammation may albumin:globulin ratio, the product of hypoalbuminaemia be found anywhere along the GI tract from mouth to anus. and increased globulin fraction due to immune activation. Grossly, the inflammation is evident as discrete areas of More recently, serological testing for antibodies directed erythema, oedema, and haemorrhage with intervening areas against common bacterial antigens have helped in the of normal appearing mucosa. Aphthous ulcers are often diagnosis and prognosis of patients with CrD. Patients often seen, and these may take on a linear or serpiginous have an elevated titre of antibodies directed against a appearance (11.15). Often, the rectum is spared gross common yeast antigen, called the anti-Saccharomyces inflammation. cereviseae antibody (ASCA). Other antibodies that predict A skilled endoscopist typically will locate the ileocaecal disease complications include those directed against flagellin valve during colonoscopy and intubate the terminal ileum, (CBir), the outer membrane porin C on Escherichia coli obtaining biopsies there. While patients with UC may have (OmpC), and a common Pseudomonas antigen (I2). mild inflammation in the terminal ileum (‘backwash ileitis’), Crohn’s disease 115

patients with CrD may have evidence of stricture formation, Management granulomas, fissures, or linear ulcers. The finding of ileitis is most often associated with a diagnosis of CrD. Surgery Inflammation of the upper GI tract may be seen in as At least 50% of patients with CrD will require surgical many as 30% of patients with CrD, but it has also been treatment (most often small bowel resection) to treat compli - reported in patients with UC. Gastritis can even cause delay cations, such as a chronic intestinal stenosis, within the first in gastric emptying. Approximately 12–28% of patients with 10 years of diagnosis, and between 70–80% of patients will CrD will have noncaseating granulomas detected in biopsies eventually have surgery over the course of a lifetime18. The of the upper GI tract (most often in the stomach). Fewer resected bowel specimen may have the appearance of fat on patients have evidence of duodenal cryptitis. the anti-mesenteric border, termed ‘creeping fat’.

Capsule endoscopy Medical therapy Capsule endoscopy, an imaging modality in which the Pharmacotherapy for both the ‘induction’ and patient ingests a capsule containing a tiny camera, has ‘maintenance’ treatment of CrD depends largely on the proven to have remarkable sensitivity that rivals that of activity of the disease. Patients with mild disease may enter barium radiography. The capsule endoscope produces remission with a course of oral antibiotics such as thousands of still digital images that must be interpreted by ciprofloxacin or metronidazole. Other patients with mild a skilled reader, and differentiated from normal ‘mucosal disease may respond well to locally, topically acting breaks’. The use of this test is limited because of its cost and aminosalicylate preparations or similar steroid derivatives the time and expertise required of the reader. such as budesonide. However, the majority of patients will require maintenance treatment with immunomodulator Histology therapy such as 6-mercaptopurine or methotrexate. Those The finding of noncaseating granulomas in the intestine of a patients who are intolerant or unresponsive to these drugs, patient who does not have chronic granulomatous disease is or who have complicated disease, may benefit from diagnostic for CrD (12.16, 12.17). Early findings may only biological therapy with anti-TNF antibodies. show focal active inflammation associated with a lymphoid aggregate.

12.16 Medium power view of a section of colon from a 12.17 Histological images from the ileal biopsy of a patient with Crohn's disease. The mucosa shows crypt patient with Crohn’s disease. Top: a dense, chronic, architectural distortion and an increased amount of acute inflammatory cell infiltrate, lymphoid follicles, and a and chronic inflammation in the lamina propria. No granuloma (arrows) can be seen. Bottom: same granulomas are present. sample in a higher resolution. 116 Crohn’s disease

References

1 Kugathasan S, Judd RH, Hoffmann RG, et al. 13 Duerr RH, Taylor KD, Brant SR, et al. A genome-wide Epidemiologic and clinical characteristics of children with association study identifies IL23R as an inflammatory newly diagnosed inflammatory bowel disease in bowel disease gene. Science 2006;314(5804):1461–3. Wisconsin: a statewide population-based study. J P e d iat r 14 Podolsky DK. Inflammatory bowel disease. N Engl J 2003;143(4):525–31. Med 2002;347(6):417–29. 2 Baldassano RN, Piccoli DA. Inflammatory bowel disease 15 Gewirtz AT, Madara JL. Periscope, up! Monitoring in pediatric and adolescent patients. Gastroenterol Clin microbes in the intestine. Nat Immunol North Am 1999;28(2):445–58. 2001;2(4):288–90. 3 Loftus E. Update on incidence and prevalence of Crohn’s 16 Singh B, Read S, Asseman C, et al. Control of intestinal disease (CD) and ulcerative colitis (UC) in Olmsted inflammation by regulatory T cells. Immunol Rev county, Minnesota. Gastroenterology 2003;124(4; 2001;182:190–200. S1):A36. 17 Brimnes J, Allez M, Dotan I, et al. Defects in CD8+ 4 Barton JR, Gillon S, Ferguson A. Incidence of regulatory T cells in the lamina propria of patients with inflammatory bowel disease in Scottish children between inflammatory bowel disease. J Immunol 1968 and 1983; marginal fall in ulcerative colitis, three- 2005;174(9):5814–22. fold rise in Crohn’s disease. Gut 1989;30(5):618–22. 18 Vermeire S, van Assche G, Rutgeerts P. Review article: 5 Bach JF. The effect of infections on susceptibility to Altering the natural history of Crohn’s disease: evidence autoimmune and allergic diseases. N Engl J Med for and against current therapies. Aliment Pharmacol 2002;347(12):911–20. Ther 2007;25(1):3–12. 6 Tysk C, Lindberg E, Jarnerot G, et al. Ulcerative colitis and Crohn’s disease in an unselected population of monozygotic and dizygotic twins. A study of heritability and the influence of smoking. Gut 1988;29(7):990–6. 7 Russell RK, Satsangi J. IBD: a family affair. Best Pract Res Clin Gastroenterol 2004;18(3):525–39. 8 Orholm M, Binder V, Sorensen TI, et al. Concordance of inflammatory bowel disease among Danish twins. Results of a nationwide study. Scand J Gastroenterol 2000;35(10):1075–81. 9 Hugot JP, Chamaillard M, Zouali H, et al. Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn’s disease. Nature 2001;411(6837):599–603. 10 Ogura Y, Bonen DK, Inohara N, et al. A frameshift mutation in NOD2 associated with susceptibility to Crohn’s disease. Nature 2001;411(6837):603–6. 11 Abreu MT, Taylor KD, Lin YC, et al. Mutations in NOD2 are associated with fibrostenosing disease in patients with Crohn’s disease. Gastroenterology 2002;123(3):679–88. 12 Peltekova VD, Wintle RF, Rubin LA, et al. Functional variants of OCTN cation transporter genes are associated with Crohn disease. Nat Genet 2004;36(5):471–5. Chapter 13 117 Short bowel syndrome Javier Bueno, MD

Introduction Adaptation process

Short bowel syndrome (SBS) is a transitory or permanent After a massive small bowel resection, the remnant intestine intestinal failure due to the anatomic loss of extensive suffers an adaptation process that includes an increase in segments of small intestine clinically manifested with villous height and mucosal surface area, as well as in bowel diarrhoea, malabsorption, and malnutrition. SBS is the luminal circumference and wall thickness5. most frequent cause of intestinal failure in the paediatric Enteral nutrition is the principal adaptation stimuli by its population and occurs perinatally in 85%1, 2. Although it trophic effect, avoiding mucosa atrophy2. It promotes the can be congenital, it occurs most frequently after small enterohepatic recirculation of biliary salts and the release of bowel resection due to gut disorders (13.1) (Table 13.1). hormones and pancreato-biliary secretions that maintain the The intestinal length in the term newborn is 2.5–3 m and integrity and intestinal function. The length and site of between 6 and 8 m in the adult3. The definitive intestinal resection are obviously important: ileal resection is worse length to develop SBS is not well established. In adults it is tolerated than jejunal2, 6. The presence of the ileocaecal considered if the intestinal length is <200 cm. In children it valve improves the prognosis. It increases transit time and depends on age, but it is considered if the length is <80–100 the contact of nutrients with the mucosa. In addition, it cm, and it will be severe if <40 cm1, 2, 4. The patho- avoids bacterial overgrowth. In children, if intestinal length physiological consequences of a bowel resection depend on is <40 cm without ileocaecal valve there is 40% of the extent and site of the intestinal resection, and the probability of permanent parenteral nutrition (PN) adaptability of the remaining intestine. dependence. If the intestinal length is between 40 and 80 cm

13.1 Necrotizing Table 13.1 Main causes of short gut in children enterocolitis with multiple bowel perforations resulting in short • Necrotizing enterocolitis bowel syndrome. • Gastroschisis • Volvulus • Intestinal atresia • Hirschsrpung´s disease • Trauma 118 Short bowel syndrome

and the valve is present, 80% can achieve nutritional preserve the veins. autonomy in 1 year5. Long-term PN may be associated with complications that Preservation of colon is not only important for the include recurrent central venous line sepsis and liver failure absorption of fluid and electrolytes, but it also has (Table 13.2). In children, hepatic dysfunction is a major nutritional advantages: malabsorbed carbohydrates undergo prob lem(13.5)1, 2, 4. Patients with permanent intestinal bacterial fermentation in the residual colon where they are failure sooner or later will develop cirrhosis and liver converted into short-chain fatty acids7. The presence of a failure1. Sondheimer et al. reported that 67% of neonates jejunostomy or a terminal ileostomy can produce high with PN-dependent SBS developed cholestasis, and 17% output with dehydration and electrolytes disturbances, progressed to liver failure9. Strategies to avoid or delay liver delaying the adaptative process (13.2)4. failure are shown in Table 13.3. Patients with SBS Bacterial overgrowth is frequent due to the absence of the frequently develop other clinical problems which may ileocaecal valve, presence of intestinal strictures, and require specific therapy (Table 13.4). intestinal dysmotility. It can produce enteritis that worsens the adaptation process8. It is also involved in the pathogenesis of the PN-related liver failure. Established liver 1 damage also interfere with adaptation . Table 13.2 Complications of parenteral nutrition use

Initial supportive management • Sepsis • Thrombosis. Vanishing venous access Treatment of children with intestinal failure should be • Complications related to central line insertion predicated upon three goals: (1) to keep the patient well (embolism, haemothorax) nourished by PN, (2) to minimize the faecal losses of fluid, • Liver failure electrolytes, and nutrients, and (3) to enhance the natural • Electrolytes disturbances process of intestinal adaptation whenever possible. • Bone disease • Gallblader stones Parenteral nutrition • TPN related social problems: Most patients require PN until their gut has undergone – Limited personal(social/life) sufficient adaptation to allow survival on an oral diet. This – Psychological depression period is variable and can take 18–45 months6. PN is the – Pain medication dependance practice of feeding a person intravenously (13.3). It is – Poor quality of life usually administered through a permanent central line4 – Expensive: US$100–200,000/year (13.4). Surgical venotomies should be avoided in order to

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

A B Short bowel syndrome 119

13.3 Parenteral nutrition administration. The patient receives nutritional formulas containing glucose, amino acids, lipids, trace elements, and vitamins that A are stored in sterile bags and delivered 13.4 Permanent central by a medical venous catheters. A: One B infusion pump. lumen subcutaneous tunnelled catheter with cuff (Broviac–Hickman); B: reservoir (Port-a-cath). Thorax X-ray with Port-a-cath in place.

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

Table 13.3 Strategies to ameliorate liver dysfunction

• Optimize PN (fewer lipids) • Cyclic parenteral nutrition • Enteral nutrition (even small amount) • Avoid bacterial overgrowth (oral decontamination) • Ursodeoxycholic acid • Avoid sepsis 120 Short bowel syndrome

Table 13.4 Other complications related to short bowel

• Behavioural feeding problems (phobia to oral foods and hyperphagia) • Metabolic acidosis (including D-lactic acidosis) • Cholelithiasis • Urolithiasis • Electrolytes disturbances • Gastro-oesophageal reflux • Bone disease • Dystrophy • Diarrhoea 13.6 Placement of a gastrostomy should be contemplated • Bacterial overgrowth in initial surgery based on the severity of the short gut to administrate continuous enteral feeding.

Medical therapy Enteral nutrition Drugs that reduce motility as opioid substances Drip enteral nutrition can be advanced as soon as the (loperamide, diphenoxylate, codeine phosphate) increase patient can tolerate it, followed by bolus feedings (13.6). the contact time between nutrients and the mucosa. Enteral nutrition stimulates the release of pacreatico-biliary Therefore, they are used to decrease the stomal output. secretions that maintain the structure and function of the Gastric hyperacidity and increase in serum gastrin levels are intestine and the release of regulatory peptides from the frequently observed transiently (6–12 months) following a intestine. Specific nutrients can be delivered to the cells of massive bowel resection. Unless controlled with proton the intestinal mucosa. They promote intestinal structure

pump inhibitors or H2 receptor blockers, it may result in and function by providing substrates for the synthesis of extensive gastric or duodenal ulceration. On the other hand, essential molecules or by providing energy, as happens with long-term administration can promote bacterial overgrowth. fermentable fibre (pectin) and their products (i.e. short- The use of cholestiramine is useful if the diarrhoea is due to chain fatty acids). The amino acid glutamine is the main fuel the cathartic effect of unabsorbed bile salts, and to treat for enterocytes and is also a substrate for the synthesis of periostomy or perianal irritation. Ursodeoxycholic acid may nucleic acids10. Medium-chain triglycerides increase the improve liver dysfunction. absorption of energy in SBS with a functioning colon2. High-volume output from a jejunostomy requires Short-chain fatty acids are readily absorbed across the restriction of oral fluids, a high-energy iso-osmolar diet, and colonic mucosa, whereas long-chain fatty acids are not the use of antisecretory drugs. Ocreotride is a universal absorbed by the colon. Glucagon-like peptide-2, released by inhibitor of exocrine and endocrine gastrointestinal and the intestinal L cells, plays a role in the trophic effect of pancreatic secretions. However, ocreotride is detrimental to short-chain fatty acids on intestinal adaptation. In addition, gut adaptation because it reduces nutrient transport. In the use of either specific (e.g. intestinal growth factor-1 addition, it can interfere with growth. [IGF-1]) or general growth factors (e.g. growth hormone) can promote intestinal adaptation11, 12. Short bowel syndrome 121

Surgical treatment Techniques to avoid bacterial overgrowth • Enteroplasty. Dilated intestine causes stasis and When a paediatric surgeon deals with an intestinal ineffective peristalsis. Anti-mesenteric tapering catastrophe, it is important to be conservative and preserve enteroplasty is an alternative to resection in dilated as much length of the small and as possible . bowels to preserve bowel length and improve bacterial A ‘second look’ laparotomy is indicated because overgrowth14. A different approach is the tapering delimitation of the viable intestine will be clearer 24–48 enteroplasty with plication of the mesenteric bowel with hours later. It is a gold standard rule to try to preserve the stitches. There is a high incidence of recurrence in the ileocaecal valve as well as to perform jejuno-colic long-term follow-up. anastomosis whenever possible. Stomas should be reserved • Stricturoplasty. Longitudinal stricture incision with only in those situations in which it is strictly necessary to transverse suture. avoid an additional loss of intestinal length and to preserve colonic function. Patients with a jejuno-colic anastomosis Lengthening procedures rarely have problems with their fluid and electrolyte balance. All lengthening procedures require bowel dilatation. Maintaining colonic continuity serves to delay gastric The longitudinal lengthening procedure was described by emptying and decreases energy/carbohydrate losses8. Bianchi in 1980. It is the most commonly used method of To evaluate the severity of the short gut syndrome, gastrointestinal reconstruction for SBS15. The bowel is imaging studies are required. Gastrointestinal series and divided into two longitudinal leaves based on the bifurcated barium enema are crucial to study the intestinal anatomy mesenteric blood supply, and then the two hemi-loops are and to rule out strictures. Abdominal ultrasounds rule out reconnected in an isoperistaltic way in series with the rest of gallbladder stones or sludge. CT scan with oral contrast and the intestine. There are improvements in stool output, 3-D reconstruction provides the same information about the intestinal transit time, and D-xylose and fat absorption. pancreas. Recently, Waag et al. reported their experience with 25 A definitive surgical treatment is indicated after failure of patients with 72% survival, 17 were weaned of TPN with a medical management. The type of operation will be defined mean follow-up of 6 years16. Bueno et al. have recom - by different factors: age, length, and function of remaining mended avoiding the procedure in neonates, ultra-short gut, bowel, the presence of dilatation, bacterial overgrowth, and established cirrhosis17. Complication rate is high with transit time, and the development of total parenteral intestinal necrosis, leaks, strictures, and bowel obstruction. nutrition (TPN) related complications. In the presence of In the Kimura procedure, initially the anti-mesenteric liver dysfuntion, a liver biopsy is recommended. surface of a segment of bowel is coapted to host organs such as liver and abdominal wall18. After vascular collaterals Techniques to slow transit time across the coaptation site have developed from these host None of the following procedures have been associated with organs, secondary longitudinal split of the bowel is significant clinical success. performed to provide two bowel loops, one from its anti- • Reversed intestinal loop. It consists of the interposition of mesenteric half and the other from its mesenteric half. a segment of bowel in which peristalsis is in the opposite These are arranged in series by end-to-end anastomosis to direction. The recommended minimal length of the anti- double the original bowel length. So far, there are only peristaltic loop is 10 cm in adults and 3 cm in children13. anecdotal reports. • Isoperistaltic colon interposition. Interposition of a Serial transverse enteroplasty (STEP) is a simple and segment of colon between two limbs of the small bowel14. effective procedure introduced in 2003, but also requires • Artificial valves. Based on the importance of the bowel dilatation (13.7). The International STEP Registry ileocaecal valve6. Although different types of valve have until May 2006 has reported 38 cases19. The length of the been created, their use has been anecdotal. When used, intestine in this series was duplicated (pre-STEP 68 cm; post- they are often combined with other procedures. STEP 115 cm). It can even be applied in intestines with prior • Recirculation circuits. The idea is to produce a loop of Bianchi procedure. In the short-term follow-up it is effective; intestine in which nutrients can recirculate several times6. however, longer follow-up is needed. Surgical compli cations It is not used because it facilitates bacterial overgrowth. such as obstruction and leaks have been described. 122 Short bowel syndrome

A B

C D 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.

Small bowel transplantation immunosuppressive agents and greater incidence of side- Intestinal transplantation is indicated when patients effects such as a high incidence of opportunistic infections developed PN complications1, 2, 4, 19. Vanishing venous and lymphoproliferative disorder are still a barrier for its access is the main indication for isolated small bowel success19. Endoscopic surveillance with intestinal biopsy is transplantation (13.8), while recurrent sepsis and frequent the only tool to detect allograft rejection. The Intestinal hospital admission due to dehydration and electrolyte Transplant Registry has recently reviewed the world disturbances are relative indications. PN-related liver failure experience on 772 transplants in 721 paediatric recipients, is an indication for combined liver–small bowel with an overall survival of 55.4%20. The most common transplantation. If the whole gastrointestinal tract is affected indication for transplantation was SBS. Nowadays, the 1- by disease such as pseudo-obstruction and desmoid year graft survival in experienced centres is above 80%. tumours the choice is multivisceral grafts. New immunosuppressant protocols, major expertise, and References new strategies have contributed to dramatic improvements in survival in recent years, such that survival rates are 1 Bueno J, Ohwada S, Kocoshis S, et al. Factors impacting approaching those of other solid organ transplantation. The the survival of children with intestinal failure referred for risk of acute rejection is very high and it is the leading cause intestinal transplantation. J Pediatr Surg for graft and patient loss. The requirements of high doses of 1999;34(1):27–32. Short bowel syndrome 123

12 Thompson JS, Langnas AN, Pinch LW, et al. Surgical approach to the SBS. Ann Surg 1995;22:600–7. 13 Zhou Y, Wu XT, Yang G, et al. Clinical evidence of growth hormone, glutamine and a modified diet for short bowel syndrome: meta-analysis of clinical trials. Asia Pac J C l in N u t r 2005;14(1):98–102. 14 Garcia VF, Templeton JM, Eichelberger MR, et al. Colon interposition for the SBS. J Pediatr Surg 1981;16(6):994–5. 15 Bianchi A. Longitudinal intestinal lengthening and tailoring: results in 20 children. J R o yal So c M e d 1997;90:429–32. 13.8 Small bowel transplantation. 16 Waag KL, Hosie S, Wessel L. What do children look like after longitudinal intestinal lengthening? Eur J Pediatr Surg 1999;9(4):260–2. 2 Goulet O. Irreversible intestinal failure. J P e d iat r 17 Bueno J, Guiterrez J, Mazariegos GV, et al. Analysis of Gastroenterol Nutr 2004;38(3):250–69. patients with longitudinal intestinal lengthening 3 FitzSimmons J, Chiin A, Shepard TH. Normal length of procedure referred for intestinal transplantation. J P e d iat r the human gastrointestinal tract. Pediatr Pathol Surg 2001;36(1):178–83. 1988;8:633–41. 18 Kimura K, Soper RT. A new bowel elongation 4 Buchman AL, Scolapio J, Fryer J. AGA technical review technique for the short-bowel syndrome using the on SBS and intestinal transplantation. Gastroenterology isolated bowel segment Iowa models. J Pediatr Surg 2003;124(4):1111–34. 1993;28(6):792–4. 5 Shanbonhogue L, Molenaar J. SBS: metabolic and 19 Modi BP, Javid PJ, Jaksic T, et al. International STEP surgical management. Br J Surg 1994;81:486–99. Data Registry. First report of the international serial 6 Goulet O, Baglin-Gobet S, Talbotec C, et al. Outcome transverse enteroplasty data registry: indications, efficacy, and long-term growth after extensive small bowel and complications. J Am Coll Surg 2007;204(3):365–71. resection in the neonatal period: a survey of 87 children. 20 Reyes J, Bueno J, Kocoshis S, et al. Current status of Eur J Pediatr Surg 2005;15(2):95–101. intestinal transplantation in children. J Pediatr Surg 7 Nordgaard I, Hansen CS, Mortensen PB. Colon as a 1998;33(2):243–54. digestive organ in patients with short bowel. Lancet 1994;343:373–6. 8 Kaufman SS, Loseke CA, Lupo JV, et al. Influence of Further reading bacterial overgrowth and intestinal inflammation on duration of parenteral nutrition in children with SBS. J Moreno Villares JM. Parenteral nutrition-associated liver Pediatr 1997;131(3):356–61. disease. Nutr Hosp 2008;23(suppl 2):25–33. 9 Sondheimer JM, Asturias E, Cadnapaphornchai M. Duro D, Kamin D, Duggan C. Overview of pediatric short Infection and cholestasis in neonates with intestinal bowel syndrome. J Pediatr Gastroenterol Nutr resection and long-term parenteral nutrition. J P e d iat r 2008;47(suppl 1):533–6. Gastroenterol Nutr 1998;27(2):131–7. Ching YA, Gura K, Modi B, et al. Pediatric intestinal 10 Michail S, Mohammadpour H, Park JH, et al. Effect of failure: nutrition, pharmacologic, and surgical glutamine-supplemented elemental diet on mucosal approaches. Nutr Clin Pract 2007;22:653–63. adaptation after small bowel resection in rats. J P e d iat r Ruiz P, Kato T, Tzakis A. Current status of transplantation Gastroenterol Nutr 1995;21:394–8 of the small intestine. Transplantatio n 2007;83:1–6. 11 Byrne TA, Persinger RL, Younf LS, et al. A new treatment for patients with short-bowel syndrome. Growth hormone, glutamine, and a modified diet. Ann Surg 1995;222:243–55. 124 Chapter 14 Congenital gastrointestinal malformations Iñaki Eizaguirre, MD, and Agustín Nogués, MD

Introduction Meckel’s diverticulum

The most significant congenital gastrointestinal This is a formation in the shape of a cone or the finger of a malformations are Meckel’s diverticulum and anorectal glove attached to the anti-mesenteric margin of the ileum malformations1, 2 (Table 14.1). The majority are develop- (14.1A, B). It can present in a variety of anatomical forms mental disturbances or embryopathies. These from the complete persistence of the yolk stalk, with the embryopathies occur in a phase in which all the organs are discharge of intestinal fluid through the umbilicus, to the forming (3rd to 8th week), thus the presence of multiple presence of a fibrous cord that can give rise to intestinal anomalies is common. Other digestive tract malformations obstruction by trapping a loop of bowel. There is also an are foetopathies, probably due to ischaemic accidents that infrequent giant form of Meckel’s diverticulum, which give rise to duodenal, intestinal, and colonic or rectal usually gives rise to episodes of occlusion in the neonate atresias. The interruption of the blood supply to a segment (14.1C) of the primitive intestine leads to the reabsorption of that Meckel’s diverticulum is found in 2% of autopsies, and is segment, with the consequent atresia. This mechanism found in a 2:1 male/female ratio. It cause symptoms in only occurs later in the foetal period and is therefore not 4% of individuals; 50% have symptoms before 2 years of age necessarily associated with other malformations3. and 80% before 10 years. Its histological structure is similar to that of the ileum. It can contain ectopic pancreatic tissue or gastric mucosa, explaining possible haemorrhage. Table 14.1 Frequence of gastrointestinal Meckel’s diverticulum may present as haemorrhage malformations (number of cases/10,000 births) (25–30%); it can invaginate and give rise to intestinal obstruction or as a diverticulitis with or without perforation The most reliable diagnostic test is a 99mTc gamma scan • Meckel's diverticulum: 220 (14.2). When the diverticulum contains ectopic gastric • Anorectal malformations: 3.01 mucosa, this test shows an abnormal uptake in the centre of • Oesophageal atresia: 2.23 the abdomen. Treatment consists of resection of the diverticulum. • 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 Congenital gastrointestinal malformations 125

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

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.

Anorectal malformations

Anorectal malformations are usually embryopathies, with Diagnosis associated abnormalities in 60% of cases: cardiovascular Diagnosis uses perineal examination and ultrasound. It is (tetralogy of Fallot); bone, particularly hemivertebrae; worth waiting 24 hours for the rectal pouch to fill, gastrointestinal: oesophageal atresia, duodenal atresia, facilitating evaluation of the malformation. A flat perineum Hirschsprung’s disease, or genitourinary: vesico-ureteric is a poor prognostic indicator as it suggests an absence of reflux. In 90% of cases there is an abnormal communication musculature. Ultrasound is used to measure the distance between the rectum and the urinary tract (in males) or the from the rectal pouch to the skin. When this measures more genital structures (in women). The description of the fistula than 1 cm, it is considered a severe form (14.3). gives an idea of the severity of the malformation: in males, rectoperineal, rectobulbar, rectoprostatic and rectovesical fistulae; in females, rectoperineal, rectovestibular, and rectovaginal fistulae and cloaca. All forms are considered severe with the exception of the rectoperineal forms, and require complex surgical treatment. 126 Congenital gastrointestinal malformations

Treatment Diagnosis In the milder forms (perineal fistula or <1 cm distance on • Prenatal ultrasound shows an absence of the gastric ultrasound) treatment consists of performing a direct bubble in types I and II. opening of the rectal sac (cut-back). In other cases, a • Difficulty passing a nasogastric tube (14.5, 14.6). colostomy and, in a second phase, descent via a posterior • Plain X-ray: sagittal approach (Peña’s posterior sagittal anorectoplasty). – Nasogastric tube – Intestinal meteorism (III, IV, V) (14.5) – Absence of gas (types I and II) (14.6) Oesophageal atresia Prognosis and treatment The abnormal separation of the tracheo-oesophageal bud Survival varies from 97% in group I on the Spitz gives rise to a large number of possible anatomical variations classification (weight >1500 g with no heart disease), to 47% of this malformation, although the most frequent is type III in group II (weight <1500 g or heart disease) and 20% in (Table 14.2). Associated malformations are very common: group III (weight <1500 g and heart disease)2. bone 30%, heart defects 20%, urological 20%, digestive Surgical treatment consists of a primary anastomosis tract 20%, and VACTERL association: (Vertebral, Anal, when the separation between the ends allows this. Otherwise Cardiac, Tracheal, oEsophageal, Renal, Limb). a gastrostomy and an oesophagostomy can be performed in Patients usually present with salivation, respiratory order to replace the oesophagus later with stomach or colon. distress, and abdominal distension (forms with a distal Recently, an external elongation of the two oesophageal fistula: III, IV, V). ends has been performed in order to approximate them sufficiently to be able to perform an anastomosis4, 5.

Table 14.2 Different types of oesophageal atresia

• Type I: 8%.The two ends of the oesophagus are separated and do not communicate with the respiratory tract (no fistula) • Type II: 1%. Proximal tracheo-oesophageal fistula and blind inferior pouch • Type III: 86%. Distal tracheo-oesophageal fistula and blind superior pouch • Type IV: 1%. Proximal and distal tracheo- oesophageal fistulae • Type V: 1%. ‘H’ fistula. This is not a true atresia as the oesophagus is permeable (14.4) 14.4 Type V oesophageal atresia. Congenital gastrointestinal malformations 127

14.5 Radiographic plain film in oesophageal atresia with 14.6 Radiographic plain film showing absence of tracheo-oesophageal fistula. Reports air filled stomach abdominal air and feeding tube in the superior and intestinal metheorism. Note the coiled feeding tube in oesophageal pouch. the upper pouch oesophagus.

Hirschsprung’s disease

In Hirschsprung’s disease (HD) the affected intestine Clinical presentation presents a spastic contraction, as occurs in any denervated Functional obstruction, the intensity of which depends on intestine. It is unable to dilate, giving rise to a functional the intestine affected. There are two clinical forms: obstruction (14.7). HD can affect more than one member of neonatal, with the absence of emission of meconium in the the same family. There is a genetic abnormality, the deletion first 24 hours and symptoms of low intestinal obstruction of the long arm of chromosome 10, that is located close to (abdominal distension and vomiting), and the form the region of the RET proto-oncogene that has been found presenting in the older child, with severe constipation that in some patients with HD6. There may be associated does not resolve with the usual measures. abnormalities including trisomy 21 and 18, anorectal atresia, von Recklinghausen’s disease, Waardenburg´s Complications disease, or multiple endocrine neoplasia type 2. Severe enterocolitis and sepsis, which may lead to intestinal perforation. This is a life-threatening situation that Histopathology sometimes requires emergency colostomy. • Absence of ganglion cells in the plexus. • Hypertrophy of the nerve fibres. Diagnosis • Neuronal and peptide markers: Barium enema (14.8), anorectal manometry, demonstrating – Increased acetylcholine and neuropeptide Y secretion. an absence of the rectoanal inhibitory reflex (14.9), and – Decreased vasoactive intestinal peptide, substance P, and biopsy are the decisive tests. nitric oxide synthase. 128 Congenital gastrointestinal malformations

2 2 1

1

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.

14.8 Barium Rectum enema in neonatal Canal 4 Pressure Hirschsprung’s mmHG escala: 10.0 disease. Narrow rectosigmoidium segment and dilated Anal canal suprastenotic colon which presents Canal 5 Pressure inflammatory mmHG mucosal changes. escala: 10.0 Distention of intestinal loops.

A

Rectum

Canal 4 Pressure mmHG escala: 10.0

Anal canal

Canal 5 Pressure mmHG escala: 10.0

14.9 Recto-anal inhibitory reflex. A: Present; anal canal relaxation after a pressure increase in the rectum. B: Absent; B no anal canal relaxation. Congenital gastrointestinal malformations 129

Treatment The aims of the classical surgical techniques (Duhamel, • Absence of the final 90° rotation: the right colon remains Soave, Rehbein, Swenson) are to resect the aganglionic in the midline, fixed by peritoneal bands (Ladd’s bands) intestine, leaving 1–2 cm of the final part, necessary to which compress and obstruct the duodenum. Treatment guarantee continence. In recent years, new techniques and is by section of the bands and repositioning of the caecum the introduction of minimally invasive surgery have led to a in the right iliac fossa. reduction in the age at which patients are operated on, • Internal hernias: abnormalities of the mesentery of the which was classically between the 8th and 10th month. The duodenum or right or left colon can create spaces into recently described De la Torre Mondragón technique7 with which the intestinal loops can prolapse as hernias. These or without laparoscopic assistance, is currently the most are very variable situations which require individualized accepted technique in several paediatric surgical surgical approaches. departments. Diagnosis A barium enema may be helpful showing the whole colon on Intestinal malrotation the left (no rotation), or the caecum high close to the liver (lack of the last 90º twist). In cases of no rotation an Alterations of the process of intestinal rotation and fixation ultrasound can show a reverse position of the mesenteric during the process of re-entry of the primitive intestine into vessels with the vein situated on the left and the artery on the the abdominal cavity give rise to multiple types of right. malrotation. These are uncommon but very variable and sometimes complex abnormalities, though the clinical presentations can be summarized into three situations: • A complete absence of rotation (14.10). There is a risk of volvulus and intestinal necrosis if it is not treated in time (14.11). The symptoms include bilious vomiting and the treatment is by devolvulation and fixation in an uncompli- cated position for the common mesentery, with the small intestine on the right side and the colon on the left.

14.11 Midgut volvulus. Intestinal necrosis, twisted mesenteric vessels (arrow).

14.10 Twisted duodenum not crossing the duodenal vessels. 130 Congenital gastrointestinal malformations

Duodenal atresia

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

Diagnosis Patients present with bilious vomiting. Prenatal ultrasound shows a typical image of a ‘double bubble’, which is 14.12 Prenatal ultrasound. Stomach and duodenum are confirmed on plain X-ray and postnatal ultrasound (14.14). dilated.

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

14.13 Duodenal dilatation caused by diaphragm. Minimal 14.14 Radiographic plain film. Double amount of contrast is delivered in distal duodenum across bubble air sign in duodenal atresia. a small perforation. Oesophageal atresia and aspirative pneumonia in posterior segment of right upper lobe. Congenital gastrointestinal malformations 131

Jejuno-ileal atresia

It is a true atresia in 95% of cases. The remaining 5% are The intestine distal to the atresia receives a precarious, due to intestinal stenosis, i.e. a partial intraluminal retrograde blood supply via the ileocolic, right colic, or occlusion. There is polyhydramnios on the prenatal inferior mesenteric arteries (14.15D). ultrasound and dilated loops may be observed. Associated • Type IV: multiple atresias. abnormalities are present in <10%. The Grosfeld classification2 divides this malformation into: Diagnosis • Type I: atresia in the form of a mucous membrane or Diagnosis is on clinical presentation, with vomiting, which septum with intact intestinal wall and mesentery occurs earlier the higher the atresia. The plain abdominal X- (14.15A). ray shows dilated loops, of which there are few if the atresia • Type II: two blind, atretic pouches connected by a fibrous is in the proximal jejunum (14.16A) and many if it is ileal, cord, with an intact mesentery (14.15B). more distal (14.16B). The barium enema shows a colon of • Type IIIa: two blind, disconnected, atretic pouches with small diameter due to a lack of use. a defect in the mesentery in the form of a ‘V’ (14.15C). • Type IIIb: also called ‘apple peel’. Very high jejunal Treatment atresia, close to the duodenojejunal flexure. It gives rise to Treatment is resection of the grossly dilated loops and end- a very short intestine with a large defect in the mesentery. to-end anastomosis.

A B

C D 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). 132 Congenital gastrointestinal malformations

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

A B

Gallbladder

Duodenum

Bladder Ileal duplication

14.17 MR T2 image shows evidence of a cystic right flank 14.18 Surgical procedure revealed spherical mass. ileal duplication.

Intestinal duplications

Duplications are always situated on the mesenteric margin, Approximately half of all duplications affected the small can be spherical or tubular, of variable length, and can bowel (50%), followed in frequency by duplications of the involve up to the whole length of the digestive tube (14.17, oesophagus (20%), and of the colon. Duplications can give 14.18). Duplications have all the layers of the gut, including rise to intestinal obstruction or haemorrhage. Treatment is the mucosa, and often present heterotopic gastric mucosa8. surgical. Congenital gastrointestinal malformations 133

Atresia of the colon

This is less frequent than the other intestinal atresias. It is 6 Puri P, Shinkai T. Pathogenesis of Hirschsprung’s disease associated with jejuno-ileal atresia and Hirschsprung’s and its variants: recent progress. Semin Pediatr Surg disease. Prenatal ultrasound shows dilated loops of 2004;13:6–24. intestine. The symptoms are those of a low intestinal 7 De la Torre-Mondragon L, Ortega-Salgado JA. obstruction and the diagnosis is not difficult with plain Transanal endorectal pull-through for Hirschsprung’s abdominal X-rays, in which multiple dilated loops of disease. J Pediatr Surg 1998;33(8):1283–6. intestines are observed. 8 Stern LE, Warner BD. Gastrointestinal duplications. J Treatment is primary anastomosis of the ends of the Pediatr Surg 2000;9:135–40. intestine, as long as there is no contraindication, such as perforation with peritonitis, in which case it is better to perform a colostomy with anastomosis at a later stage. Further reading

Dasgupta R, Langer JC. Evaluation and management of Annular pancreas persistent problems after surgery for Hirschsprung disease in a child. J Pediatr Gastroenterol Nutr 2008;46: The presence of pancreatic tissue around the duodenum in 13–19. the form of a ring can give rise to duodenal obstruction Keckler SJ, St Peter SD, Valusek PA, et al. VACTERL similar to that of duodenal atresia, with which it is anomalies in patients with esophageal atresia: an updated frequently associated. It is sometimes a casual finding. delineation of the spectrum and review of the literature. When symptoms arise, they are of a high obstruction. Pediatr Surg Int 2007;23:309–13. Surgical treatment is similar to that for duodenal atresia, Levitt AA, Peña A. Anorectal malformations. Orphanet J with a side-to-side anastomosis between the proximal and Rare Dis 2007;26:2–33. distal segments.

References

1 EUROCAT Website Database: www.bio.medical.co.uk./eurocatline (data uploaded 17/11/2006). 2 Grosfeld JL. In: JA O’Neill Jr, MI Rowe, EW Fonkalsrud, AG Coran (eds). Pediatric Surgery, 5th edn. Mosby-Year Book, St. Louis, 1998. 3 Sadler TW. Langman´s Medical Embryology, 8th edn. Lippincot Williams & Wilkins, Philadelphia, 2003. 4 Diez-Pardo JA, Baoquan Q, Navarro C, Tovar JA. A new rodent experimental model of oesophageal atresia and tracheoesophageal fistula: preliminary report. J P e d iat r Surg 1996;31:498–502. 5 Foker JE, Kendall TC, Catton K, Khan KM. A flexible approach to achieve a true primary repair for all infants with oesophageal atresia. Semin Pediatr Surg 2005;14(1):8–15. 134 Chapter 15 Paediatric appendicitis Adolfo Bautista Casasnovas, MD

Introduction

Acute appendicitis is a common paediatric surgical disease of the caecum and appendix is the appendiceal branch of the requiring urgent attention. Appendectomy is the most ileocolic artery, which passes behind the terminal ileum. common surgical procedure performed for acute abdominal The arterial supply is terminal, so that thrombosis leads to pain in children (15.1)1. The diagnosis of acute appendicitis rapid necrosis (15.3). The malpositioned appendix may give in childhood can sometimes be difficult. rise to signs of inflammation in unusual locations, that make The incidence of acute appendicitis has been estimated at diagnosis difficult. about 1 case per 1,000 children per year, with slightly higher incidence among boys. The lifetime risk of appendicitis is estimated to be 8.67% for boys and 6.7% for girls. Incidence among preschool children is unusual, but in this age group delayed diagnosis and complications are more frequent. Around one-third of children with acute appendicitis are found to be perforated at surgery. Children who have appendicitis are twice as likely to have a positive family history as are those with right lower quadrant pain, but no appendicitis2. Early diagnosis continues to be the most important factor for prognosis. The rate of negative appendectomy is considered acceptable for up to 10% of laparotomies for suspected acute appendicitis. Paediatric surgeons performed significantly fewer negative appendectomies than general surgeons3. The development of the caecum and appendix begins in the caecal diverticulum on the anti-mesenteric side of the caudal end of the medial intestine, around the fifth week of gestation. The appendix does not elongate as rapidly as the rest of the colon. After rotation and descent, the base of the appendix is located at the posteromedial wall of the caecum about 2.5 cm below the ileocaecal valve, but this descent finishes after childhood. The variability of its descent and rotation leads to multiple possible final positions of the 15.1 McBurney´s point is located two-thirds of the appendix4. The infant caecum is located in the right iliac distance from the umbilicus to the anterior superior iliac fossa in about 55% of individuals (15.2). The blood supply spine. Paediatric appendicitis 135

Ileocolic Ramus artery colicus Ileal 4% Retrocecal 65% Ramus ilealis

Appendicularis artery

Pelvic 31%

15.2 Possible positions of appendix and their relative 15.3 Normal vascular supply of the appendix. frequency4.

Pathophysiology

Obstruction is a fundamental factor in the development of acute appendicitis. Obstruction increases intraluminal pressure leading to ischaemia, bacterial invasion, bacterial overgrowth, necrosis, and perforation. In the early phases, activation of receptors in the intestinal wall leads to perception of pain in the periumbilical region. In later phases, when the purulent secretion from the appendiceal wall contacts the parietal , somatic pain fibres are triggered and the pain localizes near the appendiceal site, McBurney’s point. The characteristic organisms responsible of appendiceal inflammation are predominantly anaerobic, including Escherichia coli, Enterococcus, Bacterioides fragilis, Pseudomonas, Klebsiella, and Clostridium5. Many terms have been used to describe the pathologic stages of appendicitis, from the normal state to perforation. 15.4 Typical appearance of simple appendicitis during Only the clinically relevant distinctions of simple surgery. It is possible to observe the caecum, appendix, appendicitis (15.4) and complicated appendicitis should be and mesoappendix with congestion of the blood vessels made. and inflammatory exudates. 136 Paediatric appendicitis

Diagnosis Physical examination Palpation should always be first superficial and then deep. The diagnosis of appendicitis should be based on a careful The palpation should start in an area without pain, and the history and physical examination. The paediatric surgeon patient’s face should be watched for signs of discomfort. In may expect to make the accurate diagnosis in 80–90% of fact the important thing to look for during examination is cases. White blood count (WBC) and imaging rarely add any localized area of abdominal pain. Abdominal tenderness significant information. is the most constant physical finding. The point of maximal Acute appendicitis typically occurs in older children. The tenderness is localized at McBurney’s point. Associated with incidence of appendicitis gradually increases from age 1 year tenderness progressively are abdominal muscle spasms. onwards, peaking at around age 11–12 years. Although Rebound tenderness or Blumberg’s sign (i.e. pain felt on appendicitis is uncommon in infants, this age group has a sudden release of steady pressure in the right iliac fossa high rate of complications because of delayed diagnosis. region) reflects irritation of the parietal peritoneum of the Difficulties of diagnosis may arise with patients younger inflamed appendix, and associated fluid secretion. than 2 years, and with preadolescent obese girls. In these The routine use of rectal examination is controversial. two patient categories, analytical and imaging studies can Invariably this exploration causes discomfort to children, provide additional information. and pain during examination is not specific to appendicitis. It may be useful for detection of possible pelvic abscess or Clinical presentation ovarian pathology. The classic sequence (persistent abdominal pain, fever, and localized pain on palpation at McBurney’s point) starts with Laboratory tests periumbilical pain, preceded by appetite loss in about WBC is of limited diagnostic value. Typically leukocyte 50–60% of children. The main symptom is abdominal pain, count is mildly elevated, 10,000–16,000/mm3, with usually beginning as a vague periumbilical pain or mild increased polymorphonuclear leukocytes, neutrophils, and gastrointestinal discomfort. After several hours, this pain immature neutrophils. 20% of patients with acute gradually migrates to the right iliac fossa. Characteristically appendicitis will have a normal WBC. Very high WBC the pain is implacable and is exacerbated by movements and suggests perforation or another diagnosis. pressure, making ambulation painful and difficult. A child Neutrophilia is more decisive for diagnosis than with acute appendicitis typically walks bent over and slowly. leukocytosis. In doubtful cases it is useful to monitor WBCs, Anorexia is a helpful sign. Nausea and vomiting appear after as long as the patient is not receiving antibiotics. Urine the onset of pain. If vomiting precedes abdominal pain, sediment analyses are useful for detecting patients requiring other diagnoses should be considered. fluid resuscitation and diseases of the urinary tract. The The last symptom in the clinical evolution is fever, which specific gravity and ketones are elevated. If the appendix is appears after pain and vomiting, and no more than 1ºC located adjacent to the ureter or the bladder, the red blood above normal. Fever higher than 39ºC is usually associated count and WBC in urine may be elevated. with complicated appendicitis (gangrenous and perforated). Symptoms may be influenced by the anatomical location of Diagnostic imaging the appendix. Pain of a retrocaecal appendix may be in the Imaging studies rarely add significant information in cases of flank or back. A pelvic appendix resting near the ureter or classic appendicitis, and should be reserved for equivocal cases testicular vessels can cause urinary frequency, inguinal or and when patient observation is indicated. Plain film, although testicular pain, or ureteral compression with hydro- it has a lower sensitivity and specificity, remains useful for nephrosis. Young patients aged 1–4 years, typically show detecting secondary problems associated with inflam mation vomiting and irritability, and draw up their legs to reduce (Table 15.1) (15.5). The presence of faecalith is highly pain. Other common manifestations include abdominal suggestive of acute appendicitis; however, faecalith is observed distension, diarrhoea, lethargy, and anorexia, together with only in 10–15% cases of confirmed appendicitis (15.6). fever. In 50% of cases an abdominal mass is detectable on Ultrasonography has constituted a significant advance in palpation. The key point in this group of patients is the diagnosis of acute appendicitis, based on its rapidity, vomiting. noninvasiveness, sensitivity (85–90%), and specificity Paediatric appendicitis 137

Table 15.1 Abnormal signs usually found in plain (92–96%). It is of particular value in adolescent and film in acute appendicitis prepubertal girls. It should be the first approach in doubtful cases. Reports of centres with skilled radiologist often • Dilated caecum with air-fluid level recommended ultrasonography for all children with suspected appendicitis (15.7, 15.8)6. • Appendiceal faecalith Abdominal computed tomography (CT) with sensitivity • Antalgic scoliosis of the right concavity and specificity of 98%, has become the most informative • Dilated loops imaging technique in the study of patients with atypical • Obliteration of the lower-right psoas margin manifestations (15.9)7. • Obliteration of the preperitoneal fat line Differential diagnosis • Free peritoneal fluid Appendicitis in childhood presents with uncommon features • Free peritoneal air in 50% of cases, and may mimic many others diseases such • Paucity of gas in the right-lower quadrant as gastroenteritis, basal pneumonias, constipation, and • Small bowel obstruction urinary pathology (tract infections, hydronephrosis, lithiasis) (Table 15.2).

15.5 Upright film 15.6 Simple shows multiple radiography of air-fluid levels in the abdomen in a small bowel and patient with acute absence of gas appendicitis, in colon. Typical showing of bowel appendicolith in obstruction. the right iliac fossa.

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. 138 Paediatric appendicitis

15.8 Ultrasonography, longitudinal and transverse view. 15.9 Classic pelvic CT scan shows a distended appendix. The appendix is distended with increased wall thickness The following findings are found in appendicitis: fluid-filled and faecalith inside. tubular structure measuring >6 mm in maximum diameter, fat stranding, abscess or phlegmon in adjacent tissue, faecalith, and focal caecal apical thickening.

Table 15.2 Possible differential diagnoses of acute appendicitis

Urogenital tract Small bowel diseases • Pleuritis • Hydronephrosis • Gastroenteritis • Primary peritonitis • Urinary tract infections • Mesenteric adenitis • Henoch–Schönlein purpura • Lithiasis • Duodenal ulcer • Viral exanthematous diseases • Wilm’s tumour • Meckel’s diverticulitis • Sickle cell anaemia • Premenstrual syndrome • Inflammatory bowel disease • Diabetic ketoacidosis • Ovarian pathology • Intussusception • Pancreatitis • Pelvis inflammatory disease • Intestinal obstruction • Omentum infarction • Salpingitis • Intestinal tuberculosis • Parasitic infection • Ectopic pregnancy • Typhoid infection • Abdominal migraine • Acute porphyria Colon Hepatobiliary • Psoas abscess • Appendiceal tumours • Cholecystisis • Burkitt´s lymphoma • Appendiceal mucocoele • Viral hepatitis • Familial Mediterranean fever • Constipation • Cholangitis • Haemolytic uraemic syndrome • Crohn’s disease • Kawasaki disease • Intestinal obstruction Miscellaneous • Diverticulitis • Cytomegalovirus • Typhlitis • Pneumonia Paediatric appendicitis 139

Treatment

The treatment of choice is surgical excision appendectomy if the patient improves within 24–72 hours. (appendectomy), and depends on both the general Interval appendectomy after nonoperative management is condition of the patient and the state of appendix. In many controversial. cases children are dehydrated, septic, or acidotic. Rapid Indications for an open appendectomy (OA) or administration of intravenous fluid and electrolytes (to laparoscopic appendectomy (LA) are based on hospital restore acid–base balance) is essential for a successful personal and facilities, surgeon skills, and experience. outcome. Frequently, laparoscopic approach is avoided when bowel obstruction is present or an abdominal mass is palpable. In Antibiotics young and slim patients, open appendectomy through a It is widely accepted that the use of antibiotics is clearly small incision is easier and faster. beneficial8. Antibiotics must be administered prior to skin Although the McBurney approach is still widely used, the incision. It is unnecessary to culture peritoneal fluid author prefers a Rockey–Davis approach, transverse right- routinely in each case of acute appendicitis. Intraoperative lower quadrant incision, placed above anterior superior iliac cultures have not shown to alter the treatment outcome9. spine and lateral to rectus abdominus (15.10). When the For many years the gold standard for complicated peritoneum is exposed and incised, if free fluid is present it appendicitis was a 10-day course of ampicillin, gentamicin, should be aspirated. Once the appendix is accessible the and clindamicin or metronidazole; in recent years many mesoappendix is taken down between clamps and divided surgeons have dropped ampicillin coverage. For simple (15.11). The appendix is released from its mesoappendix appendicitis a single agent such as cefotetan, cefoxitin, and vascular attachment and prepared for ligature (15.12). ticarcillin/clavulanate, or piperacillin/tazobactan is typically The base of the appendix is crushed with a clamp and prescribed. For complicated appendicitis a combination ligated (15.13). In cases of peritonitis, if the caecum walls such as ceftriaxone/metronidazole or ticarcillin/clavulanate are thickened, congestive or friable, invagination of the plus gentamicin are used10. appendiceal stump should be avoided. When a faecalith is Standard antibiotic therapy at the author’s institution is present, it should be located and removed. preoperative treatment with gentamicin (or tobramycin) plus metronidazole in all cases of acute appendicitis, with a low incidence (<4%) of postoperative infections and abscesses. In simple appendicitis, treatment is continued for 24–48 hours, and in complicated appendicitis for as long as 5–10 days. A prospective randomized study demonstrates equivalence between prolonged intravenous therapy and intravenous therapy followed by conversion to oral antibiotic therapy in children with perforated appendicitis11.

Appendectomy Appendectomy is not an emergency procedure, it should be treated as a semiemergency procedure. A recent study concluded that in children with acute appendicitis, delaying surgery until the daytime hours did not significantly affect operating time, perforation rate, or complications12. When the appendix is perforated, surgery is less urgent. If peritonitis is present most surgeons will proceed with appendectomy after preoperative fluid resuscitation and antibiotics have been started. Another group of surgeons 15.10 Skin incisions: red: transverse Rockey–Davis will continue nonoperative management and avoid approach; Blue: oblique classic McBurney approach. 140 Paediatric appendicitis

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

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

15.12 Perforated appendix released from its mesoappendix attachment.

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

Table 15.3 Advantages and disadvantages of laparoscopic appendicectomy

Advantages Disadvantages • Initial laparoscopy reduces the risk of incorrect • The operation takes longer diagnosis • Higher cost • Less traumatic • Requires paediatric surgeons with experience in this • Reduction of postoperative pain and better technique 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 Paediatric appendicitis 141

Table 15.4 Indications for laparoscopic technique is the three trocars technique, the sites of trocars appendectomy vary depending the surgeon preferences, appendiceal position, and the presence of complications (15.14, 15.15). Independent of the type of appendectomy, the patients • Acute appendicitis with simple appendicitis are usually ready to start oral fluids 8–24 hours after surgery. Intravenous fluid requirements are • Suspected appendicitis in patients with abdominal assessed regularly and discontinued as soon as possible. pain Patients can be discharged home within 48–72 hours. They • Appendicular mass and/or peritonitis may be checked after 1 week to ensure that they have no • Chronic abdominal pain postoperative infective complications. • Suspected neoplasia In complicated appendicitis, antibiotic are continued • Incidental appendectomy during laparoscopy for other depending on clinical progress. These patients may require indications nasogastric tubes and intravenous fluids for longer.

15.14 Possible trocar situations.

15.15 Typical appearance of appendix during laparoscopy. 142 Paediatric appendicitis

Complications

The most frequent complication of acute appendicitis is longer the period required for recovery of normal intestinal infection. The risk is increased when the appendix is transit. perforated. The overall complication rate is 10% and major Small bowel obstruction occurs in 2% of patients with complication rate of 4%. complicated appendicitis, and if not responsive to medical Wound infection rate should be below 4% in simple treatment (nasogastric suction, intravenous fluids, and appendicitis and below 8% in complicated cases. It typically parenteral nutrition) may require surgery. presents in the first week after surgery as localized pain, Other unusual complications include postoperative reddening, hypersensitivity, and tumefaction; spontaneous intussusception, faecal fistulae (15.17), pylephlebitis. Some suppuration may also occur. It should be treated with controversy exists about fertility after abdominal sepsis; antibiotics, opening the edge of the wound, or incision and different studies report than perforated appendicitis did not drainage. increase the risk of infertility14. Intra-abdominal abscess rate is less than 7%. The patient Current mortality rates for complicated appendicitis is has persistence of pain and ileus, fever, and leukocytosis, below 0.5%, and rather higher in children aged less than 2 Abscesses are usually located in the pelvis, sometimes in the years15. The incidence of postoperative complications have subphrenic space or medial zone of the abdomen. A painful markedly decreased, perhaps due to the use of broad- fluctuant mass can be palpated in rectal examination, if the spectrum antibiotics, the progress in pre- and postoperative abscess is located in Douglas’ pouch. The abscess can be care, and improved anaesthesia techniques. The best results treated conservatively, or drained percutaneosly under for children with appendicitis are obtained with the ultrasound or CT guidance or transrectally in the operating combination of surgical evaluation, rapid surgery when room. Exceptionally open drainage may be required (15.16). diagnosis is clear, a period of observation if diagnosis is Prolonged intestinal paralysis (ileus) is directly related to unclear, radiology imaging if necessary, and care provided peritoneal infection; the more severe the peritonitis, the by experienced clinicians and institutions16.

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. Paediatric appendicitis 143

References

1 McBurney C. Experience with early operative 14 Puri P, McGuinness EP, Guiney EJ. Fertility following interference in cases of diseases of the vermiform perforated appendicitis in girls. J Pediatr Surg appendix. NY State J Med 1889;50:676–84. 1989;24(6):547–9. 2 Gauderer MW, Crane MM, Green JA, et al. Acute 15 Blomqvist PG, Andersson RE, Granath F, et al. appendicitis in children: the importance of family history. Mortality after appendectomy in Sweden, 1987–1996. J Pediatr Surg 2001;36:1214–17. Ann Surg 2001;233:455–460. 3 Somme S, To T, Langer JC. Effect of subspecialty 16 Morrow SE, Newman KD. Current management of training on outcome after pediatric appendectomy. J appendicitis. Semin Pediatr Surg 2007;16:34–40. Pediatr Surg 2007;42:221–6. 4 Wakeley CP. The position of the vermiform appendix as ascertained by an analysis of 10,000 cases. J An at Further reading 1933;67:277–83. 5 St Peter SD, Little DC, Calkins CM, et al. A simple and Bautista Casasnovas A. Acute appendicitis. In: Guandalini more cost-effective antibiotic regimen for perforated S (ed). Textbook of Pediatric Gastroenterology and appendicitis. J Pediatr Surg 2006;41:1020–4. Nutrition. Taylor & Francis, London, New York, 2004, 6 Lander A. The role of imaging in children with suspected Chapter 45, pp. 739–49. appendicitis: the UK perspective. Paediatr Radiol Dunn JC. Appendicitis. In: Grosfeld JL, O´Neill JA Jr, 2007;37:5–9. Coran AG, et al. Pediatric Surgery, 6th edn. Mosby 7 Doria AS, Moineddin R, Kellenberger CJ, et al. US or Elsevier, Philadelphia, 2006, Chapter 98, pp. 1501–12. CT for diagnosis of appendicitis in children and adults? A Ein SH. Appendicitis. In: Ashcraft KW, Murphy JP, Sharp meta-analysis. Radiology 2006;241:83–94. RJ, et al. (eds). Pediatric Surgery, 3rd edn. WB Saunders 8 Andersen BR, Kallehave FL, Andersen HK. Antibiotics Company, Philadelphia, 2000, Chapter 43, pp. 571–9. versus placebo for prevention of postoperative infection Lund DP, Folkman J. Appendicitis. In: Walker WA, Durie after appendicectomy. Cochrane Database Syst Rev PR, Hamilton JR, et al. (eds). Pediatric Gastrointestinal 2005;20(3):CD001439. Disease: Pathophysiology, Diagnosis and Management, 9 Moawad MR, Dasmohapatra S, Justin T, et al. Value of 3rd edn. BC Decker, Hamilton, 2000, Chapter 48, pp. intraoperative abdominal cavity culture in 821–9. appendicectomy: a retrospective study. Int J Clin Pract Morrow SE, Newman KD. Appendicitis. In: Ashcraft KW, 2006;60:1588–90. Holcomb GW, Murphy JP (eds). Pediatric Surgery, 4th 10 Rodriguez JC, Buckner D, Schoenike S, et al. edn. Elsevier Saunders, Philadelphia, 2005, Chapter 42, Comparison of two antibiotic regimens in the treatment pp. 577–585. of perforated appendicitis in paediatric patients. Int J Clin Stevenson RJ. Appendicitis. In: Ziegler M, Azizkhan R, Pharmacol Ther 2000;38:492–9. Weber TR (eds). Operative Pediatric Surgery. McGraw- 11 Rice HE, Brown RL, Gollin G, et al. Results of a pilot Hill Professional, New York, 2003, Chapter 60, pp. trial comparing prolonged intravenous antibiotics with 671–89. sequential intravenous/oral antibiotics for children with perforated appendicitis. Arch Surg 2001;136:1391–5. 12 Yardeni D, Hirschl RB, Drongowski RA, et al. Delayed versus immediate surgery in acute appendicitis: do we need to operate during the night? J Pediatr Surg 2004;39:464–9. 13 Sauerland S, Lefering R, Neugebauer EA. Laparoscopic versus open surgery for suspected appendicitis. Cochrane Database Syst Rev 2004;18(4):CD001546. 144 Chapter 16 Paediatric clinical dietetics Am aya Peñalva Arigita, RD

Introduction

Dietetics is defined as the application of the principles of supplements. nutrition to the selection of food and the feeding of There are infants with certain diseases (metabolic, individuals and groups1. Clinical dietetics covers the allergies) who need special enteral formulas to adapt the nutritional management of sick infants and children (either whole diet. Others may need supplementation, using in an acute or chronic phase) to fulfill their requirements in nutritional modules that are added to a formula (Table 16.1). a clinical and/or outpatient setting. This can be done in Many studies demonstrate the advantages of nutritional terms of adjusting the diet, adjusting menus, recommending supplementation in different groups of patients, improving certain foods, and/or using commercial nutritional the evolution of the disease, and decreasing the incidence of

Table 16.1 Nutritional modules2

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 Paediatric clinical dietetics 145

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

Formula Kcal/ml (per unit) Proteins (g) (per unit) Administration Pediasure 1 (201) 5.6 Oral Pediasure Fibre 1 (201) 5.6 Oral Pediasure Plus 1.5 (300) 8.4 Oral Isosource Junior 1.2 (305) 6.75 Oral Isosource Junior Fibre 1.2 (300) 6.75 Oral Resource CF 151/pack 4.9 Oral Resource Protein 1.6/g (200/pot) 6 g per pot Oral Resource Junior 1.5 (300) 12 Oral Fortini 1.5 (300) 6.8 Oral Nutrini Energy 1.5 (300) 8.2 Enteral Nutrini Energy Multi Fibre 1.5 (300) 8.2 Enteral Novasource Junior Peptinex 1 (250) 7.5 Enteral/oral

complications3. Some children may require the use of development. Growth can be compromised in the presence paediatric supplements to increase their poor oral intake of a chronic disease especially when it coincides with peaks (Table 16.2). Other children may need a complete of growth (infancy, puberty). nutritional support via nasogastric tube (16.1), via During growth, size increases and body composition gastrostomy (16.2), or by means of parenteral nutrition changes. This implies certain nutritional requirements when the gastrointestinal tract is not functional. An which are higher than those of the adult. Besides, the adequate nutritional status allows a normal growth and immaturity at birth involves special requirements in terms of

16.1 A nasogastric tube may be useful for supplementing 16.2 A gastrostomy tube in a child with Menkes’ disease. the oral intake. This is a girl with failure to thrive. She has As the disease progressed the child was unable to be fed a tracheostomy due to a laryngomalacia. She takes by normally and it became essential to find an alternative mouth what she can and the rest is given by the way: a gastrostomy tube placed by endoscopic procedure nasogastric tube. was the solution. 146 Paediatric clinical dietetics

Nutritiional assessment

Clinical assessment Anthropometry Dietary assessment

Weight/height Physical features 24 hour recall Head circumference Biochemistry 3–7 day record history (food diary) Mid-arm circumference Haematology Frequency test Skin folds

16.3 Algorithm of nutritional assessment.

quality of nutrients, types of foods, and a limited response to Table 16.3 Physical signs of malnutrition4, 5 overloading which can lead to complications. Therefore, there is a need to assess adequately nutritional status before starting any nutritional support. • Skin: dry, scale, paleness, bruising • Hair: thin, sparse, straight (‘lifeless’), change in colour • Lips/mouth: stomatitis, cheilosis, lingual atrophy, Nutritional assessment colour changes of tongue, problems with teeth, gums • Face: fullness of cheeks (oedematous malnutrition), In the dietetic approach to a sick infant or child, it is thyroid enlargement essential to perform a correct nutritional assessment. There • Eyes: xerosis, keratomalacia, pale conjuctiva are a number of methods assessing specifics aspects of nutritional status, but no one measurement will give an • Nails: spoon shape, koilonychie overall picture of the status of all nutrients (16.3).

this rate also appears altered. This growth retardation is an Clinical assessment important sign of malnutrition. Weight measurement is an easy and routine procedure This includes a complete medical history and physical (16.4). Children can be weighed in beam balance scales or examination (Table 16.3). It is important to watch out for electronic scales. Weight shows variability during the day, the constitution of the child; especially differentiating those and it would be advisable to weigh always at the same time who are skinny by genetics from those who have lost muscle and with the same conditions7. Height measurement for mass. The presence of malnutrition signs such as abdominal infants and children less than 2 years old, is measured distension, presence of oedema, and hepatomegaly, should supine (16.5). From 2 years old, standing height is then be evaluated, along with mood and behaviour as children measured whenever possible (16.6). may be apathetic and irritable. Biochemistry and Skinfolds provide information about the changes haematological tests are also useful (Table 16.4) produced in the subcutaneous components of the fat and Anthropometry is a physical examination which provides fat-free mass. There are seven sites of measure: triceps, an indirect assessment of body composition and abdomen, chest, thigh, suprailiac (iliac crest), mid-axillar, development. The child is growing continuously, and in and subscapular. They are measured with a skinfold caliper. each moment there is an ideal weight for a determined Mid-arm circumference is useful to determine the state of height. In acute malnutrition the weight may be altered muscle mass, as this area is hardly affected by oedema. This maintaining the rate of height, although in a chronic state measurement is used in conjunction with the skinfold Paediatric clinical dietetics 147

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)

16.5 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 16.4 Infant scale (10 g precision). Ideally infants should the back, legs, and head are straight, the heels are be weighed naked or just with a clean nappy, but if it is against the footboard, the shoulders are touching the not possible it is important to record the way it has been baseboard, and the crown of the head is touching the measured. headboard. 148 Paediatric clinical dietetics

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

Table 16.5 Nutritional indexes11

Waterloo index (weight): 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 score

Real 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) Paediatric clinical dietetics 149

Dietary assessment

A diet history provides a record of food intake which reflects Table 16.6 Aims of the dietary assessment eating habits, possible nutrient imbalances, and other factors which can affect food intake. This information will provide the background for developing discussion with the • Search for information carers (usually parents) on realistic nutritional goals with a • Analysis of the information nutritional intervention (Table 16.6). This is time • Dietetic diagnosis (estimating requirements, consuming and requires skill. There are different ways of fulfillment of those requirements) obtaining the information depending on the need for • Prioritizing objectives accuracy. • Dietetic intervention A 24-hour recall is the first-line approach as it is quick and easy to do by a skilled professional. The usual carers or • Monitoring/assessment the child are interviewed to recount what the patient normally eats in a usual day, using what has been eaten the day before. In infants, estimating food intake is particularly Table 16.7 Food diary information difficult in those taking solids as it is difficult to know how much food is lost in spitting, drooling and so on (Table 16.7). A food frequency test is used to obtain more precise • Food frequency information. It enables the assessor to double check the • Quality/quantity of food information obtained previously. A 3–7-day record history • Fluids/type and frequency (food diary) provides an accurate account of food intake and • Feeding routine eating behaviour. It is a good way of making the record keeper responsible for personal food choices and eating habits (in grown children). Table 16.8 Dietetic diagnosis and intervention Analysis of food intake data A skilled dietitian has to estimate quickly the amount of calories and protein intake. This can be confirmed manually • Defining nutritional status by using food composition tables or using a computer • Intervention after checking nutritional requirements dietetic analysis program. This information has its • Changes done in the register. Start a new register limitations as it is always an estimated approach. It can give • Monitor in the outpatient clinic an idea of the food ingested but not absorbed. Adequate nutrient intakes do no guarantee adequate nutrient status6. Once the calculations are made they are compared with the requirements calculated for the child. A dietetic diagnosis is made, followed by the appropriate intervention state. Others such as inborn errors of metabolism which includes the adjustment of the diet, followed by a (phenylketonuria, maple syrup disease) involve a thorough close monitoring plan agreed and adjusted to the needs of understanding of the deleterious effects of the precise error the patient and family (Table 16.8). of metabolism. In these cases there are various approaches but often the cornerstone of treatment is diet. Substrate restriction by an individualized diet is necessary and in times Intervention of illness a careful calorie support adjustment is essential to avoid catabolism12. Furthermore, close dietary advice is Several diseases and/or the effects of treatment can result in necessary to address deficiencies which may develop from decreased appetite, nausea, vomiting, eating difficulties, and such a restricted diet. Other diseases may need only nutri- malabsorption which can compromise the child’s nutritional tional advice and guidance. Cases A–D are such examples. 150 Paediatric clinical dietetics

Case A: Fortification with nutritional modules of an infant diet Female, 3 months old, congenital heart disease

Nutritional assessment

Weight: 4.010 kg (

Food intake: The baby is fed by formula as 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

360 ml x 0.68 kcal/ml Analysis ≈ 245 kcal ≈ 61 kcal/kg/day

Adjust the diet with a nutritional module (Duocal®) of carbohydrates and lipids: first at 3% to increase to 5%:

Quantity *1 scoop (sc) = 1.2 g (each pot of different Percentage 60 cc 90 cc 120 cc brands has its own measure) 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 The mother is recalled for the following week and 2.5 sc ~4 sc 5 sc 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).

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. Paediatric clinical dietetics 151

Case B: Supplementation with common foods Male, 4 years old, medulloblastoma

Chemotherapy has been initiated, with several visits to hospital. The boy has mild anorexia and presents with weight loss.

Nutritional assessment

• Weight: 15 kg (P25); Usual weight (4 months before): 17 kg (P50) • Height: 100 cm (P25) • Requirements*: *Schofield: (4 years) – Energy: 1500–1700 kcal; 130–150 Kcal/kg/day 0.082 x w (11.3 kg) + 0.545 h (0.95) + 1.730 = – Protein: minimum 30 g/day 0.9266 + 0.518 +1.730 = 3.1746 Z (weight): –1.03; Z (height): 0.65 min x 239 kcal = 758.72 kcal WI (w): 94%; WI (h): 98% x 1.5 (activity) = 1138 kcal BMI: 15 (

Food intake: The patient shows a decreased appetite, although still maintains some intake.

Diet – register: 24 recall: Possible diet adaptations Breakfast: Breakfast: Glass of milk (200 ml) Analysis of food intake: A glass of milk (150 ml) + cocoa powder Small muffin (30 g) Energy intake: 750 kcal (15 g) Protein intake: 34 g A small muffin (30 g) + marmalade (15 g) Mid-morning snack: Nothing 18% Mid-morning snack: Carbohydrates Peanuts (25 g) 39% Dinner: Lipids Chicken soup (200 cc) + 43% Proteins Dinner: 20 g of pasta Chicken soup (200 cc) + 20 g of pasta + Steak (60 g) 30 g egg 1 fromage frais (60 g) Steak (60 g) + breadcrumbs (15 g) + oil (5 cc) Mid-afternoon snack: Analysis of food intake: 1 fromage frais (60 g) + milk powder (5 g) Nothing Energy intake: 1485 kcal Protein intake: 56 g Mid-afternoon snack: Supper: Milkshake (banana 50 g + icecream 60 g Creamed courgette (150 g) 15% + hazelnuts10 g) Fish in batter (50 g) Carbohydrates 42% Lipids 1 pear 43% Supper: Proteins Creamed courgette (150 g) + parmesan cheese (10 g) Fish in batter (50 g) 1 pear + condensated milk (20 g)

The boy will attend the outpatient clinic to be continuously assessed, as well as during hospitalization. Future possible adaptations may require the use of oral commercial supplements. 152 Paediatric clinical dietetics

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) Courtesy Fundación Orgebozo, Bilbao, Spain

7 months: (PN in 16 h) w = 6.1 kg; h = 63.5 cm 12 months: (PN in 14 h) w = 8 kg; h = 71 cm Energy Protein Lipids Carb Energy Protein Lipids Carb 90 kcal/kg/d 3 g/kg/d 1.4 g/kg/d 16 g/kg/d 90 kcal/kg/d 3 g/kg/d 1.4 g/kg/d 16 g/kg/d 540 kcal 18 g/d 8.4 g/d 96 g/d 720 kcal 24 g/d 11.2 g/d 128 g/d

Oral diet: Oral diet: (609 kcal/16.4 g protein/19.7 g lipid/63.5 g carb) (201 kcal/8.4 g protein/16.5 g lipid/32.17 g carb) 6 btl. elemental milk formula (15%) + gluten free 1 btl. elemental milk formula (15%) + gluten-free cereals (5%) cereals (5%) 60 cc cereal purée 60 cc cereal purée 100 cc potato + carrot + 30 g chicken purée 100 cc potato + carrot + 40 g chicken purée

Total intake: 1149 kcal = 188 kcal/kg/d Total intake: 921 kcal = 115 kcal/kg/d

34 32 Proteins (g) Proteins (g) 28 28 Lipids (g) Lipids (g) 160 160 Carbohydrates (g) Carbohydrates (g)

The gastrostomy is set at 16 months as the child following rehabilitation continues to refuse food. It is then complementary to HPN. Furthermore keep trying with introduction of new oral food to test tolerance until he is able to decrease and at last (if possible) leave parenteral nutrition.

(18 months) w = 10.3 kg; h = 71 cm PN- 7 days/week (12 h) Energy: 60 kcal/kg/d; 618 kcal Protein: 2.5g/d; 26 g Lipids: 1.5 g/kg/d; 15.45 g Carbohydrates: 21 g/kg/d; 216 g Total intake: 1140 kcal = 110 kcal/kg/d Gastrostomy: 44.5 250 cc cereal purée (with elemental milk formula 15% + cereal 12%) 30.45 Proteins (g) 250 cc savoury mashed purées (50 g protein portion) Lipids (g) Energy: 523 kcal; Protein: 18.5 g/d; Lipids: 15 g; Carbohydrates: 78 g 294 Carbohydrates (g) Paediatric clinical dietetics 153

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 Courtesy Estrategia NAOS. Ministerio de Sanidad y Consumo. Gobierno de España, 2006 154 Paediatric clinical dietetics

Conclusion

The dietitian is part of a multidisciplinary team who takes 11 Martinez Costa C, Sierra C, Pedrón Giner C, et al. care of the patient, and their role is not simply dispensing a Nutrición enteral y parenteral en pediatría. An Esp particularly diet but to provide effective nutritional care, Pediatr 2000;52(Supl.3):1–33. from advice to food provision. Many dietetic skills are 12 Wilken B. An introduction to nutritional treatment in unique and cannot be undertaken by other professionals. An inborn errors of metabolism: different disorders, different effective nutritional support service relies heavily on dietetic approaches. South Asia J Trop Med Pub Health expertise to optimize patient care. However, standards of 2003;34(3S):198–201. practice vary significantly throughout Europe13. There are 13 Howard, JP, Jonkers-Schuietema CF, Kyle U. The role many examples where the use of dietetics in the clinical of the nutritional support dietitian in Europe. Clinical setting is essential. Nutrition1999;18(6):379–83.

References Further reading

1 Martin EA (ed). Concise Medical Dictionary, 2nd edn. ASPEN Board of directors. Standards for specialized Oxford University Press, Oxford 1998. nutrition support: hospitalized pediatric patients. Nutr 2 Moreno JM, Oliveros L, Galiano MJ. Cómo enriquecer la Clin Pract 2005;20(1):103–16. alimentación del lactante: Uso de los módulos Dwyer J. Dietary fibre for children: how much? Pediatrics nutricionales. Act Pediatr Esp 2003;61(8):406–12. 1995;96:1019–22. 3 Stratton RJ, Green CJ, Elia M. Disease-Related Gil Hernandez A. Bases para una alimentación Malnutrition: An Evidence-Based Approach to complementaria adecuada de los lactantes y los niños de Treatment. CABI Publishing, Oxford, 2003. corta edad. An Pediatr (Barc) 2006;65(5):481–95. 4 Golden MHN, Golden BE. Severe malnutrition. In: Garrow JS, James WPT, Ralph A (eds). Human Nutrition and Dietetics, 10th edn. Churchill Livinsgstone, Edinburgh, 2000, pp. 515–26. 5 Shaw V, Lawson M. Clinical Paediatric Dietetics, 2nd edn. Blackwell Science, Oxford, 2001. 6 Whitney EN, Cataldo CB, Rolfes SR. The nutrition care process: assessing anthropometric and biochemical data. In: Understanding Normal and Clinical Nutrition, 5th edn. Wadsworth Publishing Company, Belmont, 1998, pp. 543–58. 7 Ballabriga A, Carrascosa A. Nutrición en la Infancia y Adolescencia, 3rd edn. Nestle Nutrition Institute, Spain, 2006. 8 Schofield WN. Predicting basal metabolic rate, new standards and review of previous work. Hum Clin Nutr 1985;39C(Suppl):5–41. 9 Dewey KG, Beaton G, Fjeld C, et al. Protein requirements of infants and children. Eur J Clin Nutr 1996;50(1):119–47. 10 www.fao.org