9789350903698

IAP Specialty Series on
Pediatric
Gastroenterology
IAP Specialty Series on
Pediatric
Gastroenterology
S e c o n d E d i t i o n
Founder Editor
Dr Nitin K Shah
Editors
Dr Ashish Bavdekar Dr Malathi Sathiyasekaran
DCH DNB MD (Ped) DCH MNAMS DM (Gastro)
Consultant Pediatric Gastroenterologist Consultant Pediatric Gastroenterologist
Liver and Gastroenterology Unit KKCTH and Apollo Children’s and
Department of Pediatrics, KEM Hospital Sundaram Medical Foundation, Chennai
Pune, Maharashtra, India Tamil Nadu, India
Dr John Matthai Dr SK Yachha
DCH MD Fel Ped Gastro (Aus) FIAP MD (Ped) DM (Gastro)
Pediatric Gastroenterologist Professor and Head
Professor and Head Department of Pediatric Gastroenterology
Department of Pediatrics Sanjay Gandhi Postgraduate Institute of
PSG Institute of Medical Sciences and Medical Sciences
Research, Coimbatore Lucknow, Uttar Pradesh, India
Tamil Nadu, India
Co-ordinating Editor
Dr Sailesh Gupta
Honorary Secretary General
Indian Academy of Pediatrics
Kailash Darshan, Kennedy Bridge
Mumbai, Maharashtra, India
Foreword
Dr CP Bansal
IAP President 2013
Dr Rohit Agrawal
IAP President 2012
iap National publication house, gwalior

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Pediatric Gastroenterology
First Edition: 2008
Second Edition: 2013
ISBN: 978-93-5090-369-8
Printed at
Contributors
A Riyaz MD DCH DNB DM (Gastro) BR Thapa MD

Pediatric Gastroenterologist Professor and Head
Professor and Head of Pediatrics Division of Pediatric Gastroenterology
Govt Medical College Hepatology and Nutrition
Calicut, Kerala, Karnataka, India Postgraduate Institute of Medical Education
and Research
Akshay Kapoor Chandigarh, India
Attending Consultant
Division of Pediatric Gastroenterology and John Matthai DCH MD Fel Ped Gastro (Aus) FIAP
Hepatology Pediatric Gastroenterologist
Apollo Centre for Advanced Pediatrics Professor and Head
Indraprastha Apollo Hospitals, New Delhi, India Department of Pediatrics
PSG Institute of Medical Sciences and
Anshu Srivastava MD (Ped) DM (Gastro) Research
Associate Professor Peelamedu, Coimbatore
Department of Pediatric Gastroenterology Tamil Nadu, India
Sanjay Gandhi Postgraduate Institute of
Medical Sciences
Malathi Sathiyasekaran
Lucknow, Uttar Pradesh, India
MD (Ped) DCH MNAMS DM (Gastro)
Consultant Pediatric Gastroenterologist
Anupam Sibal
Group Medical Director KKCTH, Apollo Children’s and
Apollo Hospitals Group Sundaram Medical Foundation, Chennai
Senior Consultant, Pediatric Gastroenterology Tamil Nadu, India
Hepatology and Nutrition
Apollo Centre for Advanced Pediatrics Narendra Kumar Arora MD MNAMS FIAP
Indraprastha Apollo Hospitals, New Delhi, India Executive Director
INCLEN Trust international
Ashish Bavdekar DCH DNB F 1/5, 2nd Floor
Consultant Pediatric Gastroenterologist Okhla Phase 1
Liver and Gastroenterology Unit New Delhi, India
Department of Pediatrics
KEM Hospital, Pune, Maharashtra, India Neelam Mohan
Director
Bhaskar Raju MD DCH MNAMS (Ped) DM (Gastro) Department of Pediatric Gastroenterology
Pediatrician and Pediatric Gastroenterologist Hepatology and Liver Transplantation
Dr Mehta Children’s Hospital Medanta
2. McNichol’s Road, Chetpet The Medicity Hospital, Sector–38
Chennai, Tamil Nadu, India Gurgaon (Haryana), India
Nitya Wadhwa Saravanapandian MD

Centre for Diarrheal Disease and Nutrition Assistant Professor
Research Department of Pediatrics
Department of Pediatrics PSG Institute of Medical Sciences and Research
All India Institute of Medical Sciences Peelamedu, Coimbatore, Tamil Nadu, India
New Delhi, India
Sheila Bhave MD MRCP (UK)
Pankaj Vohra Associate Professor in Pediatrics and
MBBS MD Diplomate Am Bd (Ped Gastro) Consultant in Pediatric Research
Senior Consultant, Pediatric Gastroenterology KEM Hospital
Hepatology and Nutrition Pune, Maharashtra, India
Max Healthcare and Holy Family Hospital
New Delhi, India Shinjini Bhatnagar
Centre for Diarrheal Disease and Nutrition
Research
Prashant Mathur MBBS DCH DNB PhD MNAMS
Scientist ‘D’
All India Institute of Medical Sciences
Division of Noncommunicable Diseases
New Delhi, India
Indian Council of Medical Research
Ansari Nagar, New Delhi, India
Smita Malhotra
Fellow, Division of Pediatric Gastroenterology
S Srinivas and Hepatology
DCH DNB PDCC (PedGastro) Fellowship (AUS)
Apollo Centre for Advanced Pediatrics
Consultant Pediatric Gastroenterologist Indraprastha Apollo Hospitals, New Delhi, India
Department of Pediatric Gastroenterology
Kanchi Kamakoti Child Trust Hospital So Shivbalan MD (Ped) DNB MNAMS
Nungambakkam, Chennai, Tamil Nadu, India Consultant Pediatrician
Sundaram Medical Foundation
Sarah Paul DCH MD (Ped) Dr Rangarajan Memorial Hospital
Professor Chennai, Tamil Nadu, India
PSG Institute of Medical Subash Gupta
Sciences and Research Senior Consultant Liver Transplant Surgery
Peelamedu, Coimbatore, Tamil Nadu, India Centre for liver Disease and Transplantation
Indraprastha Apollo Hospitals, New Delhi, India
Sarath Gopalan
Senior Consultant in Pediatric SK Yachha MD DM
Gastroenterology Professor and Head
Hepatology and Clinical Nutrition Department of Pediatric Gastroenterology
Pushpawati Singhania Institute for Liver Sanjay Gandhi Postgraduate Institute of
Renal and Digestive Diseases Medical Sciences
New Delhi, India Lucknow, Uttar Pradesh, India
vi
Contributors
Sutapa Ganguly VS Sankaranarayanan

Professor and Head HOD and senior consultant
Department of Pediatrics Department of Pediatric
Malda Medical College and Hospital Gastroenterology
Malda, West Bengal, India Kanchi Kamakoti Child Trust Hospital
Numgambakkam, Chennai
Ujjal Poddar MD DNB DM Tamil Nadu, India
Additional Professor
Department of Pediatric Gastroenterology
Sanjay Gandhi Postgraduate Institute of
Medical Sciences, Lucknow
Uttar Pradesh, India
vii
Foreword
Dear Reader,
The book that you hold is the fulfliment of the dreams of the doyens of Indian Academy of
Pediatrics. For many years, the need for good Indian books in every specialty of Pediatrics was
felt. Indian Academy of Pediatrics has no dearth of great teachers and writers in the various
subspecialties to author these books. Their dedicated and diligent labor has created the beautiful
and eminently readable book that you hold. An Indian book by Indian authors will appropriately
suit the needs of the readers in India and in countries with similar geographical and sociocultural
milieus. While the first editions of the IAP subspecialty series were published in 2006, we proudly
present to you a second, completely revised and updated edition.
The IAP specialty series books serve the purpose of providing evidence based, authentic
and uniform information to IAP members, other Pediatricians, and students of Pediatrics in the
country. Guidelines and established protocols on disease management will be very helpful for
pediatricians in their everyday practice.
Creating a book is like the birth of a baby. Right from conception to delivery, there is a long
and complex process. It is very labor intensive, time consuming work that involves considerable
financial expense too. To streamline the entire process from writing to editing to publishing to
distribution and sales of books, it was envisioned to have an additional wing of IAP, and which is
established as "IAP National Publication House" at Gwalior.
Knowledge has no limits and seekers of knowledge can access the subject from anywhere in
the world. We understand that books published by IAP NPH will be read and referred not only in
India but in many parts of the world. Objective of IAP NPH therefore is to provide standardised
content and world class quality. With this objective, printed books are to be made available
throughout the globe and distribution will also be done through online editions. Publishing 7
books at a time is a mammoth task and for this we collaborated with second largest medical
publisher in the world, i.e. Jaypee Brothers Medical Publishers (P) Ltd., New Delhi.
What you are reading, the world is also reading. Our writers are getting worldwide exposure
and readers are getting world class books at reasonable cost.
It needs to be mentioned here that all authors and editors have dedicated the royalty from
sale of books to IAP and have thereby done a selfless service for our mother organization. By
buying this book you are also contributing to IAP in a significant manner.
Finally, we express our pride and happiness in being associated with this project and in
reaching this valuable book to you. We wish you a happy and contented reading.
Dr CP Bansal
IAP President 2013
Dr Rohit Agrawal
IAP President 2012
Message
Dear Colleague,
It gives me great pleasure to present this IAP Specialty Series book on Pediatric Gastroenterology.
Need to have IAP books in pediatric specialties was always felt by many. While we have many
such specialty books written by individuals, we do not have these books under the fold of IAP.
We can standardize the format, contents, style and size by having these books under the banner
of IAP. Looking at the need of having IAP Specialty Books and availability of experts within IAP to
do this job, we had targeted to publish books on major pediatric specialties under IAP Specialty
Series.
IAP published four books under IAP Specialty Series, i.e. Pediatric Infectious Diseases, Rational
Antimicrobials Practice in Pediatrics, Pediatric HIV and Pediatric Hematology and Oncology last
year. These books were highly appreciated by one and all and this has encouraged us to bring
out four more books under the IAP Specialty Series this year, i.e. Pediatric Cardiology, Pediatric
Intensive Care, Rational Antimicrobial Practice in Pediatrics and Pediatric Endocrinology besides
this book of course!
I am thankful to Editors Dr Ashish Bavdekar, Dr John Matthai, Dr Malathi Sathiyasekaran and
Dr SK Yachha for their wonderful and painstaking work. I am thankful to the experts who have
contributed articles in this book and the IAP office bearers 2006 and 2007 for helping us with
concept and editorial work of the entire IAP Specialty Series. I am sure you will find this book
useful and informative and hope that this book become a desk companion for all the practicing
pediatricians and postgraduates in pediatrics.
Yours Sincerely
Nitin K Shah
Founder Editor, IAP Specialty Series
Preface to Second Edition
Dear Readers
Pediatric Gastroenterology in India has made giant strides in the last few decades. We have moved
from Malnutrition, ICC and ORS to Obesity, metabolic liver diseases and liver transplantation.
From a handful of trained personnel in few tertiary centers, we now have qualified specialists in
almost all regions of India. Advanced laboratory support now enables diagnosis of uncommon
GI and liver diseases. The professional competence and technological capabilities available in
India in our field are far ahead of any other developing country, and even comparable to the
west.
It is time this expertise translates into better medical care of all children in our country.
Sharing of knowledge with practicing pediatricians and students is the only way this can be
achieved. This book is a small step in that direction. This is the second edition of the book and
almost all chapters have been revised and three new chapters have been included. A number of
experts have graciously contributed to this book and we express our gratitude to them.
We thank the Indian Academy of Pediatrics and the publishers for supporting this academic
initiative. Suggestions from readers to improve the book are welcome.
Ashish Bavdekar
John Matthai
SK Yachha
Preface to First Edition
In the last two decades, pediatric gastroenterology has come of age as a subspeciality in India.
Newer methods of diagnosis and increasing number of pharmaceutical agents have given us
more and more alternatives in evaluating and treating children with gastrointestinal disease.
We are now able to identify and successfully manage many children with GI problems. On
the research side, many important scientific contributions have come from various pediatric
gastroenterology and liver units around the country.
This book attempts to cover most of the important problems of GI tract, liver, pancreas and
nutrition in children and we hope that it can bridge the gap between general discussions of
gastrointestinal problems in standard pediatric textbooks and the otherwise large encyclopedic
volumes available to the pediatric gastroenterologist.
A number of experts in pediatric gastroenterology have contributed to this book and we
would like to thank all of them for their valuable time and effort in preparing these manuscripts.
It is our hope that this book will benefit the practicing pediatrician as well as the young
postgraduate who wishes to make his career in pediatric gastroenterology.
We thank the Indian Academy of Pediatrics for the opportunity to edit this important book.
We welcome feedback from our readers to help us improve the quality of the subsequent
editions.
Ashish Bavdekar
John Matthai
Surender Kumar Yachha
Contents
1. Gastroesophageal Reflux 1
John Matthai, Sarah Paul
2. Helicobacter Pylori in Children 11
Ujjal Poddar
3. Recurrent (Chronic) Abdominal Pain in Children 22
BhaskarRaju
4. Recent Trends in the Management of Acute Watery Diarrhea in Children 37
Shinjini Bhatnagar, Nitya Wadhwa
5. Persistent Diarrhea 43
Sarath Gopalan
6. Chronic Diarrhea and Malabsorption Syndrome 54
Anshu Srivastava
7. Celiac Disease 74
Anshu Srivastava, Barath Jagadisan
8. Abdominal Tuberculosis 84
A Riyaz
9. Inflammatory Bowel Disease in Children and Adolescents 96
Malathi Sathiyasekaran, So Shivbalan
10. Intestinal Parasites in Children 109
Pankaj Vohra
11. Constipation in Children 126
BR Thapa
12. Childhood Pancreatitis 145
Neelam Mohan
13. Symptoms and Signs of Liver Disease in Childhood 169
S Srinivas, VS Sankaranarayanan
14. Liver Function Tests 179
Saravanapandian, Sarah Paul, John Matthai
15. Acute Hepatitis 189
16. Acute Liver Failure in Children 202
Prashant Mathur, Narendra Kumar Arora
17. Neonatal Cholestatic Jaundice 219

SK Yachha
18. Chronic Liver Disorders in Children 231
Sheila Bhave
19. Portal Hypertension 240
Sutapa Ganguly
20. Metabolic Liver Diseases 259
Ashish Bavdekar
21. Ascites in Children 270
VS Sankaranarayanan
22. Liver Transplantation in Children 281
Smita Malhotra, Akshay Kapoor, Subash Gupta, Anupam Sibal

Index293
xviii
1
Gastroesophageal
Reflux
INTRODUCTION
Gastroesophageal reflux (GER) is the most common esophageal disorder in children. GER
is defined as the involuntary passage of gastric contents into the esophagus with or without
regurgitation and vomiting. The regurgitated gastric content may be saliva, ingested food,
gastric secretions, pancreatic or biliary secretions.
Gastroesophageal reflux, which manifests as “bringing up” or “regurgitation” of feeds is
physiological in most infants and needs no investigations or treatment. A few, however, have
pathological symptoms and are referred to as having gastroesophageal reflux disease (GERD).
Mothers often confuse between ”regurgitation” and “vomiting”. Vomiting is the forceful expulsion
of gastric contents through the mouth and involves intense muscular activity of the respiratory
and abdominal muscles. Regurgitation is passive and effortless and involves no muscular activity.
PREVALENCE AND NATURAL HISTORY

The prevalence of GER is high in western countries and is now being increasingly recognized
in India. Formula feeding and restraining of infants in car seats are probable reasons in western
countries. The prevalence of GERD in infants and children ranges from 1 to 8%.1 More than 85%
of premature infants have GERD with up to 10% of them having extra intestinal manifestations
like bradycardia and apnea. GER is an age-related problem in infants. Almost all babies will have
some reflux at 3 months of age. However, only around 33% will be brought for medical attention
at that age and it declines to 20% by 6 months of age. In most symptomatic infants, regurgitation
decreases appreciably by 12 to 24 months of age.2 GERD changes in clinical character with
advancing age. In a study on 1700 children followed from infancy to 21 years, it was noted
that the predominant symptom changed from regurgitation in infancy to pain in adolescence.
While 1.8% had heart burn by 9 years, 22% had epigastric pain or heart burn by 21 years. Older
children with persisting regurgitation are unlikely to improve with age and may continue to
remain symptomatic. Chronic untreated esophagitis can result in strictures, Barrett’s esophagus
and adenocarcinoma in adults. Data from US centers have shown a rise in incidence of Barrett’s
esophagus in children from less than 2% in 1997 to 4% in 2000.
PATHOPHYSIOLOGY OF REFLUX
The esophagus is not under voluntary control. Distal to the mid-esophagus the muscular layer
is composed of smooth muscle fibers. Peristaltic waves involving the external circular muscular
layer propel the ingested food through the esophagus into the stomach. The lower esophageal
sphincter is an area of thickened circular muscle that is tonically contracted at rest. A well-
coordinated relaxation of the lower esophageal sphincter is essential for the transport of food
into the stomach. Basal LES pressure is maintained above 4 mm Hg to prevent reflux. Pressure
studies have disproved the earlier theory that infants with GER have abnormally low basal tone.
Reflux is now thought to occur due to transient LES relaxations (TLESR) in the absence of
esophageal peristalsis and mediated primarily through vagal pathways via the brain stem.3 The
pressure changes at the gastroesophageal junction are dependent on the volume-pressure
relationship in the stomach as well as the proximal esophageal clearance of the refluxed material.
Sensory pathways not only cause pain symptoms but also serve as the gastric afferent limb of the
TLESR. The TLESR can thus be thought of as either a “belch equivalent” releasing gastric pressure
(afferents being in the stomach) or as an “aborted swallow” (afferents in the esophagus).4 Nitric
oxide and cholecystokinin are thought to mediate TLESR, because their antagonists reduce the
frequency of reflux.
Relaxation of the LES may also be mediated by inhibitory neurotransmitters like vasoactive
intestinal peptide ( VIP) released from the enteric neurons.5 Thus, abnormal functioning of the CNS
can result in abnormal gastric motor activity, retrograde peristalsis and relaxation of the LES. The
crural diaphragm that surrounds the LES increases its tone especially during straining. Complex
neural connections ensure that TLESRs are physiologically accompanied by coordinated crural
relaxation. This explains the association of hiatus hernia with GERD.6 A recent study reported
hiatus hernia in 6% of children with GERD.7 A genetic predisposition has been postulated in the
etiology of hiatus hernia and complicated GERD. A locus for “Severe Pediatric GERD” has been
identified on chromosome 13q14.8
Esophagitis does not occur in all children with reflux. The development of esophagitis
depends on the frequency and duration of the reflux, the nature of the refluxate and the
protective mechanisms in the esophageal mucosa.9
PATHOGENESIS OF REFLUX DISEASE

GER in normal children occurs in the postprandial period, lasts less than 3 minutes and is
asymptomatic. Physiologic reflux is uncommon in sleep. In children with GERD, nocturnal reflux
is frequent.10 Reflux occurring at night is associated with increased complications, since the
normal protective mucosal clearance, gravitational clearance and salivation are less effective
during sleep.
The pathogenesis of reflux in premature infants is not well understood.11 They require
good calorie intake but have limited gastric capacity. The refluxate tends to be of large volume
and usually reaches the upper esophageal sphincter (UES). The response of the UES in most
situations is to increase the sphincter pressure and protect the airway, but when esophageal
2 pressure is excessive, it relaxes and allows the refluxate to escape. Gravitational force may,
Gastroesophageal Reflux
however, sometimes lead to aspiration into the lung. Laryngeal stimulation can also cause apnea
in premature babies. The refluxate is usually not acidic in premature babies because frequent
feedings buffer the gastric acid. Nasogastric tubes impair clearance of the refluxed material if
they are of large size.12
Reflux is affected by environmental factors such as posture, activity, clothing and diet.
Increased volume, acidity and osmolality of feeds are known to trigger regurgitation. In infants,
supine and seated position (as in car seats) can result in reflux. Children with neurologic
impairment, obesity, hiatus hernia and repaired esophageal atresia or achalasia are at high risk
for chronic GERD.
SYMPTOMS AND MANIFESTATIONS

Some degree of reflux is normal in the first year of life and parents of healthy, thriving infants
with reflux, should be reassured. “Regurgitating” or “bringing out” is the visible form of GER and
can cause failure to thrive from loss of calories. Significant GERD can, however, exist even in the
absence of this symptom.
Other manifestations of GERD include symptoms of esophagitis and respiratory tract related
problems like apnea, acute life-threatening episode (ALTE), recurrent pneumonia or asthma.13
Reflux esophagitis may present as irritability (colic), failure to thrive, melena or hematemesis,
in infants and young children. A symptom complex called “Sandifer’s syndrome” has been seen
in some infants with reflux and consists of abnormal posturing with tilting of the head to one
side and bizarre contortions of the trunk. Older children with esophagitis complain of epigastric/
retrosternal pain, dysphagia, odynophagia, belching or postprandial fullness. Anemia can result
from chronic GI blood loss due to melena/hematemesis. Grading of lesions on endoscopy or
biopsy does not correlate well with the severity of symptoms and proven severe esophagitis may
have only minimal symptoms and vice versa.
There seems to be an association between GERD and dental erosions. Young children and
children with neurologic impairment are at higher risk. There is no convincing evidence that GER
is the primary cause of apnea and ALTE in most infants.14 However, in a subgroup of infants, it may
play a significant role.15 Chronology of events, relationship with feeds, presence of feeds in the
pharynx and evidence of chronic inflammation in the larynx indicate an etiological association.
GERD has long been suspected to be responsible for asthma and recurrent pneumonia in
infants. In the absence of well-designed controlled trials, it is not possible to conclude if reflux
is the cause or an effect of the problem.16 Respiratory mucosa is very sensitive to acidic pH and
exposure to gastric acid can result in inflammation leading to wheezing or infection. Reflux may
also occur secondary to increased respiratory effect or persistent coughing in children with
severe asthma. GERD may be considered as a possible cause of asthma in children who respond
poorly to treatment/prophylaxis, infants with severe wheezing without a family history and in
those without eosinophilia/elevated serum IgE. Neurologically abnormal children have more
severe and complicated GERD than normal children. Increased gastric pressure due to spasticity,
impaired refluxate clearance due to supine posture as well as inability to move and communicate
predispose them to severe disease.17 3
EVALUATION
Detailed evaluation is necessary only in children with GERD. Available investigations have
different goals and they include: documenting GER, excluding precipitating causes and
associated anomalies, documenting tissue damage, or establishing a cause and effect
relationship between GER and the symptom. Tests, therefore, need to be individualized, so that
appropriate therapeutic decisions can be made. Standardized questionnaires for mothers are
useful to diagnose and quantify the severity of regurgitation.18 It is a good objective assessment
and repeated assessments can document improvement, stability, or worsening of disease.
Contrast Studies
Barium study which has been in use for many decades has low sensitivity and specificity in
diagnosis of GERD. It is now done to rule out structural abnormalities like a large hiatus hernia,
esophageal stricture, duodenal web or atypical pyloric stenosis.19 Mere demonstration of
reflux on a barium study has little significance, since it is normal in infants. Dynamic barium
esophagography is used to identify abnormalities in pharyngeal, laryngeal and upper esophageal
function.
Esophageal pH Studies
Esophageal pH monitoring has considerably improved our understanding of GER.20 Flexible
pH probes can be placed in the esophagus while allowing the infant normal activity. A drop in
intraesophageal pH < 4 is considered an acid reflux episode. A random pH probe study is of no
value in the evaluation of GER disease. Ambulatory pH probes permit 24-hour monitoring while
the infant carries on normal activities like sleep, food intake and change of position. Prolonged
pH monitoring can determine the frequency of reflux, the time taken to clear the refluxate as
well as the effect of feeding, body position and state of consciousness on GER.21 Correlation of
episodic events like apnea in newborns, behavioral disturbances in infants and heart burn in
older children, with acid reflux is also possible. A major drawback is that postprandial reflux may
sometimes be missed, since foods neutralize gastric acidity and pH probes cannot detect non-
acidic reflux. There is also no consistent correlation between the severity of acid reflux and the
severity of symptoms and complications.
Nuclear Scintigraphy
This is also called “Milk Scan” wherein isotopes like 99mTC can be added to the infant’s feed and
monitored with a gamma counter. It is noninvasive and low in radiation but requires considerable
expertise and experience. The gastric emptying time and the amount of radionucleotide refluxed
into the esophagus or lungs can be studied. It is particularly useful in situations where GER is
thought to be the cause of asthma or pneumonia. A negative test does not rule out possible
pulmonary aspiration.
Endoscopy and Biopsy

4
Endoscopy allows direct visualization of the esophageal mucosa and the dynamics of the LES as
well as provides a biopsy specimen for histopathology.22 Esophagitis always occurs in the lower
part of the esophagus and can be recognized as redness of the mucosa with loss of the normal
vascular pattern. The severity of the endoscopic esophagitis in children is graded according to the
classification of Savary and Miller. A large majority of reflux esophagitis in children are restricted
to grades 1 and 2. A good visual inspection must be done before multiple punch biopsies of the
esophagus are taken. Histological criteria for the diagnosis of esophagitis have been graded.
Basal cell zone hyperplasia of the esophageal squamous epithelium and increased stromal
papillary length are the most commonly used criteria. Basal zone hyperplasia of more than 20%
of the epithelial thickness and papillary height extending into the upper third of the epithelium
are reliable criteria for histological diagnosis. It is important to recognize that esophagitis can
occur from causes other than GERD. These include eosinophilic esophagitis, infections (Candida,
herpes, CMV), Crohn’s disease, caustic ingestion, etc. Longstanding untreated reflux esophagitis
results in aberrant columnar epithelium lining the distal esophagus (Barrett’s esophagus).
The diagnosis requires multiple biopsies to show the transition from squamous to columnar
epithelium. This is potentially malignant and aggressive medical or surgical therapy can reverse
the mucosa to normal.
Empirical Acid Suppression as Diagnostic Test

Some experts recommend that in older children with typical pain symptoms of GERD, an
empirical trial of PPIs for 4 weeks is justified. However, such an approach is not recommended for
infants and young children in whom symptoms of GERD are nonspecific.
Miscellaneous Techniques
Esophageal manometry is used to assess pressure profile and dynamic changes. It can rule
out achalasia and other motility disorders. Multiple intraluminal impedance monitoring is useful
in demonstrating nonacidic reflux. It complements an esophageal pH study, but is difficult to
perform and analyze.23
Bilirubin monitoring in the esophageal lumen is mostly of interest in research studies.
Duodenogastric refluxate does not cause esophagitis except in the presence of acid.24 Surface
electrogastrography records the myoelectrical activity generated by the pacemaker interstitial
cells of Cajal. This is a non-invasive technique which may be useful in identifying motor
abnormalities in the stomach that predispose to GERD. It may be of use in the evaluation of
functional symptoms such as nausea, anorexia and dyspepsia, without an organic basis.25
Congenital abnormalities of the upper airway, e.g. Laryngeal clefts may result in aspiration
during reflux or swallowing. Laryngobronchoscopy allows direct visualization of the area.
It can also detect the presence of vocal cord erythema or nodules secondary to acid reflux.
Polysomnography (sleep study), in association with esophageal pH study, is useful to identify
apneic episodes that may be associated with acid reflux.
DIFFERENTIAL DIAGNOSIS
The differential diagnosis of regurgitation in children is varied and requires a careful history
and evaluation. Faulty feeding/overfeeding particularly in artificially fed infants is of particular 5
concern. Cow’s milk protein allergy is an important consideration in young infants who are
exclusively formula-fed and are failing to thrive. In young infants with acute onset of symptoms,
systemic infections should be ruled out. Gastrointestinal obstruction (malrotation/volvulus,
pyloric stenosis, duodenal stenosis, stricture), achalasia, food intolerance and food allergy are
other important differential diagnoses.
MANAGEMENT
Regurgitation being physiological in infancy, only those with pathological GER need to be treated.
The risks and benefit of therapy should be carefully assessed in terms of age of the patient.
In adolescents and adult GERD, esophagitis and consequently proton pump inhibitors are of
prime importance. In infants the refluxate is less acidic and of large volume; and so positioning,
consistency of feeds and probably prokinetics are more important.26
Lifestyle Measures
The “head elevated prone position” is clearly effective in reducing the reflux when compared
to the supine or seated positions. However the risk of sudden infant death syndrome (SIDS)
outweighs the benefits of prone or lateral positions and hence it is not recommended as a sleep
position in infants less than 12 months.27 Positioning in an “infant chair” reclining at a 45 degree
angle has not been shown effective. Small, frequent feeds are useful in reducing the reflux since
they reduce the available volume in the stomach for reflux. Continuous nasogastric drip feeding
is effective in reducing the reflux and improving weight gain in severe cases. Thickening of feeds
does not improve the volume of refluxate, but decreases the number of episodes of ‘vomiting’.28
Thickened formula may, however, increase coughing during feeds. Thickening of feeds is usually
achieved by adding rice cereal. In older children, positioning, control of obesity and avoidance
of large meals may be beneficial.
Pharmacologic Therapy
Pharmacotherapy consists of acid–lowering agents, barrier agents and prokinetics. There is a
paucity of data on the relative benefits of the various drugs in children.
Acid Lowering Agents

They are useful only in situations where the symptoms are acid related, like esophagitis, or
heartburn. In order of increasing potency these include the conventional antacids, H2 receptor
antagonists and proton pump inhibitors (PPI). Conventional antacids (1 ml/kg/dose qid) are not
recommended now. Among the H2 blockers, Ranitidine (3–5 mg/kg/dose bd/tid) and Cimetidine
(10–15 mg/kg/dose qid) have been used extensively, with the former being better tolerated
and having lesser side effects.29 PPIs the most effective acid suppressants, covalently bond and
deactivate the H+K+ ATPase pumps.30 They require acid for activation and should be administered
1 hour before breakfast. Omeprazole at 0.5–0.7 mg/kg/day is commonly used.31 Higher doses
may be used in selected cases if esophageal pH studies show no response to treatment. For
children unable to swallow the capsules, granules can be administered orally in weakly acidic
6 foods such as apple juice or yogurt. Other PPIs like Lansoprazole (1.4 mg/kg/day), Pantoprazole
and Rabeprazole are also effective. PPIs are superior to H2 blockers in relieving symptoms and
healing esophagitis. Once daily dosing is sufficient in most children. In patients with nocturnal
acid breakthrough, a morning dose of PPI and night dose of H2 blocker is used. No PPI has been
approved for use in infants less than one year, even though they are widely prescribed.
Barrier Agents
Sucralfate and Alginate form complexes with the base of ulcers/erosions and is effective in settings
where the esophageal epithelium has been severely damaged. The action is comparable to H2
receptor antagonists in adults but its safety and usefulness in children is unproven. While short-
term use may be justified in older children with severe pain, chronic use is not recommended
especially in infants.
Prokinetic Agents
Since GERD has many features of intestinal motility disorders, prokinetic agents have been used
in these patients. However, the potential side effects and toxicity have dampened the enthusiasm
in their use. Bethanechol has no clear benefit and is not used. Metoclopranide has a narrow
therapeutic range and extra-pyramidal side effects are not uncommon in children. Domperidone
has not been proven effective in healing of reflux esophagitis in controlled trials. Cisapride
(0.2 mg/kg/dose qih) a 5HT antagonist is thought to act by enhancing neurotransmitter release
that stimulates smooth muscle contraction throughout the intestinal tract. It has been shown
beneficial in reflux esophagitis, but not as dramatic as was earlier claimed. Studies comparing
cisapride with other prokinetics have shown statistically significant better outcome with the use
of cisapride in esophagitis—endoscopic assessment, duration of reflux episodes, esophageal
clearance and improvement in symptoms. However, cardiotoxicity is the major side effect. The
2009 ESPGHAN/NASPGHAN consensus statement does not support the use of cisapride or any
other prokinetic in GERD.32,33
Surgical Treatment
Surgery is indicated only in children with GERD which is refractory to adequate medical
treatment— “Chronic relapsing GERD”. Indications include failure of optimal medical therapy,
dependence on long-term medical therapy, non-adherence to medical therapy or recurrent
pulmonary complications. Nissen Fundoplication is commonly done. Although efficacious in
many children, side effects are common and often distressing.34 Moreover, surgery may not
always be effective and some children will continue to require pharmacotherapy even after
surgery. Complications may be attributed to many factors—“Bad patient” in whom surgery was
technically challenging, “Bad diagnosis” in whom the symptoms which prompted surgery were
actually not due to GERD, and “Bad therapy” due to defective surgical competence. Complications
are more common in those with chronic neurologic or respiratory disease. A tight wrap may result
in dysphagia or gas bloat presenting with nausea, vomiting, abdominal distension, retching and
gagging. Laparoscopic fundoplication can be as effective as open fundoplication in children but
requires expertise.35 7
Extraesophageal Manifestations
In these situations, therapy must be aggressive and for longer duration.36 Twice daily PPIs
maintained for at least 3 months is recommended. Surgery may be considered early if symptoms
are refractory to medical treatment, even though complications of surgery are greater in these
patients.
SUMMARY
Gastroesophageal reflux is the involuntary passage of gastric contents into the esophagus.
While in a majority of infants it is physiological, in some, it could be pathological (GERD). Reflux
decreases by 12–24 months of age; even in those with severe symptoms. Reflux occurs due to
transient lower esophageal sphincter relaxations and not due to an abnormally low basal tone
of the LES as was earlier thought. Reflux can be triggered by posture (supine and seated), diet
(increased volume, acidity and osmolality) and activity. Nocturnal reflux is usually pathological
and associated with complications.
Children with GERD usually present with failure to thrive from loss of calories or symptoms
of esophagitis. Apnea and acute life-threatening event can occur due to reflux in newborns.
The association between asthma and recurrent pneumonia is unclear. Children with neurologic
impairment, obesity, hiatus hernia and those who have had esophageal surgery are at high risk
for chronic GERD.
Investigations in GER should be individualized. The mere demonstration of reflux in a barium
study has little significance. Barium studies are done only to rule out structural abnormalities. Upper
GI endoscopy and biopsy is the gold standard in diagnosis of esophagitis. 24-hour esophageal pH
studies help to determine the frequency of reflux and correlate reflux with episodic symptoms.
Nuclear scintigraphy is useful to demonstrate regurgitation into the respiratory tract.
Positioning in the “head elevated prone position” is beneficial, but carries an increased risk of
sudden infant death. Thickening of feeds decreases the frequency of reflux. Acid lowering agents
are useful in situations where acid is responsible for the symptoms. PPIs are most effective, but
are still not approved in infants below 1 year of age. Prokinetics are not recommended in view of
serious side effects. Fundoplication should be considered only in chronic relapsing GERD.
Key Messages
1. In most symptomatic infants, reflux decreases by 12–24 months of age.
2. Transient LES relaxations mediated by vagal pathways are responsible for reflux.
3. The association between reflux and apnea/ALTE in newborns, as well as asthma/recurrent pneumonia
in older children needs further confirmation.
4. Neurologically abnormal children have more complicated GERD.
5. Only infants with pathological reflux (GERD) need investigations and treatment.
6. Acid lowering agents are indicated only when the symptoms are acid related. PPIs are the most potent,
but are not approved in infants.
7. Prokinetics are not recommended in view of serious side effects.
8 8. GERD with extraesophageal manifestations requires aggressive management.
ACKNOWLEDGMENT
The authors wish to thank Mrs Dhanabaghyam for secretarial assistance.
REFERENCES
1. Eisen GM. The epidemiology of gastroesophageal reflux disease: what we know and what we need to
know. Am J Gastroenterol. 2001;96(8 Suppl):S16–8.
2. Nelson SP, Chen EH, Syniar GM, Christoffel KK. The Pediatric Practice Research Group. One-year follow-
up of symptoms of gastroesophageal reflux during infancy. Pediatrics. 1998;102:e67.
3. Vandenplas Y, Hassall E. Mechanisms of gastroesophageal reflux and gastroesophageal reflux disease.
J Pediatr Gastroenterol Nutr. 2002;35:119–36.
4. Mittal R, Holloway R, Penagini R, et al. Transient lower esophageal sphincter relaxation. Gastroenterology.
1995;109:601–10.
5. Dent J. Patterns of lower esophageal sphincter function associated with gastroesophageal reflux. Am
J Med. 1997;103(5A):29S–32S.
6. Van Herwaarden MA, Samsom M, Smout AJPM. Excess gastroesophageal reflux in patients with
hiatus hernia is caused by mechanisms other than transient LES relaxations. Gastroenterology.
2000;119:1439–46.
7. Gorenstein A, Cohen AJ, Cordova Z, et al. Hiatal hernia in pediatric gastroesophageal reflux. J Pediatr
Gastroenterol Nutr. 2001;33:554–7.
8. Orenstein SR, Shalaby TM, Barmada MM, et al. Genetics of gastroesophageal reflux disease: a review.
9. Orlando RC. Mechanisms of reflux-induced epithelial injuries in the esophagus. Am J Med. 2000;108
(4A):104S–8S.
10. Cibella F, Cuttitta G. Nocturnal asthma and gastroesophageal reflux. Am J Med. 2001;111(8A):31S–6S.
11. Omari T, Barnett C, Snel A, et al. Mechanisms of gastroesophageal reflux in healthy premature infants.
J Pediatr. 1998;133:650–4.
12. Noviski N, Yehuda YB, Serour F, et al. Does the size of nasogastric tubes affect gastroesophageal reflux
in children. J Pediatr Gastroenterol Nutr. 1999;29:448–51.
13. Matthai J, Paul S. Gastroesophageal Reflux. In Gupte S (Ed). Recent advances in Pediatrics Sp vol 6 New
Delhi, Jaypee Brothers. 2000;52–59.
14. Arad–Cohen N, Cohen A, Tirosh E. The relationship between gastroesophageal reflux and apnea in
infants. J Pediatr. 2000;137:321–6.
15. Orenstein SR. An overview of reflux-associated disorders in infants: apnea, laryngospasm, and
aspiration. Am J Med. 2001;11Suppl 8A:60S–3S.
16. Tolia V. Gastroesophageal reflux and supraesophageal complications: really true or ballyhoo [editorial]?
17. Orenstein SR, Khan S, Gastroesophageal Reflux. In Walker AW, Goulet O, et al (Eds). Pediatric
Gastroenterol disease. New York. BC Dekker Inc. 2004;384–99.
18. Shaw MJ, Talley NJ, Beebe TJ, et al. Initial validation of a diagnostic questionnaire for gastroesophageal
reflux disease. Am J Gastroenterol. 2001;96:52–7.
19. Meyers WF, Roberts CC, Johnson DG, Herbst JJ. Values of tests for evaluation of gastroesophageal reflux
in children. J Pediatr Surg. 1985;20:515–20.
20. Colletti RB, Christie DL, Ornstein SR. Statement of the North American Society for Pediatric Gastroenterology
and nutrition (NASPGN). Indications of pediatric esophageal pH monitoring. J Pediatr Gastroenterol Nutr.
1995; 21:253-62.
21. Bagucka B, Badriul H, Vandemaele K, et al. Normal ranges of continuous pH monitoring in the proximal
esophagus. J Pediatr Gastroenterol Nutr. 2000;31:244–7.
22. El-Serag HB, Bailey NR, Gilger MA, Rabeneck L. Endoscopic manifestations of gastroesophageal reflux 9
disease in patients between 18 months and 25 years without neurological deficits. Am J Gastroenterol
2002; 97:1635–9.
23. Wenzl TG. Investigating esophageal reflux with the intraluminal impedance technique. J Pediatr
24. Vaezi MF, Richter JE. Duodenogastroesophageal reflux and methods to monitor nonacidic reflux. Am
J Med. 2001;111(8A):160S–8S.
25. Levy J, Harris J, Chen J, et al. Electrogastrographic norms in children: toward the development of
standard methods, reproducible results, and reliable normative data. J Pediatr Gastroenterol Nutr.
2001;33:455–61.
26. Orenstein SR. Regurgitation and GERD. J Pediatr Gastroenterol Nutr. 2001;32 (Suppl 1):S16–8.
27. Carroll A, Garrison M, Christakis D. A systematic review of nonpharmacological and nonsurgical
therapies for gastroesophageal reflux in infants. Arch Pediatr Adolesc Med. 2002;156:109–13.
28. Orenstein SR, Magill HL, Brooks P. Thickening of infant feedings for therapy of gastroesophageal reflux.
J Pediatr. 1987;110:181–6.
29. Kelly D. Do H2 receptor antagonists have a therapeutic role in childhood? J Pediatr Gastroenterol Nutr.
1994;19:270–6.
30. Hassall E, Israel D, Shepherd R, et al. International Pediatric Omeprazole Study Group- Omeprazole for
treatment of chronic erosive esophagitis in children: a multicenter study of efficacy, safety, tolerability
and dose requirements. J Pediatr, 2000;137:800–7.
31. Israel D, Hassall E. Omeprazole and other proton pump inhibitors: pharmacology, efficacy, and safety,
with special reference to use in children. J Pediatr Gastroenterol Nutr. 1998;27:568–79.
32. Vandenplas Y. Rudolph CD. Pediatric Gastroesophageal reflux clinical practice guidelines. Joint
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33. Augood C, MacLennon S, Gilbert R, Logan S. Cisparide treatment for gastroesophageal reflux in
children. Cochrane database Syst Rev. 2003 CD 002300.
34. Di Lorenzo C, Orenstein SR. Fundoplication: friend or foe? J Pediatr Gastroenterol Nutr. 2002;34:117–24
35. Diaz DM, Gibbons TE, Heiss K, et al. Antireflux surgery outcomes in pediatric gastroesophageal reflux
disease. Am J Gastroenterol. 2005;100:1844–52
36. De Vault KR. Overview of therapy for the extraesophageal manifestations of gastroesophageal reflux
disease. Am J Gastroenterol. 2000;95(8 Suppl):S39–44.
10
2
Helicobacter Pylori
in Children
Ujjal Poddar
INTRODUCTION
The Medicine Nobel Prize of 2005, was awarded to an observant pathologist Robin Warren and
an enterprizing physician Barry Marshal from Australia for the discovery of Helicobacter pylori
and its role in peptic ulcer disease and gastritis in 1983.1 This organism has fulfilled Koch’s
postulations as a cause of chronic active gastritis in human.2 Since its discovery it has generated
enormous interest among medical fraternity. On MEDLINE search, till June 2012, there are 31,628
publications (3,008 of them are related to children) and a full journal (Helicobacter) has been
devoted to this organism. However, pediatric literature from India on this organism is relatively
scanty.3-9
Helicobacter pylori is a slowly growing, microaerophilic, highly motile, gram-negative spiral
organism with 4–6 flagella at one end. The organism has the striking biochemical characteristic
of abundant urease enzyme production. This enzyme is important for colonization and is an
indirect marker of the organism’s presence, as it is the basis of rapid urease test (RUT), the urea
breath test and as an antigen for a serological test. This organism has a special affinity for gastric
mucosa and is etiologically associated with chronic active gastritis, peptic ulcer (duodenal and
gastric) and gastric cancer. However, the relationship between this organism and gastroduodenal
complaints in children is less clear. The chronic, gastritis that it induces, is usually not symptomatic
but is considered to be the background of several diseases, i.e., peptic ulcer disease and gastric
malignancies that typically occur in adulthood. Helicobacter pylori infection is almost always
acquired in early childhood and usually persists throughout life unless a specific treatment is
given (spontaneous eradication is rare). At least 50% of the world’s population10 is infected with
Helicobacter pylori and socioeconomic condition is regarded as the most important risk factor
for acquisition of the infection.11 In developing countries most children reach adulthood being
H. pylori positive.12–14
EPIDEMIOLOGY
Prevalence of H. pylori Infection in Indian Children
The prevalence of H. pylori is not evenly distributed worldwide. The prevalence depends on
socioeconomic status and overcrowding. While developed countries have low prevalence,
the developing countries have high prevalence and, children are typically infected by 10
years of age. In India, like other developing countries, due to rampant poverty, overcrowding,
poor sanitation and hygiene, the prevalence of H. pylori infection is very high (Table 2.1). The
seroprevalence studies from Hyderabad and Mumbai have shown that by 10 years of age more
than 50% and by 20 years more than 80% of population are infected with H. pylori.13,14 Another
study from Bangalore15 has detected H. pylori infection in 82% of 50 children (6 to 18 years of
age) by 13C urea breath test. The studies among adults have also shown a high prevalence of H.
pylori (78%).16,17
Environmental Factors
The major risk factor for H. pylori infection is the socioeconomic status of the family during
childhood, as reflected in the number of persons in a household (person to person transmission),
sharing of bed, sanitation and personal hygiene (feco-oral transmission). Over the years, as
the socioeconomic status has improved in developed countries, the prevalence of H. pylori in
younger generation has declined.18 The age related apparent increase in the prevalence (higher
in the older generation and lower in younger generation) in developed countries could best be
explained by the “birth cohort effect”. As the organism persists almost throughout life, those
who were born at the time of relatively poorer socioeconomic status have higher prevalence
of H. pylori than those who were born recently with a better socioeconomic status (birth cohort
effect). However, this “birth cohort” phenomenon is not seen in developing countries like India as
the improvement of socioeconomic and sanitary conditions are slower. In India, the prevalence
of H. pylori is similar in children and in adults as there is no “birth cohort effect”.
Transmission of Infection
Infants are rarely infected in the developed world due to passively transferred immunity from the
mother. However, in developing countries, like other enteric infections, H. pylori is common in
infants also. In a study from Bangladesh, H. pylori infection has been shown in 46% of 90 infants
studied.19
H. pylori transmission is primarily “person-to-person” via feco-oral, gastric-oral or oral-oral
routes. Children acquire infection mainly through feco-oral route as H. pylori has been cultured
from the stool’s of infected children.20 Gastric-oral route of transmission has also been recognized,
as regurgitation and vomiting are common in children. Other modes of transmission in children
are contaminated water and oral-oral route (by kissing and feeding of premasticated food).
Table 2.1: Sero-epidemiology of H. pylori in India

Graham et al13 Gill et al14
Age group Age group
N = 238 N = 340
3 to 10 years 60% 22% 0 to 4 years
11 to 15 years 50% 56% 5 to 9 years
16 to 20 years 84% 87% 10 to 20 years
12
Helicobacter Pylori in Children
VIRULENCE FACTORS
Virulence factors help the organism to establish itself in the gastric mucosa and to produce
disease in the host. Virulence factors of H. pylori may be divided into two groups; colonization
factors and factors responsible for tissue injury (Table 2.2). The colonization factors not only
help the organism to establish itself in the stomach but also help it to persist. With the help of
flagella the organism move fast from the lumen of the stomach, where pH is low, through the
mucus layer to an area where pH is neutral to permit optimal growth. The organism stays on the
surface of the epithelium, under the mucus layer and never invades the mucosa. The enzyme
urease makes the immediate environment alkaline by converting urea to ammonia. Adherence
factors help the organism to bind to specific receptor on the surface of the gastric epithelium.
Why only one in ten H. pylori infected persons develop peptic ulcer is not clear.21 However,
in addition to host factor, and environmental factors, the virulence of the organism plays an
important role. Lipopolysaccharides possesessndotoxic properties (basically endotoxins),
stimulate the release of cytokines. H. pylori elaborates a number of soluble surface proteins like
leukocyte recruitment and activating factors with chemotactic properties to recruit and activate
monocytes and neutrophils. Vacuolating cytotoxin (VacA) gene is present in all strains of H. pylori
but only about half of them express the mature toxin.22 The Vac A gene has two families of alleles;
the middle region (m1, m2) and the signal sequence (s1a, s1b, s2). Strains with the s2m2 genotype
produce little or no toxin, whereas s1m1 is strongly associated with toxin production and the
presence of Cag A. A study by Singh et al7 from Lucknow has shown that children with upper
abdominal pain have more frequent association with H. pylori strains with s1m1 alleles compared
to children without pain abdomen. It has been shown that the presence of Cag A is associated with
more severe inflammatory tissue injury and is more frequently associated with H. pylori related
disease than in asymptomatic gastritis cases of H. pylori.23 Initially it was suggested that Cag A
positive H. pylori was associated with peptic ulcer disease and with more severe inflammation.
However, recent studies in children have shown that Cag A and Vac A positive strains of H. pylori
are equally common in asymptomatic children.24,25
Table 2.2: Virulence factors of Helicobacter pylori

Promote colonization
1. Flagella
2. Urease
3. Adherence factors
Induce tissue injury
1. Lipopolysaccharide
2. Leucocyte recruitment and activating factors
3. Vacuolating cytotoxin (VacA)
4. Cytotoxin-associated antigen (Cag A)
13
CLINICAL FEATURES
Diseases caused by H. pylori? H. pylori is etiologically associated with chronic active gastritis,
duodenal ulcer, gastric ulcer, primary gastric B-cell lymphoma or mucosal associated lymphoid
type lymphoma (MALT lymphoma) and gastric adenocarcinoma. Fortunately other than chronic
gastritis, which is an asymptomatic condition, other diseases are infrequently seen in children
and that is why most children infected with H. pylori are asymptomatic. At present there is no
evidence to suggest a link between H. pylori gastritis and pain abdomen in the absence of ulcer
disease. Therefore recurrent abdominal pain (RAP) cases should not be investigated for H. pylori.
Growth retardation: The available evidence regarding H. pylori infection and its effect on growth
is controversial. Studies from Italy, Germany and USA have shown that H. pylori infection is
associated with growth delay especially in older children.26,27 However, other investigators have
suggested that growth suppression reported in children with H. pylori infection could be due to
socioeconomic, genetic and environmental factors.28–30 We need more information, especially
from developing countries where H. pylori infection is rampant in children, before telling that H.
pylori causes growth retardation.
Iron deficiency anemia in H. pylori infection: There is some suggestion that H. pylori causes iron
deficiency anemia (IDA) especially in adolescent girls without producing any hemorrhagic lesions
in the stomach or duodenum. Kostaki et al31 from Greece first reported that IDA in 3 children
improved only after H. pylori eradication. Subsequently a report from Korea32 on 937 children
has shown that H. pylori infection was more common in IDA children (35.5%) than in non-IDA
children (19.4%). Another report from Turkey33 on 140 children (6 to 16 years) has shown that iron
deficiency (ID) and iron deficiency anemia (IDA) improved completely after H. pylori eradication
without any iron supplementation. However, recent studies have reported no relationship
between H. pylori infection and IDA.34,35 In a relatively large cohort study on Bangladeshi children
has shown that IDA as well as ID improved equally with anti-H. pylori therapy plus iron compared
with iron therapy alone.35 The postulated mechanisms for IDA in H. pylori infection are: poor
absorption of iron due to low gastric acid secretion, poor dietary intake and consumption of iron
by the bacterium itself.
Recurrent Abdominal Pain (RAP) and H. pylori

The association of recurrent abdominal pain (RAP) and H. pylori is still debatable. There are
evidences for and against this association. Firstly, if this association is true then H. pylori
should be seen more frequently in RAP cases than in controls. Different studies from India and
elsewhere have shown that there is no significant difference of H. pylori prevalence between RAP
and controls (Table 2.3). Moreover, a study on 945 children from Germany36 and 695 children
from Sweden37 have shown that there is no positive association between H. pylori status and the
occurrence of pain abdomen, in fact there was an inverse association of H. pylori positivity and
pain abdomen.37
Secondly, if this association is true then after eradication of H. pylori symptoms should
14 disappear and with relapse, symptoms should reappear. Most intervention studies including
those from India, which are uncontrolled with no documentation of eradication (rather
Table 2.3: Association of recurrent abdominal pain (RAP) and H. pylori

Positive association
Study Number of children H. pylori +ve Response to treatment
Heldenberg et al 48
50 54% 85%
Kumar et al 3
33 43% 83%
Das et al6 65 77% 83%
Biswal et al 5
76 65% Most
Negative association
H. pylori positivity H. pylori positivity in
Study Number of children in RAP Controls P
O’Donhoe et al49 640 9.9% 18.2% NS
Chong et al 30
456 17% 10% <0.05
Bansal et al 8
57 23% 19% NS
Yoshida et al47 47 30% 27% NS
NS = not significant
symptomatic improvement was assumed as eradication) and follow-up (Table 2.3), have shown
that symptoms disappeared with treatment for H. pylori. As we know a substantial proportion
(30–70%) of cases with functional abdominal pain shows a placebo response with any form
of therapy, these uncontrolled intervention trials provide weak evidence of a causal relation
between H. pylori and abdominal pain. Oderda et al38 have treated H. pylori gastritis in children
with RAP and showed that symptoms resolved in the majority after eradication but recurred
only in 13% of children while H. pylori gastritis recurred in 73% of cases. In a recent study from
Germany, Bode et al39 have done a population based cross-sectional study on 1221 children and
showed that RAP was associated with single parents, family history of non-ulcer dyspepsia but
not with H. pylori. Similarly Ashorn et al40 in a double blind randomized placebo-controlled trial on
symptomatic response of H. pylori eradication in 20 children with RAP have shown that bacterial
eradication and healing of gastric inflammation does not lead to symptomatic relief of chronic
abdominal pain in children. A recent meta-analysis41 of 38 studies has found no association
between RAP and H. pylori infection in children. Considering everything, European Society for
Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) and North American Society
for Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN) in their latest evidence-
based guidelines42 for Helicobacter pylori infection in children have mentioned that there is
inadequate evidence supporting the causal link between H. pylori gastritis and abdominal
symptoms in the absence of ulcer disease. Therefore, diagnostic testing for H. pylori infection is
not recommended in children with functional abdominal pain.
INVESTIGATIONS
How to Diagnose H. pylori? 15
There are both invasive (requires endoscopy) and non-invasive tests for H. pylori (Table 2.4).43
For diagnosis invasive tests are used and to check eradication a non-invasive test is used. Among
Table 2.4: Sensitivity and specificity of various tests used in the diagnosis of H. pylori
Tests Sensitivity Specificity
Non-invasive
Serum serology 95% 85%
Saliva serology 90% 85%
Urea breath test 95–98% 95–98%
Stool antigen 88–95% 95–98%
Invasive tests requiring endoscopy
Rapid urease test (RUT) 75–100% 98%
Histology 66–100% 98%
Culture 90–95% 100%
PCR 95% 95%
the non-invasive tests, serology is unreliable in young children as antibody production is low in
them and a positive test cannot differentiate present and past infection as antibody persists for
some time after eradication. Similarly, 13C urea breath test is difficult to perform in <5 years age
group. So far “Gold standard” for the diagnosis of H. pylori is culture of gastric biopsy. However,
positive rapid urease test (RUT) in gastric biopsy with histopathology showing H. pylori is also
accepted as alternative to culture for diagnosis of H. pylori (concordant results of at least two
tests are needed to define the H. pylori infection status).42 To check eradication (four weeks after
stopping antibiotics and at least 2 weeks after stopping PPI therapy), 13C urea breath test is the
best (UBT). Recently it has been shown that stool ELISA test for H. pylori antigen (HpSA) is also a
good non-invasive test to check eradication. The first generation ELISA test (HpSA) is based on
polyclonal antibodies and is less accurate (sensitivity 92% and specificity 93%) than the second
generation ELISA test (HpStAR) which is based on monoclonal antibodies (both sensitivity and
specificity 97%). So-called rapid or office-based fecal tests (ImmunoCard STAT! HpSA) based on
an immunochromatography using monoclonal antibodies are less accurate (sensitivity 88%,
specificity 93%).44
Whom to investigate for H. pylori and how?

European Society of Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) and North
American Society of Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN)42 have
recommended that only those children should be investigated whose abdominal symptoms are
severe enough to suspect organic causes. Primary goal of clinical investigation of gastrointestinal
symptoms is to determine the underlying cause of the symptoms and not solely the presence of
H. pylori infection. Therefore, endoscopy is the preferred method of investigation (invasive tests)
and non-invasive tests have little role in the initial evaluation. They also recommended that the
diagnostic testing for H. pylori is not recommended in children with functional abdominal pain.
In children with first-degree relatives with gastric cancer, and also in children with refractory
16 iron-deficiency anemia in which other causes have been ruled out, testing for H. pylori may be
considered. However, there is insufficient evidence that H. pylori infection is causally related to
otitis media, upper respiratory tract infections, periodontal disease, food allergy, SIDS, idiopathic
thrombocytopenic purpura and short stature. Hence, these groups of children do not merit
testing for H. pylori infection.
TREATMENT
Whom to treat and with what drugs?
As per ESPGHAN and NASPGHAN guidelines42 in the presence of H. pylori–positive peptic
ulcer disease (PUD), eradication of the organism is recommended. However, when there is no
endoscopic lesion and H. pylori is positive then anti H. pylori treatment option should be offered.
Parents should be fully informed that eradication of H. pylori does not necessarily lead to any
change of symptoms. They should also be informed of the potential adverse effects of drugs
and should be given an option of refusing treatment. A “test and treat” strategy (the detection
of the presence of H. pylori infection by a non-invasive test followed by treatment in the case of
a positive test) is not recommended in children. In children who are infected with H. pylori and
whose first-degree relative has gastric cancer, treatment may be offered. Drugs used to treat
H. pylori are given in Table 2.5.
H. pylori Infection in Children and Gastric Adenocarcinoma in Adults

World Health Organization (WHO) has classified H. pylori as group I carcinogen for gastric
carcinoma and infected individual has two to eight times higher risk of gastric carcinoma than
general population.45 So should we detect H. pylori in children and eradicate them to prevent
gastric carcinoma in adults? There are many points against this view. There are regions where
prevalence of H. pylori is very high but the prevalence of gastric carcinoma is low like India
and Africa. On the other hand countries with high prevalence of gastric carcinoma have low
prevalence of H. pylori. In China with similar H. pylori prevalence, some regions have got low
and some regions have got high prevalence of gastric carcinoma. Although H. pylori prevalence
is equal in both male and female, the gastric carcinoma is much more common in males than
in females. All these epidemiological facts indicate the role of other environmental and genetic
factors in the causation of gastric carcinoma than H. pylori alone. Therefore, at present there is
no justification in treating childhood H. pylori to prevent gastric carcinoma in adults.46 However,
children whose first-degree relative has gastric cancer, H. pylori eradication is recommended.42
Table 2.5: Drugs and doses of various drugs used in the treatment of H. pylori infection in children
Drugs Doses Maximum doses
Amoxicillin 50 mg/kg/day 1 g bid
Clarithromycin 20 mg/kg/day 500 mg bid
Omeprazole (PPI) 1–2 mg/kg/day 20 mg bid
Metronidazole 20 mg/kg/day 500 mg bid
Bismuth subsalicylate 8 mg/kg/day 262 mg qid
Ranitidine bismuth citrate 1 tablet qid 17
qid: four times daily. bid: twice daily
Recommended Eradication Therapies for H. pylori Disease in Children

First line of treatment is twice daily triple drug regimen comprising one proton pump inhibitors
(PPI) and two antibiotics (amoxicillin plus clarithromycin or metronidazole) for 10 to 14 days.
Sequential therapy involves dual therapy with a PPI and amoxicillin for 5 days followed
sequentially by 5 days of triple therapy (a PPI with clarithromycin and metronidazole/tinidazole).
Studies in children have shown that sequential therapy is at least as effective as standard triple
drug therapy and is recommended as a first line treatment option.42
First Line Options

Triple Drug Regimen
1. Amoxicillin (50 mg/kg/day) + clarithromycin (20 mg/kg/day) + Proton pump inhibitor
(Omeprazole) (1–2 mg/kg/day)
2. Amoxicillin + metronidazole (20 mg/kg/day) + PPI
3. Bismuth salts (bismuth subsalicylate or subcitrate 8 mg/kg/day) + amoxicillin +
metronidazole
Sequential Therapy
PPI (1–2 mg/kg/day) + amoxicillin (50 mg/kg/day) for 5 days then PPI (1–2 mg/kg/day) +
clarithromycin (20 mg/kg/day) + metronidazole (20 mg/kg/day) for 5 days.
Check for eradication: Even when children become asymptomatic after treatment, it is
recommended that the success of treatment regardless of the initial endoscopic findings be
evaluated. Check for eradication of the organism should be done 4 to 8 weeks after completion
of treatment with reliable non-invasive tests like 13C-urea breath test or a monoclonal ELISA for
detection of H. pylori antigen in stool. A follow-up endoscopy is not routinely indicated unless
other causes of ulceration (e.g. eosinophilic gastroenteropathy, Crohn’s disease) are suspected or
if biopsies are needed for culture and antibiotics susceptibility testing.38
In case of treatment failure: ESPGHAN and NASPGHAN recommend38 that if first line of treatment
fails to eradicate the organism, there are 3 options; (1) Repeat biopsy and culture and sensitivity
testing, (2) FISH (fluorescence in situ hybridization) on previous paraffin-embedded biopsies
for clarithromycin susceptibility testing and (3) Modified therapy by adding an antibiotic, using
different antibiotic, adding bismuth, and/or increasing dose and/or duration of therapy.
Second Line or Salvage Therapy (up to 14 days)

1. Quadruple therapy: PPI + metronidazole + amoxicillin + bismuth
2. Triple therapy: PPI + levofloxacin (moxifloxacin) + amoxicillin
SUMMARY
Helicobacter pylori is a highly motile, gram-negative spiral organism which has a special affinity
18 for gastric mucosa and is etiologically associated with peptic ulcer disease (PUD) and gastric
cancer. However, the relationship between this organism and gastrointestinal complaints in
children is less clear. Helicobacter pylori infection is almost always acquired in early childhood.
The prevalence depends on socioeconomic status and is transmitted by feco-oral route and
direct contact. Almost half of the world’s population is infected with this organism and 80% of
Indian population get infected by 20 years of age. Though the prevalence of H. pylori is very
high, just 5% of children and 10% of adults infected with H. pylori develop PUD. The host genetic
factors, environmental factors and the virulence of the organism (Vac-A, Cag-A) determine the
outcome of infection. There is some suggestion that H. pylori causes iron deficiency anemia and
growth retardation but the evidences are not strong enough to justify screening for H. pylori in
these situations. There is no evidence to suggest a link between H. pylori infection and recurrent
abdominal pain (RAP). Also, there is insufficient evidence to causally link H. pylori infection to
otitis media, upper respiratory tract infections, periodontal disease, food allergy, SIDS, idiopathic
thrombocytopenic purpura. Endoscopy (with invasive tests like RUT, biopsy) is the preferred
method of initial investigation as primary goal is to determine the underlying cause of the
symptoms and not solely the presence of H. pylori infection. There is no role of non-invasive tests
(like serology, urea breath test or stool antigen tests) of H. pylori detection in the initial evaluation.
Children with H. pylori related diseases should be treated with standard “triple drug regimen”
comprising of PPI and two antibiotics for 10 to 14 days. However, sequential therapy with PPI
plus amoxicillin for 5 days followed by triple drugs (PPI+ clarithromycin+ metronidazole) for
5 days is as effective as triple drug therapy. Eradication should be checked in all treated patients
irrespective of their symptom status with non-invasive tests like 13C-UBT or stool antigen tests.
In endoscopy negative H. pylori positive cases: treatment option should be kept open.
Key Messages
1. H. pylori infection is common in children in India but most infected children are asymptomatic.
2. There is no association of H. pylori and functional abdominal pain (RAP).
3. Endoscopy (with invasive tests like RUT, biopsy) is the preferred method of investigation as primary goal is to
determine the underlying cause of the symptoms and not solely the presence of H. pylori infection.
4. There is no role of non-invasive method of H. pylori detection in the initial evaluation.
5. Children with H. pylori related diseases (peptic ulcer, primary gastric B-cell lymphoma and atrophic gastritis with
intestinal metaplasia) should be treated with standard “triple drug regimen” comprising of PPI and two antibiotics.
6. Sequential therapy with PPI plus amoxicillin for 5 days followed by triple drugs (PPI + clarithromycin + metroni-
dazole) for 5 days is as effective as triple drug therapy.
7. Eradication should be checked in all treated patients irrespective of their symptom status with non-invasive tests
like 13C-UBT or stool antigen test.
8. In endoscopy negative H. pylori positive cases: treatment option should be kept open.
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with Amoxycillin. Arch Dis Child. 1989;64:326–9.
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Helicobacter pylori in a community-based sample of London children. Acta Pediatr. 1996;85:961–4.
3
Recurrent (Chronic) Abdominal
Pain in Children
Bhaskar Raju
Chronic or recurrent abdominal pain is the commonest pain complaint the physician or
pediatrician is confronted with, in his out patient clinic.1-3 The term recurrent abdominal pain
was defined by Apley as pain of severity significant enough to disturb daily activities, occurring
at least 3 times over a 3-month period.4 The definition has stood the test of time, though the
term chronic abdominal pain (CAP) is now preferred and the original definition requiring
demonstration of distinct pain free intervals is no longer mandatory for a diagnosis of recurrent
abdominal pain (RAP).
Over the years physicians and pediatricians handling cases of CAP, were impressed by
their inability to identify an etiology for the pain, in spite of extensive investigations, even
when the pain is quite distressing. That led to the concept of a functional CAP with no organic
cause. Where pain was related to stress, environmental and probably familial factors.5-8 Thanks
to Apley’s1 descriptions of typical functional RAP case’s phenotype, it became fashionable to
diagnose functional RAP clinically without investigations (Table 3.1). In fact, even the descriptive
term RAP was, for a while accepted as Table 3.1: Apley’s typical FRAP phenotype
definitive diagnosis. Presently, however
History : Recurrent disorders
CAP wherein diligent investigations fail
Physique : Slightly underweight
to pick up any recognizable etiology
is referred to as Functional (Recurrent/ Intelligence : Normal
Chronic) abdominal pain (FRAP/FCAP). Psyche : Emotional disturbances
The phenotype description of a typical Personality : Timid, anxious, and over conscientious
FRAP patient is also no longer accepted. In family : Recurrent pains, nervous disorders
INCIDENCE AND PREVALENCE

Apley found an incidence of 10–15% among school going children and various studies after
that have also confirmed the high incidence of CAP in pediatric population.2 There is evidence
that almost as many do suffer CAP but do not complain or seek medical attention making the
problem of CAP even more common than what studies indicate. The marked differences in data
on CAP in different studies (0.3–20%) are due to choice of populations studied-hospitalized
patients, out patient clinics or school-based studies (Table 3.2).
Recurrent (Chronic) Abdominal Pain in Children
Table 3.2: Prevalence of RAP according to various studies

Name Ref Age-range Year Sample size Prevalence %
Apley 1 3–15 yrs 1957 1000 10.8
Faull 3 6 yrs 1986 439 11.0
Alfven 5 7–15 yrs 1993 1333 19.2
Groholt 6 2–17 yrs 1996 6040 0.3–6.4
Perquin 7 4–18 yrs 2000 5423 1.6–4.6
Bode 8 5–18 yrs 2003 1221 2.5
CLASSIFICATION
1970s Classification:
Organic (10%)
Psychogenic (90%)
1980s Classification:
Organic (20%)
Dysfunctional RAP (75%)
RAP due to Psychiatric Pathology (5%)
To clear the existing confusion in defining all functional GI disorders (FGIDs), experts in the field
met in Rome in 1999, and again in 2006, to publish what is now known as Rome criteria II and III
for all functional abdominal disorders. Rome III (2006) (Table 3.3) divides FGIDs in pediatrics into
Type G for neonates and toddlers and Type H or older children and adolescents. It reduced time
duration to 2 months, did away with requirement for symptom-free interval and also introduced
many new functional disorders like postprandial distress syndrome, functional dyspepsia, etc.
Table 3.3: Functional GI disorders as per Rome III
Infants/toddlers34 Child/adolescent35
G1. Infant regurgitation H1. Vomiting and Aerophagia
G2. Infant rumination syndrome H1a. Adolescent rumination syndrome
G3. Cyclic vomiting syndrome H1b. Cyclic vomiting syndrome
G4. Infant colic H1c. Aerophagia
G5. Functional diarrhea H2. Abdominal pain-related FGID
G6. Infant dyschezia H2a. Functional dyspepsia
G7. Functional constipation H2b. Irritable bowel syndrome
H2c. Abdominal migraine
H2d. Childhood functional abdominal pain
H2d1. Childhood functional abdominal pain syndrome
H3. Constipation and incontinence
H3a. Functional constipation
H3b. Nonretentive fecal incontinence
23
Diagnostic Criteria as per Rome III

H2a. Diagnostic Criteria* for Functional Dyspepsia
Must include all of the following:
1. Persistent of recurrent pain or discomfort centered in the upper abdomen (above the umbilicus).
2. Not relieved by defecation or associated with the onset of a change in stool frequency or
stool form (i.e. not irritable bowel syndrome).
3. No evidence of an inflammatory, anatomic, metabolic, or neoplastic process that explains the
subject’s symptoms.
H2b. Diagnostic Criteria* for Irritable Bowel Syndrome

1. Abdominal discomfort (an uncomfortable sensation not described as pain) or pain associated
with 2 or more of the following, at least 25% of the time:
a. Symptom improved with defecation
b. Onset associated with a change in frequency of stool (4 or more stools per day and 2 or
less stools per week)
c. Onset associated with a change in form (appearance) (Lumpy/hard or loose/watery stool)
of stool
H2c. Diagnostic Criteria† for Abdominal Migraine10,11

1. Paroxysmal episodes of intense acute periumbilical pain that lasts for 1 hour or more.
2. Intervening periods of usual health lasting weeks to months.
3. The pain interferes with normal activities.
4. The pain is associated with 2 or more of the following: anorexia, nausea, vomiting, headache,
photophobia, pallor.
H2d. Diagnostic Criteria* for Childhood Functional Abdominal Pain

1. Episodic or continuous abdominal pain.
2. Insufficient criteria for other functional gastrointestinal disorders.
24
H2d1. Diagnostic Criteria* for Childhood Functional Abdominal Pain Syndrome

Must include childhood functional abdominal pain at least 25% of the time, and 1 or more of the
following:
1. Some loss of daily functioning
2. Additional somatic symptoms such as headache, limb pain, or difficulty in sleeping
H1c. Diagnostic Criteria* for Aerophagia

Must include at least 2 of the following:
1. Air swallowing
2. Abdominal distension due to intraluminal air
3. Repetitive belching and/or increased flatus.
* Criteria fulfilled at least once per week for at least 2 months before diagnosis; †Criteria fulfilled 2 or more times in the
preceding 12 months.
Approach to a Case of CAP

Given the myriad causes of CAP, it helps to slot children presenting with CAP into one of the
following, to narrow down diagnostic possibilities and investigations ordered.
CAP with
• Isolated paroxysmal peri-umbilical chronic abdominal pain
• Chronic abdominal pain with dyspepsia
• Chronic abdominal pain with altered bowel habits.
Functional CAP can present with any of the above presentations and whatever the
presentation, it is still the commonest cause. The probability of organic causes causing CAP
however, will be more with certain type of presentations and such classification will help narrow
the cases that need search for organic causes.
Isolated paroxysmal periumbilical abdominal pain
Functional abdominal pain 95% Organic abdominal pain <5%

Important causes
– Malrotation
– Renal colic
– Adhesions
– Abdominal epilepsy
Other causes of isolated paroxysmal abdominal pain are given in Table 3.4.
25
Table 3.4: Other causes of isolated paroxysmal abdominal pain

Obstructive disorders
– Crohn disease
– Malrotation with or without volvulus
– Intussusception with lead point
– Postsurgical adhesions
Small bowel lymphoma
Endometriosis
Infection (Tuberculosis, Yersinia)
Vascular disorders
Eosinophilic gastroenteritis
Angioneurotic edema
Appendiceal colic
Dysmenorrhea
Musculoskeletal disorders
Ureteropelvic junction obstruction
Abdominal migraine
Acute intermittent porphyria
Mental disorders (factitious disorder, conversion reaction, somatization disorder, school phobia)
Functional abdominal pain13
CAP with dyspepsia
Functional abdominal pain 90% Organic abdominal pain 10%

Important causes
– GERD
– PUD
– H. pylori
– Giardiasis
– Pancreatitis
– Cholecystitis
Other Causes of RAP with Dyspepsia

Associated with upper gastrointestinal inflammation
• Gastroesophageal reflux disease
• Peptic ulcer
• Helicobacter pylori gastritis
• Nonsteroidal anti-inflammatory drug ulcer
• Crohn disease
• Eosinophilic gastroenteritis
26 • Ménétrier disease
• Cytomegalovirus gastritis
• Parasitic infection (Giardia, Blastocystis hominis)
• Varioliform gastritis
• Lymphocytic gastritis/celiac disease
• Henoch-Schönlein purpuras
Motility disorders
• Idiopathic gastroparesis
• Biliary dyskinesia
• Intestinal pseudo-obstruction
Other disorders
• Chronic pancreatitis
• Chronic hepatitis
• Chronic cholecystitis
• Ureteropelvic junction obstruction
• Abdominal migraine
• Psychiatric disorders.13
RAP with altered bowel habits
Functional abdominal pain 75% Organic abdominal pain 25%

Important causes
– Simple constipation
– Inflammatory bowel disease
– Koch’s abdomen
– IBS
– Immunodeficiency syndromes (IgA)
– HIV
Idiopathic inflammatory bowel disorders
• Ulcerative colitis
• Crohn disease
• Microscopic colitis with crypt distortion
• Lymphocytic colitis
• Collagenous colitis
Infectious disorders
• Parasitic (Giardia, Blastocystis hominis, Dientamoeba fragilis)
• Bacterial (Clostridium difficile, Yersinia, Campylobacter, Tuberculosis)
• Lactose intolerance
• Complications of constipation (megacolon, encopresis, intermittent sigmoid volvulus)
• Drug-induced diarrhea, constipation
• Gynecologic disorders
• Neoplasia (lymphoma, carcinoma)13
Pathogenesis of Functional Abdominal Pain 27
Functional abdominal pain wherein no organic cause can be identified is genuine pain. While in a
few cases the motivation for pain complaint may be to avoid unpleasant experience or modeling
of parental pain, in the vast majority it is genuine pain whose etiology is still poorly understood.
Enough evidence however has accumulated to suggest that it is a disorder of the extensive Gut-
Brain axis. Elaborate connections exist between the gut and the brain and it is no surprise that
both can influence each other in a major way. Two factors have been described as of primary
importance in the perception of pain in functional RAP are:
• Visceral hypersensitivity
• Altered intestinal motility14
Visceral hypersensitivity, otherwise known as augmented visceral perception, refers to the
ability of FCAP children to feel events in the gut that are generally imperceptible to normal children.
Afferent impulses from gut processed through Meissner’s plexuses are filtered to a variable extent
at the level of the hypothalamus (Hypothalamic Gate) and only limited impulses go up to cortex
for perception. This is how most routine impulses generated in the gut are not felt as events,
painful or otherwise. Physiological events like peristaltic and non-propulsive contractions of the
small and large bowel, postprandial gastric and intestinal distension/contractions, intestinal gas
are often felt by FCAP children as dyspepsia or pain. Quasi-pathological problems like lactose
intolerance,15 cows milk protein intolerance,44 simple constipation and aerophagia can also
initiate sensation of pain through distension of bowel.16-18
Evidence for such augmented visceral perception comes from enhanced awareness of
balloon distension of rectum, and demonstrable pain associated with intestinal migrating
motor complexes.19,20 Involvement of the autonomic nervous system in FCAP is indicated by the
presence of headaches, vomiting, pallor, dizziness motion sickness and temperature intolerance
in almost a third of patients with FCAP. This further buttresses the concept of disordered enteric
nervous system playing a major role in perception of pain in FCAP. Autonomic testing too is often
abnormal in these patients.21
Along with augmented visceral perception, FCAP children have significantly increased
contractions of the gut—both peristaltic and non-peristaltic. The increased contractile activity
is seen both in amplitude and length are attributed to impulses from the brain often triggered
by environmental factors. Levine’s hypothesis tries to understand this phenomenon of increased
cortical stimulation of the gut musculature through his conceptual model, which attributes
several environmental factors triggering cortical stimulation of increased gut activity22 (Fig. 3.1).
Lifestyle and habits refer to the role of active lifestyle and regular habits esp. eating and toilet
habits significantly reducing incidence of FCAP. Sedentary lifestyle and irregular eating and
bowel habits, substance abuse and addictions predispose to FCAP.
• Temperament and learned responses: Children who are petted and pampered and have grown
up with little disciplining, handle discomfort and disappointment poorly. Secondary gain can
make such children exaggerate discomfort to pain.
• Somatic predisposition refers to the frequent finding of “Pain Families”. While some of the pain
in such families can be modeling, there seems to be definite predisposition for FCAP to show
a familial occurrence.9,12
Milieu and critical events: Many events in a child’s life could be of intense stress besides
exams. Loss of a friend, change of school, family tragedies can heighten the child’s perception of
28 discomfort and induce painful contractions of the bowel.
Summarizing, the presently accepted concept of functional CAP suggests that environmental
and lifestyle factors cause abdominal pain in a susceptible population of children. The susceptible
Fig. 3.1: Environmental factors and cortical stimulation of increased gut activity
population is characterized by a heightened cortical sensitivity to afferent stimuli originating

from gut.
Approach to Case of RAP

When a child presents with symptom of abdominal pain, a structured approach to identify the
etiology should be adopted. It includes:
A detailed history that includes all details of:
• Pain
– Its relationship to food and defecation
– Nocturnal pain
– Radiation
– Localization, if any
– Dysphagia
– Heartburn
• Bowel movements
• Dyspepsia/Bloating/Early satiety
• Headaches/Photophobia/Giddiness
• Weight loss
• Fevers/Fatigue/Muscle pains
• Disturbance of daily activities
• H/O Medications
• Mental health/Life stresses/Depression
• Menstrual history/Sexual activity, if any.
Complete and Diligent Physical Examination
In particular, take care not to miss 29
• RIF/Epigastric tenderness
• Any organomegaly
• Loaded colon
• Spastic sigmoid
• Visible peristalsis
• Rashes/Purpura
• Bone tenderness
• Any spinal lesions
Typical pain pattern in functional pain
• Paroxysmal with variable severity
• Clustering of pain
• Gradual onset
• Usually periumbilical, occasionally epigastric
• Poor relationship to food, defecation
• Inability to clearly describe nature or location of the pain.
May be associated with other symptoms like pallor/nausea/fatigue/anxiety
• In about 10% of the cases.
Typical pain pattern in organic pain (Red Flag Symptoms/Signs)
• Clearly localized pain (away from the umbilicus)
• Radiating pain
• Well-defined pain (burning, stabbing, etc.)
• Pain awakening the child at night
• Pain with fever
• Pain with weight loss
• Tenderness/organomegaly
• Blood in stools (occult and obvious)
• Altered bowel movements
• Anemia
• Urinary symptoms
• ESR/CRP
• Arthralgia/Rash/Purpura.
Besides detailed history and physical exam, case of RAP requires evaluation of the:
• Child’s interpersonal relationship with the rest of family especially parents, sibs, grand parents
and friends
• Child’s immediate emotional environment in school and home
• Child’s Personality
• Child’s response to discomfort and pain
• Sociability
• School performance, etc.
They would throw light on stress factors that may or may not be obvious to parents or care
givers.
Detailed history and a diligent physical exam should normally be sufficient to make a diagnosis
of functional CAP and many experienced pediatricians do not insist on any investigations to
30 confirm the diagnosis of FCAP. However, much of treatment of functional CAP depends on the
rapport one establishes with the child and family and much of that rapport depends on the
seriousness with which the physician approaches the problem. Investigations are one way of
reassuring the family and the child that his/her complaint is being taken seriously. Further, it
is not unusual for some common (GERD) and some uncommon (HSP/Porphyrias23) causes of
CAP to be missed on clinical exam. Hence, a structured investigatory approach is needed in all
cases wherein CAP is diagnosed and the pain is found disturbing enough to be brought to the
attention of the physician.
Level I: Investigations
All cases of CAP must go through the following investigations:
• Complete hemogram
• S Amylase/S Lipase/Liver and renal function tests
• Stool, urine analysis
• Screening for TB
• Skiagrams of chest and abdomen (Optional)
• USG–abdomen.
Generally, the above should be adequate for >80% of cases that report to out patient
department with complaints of CAP since most will show no abnormality in the investigations or
be obvious clinically as FCAP. In selected cases one may need to resort to further investigations.
Level II: Investigations

Indications
Presence of red flag signs/symptoms with strong clinical suspicion of organic cause for pain.
Persistent and severe pain in clinically suspected FCAP under adequate therapy.
Investigations should include:
• Contrast studies on the GI tract
• Upper GI scopy with biopsies of cardia, antrum, and duodenum
• Colonoscopy.
Persistent dyspepsia, vomits, epigastric pain and tenderness would merit UGI endoscopic
evaluation. Diarrheas esp. with mucus and/or blood, evidence of gastrointestinal bleeding, occult
or overt, involuntary weight loss or growth deceleration, iron deficiency anemia, suspected cows
milk protein allergy, elevated acute-phase reactants (sedimentation rate, C-reactive protein),
extraintestinal symptoms suggestive of inflammatory bowel disease (fever, rash, joint pains,
recurrent aphthous ulceration) would merit colonoscopic evaluation and/or a Barium enema.13
In a small percentage of cases wherein there is persistence of troublesome pain and/or other
red flag signs, with no organic cause made with the above protocol, one may have to resort to
level III investigations.
Level III: Investigations

• EEG to R/O abdominal epilepsy/cyclical vomiting syndrome.
Investigations to R/O
• Porphyrias 31
• Collagen vascular disorders
• Lead poisoning
• Lactose intolerance
• Food allergy
• Motility disorders.
Generally, speaking such extensive work up should pick up a diagnosis in most, if not all
causes of CAP in pediatric practice. Still experience tells us some causes if not looked for diligently
and with strong suspicion, can still be missed and the child be dubbed FCAP even though it has
an organic cause for the pain. They include:
• GERD
• H. pylori gastritis/duodenitis
• Chronic constipation
• Chronic appendicitis/appendicular colic24, 25
• Giardiasis/Pin worms
• Leukemias (Bone Pain)
• Hernias (Linea alba)
• Spinal lesions (Discitis)26.
One should diligently rule out the above, before a final diagnosis of FCAP is made.
Management of Recurrent Abdominal Pain

Wherever a recognizable organic cause for the abdominal pain is identified it will need
appropriate treatment for the same. It is beyond the scope of this chapter to deal with them.
Hence, we will discuss only management of the commonest and probably the most difficult CAP
to treat—functional CAP.
Management Includes:
• Make a positive diagnosis
• Explain the suspected pathophysiology and the cause for pain
• Establish goals of therapy and explain complete relief of pain is not one of them
• Identify and modify triggers
• Physical/psychological stress factors
• Diet
• Drug therapy in selected cases
• Active psychological support.
Avoid as much as possible
• Hospitalization
• Psychiatric consults.
Make a Positive Diagnosis
Making a positive diagnosis of FCAP when all investigations are normal and explaining the
pathophysiology to parents and to the extent possible to the child, is a major part of management
of functional CAP and often the only part. In many cases, all that we are able to offer the child as
part of treatment is just reassurance that there is nothing physically wrong with him/her and he/
32 she will mostly get over the problem by puberty or earlier. The other point to be emphasized to
parents is that, once the child is made to understand and accept this, the pain relief is earlier and
more complete, since the stress contributed by the pain itself is reduced.
Goals of Therapy
The major and the only goal of therapy is to normalize lifestyle and not allow the pain to curtail
either the daily activities or achievement expectations from the child. Attainable goals would
include:
• Normal school attendance
• Scholastic and extracurricular performances to the child’s potential
• Normal growth pattern
• Normal sleep pattern.
Identify and Assuage Stress and Trigger Factors
Many of the known factors that trigger and sustain pain in FCAP were discussed earlier and they
need to be addressed and some can be removed and others modified enough to reduce its impact
on the child’s gut. Greater success would be obtained from abolishing secondary gain from pain
by preventing the child from using the pain to avoid unpleasant but essential responsibilities.
A talk with teachers and school authorities not to panic over the pain but to respond to it with
reasonable care and attention is a big part of treatment. The child may be allowed to rest at
school till the pain abates and not be sent home every time he/she complains of pain. Similarly,
the family and immediate society around the child must be encouraged to be supportive and
sympathetic to the child’s complaints but not go overboard with undue over-reactions, which
may make the child believe he/she has a major disease and/or lead to secondary gain behavior.
Diet
Diet has very little role in modifying pain though, avoiding carbonated and sweetened drinks,
high carbohydrate diets, milk and milk products and diet containing complex carbohydrates that
may escape digestion and generate gas in the colon, may help. Timely meals and a balanced diet
would translate to better lifestyle and general sense of well-being that would help reduce the
pain and increase capacity of the child to handle it.
Drug Therapy
True FCAP does not need any drugs and drug therapy is often useless. Antispasmodics may be
judiciously used to relieve severe pain, remembering that, they may predispose to constipation—
another major cause of CAP. Documented acid peptic disease will benefit from anti-acid therapy.27
H. pylori if identified will create a dilemma with reports suggesting good response to therapy and
with equal reports refuting its benefits.28 High incidence of H. pylori positivity in the third world
and the high incidence of re-infection make decision regarding benefits of therapy for H. pylori
difficult. High incidence of giardiasis in many Indian studies would make the use of a course of
metronidazole in all cases of CAP a worthwhile idea.29‑31
Other drugs/modalities that may have a role in FCAP include moderate fiber diet (Child’s
age + 5 gm per day) prokinetics, mineral oil/PEG/Lactulose/esp. in constipation predominant IBS
with CAP. Antimotility agents are generally not advised unless there is disturbing diarrhea with
FCAP. Enteric-coated peppermint oil has found anecdotal benefit in some cases of FCAP.32 33
Abdominal migraine, if suspected will benefit from Cyproheptadine and Propranolol.33,34
Drugs like 5HT receptor antagonists, which have been found useful in adults with pain,
predominant IBS have not been tried in FCAP in children. They include Alosetron (5HT3 antagonist)
in diarrhea predominant IBS35 and Tegaserod (5HT4 agonists) in constipation predominant IBS.36
Psychiatric Help
As a rule FCAP responds badly to psychiatric consults and children with FCAP and parents react
badly to suggestion that psychiatric pathology may be responsible for the pain. However, some
situations do need psychiatric help and they are best obtained from a psychiatrist with pediatric
experience. Such situations include:
• Conversion reaction
• Anxiety, depression
• Low self esteem
• Maladaptive family
• Modeling/Imitating family pain behavior
• Poor response to conservative therapy.
Whenever psychiatric help is needed, it is ideally done as a part of a multidisciplinary approach.
Other modalities of psychological therapy include cognitive behavioral therapy, which aims to
help the child accept his pain as not indicative of impending or existing disease and to lead
socially active lives. Some reports of success with this approach are available.37‑39 While short-term
success was not different from conservative management, long-term pain relief was attained in a
higher (56% vs. 24% at 6 months and 59% vs. 37% at 12 month follow-up) percentage of children
who underwent cognitive behavioral therapy.
Hospitalization is ideally avoided in children with FCAP since it is likely to reinforce pain
behavior.
Prognosis
A significant section of children with FCAP have complete relief of pain within 6 to 8 weeks of
diagnosis indicating the role of a positive diagnosis of FCAP. Many do get recurrences of pain but
handle it better without affecting their daily activities. In 30–50% of children the pain follows
them into adult life, though 70% of such adults do not allow the pain to affect their daily life
activities.40-42 A third of them develop other chronic complaints like headaches, back pains, and
menstrual abnormalities.
Apley described some useful prognostic factors that suggest possibility of persistence of
pain into adulthood.43
• Male sex
• Onset of pain before 6 years
• More than 6 months of pain by the time medical relief is sought and FCAP as a diagnosis is
established.
• Strong family history of pains.
Key Messages
34 1. CAP is a common problem in school going children.
2. Most cases of CAP in childhood are functional abdominal pains.
3. Functional abdominal pain is genuine pain caused by centrally driven (stress induced) spasmodic intestinal
contractions and heightened visceral hypersensitivity.
4. Approaching CAP as, CAP where pain is isolated and periumbilical, CAP with dyspepsia, and CAP with altered
bowel habits helps in differential diagnosis.
5. Complete clinical examination, looking diligently for red-flag signs is essential.
6. A structured set of investigations is advised. Level I for all CAPs. Level II for CAP with redflag signs and Level III for
recalcitrant cases.
7. Treatment is mostly reassurance and help with coping with pain. Complete pain relief is not one of the aims of treatment.
8. Prognosis in functional CAP is good with most children outgrowing their pain, though a small subset will continue
to have functional pain well into adulthood.
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18. Pineiro-Carrero VM, Andres JM, Davis RH, et al. Abnormal gastroduodenal motility in children and 35
adolescents with recurrent functional abdominal pain. J Pediatr. 1988;113:820–5.
19. DiLorenzo C, Youssef NN, Sigurdsson L, et al. Visceral hyperalgesia in children with functional abdominal
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20. van Ginkel R, Voskuijl WP, Benninga MA, et al. Alterations in rectal sensitivity and motility in childhood
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21. Chelimsky G, Boyle JT, Tusing L, Chelimsky TC. Autonomic abnormalities in children with functional
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35. Lembro T, Wright RA, Lotronen Investigator Team, et al. Alosetron controls bowel urgency and provides
global symptom improvement in women with diarrhea-predominant irritable bowel syndrome. Am J
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37. Sanders MR, Rebgetz M, Morrison M, et al. Cognitive-behavioral treatment of recurrent nonspecific
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38. Sanders MR, Shepherd RW, Cleghorn G, Wolford H. The treatment of recurrent abdominal pain in
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40. Walker LS, Garber J, van Slyke DA, Greene JW. Long-term health outcomes in patients with recurrent
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41. Magni G, Pierri M, Donzelli F. Recurrent abdominal pain in children: a long-term follow-up. Eur J Pediatr.
1987;146:72–4.
42. Campo JV, DiLorenzo C, Chiapelta L, et al. Adult outcomes of pediatric recurrent abdominal pain: do
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36 43. Apley J, Hale B. Children with recurrent abdominal pain: how do they grow up? BMJ 1973;3:7–9.
44. Miguel Saps, Peter Lu, and Silvana Bonilla Cow’s-Milk Allergy Is a Risk Factor for the development of
FGIDs in children
4
Recent Trends in the Management
of Acute Watery Diarrhea in Children
Shinjini Bhatnagar, Nitya Wadhwa
Diarrhea is responsible for 15% of the 10.5 million deaths among children less than 5 years old in
all developing countries.1 In India, diarrhea constitutes 13% of all common illnesses in children
under 3 years of age.2 The ideal recommended management of diarrhea is use of WHO ORS for
treating dehydration and maintaining hydration, restricted antimicrobial use and continued
feeding with energy dense feeds. In the last few years extensive research done in India and other
similar settings has led to significant changes in the treatment of acute watery diarrhea.
NEW REDUCED OSMOLARITY ORS

WHO Expert Group (2001) recommended that reduced osmolarity ORS with 75 mEq/l of sodium
and 75 mmol/l of glucose (osmolarity 245 mOsm/l) should be the universal solution for all causes
of diarrhea and at all ages. These recommendations were endorsed by the National Task Force of
the Indian Academy of Pediatrics (2003, 2006). The new formulation was approved by the Drug
Controller of India and was introduced in the National DiarrheaI Disease Control Programme by
the Government of India in June 2002.
COMPOSITION OF REDUCED OSMOLARITY ORS

Component Concentration (mmol/l)
Sodium 75
Chloride 65
Potassium 20
Citrate 10
Glucose 75
Osmolarity 245
Why was there a Need for a New ORS Formulation?

The standard WHO ORS with a sodium concentration of 90 mEq/L (glucose 110 mmol/l, osmolarity
311 mOsm/l), was evolved based on the stool electrolyte composition in toxin-mediated diarrhea.
Over the last 30 years this ORS has worked well even in young children with non-cholera diarrhea
when used, according to the recommended guidelines, with plain water given ad-libitum. Initially,
the main concern among pediatricians with use of standard WHO-ORS was the potential risk of
hypernatremia in children with non-cholera diarrhea and the increased incidence of recurrent
dehydration in young infants that was reversed when patients were kept fasting and on
intravenous fluid regimens. Further, it was also perceived that use of oral rehydration solution in the
treatment of diarrhea reduces the risk of diarrheal mortality through prevention and treatment of
dehydration but does not decrease diarrheal duration or stool output. It prompted care givers and
physicians to prescribe irrational antimicrobial and antidiarrheal therapy. The above concerns and
results from laboratory experiments that showed water and sodium is absorbed more efficiently
from reduced osmolarity solutions (sodium 60 mmol/l, glucose 80–120 mmol/l, osmolarity
240 mOsmol/l) than the standard WHO-ORS lead to the clinical evaluation of reduced osmolarity
oral rehydration salts solutions in many large double blind randomized clinical trials.
Efficacy of the New Reduced Osmolarity ORS in non Cholera Diarrhea

Most of the evidence comes from twelve large randomized trials that evaluated reduced
osmolarity3 ORS solutions containing glucose, maltodextrin or sucrose (total osmolarity 210–268
mOsmol/l) and a sodium concentration ranging from 50–75 mEq/l. These studies were conducted
mainly in developing countries and included both well-nourished and malnourished children
aged 1 month to 5 years, with acute diarrhea (<7 days) and dehydration. It is important to note
that four of the studies were done in India, two as part of large multi-center trials. The results of
a meta-analysis of these trials showed that use of reduced osmolarity ORS was associated with
a significant 39% (95% CI 19%, 53%), reduction in need for intravenous fluids, 19% (12%, 26%),
reduction in stool output and 29% (8%, 45%) lower incidence of vomiting as compared with the
standard WHO ORS, (sodium 90 mEq/L glucose 110 mmol/l, osmolarity 311 mOsm/l). The need
for intravenous fluids is considered an important outcome measure as in many peripheral health
facilities, where IV therapy may not be available; reducing the need for unscheduled IV therapy
would reduce the risk of death from dehydration.
Efficacy of the New Reduced Osmolarity ORS in Cholera Diarrhea

Reduced osmolarity ORS was found to be as effective in adults with cholera (no statistically
significant differences in the stool output between groups receiving reduced osmolarity or
standard WHO ORS). Although, evaluated in a small number of children with cholera, there was a
30% reduction in the initial 24 hour stool output with reduced osmolarity ORS.4
Is Reduced Osmolarity ORS Safe?

The incidence of hyponatremia (serum sodium <130 mEq/l) at 24 hours among children with
non cholera diarrhea given reduced osmolarity ORS was marginally greater as compared to the
standard WHO ORS.3,4 However, these differences were not statistically significant and none of
these children were symptomatic.
The safety data in patients with cholera, while limited, are reassuring. In the pooled data4
of all studies with cholera diarrhea in children there was a small reduction (mean difference
0.8 mEq/l, 95% CI: 0.6 to 1.0) in mean serum sodium at 24 hours in patients receiving reduced
38 osmolarity ORS (sodium 70-75 mEq/l, glucose 75-90 mmol/l, osmolarity 245-268 mOsm/l)
when compared with those given standard WHO ORS. This was similar to results seen in adults
Recent Trends in the Management of Acute Watery Diarrhea in Children
with cholera, who had a small, but statistically significant reduction in mean serum sodium of
1.3 mEq/l (95% CI: 0.3 to 2.3) at 24-hours in those treated with reduced osmolarity ORS (sodium
75 mEq/l, glucose 75 mmol/l, with an osmolarity of 245 mOsm/l). None of these patients who
developed hyponatremia became symptomatic.
Zinc in Diarrheal Diseases

Zinc deficiency is common in children from developing countries due to lack of intake of animal
foods, high dietary phytate content, which limits zinc absorption, and inadequate food intake.5
There are also increased fecal losses of zinc during diarrhea which aggravates pre existing zinc
deficiency.6,7 The initial evidence that low plasma zinc was associated with increased severity
of diarrhea came from observational studies.8,9 A large body of evidence shows that zinc
supplementation reduces morbidity from diarrhea in high risk populations. Convincing evidence
of zinc supplementation given during a diarrheal episode on therapeutic benefits comes from
large randomized placebo controlled studies. Over the last 5–6 years10,11 majority of the studies
were conducted in South East Asia, in subjects’ aged between 6 months and 3 years, and the
daily elemental zinc dose ranged from 10 to 30 mg per day. The pooled analysis has shown
that zinc supplemented children had 16% faster recovery (95% CI 6–22%) with a 34% reduction
(95% CI 17–48%) in the acute episodes lasting more than 7 days. Additionally, in the zinc treated
children, the total stool output was reduced by 31% (95% CI 1–52%) as compared to the placebo
group. This is an important finding as stool output is the most objective marker of severity and
a useful proxy indicator for risk of dehydration, in hospitalized children with acute diarrhea and
dehydration.12 The three different zinc salts evaluated zinc sulfate, zinc acetate or zinc gluconate
have been found to be equally effective. Further the significant beneficial effects on morbidity
were not restricted to children with low baseline concentrations of plasma or serum zinc. There
was little gain in efficacy when the commonly used 20 mg daily dose of elemental zinc was
increased to 30–40 mg daily.10-13 Some studies also reported reduction in diarrhea morbidity in
the subsequent 2–3 months without further supplementation.10
Effect of providing daily zinc for 14 days to children with diarrhea as part of the diarrhea
treatment program in the community using a cluster randomized design was evaluated in
Bangladesh.14 There was a 24% shorter duration (95% CI 0.65–0.90) and 15% lower incidence
of diarrhea (95% CI 0.76–0.96) in the zinc cluster than those in the comparison group. The zinc
treated cluster had a 24% (95% CI 0.59–0.98) lesser rate of admission to hospital of children with
diarrhea and 51% (95% CI 0.25–0.94) lower mortality due to noninjury deaths, notably diarrhea
or pneumonia.
Zinc was also found to have significant therapeutic effects in persistent diarrhea by decreasing
duration of episodes, lowering stool frequency and resulting in a 42% reduction of treatment
failures or deaths.10
Therapeutic benefits of zinc administration during diarrhea are biologically plausible because
of its effects on various components of the immune system and its direct gastrointestinal
effects. Zinc affects various immune mechanisms and modulates host resistance to several
pathogens.15 Zinc deficiency is associated with lymphoid atrophy, decreased cutaneous delayed 39
hypersensitivity responses, lower thymic hormone activity, a decreased number of antibody
forming cells, impaired T killer cell activity and differentiation of CD4 response towards Th1
rather than Th2 pathway. Zinc is said to improve absorption of water and electrolytes by helping
in early regeneration of intestinal mucosa, and restoration of enteric enzymes. Zinc deficiency
enhances secretory response to cholera toxin, and alters intestinal permeability, which is reversed
by supplementation.
Should Zinc be Mixed with ORS?

Currently there are no recommendations for mixing zinc with ORS for the global or national
diarrhea control program. Zinc (mixed with ORS) is consumed over a period of time making it
difficult to ensure a standardized zinc exposure during a diarrheal episode.
WHO, IAP and Govt of India Recommendations for use of Zinc as an Adjunct to
ORS in the Treatment of Diarrhea
WHO Task Force (2001) reviewed all the evidence available and recommended that 20 mg (once
or in two divided doses) per day should be given for 10–14 days starting as early as possible
after onset of diarrhea.11 Any of the three zinc salts, e.g. sulphate, gluconate or acetate may be
recommended. These recommendations were endorsed by Indian Academy of Pediatrics (2003
and 2006)16 and the Govt of India (2007). It is emphasized that ORS remains the mainstay of
therapy during acute diarrhea and zinc has an additional benefit in the reduction of stool volume
and duration of diarrhea as an adjunct to ORS.
There is little evidence on the efficacy of zinc during diarrhea in children less than 6 months,
including young infants, and ongoing trials will allow clearer interpretation of its role. Currently
for infants aged 2–6 months, 10 mg per day of elemental zinc is recommended.
The present WHO and the Govt of India strategy to focus on introduction of zinc along with
reduced osmolarity ORS in the current case management of diarrhea is an important step in
public health. The administration of zinc with oral rehydration salts for diarrhea in the program
settings has resulted in increased use of these salts, decreased use of antimicrobials and
antidiarrheals, and reduction in hospital admissions.17
Lack of Evidence to use Probiotics and Antisecretory Drugs in

Treatment of Diarrhea Probiotics
There is presently insufficient evidence16 to recommend probiotics in the treatment of acute
diarrhea in our settings as almost all the studies till now were done in developed countries. It may
not be possible to extrapolate the findings of these studies to our setting where the breastfeeding
rates are high and the microbial colonization of the gut is different. The effect of probiotics is
strain related and there is paucity of data to establish the efficacy of a single strain available in
the Indian market. The earlier studies have documented a beneficial effect on rotavirus diarrhea
which was present in more than 75% of cases in studies from the west. Rotavirus constitutes
about 25% of diarrhea in hospitalized children and 15% in outpatient practice in India. The
primary outcome analyzed in all the studies was the duration of diarrhea. The more objective
parameter of stool output has not been evaluated. To recommend a particular species it will
40 have to be first evaluated in randomized controlled trials in Indian children. Further there is an
additional need to study the doses and the duration of therapy with different strains.
Recent Trends in the Management of Acute Watery Diarrhea in Children
A recent meta-analysis18 analyzed the preventive role of probiotics in acute diarrhea. All 34
reported randomized placebo controlled trials were conducted in developed countries in health
care settings except one which was carried out in the community in a developing country. The
analysis concluded that while there is a role of probiotics in the prevention of acute diarrhea
there is insufficient evidence for extrapolation of these results for use in developing countries as
studies in these settings are lacking.
Antisecretory Drugs in Diarrhea

There is presently not enough evidence on either safety or efficacy of antisecretory drugs like
racecadotril for its routine use in the treatment of diarrhea.19 There is no data from our settings.
Methodology of most of the published studies is questionable in addition to them being
sponsored by a drug company. More importantly all results are not made available after another
large multicenter study evaluating efficacy and safety of the same drug.
REFERENCES
1. National Family Health Survey (NFHS-2) India, 1998–9.
2. Bhandari N, Bhan MK, Sazawal S. Mortality associated with acute watery diarrhea, dysentery and
persistent diarrhea in rural north India. Acta Paediatr. 1992;S381:3–6.
3. Hahn SK, Kim YJ, Garner P. Reduced osmolarity oral rehydration solution for treating dehydration due
to diarrhea in children: systematic review. British Medical Journal. 2001;323:81–5.
4. Reduced osmolarity oral rehydration salts (ORS) formulation. A report from a meeting of experts jointly
organized by UNICEF and WHO. UNICEF HOUSE, New York, USA, 18 July, 2001; WHO/FCH/CAH/0.1.22.
5. World Health Organization. Complementary Feeding of Young Children in Developing Countries:
A Review of Current Scientific Knowledge. Document ref. WHO/NUT/98.1. Geneva: World Health
Organization;1998.
6. Castillo-Duran C, Vial P, Uauy. R. Trace mineral balance during acute diarrhea in infants. J Pediatr.
1988;113:452–7.
7. Ruz M, Solomons NW. Fecal zinc of endogenous zinc during oral rehydration therapy for acute diarrhea.
J Trace Elem Exp Med. 1995;7:89–100.
8. Bhandari N, Bahl R, Hambidge KM, et al. Increased diarrheal and respiratory morbidity in association
with zinc deficiency: a preliminary report. Acta Pediatr. 1996;85:146–50.
9. Bahl R, Bhandari N, Hambidge KM, et al. Plasma zinc as a predictor of diarrhoel and repiratory morbidity
in children in an urban slum setting. Am J Clin Nutr. 1998;68(Suppl 41):4–7.
10. Zinc Investigators Collaborative Group: Bhutta ZA, Bird SM, Black RE, Brown KH, Gardner JM, Hidayat
A, et al. Therapeutic effects of oral zinc in acute and persistent diarrhea in children in developing
countries; pooled analysis of randomized controlled trials. Am J Clin Nutr. 2000;72:1516–22.
11. Fontaine O. Report of a meeting, New Delhi 7-8 May 2001. Effect of zinc supplementation on clinical
course of acute diarrhea. J Health Popul Nutr. 2001;19(4):338–46.
12. Bhatnagar S, Bahl R, Sharma PK, Kumar GK, Saxena SK, Bhan MK. Zinc treatment with oral rehydration
therapy reduces stool output and duration of diarrhea in hospitalized children; a randomized controlled
trial. J Pediatr Gastroenterol Nutr. 2004;38:34–40.
13. Black RE. Zinc deficiency, Infectious Disease and Mortality in the Developing World. J Nutr. 2003; 133(5
Suppl 1):1485S–9S.
14. Baqui AH, Black RE, El Arifeen S, Yunus M, Chakraborty J, Ahmed S, Vaughan JP. Effect of zinc
supplementation started during diarrhea on morbidity and mortality in Bangladeshi children:
community randomized trial. BMJ 2002;325(7372):1059. 41
15. Shankar AH, Prasad AS. Zinc and immune function: the biological basis of altered resistance to
infection. Am J Clin Nutr. 1998;68 (suppl. 2):447S–63S.
16. Bhatnagar S, Bhandari N, Mouli UC, Bhan MK. Consensus statement of IAP National Task Force: Status
report on management of acute diarrhea. Indian Pediatr. 2004;41:335–48
17. Baqui AH, Black RE, EI Arifeen S, Yunus M, Zaman K, Begum N, Roess AA, Santosham M. Zinc therapy
for diarrhea increased the use of oral rehydration therapy and reduced the use of antibiotics in
Bangladeshi children. J Health Popul Nutr. 2004;22(4):440–2.
18. Sazawal S, Hiremath G, Dhingra U, Malik P, Deb S, Black RE. Efficacy of probiotics in prevention of acute
diarrhea: a meta-analysis of masked, randomised, placebo-controlled trials. Lancet Infect Dis. 2006
Jun;6(6):374–82.
19. Bhan MK, Bhatnagar S. Editorial: Racecadotril-Is there enough evidence to recommend it for treatment
of acute diarrhea? Indian Pediatr. 2004;41:1203–4.
42
5
Persistent Diarrhea
Sarath Gopalan
DEFINITION
The World Health Organization defines persistent diarrhea as diarrhea associated with an abrupt
onset of symptoms, usually of infective etiology and of more than 14 days duration.
This definition excludes specific conditions like coeliac disease, tropical sprue, or other
congenital, biochemical or metabolic disorders. The predominant causes of persistent diarrhea
(PD) are listed below (Table 5.1).
Unlike acute diarrhea, an important observation in most patients with persistent diarrhea is
that their hydration status is relatively well-preserved despite a high stool output. Dehydration
develops only in some patients because of the high stool output or when oral intake is reduced
due to associated systemic infection. However, most patients with persistent diarrhea have
varying degree of malnutrition which can be attributed to the long duration of diarrhea. The
major consequences of persistent diarrhea are growth faltering, worsening of malnutrition and
death during a subsequent diarrheal or non-diarrheal illness.
The growth failure associated with persistent diarrhea is not exclusively the result of
malabsorption but may be a consequence of suboptimal energy and nutrient intake during
the diarrheal episode due to anorexia associated with the illness, faulty feeding practices and
inappropriate advice by medical practitioners and caregivers.
Where should children with persistent diarrhea be treated?
Nearly two-thirds of persistent diarrhea patients can be treated at home but it is better to
hospitalize when in doubt. Treatment approach to patients selected for home care is given in
(Fig. 5.1).
Table 5.1: Main entities presenting as persistent diarrhea
• Re-infection or protracted course of the initial infection

Adenovirus, EPEC, EAggEC
Salmonella, Shigella, C. difficile
• Small-intestinal bacterial overgrowth
Malabsorption particularly of carbohydrates due to a combination
of trition and enteric infections
• Milk or other dietary protein intolerance
Fig. 5.1: Algorithm for the treatment of persistent diarrhea in outpatients
Patients with one or more of the following features are more appropriately treated in a
hospital setting (Fig. 5.2):
• Age less than 4 months and not breastfed
• Presence of dehydration
• Severe malnutrition (visible wasting, weight for length <70%, or weight for age <60%, of
the National Center for Health Statistics medians or the presence of symmetrical edema
involving at least the feet)
• Presence of systemic infection.
When should you suspect systemic infection?
All patients with persistent diarrhea should be carefully screened clinically for indicators of
44 systemic infection. All patients who have severe malnutrition should be assumed to have
systemic infection.
Persistent Diarrhea
Fig. 5.2: Dietary algorithm for the treatment of persistent diarrhea (> 14 days) in a hospital setting
Suspect infection if the patient has any of the following symptoms or signs:
• Fever or hypothermia
• Acute reduction in feeding
• Inability to drink
• Abdominal distension
• Lethargy or difficult to arouse
• Cold skin
• Cough with fast breathing or lower chest indrawing
• Any other features of a severely ill child.
Prevention and Treatment of Dehydration
Assess the child for signs of dehydration and give fluids according to WHO’s Treatment Plan A, B
or C, as appropriate.
Recommendations for Dietary Management of Persistent Diarrhea (Fig. 5.3)

Infants aged < 4 months
Persistent diarrhea occurs rarely in infants aged < 4 months who are exclusively breastfed. A
breastfed infant could normally be passing several soft or mushy stools each day. In such cases,
the change in character of stools will be important. The principles of treatment are summarised
in the Table 5.2. 45
Successful treatment with either diet is characterized by:

• Weight gain,
• Adequate food intake,
• Diminished number of diarrheal stools (< 2 liquid stools/day for 2 consecutive days),
• Disappearance of any fever.
Treatment failure is defined as : in the absence of initial or hospital acquire systemic infection there is:
• a marked increase in stool frequency (usually more than 10 watery stools/day) any time after at least 48th on the diet or,
• return of signs of dehydration any time after initiating treatment or,
• failure to establish weigh gain by 7 days.
Give Vitamin A 2,00,000 IU (> 12 months) or 1,00,000 IU (6–12 months) routinely. For children < 8 kg (irrespective of age)
administer 1,00,000 IU.
Give mixture of vitamins and minerals providing at least 2 RDA. If other minerals are difficult to provide, at least give element zinc
10 mg daily up to one week after recovery.
Give antibiotics for bloody diarrhea/systemic infection/severe malnutrition.
* Diet C is best administered in a hospital with appropriate facilities.
46 Patients discharged on diet B should be given small quantities of milk as part of a mixed diet after 10 days. If there are no signs of
lactose intolerance, increase milk gradually over the next few days.
Fig. 5.3: Dietary algorithm for the treatment of persistent diarrhea
Persistent Diarrhea
Older Infants and Young Children Table 5.2: For infants < 4 months with persistent diarrhea
Breastfeeding should be continued • Encourage exclusive breastfeeding.
during persistent diarrhea. Breastfed • Help mothers who are not breastfeeding to re-establish
infants continue to gain some weight lactation.
even while passing abnormal stools for • If only animal milks given, replace it with curds or
a few extra days after an acute episode lactose free milk formula (given with a cup and spoon).
of gastroenteritis. After the period of • From the third month onwards cooked/pre-cooked rise
infancy, the breast milk output is less can be mixed with milk/curd/lactose free formula.
and optimal feeding of a mixed diet is
more important.
Should Milk (Lactose) be Totally Eliminated or Only Restricted?

The Initial Diet A:
(Reduced lactose diet: milk rice gruel, milk sooji gruel, rise with curds, dalia)
• If the patient is fed entirely on animal milk, the quantity should be reduced. Total
elimination of animal milk is not required routinely. Limit daily intake of milk to 50–60 ml/
kg providing not more than 2–2.5 gm of lactose/kg/day. To reduce lactose concentration
in animal milk, do not dilute it with water as it reduces energy density critically. Milk can be
mixed with cereals e.g. milk or curd rice gruel, milk sooji gruel, or dalia.
• Start feeding as soon as the child can eat.
• To begin with offer 6–7 feeds per day and a total daily energy intake of 110 Kcal/kg: increase
energy intake steadily, upto150 Kcal/kg over next two weeks if required to achieve weight
gain.
• Many children will eat poorly, until any associated serious systemic infection is treated for
24–48 hrs. In such situations, use nasogastric feeding initially.
Basis for the Initial Reduced Lactose Diet

• Data from the All India Institute of Medical Sciences, New Delhi has clearly shown that
reduced lactose diet is as well tolerated as totally lactose free diet, without significantly
increasing stool output, or risk of dehydration1 (Table 5.3).
• Milk cereal mixtures are highly
palatable, are consumed in Table 5.3: Milk cereal (low lactose) vs milk free diets in PD
large amounts, provide good Milk cereal Milk free
quality proteins and some 60 56
micronutrients and result in
Med. stool wt in 5 d (gm/kg/h) 1.6 (0.4–7.2) 1.3 (0.1–7.6)
faster weight gain than milk free
diets. % wt gain at 120 h 2.8 (-6.2–12.3) 2.3 (-9.4–10.9)
• Lactose is better tolerated when Treatment failures (%) 17.2 23.6
milk is mixed with cereals as it Recovered by 72 h (%) 58.4 66.1
reaches the intestine slowly due
Bhatnagar et al, Pediatrics, 1996
to delayed gastric emptying and
also when it is given in many divided feeds.2‑4
• Milk or curd cereal mixtures were more efficacious than soy based formulae in clinical trials.5 47
Data from a trial in Pakistan is enclosed in Table 5.4.
The Second Diet B (Lactose-free Diet Table 5.4: Yoghurt rice lentil gruel vs soy diets in PD
with Reduced Starch) Soy KY
About 65–70% of children improve on the Mean stool vol (gm/kg/d) 63.8 (75) 38.3 (17)*
initial Diet A. Remaining children, if free Mean stool freq. (no/d) 6.6 (4) 4.4 (2)*
of systemic infection are changed to Diet Wt gain (gm/wk) 7.7 (286) 6467.7 (373)*
B which is milk (lactose) free and provides
* p= < 0.05
carbohydrates as a mixture of cereals and Bhutta et al, Pediatrics, 19945
glucose. Milk protein is replaced by chicken,
egg or protein hydrolysate.
Basis for Diet B

• Some children do not respond well to the initial low lactose diet. They may have impaired
digestion of starch and disaccharides other than lactose. Data from a study done at AIIMS to
identify prognostic markers on milk free diets in persistent diarrhea is shown in Table 5.5.
• Therefore, not only milk is eliminated but starch is also reduced and partially substituted by
glucose.
• Substituting only part of the cereal with glucose increases the digestibility but at the same
time does not cause a very high osmolarity, which would be the case if all the cereals were to
be replaced by glucose.
An example of a commercial protein hydrolysate preparation is Protinex, Pfizer. This
preparation also has sucrose and therefore the composition of the diet should be modified
accordingly.
The Third Diet C (Monosaccharide Based Diet)

Approximately 80–85% of patients with severe persistent diarrhea will recover with sustained
weight gain on the initial Diet A or the second Diet B. A minority may not tolerate a moderate
intake of the cereal in Diet B. These children are given the third diet (Diet C) which contains only
glucose and a protein source as egg white or chicken. Energy density is increased by adding oil
to the diet.
About two RDA of supplemental multivitamins and minerals should be given daily to all
children for at least two to four weeks. Recent studies (Tables 5.6 and 5.7) have shown beneficial
effects of zinc supplementation in persistent diarrhea.
It is recommended to give 10 mg per day of elemental zinc to children between 6 months and
3 years of age for at least 2 weeks. Most commercial preparations are available as zinc sulphate,
zinc chloride or zinc gluconate.7-10
Table 5.5: Prognostic factors on milk free diets in persistent diarrhea
30-35% have impaired absorption of disaccharides other than lactose
OR (95% CI)
Carbohydrate malabsorption 5.1 (3.7, 6.5)
48 Systemic infection 41.9 (39.6, 44.4)

Bhatnagar et al. J Pediatr Gastroenterol Nutr 19966
Persistent Diarrhea
Table 5.6: Zinc supplementation in PD

Studies
Age
dose/d Reduction in mean
Diarrheal duration Stool frequency
Sachdeva et al (n = 40)
6-18 mo
40 mg 18.7% 21.4%
Roy et al (n = 190)
3–24 moWt/age ≤ 70% 33%* –
20 mg Males 27%* –
Penny et al 6–36 mo, 20 mg 22% –
Overall
Lower initial zinc status 32% –
Table 5.7: Peru, Bangladesh, Pakistan results of a recent meta-

analysis; Am J Clin Nutr. 2000
Effect on recovery Effect on failure
Relative hazard (95%CI) Odds ratio (95%CI)
Pooled 0.76 (0.62, 0.92) 0.60 (0.38, 0.93)
Pooled 0.75 (0.62, 0.91) 0.58 (0.37, 0.90)
Iron supplements should be introduced only after the diarrhea has ceased.
At the least, provide vitamin A (as a single large dose) and zinc as it has shown to effect
recovery from persistent diarrhea.
Vitamin A
A single oral dose of 2,00,000 IU of vitamin A for children >12 months or 1,00,000 IU for children
6–12 months should be given routinely. Children weighing less than 8 Kg, irrespective of their
age, should be given 1,00,000 IU of vitamin A.
Additional recommendations for the severely malnourished infants and children with
persistent diarrhea:
• Intramuscular administration of a 50% solution of magnesium sulfate at 0.2 ml/kg/dose twice
a day for a period of 2–3 days. Continue with 0.8–1.2 mEq/kg/day orally for at least 2 weeks.
• 5–6 mEq/kq/day of potassium administered orally or as part of intravenous infusion during
the initial stabilization period. Continue with the usual requirement of 2–3 mEq/kg/day, for
at least 2 weeks.
• 1 mg/day of folic acid for at least 2 weeks.
• 0.3 mg/kg of elemental copper for at least 2 weeks.
• A mineral mix solution (Table 5.8) can also be used wherever available.
49
Table 5.8 : Composition of mineral mix solution

recommended by the WHO substance
Amount
Potassium chloride 89.5 gm
Tripotassium citrate 32.4 gm
Magnesium chloride (MgCl2 6H2O) 30.5 gm
Zinc acetate 3.3 gm
Copper sulfate 0.56 gm
Sodium selenate 10 mg
Potassium iodide 5 mg
Water to make 1000 ml
It is added to Resomal or liquid feed at a concentration of

20 ml/liter.
Monitoring the Response to Treatment in the Hospital
Successful treatment is characterised by:

• Diminished number of diarrheal stools (< 2 liquid stools/day for 2 consecutive days),
• Adequate food intake, and
• Weight gain.
Some examples: Riconia, Oscar Health Care Pvt. Ltd. Becadexamin, Glaxo India Ltd; Supradyn
Roche.
Some examples: Zevit, SK+F, 10 mg of elemental zinc/5 ml, 22.5 mg of elemental zinc/capsule’
Zincolac, Shalaks, 50 mg elemental zinc/capsule. Riconia @Oscar Health Care Pvt. Ltd; 15 mg of
elemental zinc/tablet, Becosule-Z, Pfizer Corp; 15 mg of elemental zinc/capsule.
Most children will lose weight in the initial 1–2 days, and then show steady weight gain as
associated infections are treated and diarrhea subsides. The weight should be clearly documented
on at least three successive days before one can conclude that weight gain is occurring; for most
children, weight on day 7 will also be greater than the weight at admission. They may return
home but should be followed regularly to ensure continued weight gain and compliance with
feeding advice.
When do you change from the initial diet (Diet A) to the second diet (Diet B) of Diet B to
Diet C?
In the absence of initial or hospital acquired systemic infection, the diet should be changed
when there is treatment failure defined as:
• A marked increase in stool frequency (usually more than 10 watery stools/day) any time after
at least 48 hrs of initiating the diet or,
• Return of signs of dehydration any time after initiating treatment or,
• A failure to establish weight gain by day 7.
50 For how long should Diet A or Diet B be given?
Unless signs of treatment failure occur earlier, each diet should be given for a minimum period
of 7 days.
Persistent Diarrhea
What should be done for the rare cases with severe glucose malabsorption?
Poor outcome on Diet C may be due to transient glucose malabsorption. This is a rare complication.
These patients are identified by:
• Presence of reducing substances in stool when glucose is the only carbohydrate in diet, e.g.
ORS and
• Diarrhea ceases promptly on fasting and IV fluids.
The practical approach is to administer IV 10% glucose with electrolytes and continue a diet
orally which contains chicken or egg white (as source of protein) and oil.
Criteria for Discharge from Hospital

Patients who have been successfully treated on the dietary algorithm can be discharged from
hospital and followed up at home or in the outpatients for resumption of regular diet.
Resumption of Regular Diet after Discharge

Children discharged on Diet A should gradually resume a diet appropriate for age 7–14 days later.
Children discharged on Diet B should be given small quantities of milk as part of a mixed
diet after 10 days. If they have no signs suggestive of lactose intolerance (diarrhea, vomiting,
abdominal pain, abdominal distension, excessive flatulence) milk can be gradually increased
over the next days. A normal diet appropriate for age can be resumed over the next week.
Recommendations for Antimicrobial Therapy in Persistent Diarrhea

Controlled trials of empirical treatment with oral gentamicin, nalidixic acid and/or metronidazole11,12
show no substantial effect on outcome of persistent diarrhea.
Antimicrobial therapy in persistent diarrhea is currently indicated:
• In the presence of gross blood in stools or for specific enteric pathogens against which such
therapy is known to be beneficial e.g. Shigella; effective anti-shigella agents such as nalidixic
acid or other quinolones should be given .
• Associated systemic infection; combination of parenteral ampicillin and aminoglycosides is
usually appropriate.
• Severe malnutrition: use combination of ampicillin and aminoglycoside as for associated
systemic infection even if uncertain whether there is systemic infection.
• If feasible, screen for urinary tract infection (UTI). 10–15% of children with persistent diarrhea
and malnutrition require antibiotics for associated lower UTI.
• When group B salmonella are isolated in stool, treat with systemic antibiotics only when
there is a suspicion of systemic infection.
Additional Drugs
Anti-motility and anti-secretory agents and bile salt binding resins have not been shown to give
any significant clinical benefit when used to treat persistent diarrhea.
Lactobacilli and Sacchromycesboulardii are of little benefit in the treatment of persistent
diarrhea. 51
Value of Laboratory Investigations

Patients with persistent diarrhea can be managed without elaborate laboratory tests using the
algorithm outlined above with very high levels of success.
Stool microscopy helps in identifying trophozoites of E. histolytica and G. lamblia. Majority
of patients who have cysts of E. histolytica are now known to have non-pathogenic E. dispar.
Acid-fast staining with modified Ziehl-Neelsen technique will identify cyclospora, isospora and
cryptosporidium. Large number of pus cells (<20/hpf ) in stool suggest invasive diarrhea but a
majority of patients with persistent diarrhea do not have these.
Stool cultures for Salmonella and Shigella should be done if feasible. Isolation of E. coli is not
helpful, as most laboratories cannot characterize for virulence properties.
In a non-hospital setting, detecting reducing substances is often impractical as testing
cannot be carried out promptly and several stools need to be examined for sufficient sensitivity.
It is, therefore, more practical to use clinical criteria to decide a change in diet as shown in
the algorithm. The fact that diet A has reduced lactose already assumes that some degree of
secondary lactose intolerance exists in children with persistent diarrhea and malnutrition.
Conclusions and recommendations from the consensus statement of the Indian Academy of
Pediatricians (IAP) Gastroenterology Chapter:13
1. Persistent diarrhea is still prevalent in India, since unhygienic living conditions and
undernutrition coexist with HIV and poor access to quality health care. However, there is
paucity of recent data on persistent diarrhea and there is an urgent need for well designed
epidemiological and outcome studies.
2. Micronutrient supplementation, step-wise diet based regimens and good supportive care
is sufficient in most children above 6 months of age. Special infant formulas are required in
those who do not respond.
3. Promotion of exclusive breastfeeding in early infancy, safe complementary feeding practices,
access to safe drinking water and scientific management of acute diarrhea can significantly
reduce the incidence of persistent diarrhea.
4. Specific diagnostic tests to evaluate the etiology of chronic diarrhea are not readily available
in India. There is a need to have regional laboratories where these tests could be done. Celiac
disease, cow’s milk protein allergy and immunodeficiency associated diarrhea are being
increasingly recognized in India.
5. Special formulas like extensively hydrolyzed 100% bovine casein infant formulas and
elemental amino acid formulas need to be made available in India. However, administrative
steps need to be taken to ensure that they are not misused or overused.
REFERENCES
1. Bhatnagar S, Bhan MK, Singh KD, Saxena SK, Shariff M. Efficacy of milk based diets in persistent diarrhea:
A randomized controlled trial. Pediatrics. 1996;198:1122–26.
2. Leichter J. Comparison of whole milk and skim milk aqueous lactose solution in lactose tolerance
testing. Am J Clin Nutr. 1973;26:393–96.
3. Martini MC, Savaiano DA. Reduced intolerance symptoms from lactose consumed during a meal. AM J
52 Clin Nutr. 1988;47:57–60.
Persistent Diarrhea
4. Solomono NW, Guerrero A-M, Torun B. Dietary manipulation of post prandial colonic lactose
fermentation: I. Effect of solid foods in a meal. Am J Clin Nutr. 1985;41:199–208.
5. Bhutta ZA, Molla AM, Issani Z, Badruddin S, Hendricks K, Synder JD, and Dietary management of
persistent diarrhea: comparison of a traditional rice-lentil based diet with soy formula. Pediatrics. 1991;
88:1010–19.
6. Bhatnagar S, Bhan MK, Singh KD, Shrwadav R. Prognostic factors in hospitalized children with persistent
diarrhea: Implications for diet therapy. J PediatrGastroenterol Nutr. 1996;23:151–8.
7. Sachdev HPS, Mittal NK, Yadav HS. Oral zinc supplementation in persistent diarrhea in infants. Ann Trop
Paediatr. 1990;10:63–9.
8. Roy SK, Tomkiro AM, Mohalanakis D, et al. Impact of zinc supplementation on persistent diarrhea in
malnourished Bangladeshi children. ActaPediatr. 1998;87:1235–9.
9. Penny ME, Pearoon JM, Marin RM et al. Randomized community based trial of the effect of zinc
supplementation, with and without other micronutrients, on the duration of persistent childhood
diarrhea in Luma, Peru J Pediatr. 199;135:208–17.
10. The Zinc investigators collaborative group therapeutic effects of oral zinc in acute and persistent
diarrhea in children in developing countries: Pooled analysis of randomized controlled trials. Am J Clin
Nutr. 2000;72:1516–22.
11. Bhatnagar S, Bhan MK, Sazanwal S, Gupta U, George C, Arora NK, Kashyap DK: Efficacy of massive
dose oral gentamicin therapy in nonbloody persistent diarrhea with associated malnutrition J Pediatr
Gastroenerol Nutr. 1999;12:117–24.
12. Bahl R. Bhandari N, Bhan MK, Saxena M, Bagati A. Efficacy of antimicrobial treatment in non-dysenteric
persistent diarrhea in a community setting. Acta Pediatr. 1996;85:1290–4.
13. Chronic and persistent diarrhea in infants and young children: Status Statement. Indian Pediatrics,
2011; 17: 37–42.
53
6
Chronic Diarrhea and
Malabsorption Syndrome
Anshu Srivastava
The term diarrhea is derived from the Greek language (dia = through, rhein = to flow), denoting
increased fluidity and frequency of stool. The duration of symptoms necessary to define
diarrhea as ”chronic’’ is taken as 2 weeks for children1 and 4 weeks2 for adults. It is important
to differentiate persistent diarrhea from chronic diarrhea as both have a duration of > 2 weeks.
According to WHO, a diarrheal episode which begins acutely and lasts for > 2 weeks is defined as
persistent diarrhea.3 On the other hand, chronic diarrhea has an insidious onset and is mostly
a manifestation of malabsorption which is defined as a state in which there is disturbance of
the digestive-absorptive sequence of nutrients across the intestinal mucosa. In order to properly
interpret chronic diarrhea and approach the precise defect involved, an understanding of the
normal process of digestion and absorption is essential.
NORMAL PHYSIOLOGY OF DIGESTION

The entire process of food assimilation after ingestion involves solubilisation, which is a prerequisite
for the absorption of nutrients like fat or calcium. Fat and fat-soluble vitamins are solubilised
through formation of micelles, and calcium through acidification. Digestion of macromolecular
compounds, like polysaccharides, triglycerides and proteins, to their molecular components,
like monosaccharide’s, fatty acids and amino acids, is achieved by digestive enzymes present in
pancreatic and gastro-duodenal juice. This is followed by mucosal absorption which may be by
active or passive carrier-mediated transport or by diffusion and post mucosal transport of absorbed
substrates. Diseases causing malabsorption of dietary fat commonly cause malabsorption of fat-
soluble vitamins, because they require similar absorptive mechanisms. The different nutrients
are absorbed in various segments of the small bowel (Fig. 6.1) and specific vitamin and mineral
deficiencies found in a patient can often point to the diseased anatomic site of the small bowel.
Etiology
Chronic diarrhea can occur due to abnormality in digestion (e.g. pancreatic insufficiency,
cholestasis) or absorption of nutrients (e.g. celiac disease, CMPA), metabolic defects (e.g.
Acrodermatitis enteropathica, Addison’s disease), abnormal gut transit (e.g. short gut, pseudo-
obstruction), secretory tumours (e.g. VIPoma, carcinoid) and intake of drugs (e.g. antacids,
antibiotics, etc.). The list of causes is extensive and is best classified according to age of onset
and frequency of occurrence as shown in Table 6.1.
Chronic Diarrhea and Malabsorption Syndrome
Fig. 6.1: Site of absorption of nutrients in gut
Table 6.1: Causes of chronic diarrhea according to age on onset

Age <1 year Age >1 year
Common causes Common causes
• Cow’s milk protein allergy (CMPA)* • Celiac disease
• Toddler’s diarrhea • CMPA*
• Lymphangiectasia • Infections, e.g. Giardiasis
• Urinary tract infection • Toddlers diarrhea
• Celiac disease • Lymphangiectasia
• Infections, e.g. Giardiasis • IBD (Ulcerative colitis and Crohn’s disease)*
• Short bowel syndrome • Gastrointestinal tuberculosis*
• Immunodeficiency states* • Immunodeficiency (both cong and acquired)*
• Cystic fibrosis • Bacterial overgrowth
• Anatomical gut defects • Pancreatic insufficiency (cystic fibrosis, chronic pancreatitis)
• Hirschsprung’s enterocolitis* • Tropical sprue
• Irritable bowel syndrome (diarrhea type)
• Drug induced: Antibiotics (including C. difficile*), laxatives,
antacids etc.
Uncommon causes Uncommon causes
• Intractable diarrheas of infancy: microvillous • Diabetes mellitus
inclusion disease, tufting enteropathy, auto- • Hyperthyroidism
immune enteropathy • Anatomical defects, e.g. blind loop, fistula
• Congenital enzyme defects: glucose galac- • Hypoparathyroidism
tose malabsorption, sucrose isomaltase defi- • Addison’s disease
ciency, congenital lactase deficiency, etc. • IPSID (immune proliferative small intestinal disease)
• Cholestasis (intra or extrahepatic) • Microscopic colitis
• Acrodermatitis enteropathica • Zollinger Ellison syndrome
• Abetalipoproteinemia • Abetalipoproteinemia
• Schwachmann Diamond syndrome • VIPoma, Carcinoid
• Drug induced • Systemic mastocytosis
• Radiation enteritis*
• Schwachmann Diamond syndrome
55
• Cholestasis intra or extrahepatic
*causes of large bowel diarrhea
Table 6.2: Published series on chronic diarrhea

Rastogi et al4 n-47 Yachha et al5 n-137 Lee et al6 n-27 Altuntas et al7 n-70
Tropical enteropathy Protracted diarrhea 33% Post infectious
47% enteropathy 10%.
Other infections 4.2%
Parasitic 15% Parasitic 9% Parasitic 26% Parasitic 19%
Celiac 7% Celiac 26% Celiac 30%
CMPI 6% CMPI 29% CMPI 17%
IBS 11% TB 5% Secondary lactose
intolerance 19%
Non specific Others (8%)-cystic fibrosis, Lymphangiectasia 7%, Cystic fibrosis 10%
diarrhea 22% short gut, acrodermatitis glucose galactose
enteropathica malabsorption 7.5%
Unknown- nil Unknown 13% Unknown 11% Unknown 10%
There is scarcity of published data on etiology of chronic diarrhea in children (Table 6.2) and
it is different in developing vs. developed world, with infections predominating in the developing
world and allergic and immune mediated causes in the western world. In nearly 10%, a definite
cause could not be found and these are labelled as indeterminate.
APPROACH TO A PATIENT WITH CHRONIC DIARRHEA

History
The following questions should be asked to get a clue to the diagnosis.
1. Confirm that there is diarrhea (compare relative to usual habit of the child). Overflow
incontinence in a child with constipation is often misinterpreted as diarrhea by parents.
2. Nature, frequency, consistency and presence of blood/mucus/visible oil in stools. Presence of
nocturnal diarrhea.
3. Age of onset of symptoms. It is important as various illnesses present at different age groups.
4. Relation with change in diet? Introduction of animal milk followed by diarrhea suggests
CMPA, whereas onset after weaning with wheat products suggests celiac disease. Symptoms
worsen after a high fat diet in patients with pancreatic insufficiency. Passage of stools only
after eating is suggestive of gastrocolic reflex. Intake of excess of fruit juices can contribute
to diarrhea.
5. Does the child have failure to thrive (FTT) and signs of nutrient deficiency like anemia, rickets,
vitamin B complex deficiency (glossitis/cheilitis)?
6. Does the patient have a history of abdominal pain? Is it suggestive of pancreatic origin or
obstructive in nature?
7. Does the child have other systemic symptoms? e.g. recurrent infections at multiple sites
in immunodeficiency, recurrent respiratory infections in cystic fibrosis, atopic dermatitis/
asthma in food allergy, joint pain/red eye/oral ulcers in IBD.
56 8. Has the patient undergone previous abdominal surgery? May point towards blind loop,
bacterial overgrowth or short gut.
9. Details of previous illnesses requiring chronic intake of antibiotics or immunosuppressive

medications.
10. Is there a family history of celiac disease, Crohn’s disease, cystic fibrosis or allergic disorders?
Nearly 4–20% of first degree relatives of celiac disease patients have CD.
Physical Examination
A complete general and systemic examination along with plotting of growth on age appropriate
charts to look for drop in growth centiles is essential. The main features to be noted are:
1. Volume status and presence of dehydration.
2. Signs of vitamin and mineral deficiencies, e.g. anemia, koilonychia, rickets, cheilitis, Bitot’s
spots, ecchymosis and peripheral neuropathy.
3. Edema—symmetric and pitting edema is seen in hypoalbuminemia.
4. Clubbing is seen in celiac disease, Crohn’s disease, cystic fibrosis, tuberculosis and IPSID.
5. Inspection of perianal area for excoriation (lactose intolerance), rash (Acrodermatitis entero-
pathica), fissures, anal tags and fistulae (IBD).
6. Oral thrush and scars of recurrent skin infections.
7. Abdominal examination, looking in particular for abdominal distension, localized or
generalized tenderness, scars of previous surgery, masses, hepatosplenomegaly and ascites.
After a detailed clinical evaluation, a differential diagnosis is made using the following steps and
then investigations are planned accordingly.
Step 1 Confirm that there is chronic diarrhea.
Step 2 Is it of small bowel or large bowel origin? The features which help in discriminating the
two are shown in Table 6.3.
Step 3 Is the diarrhea due to maldigestion or due to malabsorption? Maldigestion due to
pancreatic exocrine insufficiency or inadequate duodenal bile acid concentration produces
steatorrhea. Whereas malabsorption occurs due to mucosal diseases like celiac disease, CMPA, etc.
The following points help in differentiating between maldigestion and malabsorption (Table 6.4).
Table 6.3: Differentiating small bowel from large bowel diarrhea
Features Small bowel diarrhea Large bowel diarrhea

Stool volume Large Small
Blood in stool No Usually present
Rectal symptoms (urgency, tenesmus) No Yes
Steatorrhea (greasy stools) Yes No
Carbohydrate malabsorption Yes, explosive stools No
Protein malabsorption Yes No
Pain (if any) Peri-umbilical, no reduction Hypogastric, reduced after
after passage of stool passage of stool
Color of stool Pale Normal 57
Nutrient deficiency Frequent May occur due to blood loss
Table 6.4: Differentiating maldigestion from malabsorption

Malabsorption Maldigestion
Stool fat ++ +++
Fatty acid crystals +++ –
Flatulence/bloating ++ –
Anemia (iron/folate def.) ++ –
Hypoalbuminemia ++ –
Stools volume ++++ due to cathartic action ++ Intact triglycerides
of free fatty acids on colon have no irritant effect
Based on the type of diarrhea (small bowel, large bowel or fatty), presence/absence of growth failure
and/or nutrient deficiencies, age of symptom onset and knowledge about the common causes in the
community the likely differential diagnosis can be easily determined (Tables 6.1 and 6.2).
Investigations
The aim is to make the diagnosis with the simplest and least invasive tests. The common
investigations used are listed below:
1. Hematologic: Anemia and its type, i.e. microcytic or macrocytic. Acanthocytosis suggests
abetalipoproteinemia. Raised platelets are often seen in IBD and raised ESR suggests an
inflammatory pathology. Presence of lymphopenia points towards lymphangiectasia and
deranged INR suggests vitamin K deficiency secondary to fat malabsorption or liver disease.
2. Biochemistry: Serum protein, albumin, electrolytes, calcium, phosphorus and alkaline
phosphatase. Iron deficiency can be confirmed by estimation of serum iron, total iron
binding capacity and serum ferritin. Complete liver function tests are done if liver disease is
suspected.
3. Stool examination: Occult blood; microscopy for ova and parasites, fat globules and fatty acid
crystals; C. difficile toxin assay (if suspected) and culture sensitivity. Advanced methods like
special stains, ELISA for antigen detection and PCR are used for detection of opportunistic
infections like cryptosporidium in high risk setting. The osmotic gap of stool is calculated
by subtracting twice the sum of the sodium and potassium concentrations in stool from
290 mOsm/kg (osmolality of stool). The concentration is doubled to account for anions
that accompany these cations. Cessation of stools on fasting and increased osmotic gap
> 100 mOsm/kg is suggestive of osmotic diarrhea and persistence despite starving and low
osmotic gap < 50 mOsm/kg suggests secretory diarrhea.
4. Fat malabsorption: Microscopic examination of random stool sample for fat globules after
Sudan III staining gives clue to the presence of steatorrhea. The van de Kamer method,
which is the titrimetric measurement of fatty acid equivalents and expresses the results as
fecal fat output in grams per 24 hours, is considered the gold standard. Fecal fat excretion
is determined after supplementing the diet with 2 gm/kg body weight of fat (min 30 gm
for child < 2 yr and 50 gm for > 2 yr). Excretion of > 4.5 gm/day of fat in stools is taken as
abnormal. Accuracy depends on completeness of stool collection for 48–72 hours, adherence
58 to the diet, and a diet diary to determine fat intake.
5. Chymotrypsin or elastase concentration in stool is reduced in exocrine pancreatic
insufficiency.
6. D-xylose test: After an overnight fast, a 5 gm dose of d-xylose is given and the patient is
encouraged to drink to maintain good urine output. Urine is collected for the next 5 hours.
As an alternative, 1 hour after ingestion of d-xylose a venous sample may be taken. Less than
1.25 gm of d-xylose in the urine collection or a serum d-xylose concentration <20 mg/dL is
indicative of abnormal intestinal absorption. The test may be false-negative, if the patient is
dehydrated, has renal dysfunction/significant ascites/delayed gastric emptying or the urine
collection is incomplete. D-xylose absorption may be normal in predominantly distal small
bowel disease.
7. B12 and folate malabsorption is suggested by presence of macrocytic anemia. Measurement
of serum cobalamin and serum/RBC folate concentration is done to confirm deficiency. The
Schilling test is used to distinguish between gastric and ileal causes of vitamin B12 deficiency.
A small oral dose of radio labelled vitamin B12 and simultaneously a large intramuscular
“flushing dose” of non-radio labelled vitamin B12 is given. The latter saturates vitamin B12
carriers; thus, radioactive vitamin B12 absorbed by the intestine is excreted in the urine. If
less than 7% of the administered dose is recovered in urine within 24 hours, vitamin B12
malabsorption is confirmed. A second phase of the Schilling test is performed with oral
administration of intrinsic factor. In pernicious anemia, the Schilling test normalizes after oral
administration of intrinsic factor.
8. Endoscopy: Endoscopic inspection of the duodenal mucosa provides clues to some causes of
malabsorption like aphthae (Crohn’s disease), white punctate lesions (lymphangiectasia) and
scalloping/reduction in number of duodenal folds (celiac disease). Multiple biopsies should
always be taken even with a normal endoscopic appearance. Histology is a very important tool
for making the etiologic diagnosis in cases of chronic diarrhea. Fluid aspirated from the distal
duodenum can be examined microscopically for parasites or cultured to detect bacterial
overgrowth. Colonoscopy with intubation of terminal ileum is done when large bowel
diarrhea is suspected. Biopsies confirm the diagnosis of IBD, tuberculosis and parasitic/viral
infections like cryptosporidium/CMV.
9. Small bowel series: Evaluation of small bowel is better by an enteroclysis study rather than the
conventional BMFT (Barium meal follow through). It helps in identification of abnormalities
like diverticulum, stricture with proximal dilatation and fistulae. Most useful for evaluation of
suspected cases of Crohn’s disease, intestinal TB and bacterial overgrowth due to anatomical
abnormalities.
10. Advanced imaging by CT scan/MRI abdomen: Useful for diagnosis of pancreatic disease.
Calcification, dilatation of the pancreatic duct, fatty pancreas or atrophic pancreas can be
easily picked up. It is a sensitive test to evaluate abdominal masses and detect enlarged
abdominal lymph nodes in tuberculosis/small bowel lymphoma. Targeted aspiration and
biopsy provide useful diagnostic clues on histology/culture.
11. Special scan and endoscopic ultrasound: If malabsorption is suspected to be caused by a
neuroendocrine tumor (e.g. gastrinoma, somatostatinoma), an indium-111 octreotide
scintigraphic scan or an endoscopic ultrasound examination of the pancreas is useful.
12. Special tests: Antiendomysial and tissue transglutaminase antibodies are used for screening
59
of celiac disease. Anti-enterocyte antibodies are present in autoimmune enteropathy.
Immunoglobulin levels, T cell functions, HIV serology, thyroid function, gastrin and other
enteric hormone levels and sweat chloride test are required in specific situations.
MANAGEMENT
Supportive
1. Correction of fluid and electrolyte disturbances.
2. Correction of vitamin and mineral (mainly zinc, iron and calcium) deficiencies.
3. Nutritional support is the pillar of treatment and preference is always for the enteral route.
Night time nasogastric/nasojejunal tube feeding may be required for severely malnourished
children. Diet modification is done according to the diagnosis (e.g. CMPI, celiac disease,
etc.). Total parenteral nutrition (TPN) is required by a small subgroup especially those with
neonatal onset diarrhea and with short gut. Enteral “trophic feeds” should be given in these
patients to avoid TPN induced cholestasis.
4. Albumin infusion is needed only for severe symptomatic hypoalbuminemia.
5. Prevention of Refeeding syndrome: Aggressive and rapid nutritional therapy in chronically
undernourished children places them at risk of developing refeeding syndrome. It is
characterised by hypophosphatemia, hypokalemia, hypomagnesemia and thiamine
deficiency.8 It occurs due to the intracellular movement of phosphate, potassium and
magnesium caused by increased insulin secretion and anabolism stimulated by carbohydrate
and protein rich feeds. The clinical manifestations include muscle weakness, seizures,
congestive heart failure, arrhythmias, altered sensorium and even death. It is essential to
prevent this complication by being aware of this entity, slowly increasing the caloric intake,
appropriate supplementation of electrolytes and vitamins and monitoring of body weight,
intake/output and electrolytes in the first few days of nutritional rehabilitation.
6. Specific management is according to the cause and is discussed in detail with the individual
diseases.
Common Conditions Presenting with Chronic Diarrhea

Chronic nonspecific diarrhea/Toddlers diarrhea: Chronic non-specific diarrhea (CNSD) is a common
cause of diarrhea in children aged 6 months to 4 years. The child passes 3–6 loose stools, mostly
during waking hours and often containing undigested vegetable material. The diarrhea worsens
with low residue, low fat or high carbohydrate diet due to relative deficiency of pancreatic
amylase in children. The child is well thriving, there is no anemia or vitamin deficiencies and the
diarrhea resolves spontaneously by ~4 years of age.9 The postulated etiologies are abnormalities
of bile acid absorption in terminal ileum resulting in increased colonic secretions, incomplete
carbohydrate absorption or abnormal gut transit.
The stool examination does not show presence of parasites, fat, blood or leucocytes.
Treatment is with a high fat (> 40%), low carbohydrate (especially reduced intake of juices) and
high fiber diet. Maternal reassurance and explanation is very helpful. Medications are rarely
needed. Psyllium 1–2 teaspoon full twice a day or loperamide (0.1–0.2 mg/kg/day) in 2–3 divided
60 doses may be tried for a short duration in exceptional circumstances. In a young child with loose
stools a careful history and selected investigations help in making a positive diagnosis of CNSD
and formulating a management plan. One should take care to avoid inappropriate prescription
of various elimination diets for suspected food intolerance in these children as it can lead to
iatrogenic growth faltering secondary to inadequate caloric intake.
Cow’s milk protein allergy (CMPA): The World Allergy Organization defines any adverse reaction
to food as food hypersensitivity which can be divided into immune-mediated reactions (food
allergy) and non-immune-mediated reactions (food intolerance).10 Cow’s milk protein allergy is a
‘food allergy’ whereas lactose intolerance is ‘food intolerance’ and the two are not similar. CMPA
is the most common food allergy in small children with a prevalence of 2–5% in infants in the
West. It is most often seen in top fed infants but can also occur occasionally in breast fed children
due to passage of cow’s milk antigen in breast milk. CMPA may develop after an episode of acute
gastroenteritis due to increased gut permeability and may lead to prolongation of the diarrheal
episode. In CMPA, there are mainly two types of reactions: immediate and slow/late onset. The
immediate type is IgE mediated, occurs within minutes of milk intake and is characterized by
vomiting, pallor, shock like state, urticaria and swelling of lips. Whereas the slow onset is T-cell
mediated, has an indolent course and presents mainly with GI symptoms like diarrhea, failure to
thrive, anemia and edema.
Clinical presentation: CMPA presents with gastrointestinal, respiratory and skin manifestations. GI
symptoms are present in 50–60% children and can be broadly divided into:
i. Proctocolitis: This is a disease of infancy, usually presenting by 2–4 months of age and
represents the benign end of the spectrum of non-IgE-mediated allergy to milk protein. Well
thriving infant presents with loose stools with visible fresh blood mixed with mucus.
ii. Enteropathy: Children/infants usually have protracted diarrhea, sometimes associated with
vomiting. This may result in malabsorption and growth faltering.
Food protein-induced enterocolitis syndrome (FPIES): This is an acute, cell-mediated, GI food
hypersensitivity characterised by severe protracted diarrhea along with blood, vomiting, pallor
and hypotonia. Infants can develop dehydration and hypovolemic shock in 15–20% of cases.
The absence of fever, presence of eosinophils in the stools and negative stool cultures helps in
differentiating it from infective colitis.11
Others: Some patients with CMPA may have symptoms suggestive of GERD (regurgitation/
FTT) and even constipation. Although uncommon, upper gastrointestinal bleeding due to
hemorrhagic gastritis may also be a presentation of CMPA. Respiratory symptoms like nasal
stuffiness, sneezing and chronic cough or skin manifestations in form of atopic eczema, urticaria,
and angioedema are seen in 20–30% and 50–60% respectively.
Diagnosis
Onset of symptoms after introduction of cow’s milk along with a family/personal history of atopy,
food allergy or asthma suggests the diagnosis of CMPA.
The diagnosis of CMPA depends on the type of disease. A positive skin prick test to cow’s milk
antigen (reaction of > 3 mm) and serum assay for specific immunoglobulin (IgE) antibody against
61
milk by ELISA or RAST helps in diagnosing IgE-mediated CMPA. The atopy patch test is still not
recommended for routine clinical use.
For non-IgE-mediated CMPA, which is more common and mainly has gastrointestinal
manifestations, gastrointestinal endoscopy and biopsy is useful for making a diagnosis and
excluding other etiologies of diarrhea. UGI endoscopy may show lymphonodular hyperplasia and
histology shows partial villous atrophy and infiltration with eosinophils. Because of the patchy
disease nature, multiple biopsies should be taken. Sigmoidoscopy shows edema, erythema,
lymphonodular hyperplasia and aphthous ulcers with eosinophilic infiltrates on histology.
Sigmoidoscopy with rectal biopsy is a simple test which is very useful in making a diagnosis of
CMPA.12
The gold standard for diagnosis of food allergy is the elimination and challenge test as
suggested by Goldman. Typically the symptoms subside after milk withdrawal and recur within
48 hours of milk challenge. Three such positive challenges which are similar in onset and clinical
features are considered diagnostic. But it is difficult to fulfil these criteria in a clinical setting
and this could be potentially dangerous in subjects with immediate reaction. Documentation of
enteropathy/colitis at diagnosis, symptomatic response to milk withdrawal and histological normalcy
thereafter is usually enough for diagnosis in a patient. Challenge should be done after at least one
year of diagnosis, if positive then the same diet should continue and challenge repeated after 1
year. The subject can be placed on a normal diet if the challenge is negative. In a challenge, one
needs to look for reappearance of symptoms, presence of leucocytes, eosinophils or blood in
stool, and histological changes (duodenal or rectal biopsy).
Treatment
The primary management includes removal of all cows’ milk/milk products from diet. Extensively
hydrolyzed formulae (EHF) are the main stay of therapy for infants with CMPA. Partially hydrolyzed
formulae (contain peptides with molecular weights between 3000 and 10,000 Da) are not
recommended for therapy of CMPA. Soy and EHF are equal in terms of growth and nutrient
intake. Although soy is more palatable and cheaper, but it is not recommended for infants <6
months of age and CMPA patients with concomitant soy allergy (seen in 10–15% cases). But
as EHF is not available easily in India, soy formulae can be used as a substitute milk formula in
young infants who are not allergic to it. In addition, some patients, especially those with IgE-
mediated disease, continue to react to EHF and need an elemental amino acid formula (AAF).
Patient and carers of children with IgE-mediated reactions should be educated to recognize
and manage the reactions with antihistaminics and adrenaline (epinephrine auto-injector).
Follow-up of CMPA children is important to ensure consumption of a nutritionally complete
diet especially calcium intake, reinforce dietary restrictions and to assess growth and the
development of tolerance. Mothers who are breast feeding their babies with CMPA also need
dietary counselling. Most (90–95%) children outgrow the allergy by 4–5 years of age. Subjects
with delayed reaction develop tolerance earlier than immediate reactors.
Tropical Sprue (TS)

Tropical sprue is an acquired disease characterized by chronic small bowel diarrhea with
62 demonstration of malabsorption of two unrelated substances, abnormal small bowel histology
and response to treatment with antibiotics and folate in absence of other known causes of
malabsorption. It is a common cause of chronic diarrhea in adults but is uncommon in children.

The widespread use of antibiotics and improvement in hygiene and water quality has lead to
decrease in TS in the recent years.
The exact etiology of tropical sprue remains unknown. It is thought to occur due to persistent
bacterial colonization of small bowel by toxigenic strains of coliform bacteria. The onset is often
with acute diarrhea and then symptoms become prolonged in form of continuing diarrhea,
bloating, abdominal cramping, anemia and weight loss. After few months, fatigue and weakness
develops secondary to anemia and hypoproteinemia. On examination, pallor, glossitis, skin
pigmentation and edema are present. Both the proximal and distal small intestine is involved in
TS as evident by the folate/iron and B12 malabsorption seen in these patients.
Diagnosis
Abnormality in two of the three commonly performed tests for malabsorption, i.e. stool fat
estimation and absorption of D-xylose and vitamin B12 in the appropriate clinical setting confirms
the diagnosis of TS.13 Macrocytic anemia (folate and vitamin B12 deficiency), hypocalcemia,
hypoalbuminemia and deficiency of fat soluble vitamins is common. Small bowel histology
reveals partial villous atrophy, crypt hypertrophy and infiltration of the lamina propria and
epithelium by mononuclear cells. A completely flat mucosa, i.e. total villous atrophy as seen in
celiac disease is rare in TS. Small bowel barium study shows nonspecific changes like thickened
mucosal folds in jejunum and ileum along with luminal dilatation and flocculation of barium.
Treatment
Correction of the various nutrient deficiencies, i.e. oral folate (5 mg/day), iron, vitamin A/B
complex and parenteral vitamin B12 (100 µg intramuscularly once a month) leads to prompt
improvement in general well being. Antimicrobial agents are the main stay of treatment with
tetracycline for 3–6 months being preferred in adults. Quinolones may be used as alternative
agent in children. Prognosis is good with rapid symptomatic response and complete intestinal
healing.
Bacterial Overgrowth
2
The normal proximal small intestine is colonized by predominant aerobic flora (<10 –
3
10 organisms/ml). The presence of >105 colony-forming units/mL of colonic-type (e.g. Gram-
negative strains, strict anaerobes and enterococci) bacteria from intestinal aspirate is considered
to be diagnostic of bacterial overgrowth.14
Predisposing factors for small intestinal bacterial overgrowth (SIBO) include anatomic
abnormalities (diverticulum, duplication, stricture due to Crohn’s disease, radiation or surgery and
blind loop), abnormal motility (intestinal pseudo obstruction, diabetes mellitus, hypothyroidism
and scleroderma), abnormal communication between proximal and distal gut (gastro/jejuno
colic fistula, ileocecal valve resection), abnormal host defence (malnutrition, immunodeficiency)
and achlorhydria.
Bacterial bile salt deconjugation leads to inadequate micelle formation and fat malabsorption. 63
Deficiency of B12 occurs due to bacterial consumption and lactose intolerance due to enterocyte
damage. Symptoms may be mild or disabling and diarrhea may be predominantly watery or
fatty. Vomiting, abdominal distension, and metabolic acidosis may be seen in few cases due to
accumulation of D-lactate, produced by bacterial fermentation of carbohydrates Anemia and
growth failure may also be present. As bacteria produce folate and vitamin K, their deficiency
is not present. In the patients who are dependent on TPN, SIBO may also increase the risk of
catheter-related sepsis.
Diagnosis
Culture of direct aspirate of small bowel contents and hydrogen breath testing (HBT) are
techniques used for diagnosis of SIBO. Upper small bowel aspirate is collected during
gastrointestinal endoscopy or via nasojejunal tube insertion with a sterile catheter. HBT is a non-
invasive method that depends on the ability of intestinal bacteria to metabolize carbohydrates
like glucose or lactulose and release hydrogen and/or methane in measureable levels in the
exhaled air. It is important to measure both hydrogen and methane levels as some bacteria
only produce methane resulting in false-negative results if the measurement is restricted to
hydrogen. To overcome the difficulties in diagnosis of SIBO, newer molecular techniques in
bacterial ‘fingerprinting’ like polymerase chain reaction denaturing gradient gel electrophoresis
(PCR-DGGE) and bacterial 16S-ribosomal DNA sequencing are being used to define microbial
populations in intestinal samples.15 Barium meal follow-through shows the underlying anatomic
abnormalities.
Treatment
Correction of anatomical abnormality, if possible, will be curative. Prokinetics in subjects with
hypomotility and a low fat diet with added medium chain triglycerides (MCT) and fat soluble
vitamins and B12 are helpful. Proton pump inhibitors, H2-receptor antagonists and antidiarrheals
should be used with caution because decreased gastric acidity and motility may promote SIBO.
Repeated cyclical courses of antibiotics are the main stay of therapy and improvement often lasts
for months. Metronidazole, gentamycin, co-trimoxazole, amoxicillin-clavulanic acid, rifaximin,
ciprofloxacin and tetracycline are the most often used antibiotics. The small bowel culture may
help guide choice of antibiotics. Probiotics may have a role but more evidence is needed.
Immunodeficiency
Both congenital and acquired immunodeficiency can cause chronic diarrhea.
Congenital Immunodeficiency
The congenital immunodeficiency syndromes most commonly associated with diarrhea are
X-linked agammaglobulinemia, selective IgA deficiency, common variable immunodeficiency,
chronic granulomatous disease and severe combined immunodeficiency.
X-linked agammaglobulinemia: Gastrointestinal (GI) involvement can occur due to giardiasis,
64 cryptosporidium, bacterial overgrowth or chronic rotavirus infection. Parenteral gamma globulin
administration is required for treatment along with specific antimicrobials.
IgA deficiency (absence of secretary and serum IgA): The disease is common and GI manifestations
are frequently present. There is an increased risk of celiac and Crohn’s disease. Recurrent giardiasis,
bacterial overgrowth and nonspecific enteropathy can also lead to diarrhea. Diagnosis is made
by measuring IgA levels and treatment is mainly supportive.
Common variable immunodeficiency (CVID): It is the most common significant primary immune
deficiency, characterized by low levels of IgG, IgA and/or IgM, normal or decreased B cell numbers,
and impaired antibody response. Patients have varied age of onset of GI complaints, ranging from
infancy to late childhood. CVID patients are at increased risk of infectious (giardiasis, bacterial
overgrowth, viral enterocolitis) and inflammatory conditions in the GI tract. Small bowel histology
often shows villous atrophy similar to celiac disease but in CVID the plasma cells are absent in the
intestinal lamina propria, and crypt epithelium is not hyperplasic which helps differentiate it from
celiac disease. Although CVID patients are at an increased risk of developing IBD, a non specific, non
infectious, enterocolitis is commonly seen with histologic features resembling GVHD and microscopic
colitis. The risk of gastritis and pernicious anemia like syndrome without antibodies to intrinsic factor
and lymphomas is also increased in these patients. Treatment depends on the cause of diarrhea with
antimicrobials and intravenous immunoglobulin being the primary line of therapy.16
Severe combined immunodeficiency (SCID): The child presents in the first few months with severe
infections, chronic diarrhea and/or failure to thrive. Oral thrush is often present. The diarrhea
may become bloody or purulent due to viral colitis. Small bowel histopathology shows absence
of plasma cells, blunted villi and PAS positive macrophages in lamina propria. The child usually
dies by 1–2 years of age if untreated. Bone marrow transplantation is curative.
Chronic granulomatous disease: The child presents with recurrent infections and multifocal
abscesses in skin and liver, hepatosplenomegaly, lymphadenopathy and chronic diarrhea. Many
children present with enterocolitis like Crohn’s disease. Perianal disease may also be present.
Intestinal biopsy reveals normal villi along with lipid filled foamy histiocytes in lamina propria.
Abnormal phagocytic function is confirmed by nitro blue tetrazolium (NBT) reduction test.
Treatment involves g interferon and antimicrobial administration.
Acquired Immunodeficiency Syndrome (AIDS)

Both acute and chronic diarrhea are substantial causes of morbidity and mortality in AIDS children
especially from the developing world with limited availability of highly active antiretroviral
therapy (HAART). Vertical transmission occurs in a majority and rest are acquired parenterally
(blood transfusion/surgery). The impaired mucosal immunity results in recurrent opportunistic
infections. Altered maturation and function of enterocytes results in increased permeability and
decreased functional absorptive surface with or without bacterial overgrowth. Perinatal infection
generally presents clinically in first two years of life. Associated intrauterine growth retardation is
common. The children are often sick with other clinical manifestations but sometimes diarrhea
may be the only symptom. Presence of oral thrush, lymphadenopathy, hepatosplenomegaly and
parotiditis (10–20% cases) gives clue to the diagnosis.
Numerous studies have shown that patients with a CD4 count of <200 cells/ml are at an 65
increased risk for opportunistic infections and this risk rises exponentially when the CD4 count is
< 100 cells/ml.17
The common infections associated with diarrhea in these subjects include:

Viral—Cytomegalovirus, herpes simplex, adenovirus, astrovirus, noro virus, rotavirus.
Bacterial—Salmonella, shigella, Mycobacterium avium complex (MAC), Campylobacter jejuni,
Clostridium difficile.
Fungal—Candidiasis, histoplasmosis, cryptococcosis
Protozoa—Microsporidium, isospora belli, cryptosporidium, Entamoeba histolytica, Giardia
lamblia, Cyclospora, Blastocystis hominis
Severe diarrhea, where no pathogen is found despite intensive investigation with endoscopy
and biopsy is ascribed to HIV enteropathy. It is characterized by chronic diarrhea, marked weight
loss with partial villous atrophy, increased intraepithelial lymphocytes and no hyper-proliferative
crypts on histology. The exact pathogenesis of such diarrhea remains unclear but use of HAART
results in symptomatic improvement in these patients.
Drug-induced diarrhea is an important cause of diarrhea with protease inhibitors like
nelfinavir, lopinavir, ritonavir and fosamprenavir being the commonest agents. Often there is a
temporal association between initiation of drug and diarrhea, and the diarrhea is usually of mild
to moderate severity.
Diagnosis
The approach to diarrhea in the HIV-infected child depends upon the duration of the diarrhea as
the pathogenic spectrum of acute and chronic diarrhea is different; the CD4 counts and intake
of drugs like HAART and antibiotics (for C. difficile diarrhea). Multiple stool examinations are
required to identify the causative etiology by using special stains and PCR techniques. Colonic/
terminal ileum biopsy and duodenal fluid examination are the other ways of diagnosing
opportunistic infections.18
Treatment is with specific antimicrobials along with HAART. The lack of effective antimicrobial
therapies for many of the opportunistic infections causing diarrhea in AIDS continues to be a
problem.
Intestinal Lymphangiectasia
Intestinal lymphangiectasia (IL) is characterized by dilated intestinal lacteals resulting in lymph
leakage into the small bowel lumen. It causes protein-losing enteropathy leading to lymphopenia,
hypoalbuminemia and hypogammaglobulinemia.19 IL may be a primary intestinal abnormality
(PIL) or secondary to conditions like congestive heart failure, constrictive pericarditis or
lymphoma. PIL is often associated with abnormal lymphatics in extremities. Signs and symptoms
include peripheral edema which could be bilateral and pitting due to hypoalbuminemia or
asymmetrical and non-pitting due to lymphedema, diarrhea, abdominal distension and pain.
Hypoproteinemia may also be complicated by ascites, pleural, or pericardial effusions.
Diagnosis
Hypoproteinemia, hypoalbuminemia, hypocalcemia, lymphopenia and decreased immunoglobulins
66 are characteristic. Increased fecal concentration of alpha-1-antitrypsin confirms the protein
losing enteropathy. Barium meal follow-through shows thickening of jejunal folds with nodular
lucencies in mucosa. Lymphangiography may reveal the abnormal lymphatics. A high-fat meal
before endoscopy is helpful in suspected cases as this increases enteric lymph flow and elevates
lymphatic pressures leading to more prominent lymphatics with increased leakage of lymph into
the bowel lumen, seen as white spots on the mucosa at endoscopy. Multiple biopsies should
be taken to document presence of dilated lacteals in mucosa and submucosa in the absence of
coexistent inflammation.
Treatment
It consists of lifelong dietary modification. A high protein and low fat diet with medium chain
triglycerides (MCTs), calcium and fat soluble vitamin supplementation helps in reducing diarrhea.
Exclusion of long chain fatty triglycerides (LCT) reduces lymphatic flow and prevents rupture of
malformed lymphatics whereas MCTs are directly absorbed into the portal venous circulation.
Intravenous albumin is required for symptomatic management and total parenteral nutrition
(TPN) is reserved for management of chylous effusions. Octreotide and tranexamic acid have
been shown to be effective in some cases. Supportive care with limb elevation and stockings
avoids complications due to peripheral edema. If lesion is localized to a small part of intestine,
resection is curative.
Short gut: Short gut syndrome is a composite of signs and symptoms occurring after intestinal
resection, characterized by weight loss and malabsorption of fluids, macro- and micronutrients.
The normal small intestine is ~600 cm and colon is ~150 cm in length. Symptoms are likely to
occur in children with <150 cm of small bowel and no colon or small intestine of <70 cm with
intact colon. As the remaining intestine adapts after a variable time period of months to years,
the patients often improve with time. Management is multidisciplinary and is best done at
specialized centers. The treatment in initial period is stabilization of fluid and electrolytes status
of the patient by total parenteral nutrition (TPN) followed by gradual introduction of enteral
feeds as the next step.20 The dietary modification depends to a large extent on the presence or
absence of colon as the colon is efficient in sodium and water absorption and limiting calorie loss
by absorption of short chain fatty acids.
Abetalipoproteinemia
Abetalipoproteinemia is an autosomal recessive disease with male predominance. Mutation
in the gene for microsomal triglyceride transfer protein (MTP) results in altered chylomicron
formation and impaired transport of triglycerides from intestine and liver.21 GI symptoms are
seen early in life in form of diarrhea and failure to thrive which worsens with fat intake. Neurologic
symptoms appear after 5 years of age and include loss of tendon reflexes, loss of position and
vibration sensation and sensory ataxia with positive Romberg’s sign. Eye involvement with
retinitis pigmentosa and night blindness also appear after 5 years of age.
Diagnosis
Chylomicron, very low density lipoprotein (VLDL) and low density lipoprotein (LDL) are absent in
plasma. Anemia with increase in reticulocyte count due to vitamin E deficiency and hemolysis and 67
acanthocytosis are typical. Bone marrow examination is normal. Histopathologic examination of
duodenal biopsy reveals lipid droplet filled enterocytes at the villous tips.
Treatment
Restricted fat intake (triglycerides containing long chain fatty acids) along with MCT, fat soluble
vitamins, and linoleic acid supplementation is useful. Vitamin E 1000 to 2000 mg/d in infants and
5,000 to 10,000 mg/d in older children is given to limit neurological manifestations.
Acrodermatitis enteropathica (AE): The autosomal recessive disease is characterized by selective
inability of the intestine to absorb zinc. An eczematous rash around body orifices and extremities,
alopecia, chronic diarrhea and recurrent sinopulmonary infections are typical.22 Symptoms
appear after weaning and respond to oral zinc supplementation (2 mg/kg in young infants or
30-45 mg of zinc/day in older children). The exact nature of the intestinal defect is still uncertain.
Children with persistent diarrhea and secondary zinc deficiency may also have a similar clinical
picture.
Microscopic colitis (MC): MC is an entity which is often reported in adults with chronic watery
diarrhea and recently being recognised in children also.23, 24 It is of two subtypes: collagenous
colitis (CC) and lymphocytic colitis (LC). Both diseases are characterized by chronic watery diarrhea
with/without weight loss, abdominal pain and electrolyte disturbances, and a macroscopically
normal colonic mucosa. The diagnosis is based on colonic mucosal biopsies which show a
diffusely distributed and thickened subepithelial collagen layer of ≥10 µm in collagenous colitis
and >20 lymphocytes per 100 epithelial cells in microscopic colitis. It is important to consider
this condition and ask for a complete colonoscopy with biopsies at multiple sites in children with
chronic watery diarrhea where other common causes like infections, celiac disease, etc. have
been ruled out. Treatment modalities for MC include bismuth subsalicylate, steroids (budesonide,
prednisolone), mesalamine, and probiotics.
Drug-induced diarrhea: Diarrhea can be a side effect of many pharmacologic agents. Altered GI
motility, mucosal injury, and/or change in intestinal microflora are the main etiologic factors.
Antibiotics can cause loose watery stools secondary to altered bacterial flora or bloody stools
due to Clostridium difficile overgrowth and pseudomembranous colitis (PMC). Stopping the
offending agent is often enough. The pooled evidence suggests that probiotics are associated
with a reduction in antibiotic associated diarrhea.25 But the type (species) of probiotics
associated with maximum efficacy and the setting of antibiotic use (patient characteristics and
type of antibiotic) which will have maximum benefit is still unclear. If suspicion of PMC is present
then a toxin assay in stool and sigmoidoscopy is done for confirmation.26 Metronidazole or oral
vancomycin is the drug of choice for PMC.
Laxative abuse is often a problem and many times overflow incontinence with impaction of
solid stool in a constipated child is misinterpreted as diarrhea. A digital rectal examination and
an abdominal X-ray are sufficient to confirm the diagnosis.
Metoclopramide use for gastroesophageal reflux disease can cause significant diarrhea.
Chemotherapy and radiation therapy can lead to diarrhea secondary to mucositis and enteritis.
Sorbitol, a nonabsorbable carbohydrate present in various medications and sugar free
products as drug vehicle can lead to osmotic diarrhea.
68
Endocrinopathies
Diabetes mellitus (DM): Diarrhea is a common symptom in children with DM. Metabolic effects
of diabetes often lead to diarrhea with alternating periods of constipation and abdominal pain.
Watery diarrhea occurs secondary to altered motility, bacterial overgrowth and abnormality of
bile salt malabsorption. There is no steatorrhea or growth failure and jejunal biopsy is normal.
Treatment involves good control of glucose levels and antibiotics for SIBO. Loperamide may also
be tried. There is an increased risk of celiac disease (5–8% incidence) in patients with diabetes
and thus screening for celiac disease should be done.
Hypoparathyroidism: (congenital Di George’s syndrome or as part of multiple endocrine neoplasia—
Addison’s disease, hypoparathyroidism, mucocutaneous candidiasis)—Presents as cramps, tetany
and steatorrhea. Exact mechanism of parathormone involvement in intestinal absorption is
unknown. Treatment with Vitamin D2 results in decreased diarrhea and steatorrhea. Diagnosis
is made by estimation of parathormone levels. It is very important to rule out magnesium
deficiency as functional hypoparathyroidism occurs in severe/prolonged magnesium deficiency.
Hyperthyroidism: It is rare in pediatric age group. Symptoms of weight loss, increased appetite,
eye manifestations and hyperactive nervous system give clue to the diagnosis. Increased GI
motility contributes to diarrhea. Diagnosis is by estimation of thyroid hormones.
Secretory tumors: Neuroendocrine tumors are rare in children and often pose a diagnostic
challenge. The clinical syndrome in these conditions is due to the effect of secretory products,
e.g. gastrin in Zollinger-Ellison (ZE) syndrome, somatostatin in somatostatinoma, vasoactive
intestinal peptide in VIPoma and 5 hydroxytryptamine in carcinoid.
ZE syndrome is characterized by peptic ulceration in duodenum and jejunum along with
diarrhea. The islet cell tumor in pancreas results in increased gastrin levels causing gastric acid
hypersecretion. Jejunitis caused by increased acidification and hypermotility due to increased
gastrin leads to diarrhea. Steatorrhea occurs due to inactivation of proteolytic enzymes and bile
acid precipitation. Presenting symptoms are abdominal pain and chronic diarrhea. The diagnosis
is considered if there is presence of recurrent or multiple gastroduodenal ulcers or family history
of ZE syndrome. Increased fasting gastrin levels (>125 pg/ml) suggests the diagnosis. Surgical
resection of the tumour is curative and palliation is done with proton pump inhibitors and
octreotide.
VIPoma: VIP secreting tumor leads to increased intestinal secretion. High volume (> 20 ml/
kg/d) watery diarrhea with hypokalemia and achlorhydria is typical. Commonest VIPoma in
children is ganglioneuroma or ganglioneuroblastoma. Surgical resection is curative; intravenous
rehydration and octreotide are used for symptomatic therapy.
Disaccharidase deficiency: Most of the dietary disaccharides and starch is normally hydrolyzed
and absorbed in the proximal small intestine. If not, it presents a large osmotic load which draws
fluid into the lumen and stimulates peristalsis. The unabsorbed sugars are excreted in part
unchanged and in part after bacterial degradation in colon leading to fermentative diarrhea.
Colonic bacteria lead to production of gas (H2, methane, CO2) and short chain fatty acids. Sugar
69
malabsorption typically leads to flatulence, borborygmus, abdominal distension, pain and
diarrhea. Stools are typically watery, explosive and with flatus and there is perianal excoriation.
Lactase deficiency is the most common genetically determined disaccharidase deficiency and is
of three types: congenital, primary or secondary to mucosal damage.
Congenital lactase deficiency: Very rare.
Primary lactase deficiency (adult type hypolactasia): In majority of human beings, intestinal lactase
activity declines to 5–10% of birth levels during childhood and adolescence. Symptoms have
a variable onset from 3 years to adolescence depending on ethnicity. The effects of lactose
ingestion are related to the dose with majority having no symptoms on ingestion of small
amounts of milk (~250 ml). The diagnosis should be considered in subjects with idiopathic
chronic diarrhea especially if aggravation occurs after increase in dietary lactose.
Diagnosis is suggested by the clinical response to withdrawal and relapse on reintroduction
of lactose (milk). Stools are typically acidic (pH <6) with reducing substance of >0.5%. A lactose
tolerance test or lactose hydrogen breath test can be done to confirm the diagnosis. In this test,
lactose is given at a dose of 2 gm/kg (max 50 gm) orally and blood glucose sample (basal and 30
min) or/and breath hydrogen sample (basal and half hourly till 3 hr) are taken. A blood glucose rise
of <20 mg/dl over basal at 30 minutes or breath H2 rise >20 ppm is taken as positive and confirms
the diagnosis. Estimation of lactase enzyme in jejunal biopsy is an invasive method to document
lactase deficiency. Genetic analysis is the gold standard for diagnosis of adult type hypolactasia.
It is managed with a milk restricted diet, whole milk is better than skimmed milk. Milk mixed with
cereals and yoghurt is well tolerated. Lactose free formulae or lactase enzyme (tablets) can also be
used. Provision of adequate calcium and vitamin D in the diet and patient education is essential.
Secondary lactase deficiency: Commonly occurs after damage to intestinal epithelium by viral
gastroenteritis, usually self limiting and resolves in days to weeks. It may also be coexistent with
other conditions causing villous atrophy like Crohn’s, giardiasis, celiac disease and severe PEM
and recovers with recovery of the primary disease.
Chronic Diarrhea of Neonatal Onset

A large number of conditions lead to intractable watery diarrhea in infancy.27, 28 These require
management at a specialized center as many of these are TPN dependent and may need intestinal
transplantation for cure. They can be broadly divided into 2 groups—
With villous atrophy:
1 . Microvillous inclusion disease
2. Tufting enteropathy
3. Autoimmune enteropathy
4. IPEX syndrome (immune dysfunction regulation, polyendocrinopathy, enteropathy and
X linkage)
Without villous atrophy:
1. Congenital chloride diarrhea
70 2. Congenital sodium diarrhea
3. Ileal bile acid receptor defect
4. Glucose-galactose malabsorption
A history of maternal polyhydramnios is common and often the diarrhea may be missed due
to confusion of passing urine in place of watery stool. A detailed discussion of these uncommon
conditions is beyond the scope of this chapter.
Other common etiologies like celiac disease, inflammatory bowel disease, parasitic
infestations, tuberculosis and pancreatic disorders are discussed in detail in the other sections of
this book.
Prognosis and Outcome

The underlying cause of chronic diarrhea is the main determinant of prognosis. Nutritional
support with correction of micronutrient deficiencies is essential in all subjects. With the
availability of special formulae, enteral/ parenteral nutrition and intestinal transplant, the
mortality has significantly decreased even in intractable diarrhea of infancy. Simple dietary
measures are the mainstay of therapy in conditions like celiac disease and food allergy and
utmost importance should be given to adequate and repeated dietary counselling. Recent years
have witnessed an increase in non infectious diseases like food allergy and inflammatory bowel
disease and this should be kept in mind. Advances in understanding of disease pathophysiology,
diagnostic evaluation and therapy had lead to improve outcomes of chronic diarrhea in children
over the years.
SUMMARY
Chronic diarrhea is diarrhea with an insidious onset and more than 2 weeks duration and is
to be differentiated from persistent diarrhea in young children. A detailed clinical evaluation
including anthropometry and signs of macro/micro nutrient deficiency is essential. An attempt
should be made to differentiate small bowel from large bowel diarrhea and maldigestion from
malabsorption as this helps in making a differential diagnosis and planning relevant investigations.
Nutritional therapy in form of enteral and parenteral nutrition along with supplementation of
minerals and vitamins has a key role in management. Dietary modifications are the cornerstone
of therapy in many conditions and detailed parental counselling is essential for success. Few
of these conditions require elaborate investigations for diagnosis and management, which is
available only at specialized centers. Timely referral for these is essential to prevent morbidities
like growth failure, osteoporosis, etc. Outcome largely depends on primary diagnosis and timely
adequate therapy.
Key Messages
1. Chronic diarrhea is an important cause of failure to thrive in infants and children.
2. Celiac disease, cow’s milk protein allergy, parasitic infestations and chronic nonspecific diarrhea are the common
causes in children.
3. A detailed history and careful clinical examination often helps in clinching the diagnosis.
4. High index of suspicion, timely referral and accurate diagnosis is the key to successful management.
5. Supplementation of macronutrients (carbohydrates, fats, proteins) and micronutrients in form of minerals and
vitamins is essential. 71
6. Outcome is largely dependent on the primary diagnosis.
REFERENCES
1. Maldigestion and Malabsorption. Schmitz J. 2000 (Third edition): Chapter 5, pages 46–58 in Pediatric
Gastrointestinal Disease. Pathophysiology, diagnosis, management. Edited by Walker WA, Durie PR,
Hamilton JR, Walker-Smith JA, Watkins JB. Publishers: BC Decker Inc Canada.
2. Diarrhea. Schiller LR, Sellin JH. 2010 (Ninth edition), volume1: chapter 15, pages 211–232 in Sleisenger
and Fordtran’s Gastrointestinal and Liver disease: Pathophysiology/Diagnosis/Management. Edited by
Feldman M, Friedman LS, Brandt LJ. Publishers: Elsevier Inc India.
3. World Health Organization: Diarrhea disease control. Persistent diarrhea in children, CCD/DDM/85.1,
Geneva, World Health Organization.
4. Rastogi A, Malhotra V, Uppal B, et al. Etiology of chronic diarrhea in tropical children. Tropical
Gastroenterology. 1998;19: 45–49.
5. Yachha SK, Misra S, Malik AK, Nagi B, Mehta S. Spectrum of malabsorption syndrome in North Indian
children. Indian J Gastroenterology. 1993;12:120–5.
6. Lee WS, Boey CCM. Chronic diarrhea in infants and young children: causes, clinical features and
outcome. J Pediatr Child Health. 1999; 35:260–3.
7. Altuntas B, Gul H, Yarali N, Ertan U. Etiology of chronic diarrhea. Ind J Pediatr. 1999; 66: 657–61.
8. Afzal NA, Addai S, Fagbemi A, et al. Refeeding syndrome with enteral nutrition in children: a case
report, literature review and clinical guidelines. Clin Nutr. 2002;21: 515–20.
9. Kneepkens CM, Hoekstra JH. Chronic nonspecific diarrhea of childhood: pathophysiology and
management. Pediatr Clin North Am. 1996; 43:375–90.
10. Johansson SG, Bieber T, Dahl R, et al. Revised nomenclature for allergy for global use: report of the
Nomenclature Review Committee of the World Allergy Organization, October 2003. J Allergy Clin
Immunol. 2004;113: 832–6.
11. Sicherer SH. Food Protein—induced enterocolitis syndrome: case presentation and management
lessons. J Allergy Clin Immunol. 2005;115:149–56.
12. Poddar U, Yachha SK, Krishnani N, Srivastava A. Cow’s milk protein allergy: an entity for recognition in
developing countries. Journal of Gastroenterology and Hepatology. 2010;25:178–82.
13. Nath SK. Tropical sprue. Curr Gastroenterol Rep. 2005;7:343–9.
14. Quigley Eamonn MM, Abu-Shanab A. Small intestinal bacterial overgrowth. Infect Dis Clin N Am. 2010:
24; 943–59.
15. Malik BA, Xie YY, Wine E, Huynh HQ. Diagnosis and pharmacological management of small intestinal
bacterial overgrowth in children with intestinal failure. Can J Gastroenterol. 2011;25:41–5.
16. Khodadad A, Aghamohammadi A, Parvaneh N, Rezaei N, Mahjoob F, Bashashati M et al. Gastrointestinal
manifestations in patients with common variable immunodeficiency. Dig Dis Sci. 2007;52:2977–83.
17. Wilcox CM, Saag MS. Gastrointestinal complications of HIV infection: changing priorities in the HAART
era. Gut. 2008; 57: 861–70.
18. Feasey NA, Healey P, Gordon MA. Review article: the etiology, investigation and management of
diarrhea in the HIV-positive patient. Aliment Pharmacol Ther. 2011;34:587–603.
19. Marjet JAM. Braamskamp, Koert M. Dolman, Merit M. Tabbers. Clinical practice Protein-losing
enteropathy in children. Eur J Pediatr. 2010;169:1179–85.
20. Scolopio JS. Short bowel syndrome. J Parenteral and Enteral Nutrition 2002; 26: S11-16.
21. Peretti N, Sassolas A, Roy CC, Deslandres C, Charcosset M, Castagnetti J et al. Guidelines for the
diagnosis and management of chylomicron retention disease based on a review of the literature and
the experience of two centers. Orphanet J Rare Dis. 2010;5:24.
22. Schmitt S, Küry S, Giraud M, Dréno B, Kharfi M, Bézieau S. An update on mutations of the SLC39A4 gene
in acrodermatitis enteropathica. Hum Mutat. 2009;30:926–33.
23. El-Matary W, Girgis S, Huynh H, et al. Microscopic colitis in children. Dig Dis Sci. 2010; 55: 1996–2001.
24. Camarero C, Leon F, Colino E, et al. Collagenous colitis in children: clinico-pathologic, microbiologic
72 and immunologic features. J Pediatr Gastroenterol Nutr. 2003;37:508–13.
25. Hempel S, Newberry SJ, Maher AR, Wang Z, Miles JN, Shanman R, Johnsen B, Shekelle PG. Probiotics for
the prevention and treatment of antibiotic-associated diarrhea: a systematic review and meta-analysis.
JAMA. 2012;307:1959–69.
26. Lo Vecchio A, Zacur GM. Clostridium difficile infection: an update on epidemiology, risk factors, and
therapeutic options. Curr Opin Gastroenterol. 2012;28:1–9.
27. Goulet O, Vinson C, Roquelaure B, Brousse N, Bodemer C, Cézard JP. Syndromic (phenotypic) diarrhea
in early infancy. Orphanet J Rare Dis. 2008;3:6.
28. Sherman PM, Mitchell DJ, Cutz E. Neonatal enteropathies: defining the causes of protracted diarrhea of
infancy. J Pediatr Gastroenterol Nutr. 2004;38:16–26.
73
7
Celiac Disease
Anshu Srivastava, Barath Jagadisan
Celiac disease (CD) is an immune mediated systemic disorder elicited by gluten and related
prolamines in genetically susceptible individuals and characterized by the presence of gluten-
dependent clinical manifestations, CD-specific antibodies, HLA-DQ2 or HLA-DQ8 haplotypes
and enteropathy.1 Gluten is the term used for the complex of water insoluble proteins found
in wheat, rye, barley and other related grains and indicates a broad group of prolamines like
gliadins in wheat, secalins in rye and hordeins in barley.
PREVALENCE
CD is common in West with a prevalence of 0.7%–2% in the general population depending on
the definition of CD used and the geographical area. It is the most common cause of chronic
diarrhea in children over 2 years of age in North India.2 Amongst adults it accounts for 26% and
65% of chronic diarrhea and malabsorption in western and northern India respectively.3, 4 Recent
studies have shown that histologically proven CD has a prevalence of 0.56% amongst apparently
healthy blood donors5 and 1.04% in the general community in North India.6 In a study of 400
children attending the department of pediatrics, 1% were diagnosed to have CD.7 There is a clear
predominance of CD in northern India as compared to southern India and this has been ascribed
to differences in dietary patterns (rice being the staple cereal in South India) and in genetic
constitution (lower prevalence of HLA DQ2 and DQ8).8 The apparent increase in CD incidence
in the past few decades is a result of increased awareness of the condition, recognition of its
atypical manifestations and widespread use of serology for diagnosis.9
Various terms have been used to describe the varied clinical presentations, disease spectrum,
diagnostic scenarios and complications of celiac disease.1, 10 A clear understanding of these terms
is essential for proper ‘labeling’ and management.
Classical or Typical CD denotes a gluten-induced enteropathy presenting with signs or
symptoms of malabsorption like diarrhea, steatorrhea and failure to thrive.
Atypical CD has been used to describe patients with gluten-induced enteropathy who have
non-GI manifestations (Table 7.1).
Silent or asymptomatic CD is defined as the presence of positive serology, compatible HLA
and small bowel biopsy findings of CD but without sufficient symptoms and signs to warrant
clinical suspicion of CD. These patients are usually diagnosed through screening of high-risk
groups (Table 7.2).
Celiac Disease
Table 7.1: Clinical presentations of celiac disease

GI Chronic or recurrent diarrhea
Abdominal bloating, pain, constipation, vomiting, lethargy, anorexia
Failure to thrive or weight loss, wasting
Non-GI Short stature, delayed puberty, amenorrhea
Refractory iron-deficiency anemia
Irritability/chronic fatigue
Osteoporosis
Rise in transaminases
Dermatitis herpetiformis
Aphthous stomatitis, dental enamel defects, arthritis/arthralgia
Neuropathy, ataxia, epilepsy with intracranial calcifications
Table 7.2: Conditions at “high risk” of celiac disease

First degree relatives
Autoimmune diseases Genetic disorders of celiac disease
patients
Type 1 diabetes mellitus: 3–12% * Down syndrome: 5–12% 4.0–20%
Autoimmune thyroiditis: 1.5–6.7% Turner syndrome: 4.1–8.1%
Autoimmune liver disease: 12–13.5% Williams syndrome: up to
Sjogren’s syndrome/Juvenile chronic arthritis: 1.5% 8.2%
IgA deficiency: 1.7–7.7%
*% denotes the proportion of cases with the “high risk” condition which have CD
Potential CD is defined as positive serology and compatible HLA and normal small intestinal
mucosa. These patients may or may not develop the enteropathy in later years.
Refractory CD (RCD) is defined as persistent or recurrent malabsorptive symptoms and signs
with villous atrophy (VA) despite a strict gluten free diet (GFD) for ≥12 months. RCD is divided
into two categories: type I, in which a normal intraepithelial lymphocyte (IEL) phenotype is
found; and type II, in which there is a clonal expansion of an aberrant IEL population.
CD autoimmunity is defined as positive serology on at least two occasions with unknown
biopsy status. If the biopsy is positive, then this is CD and if the biopsy is negative it is potential
CD.
Gluten-related disorders (GRD) is a term used to describe all conditions related to gluten. It
includes disorders like Dermatitis herpetiformis (DH), non-celiac gluten sensitivity (NCGS) and
CD.
Non-celiac gluten sensitivity is a condition in which gluten ingestion leads to symptoms
in the absence of CD (as defined by no enteropathy, negative serology and normal intestinal
permeability).11 The components of grains which trigger symptoms in people with NCGS is
unknown. It is also not clear whether some patients with NCGS have subtle small intestinal
morphological changes. Currently there are no standard diagnostic criteria for NCGS.
Dermatitis herpetiformis is a cutaneous manifestation of small intestinal immune mediated 75
enteropathy precipitated by exposure to dietary gluten.12 It is characterized by clusters of
herpetiform, pruritic papules and vesicles on the skin, especially on the elbows, buttocks and
knees. Skin biopsy shows IgA deposits in the dermal papillae and patients respond well to gluten
free diet (GFD).
Thus, the clinically evident cases of CD constitute only the tip of the iceberg and the exact
magnitude and relevance of the remaining spectrum is largely unknown. The prevalence of celiac
disease in the same population may vary among studies depending on the extent to which the
above spectrum has been covered.13
PATHOGENESIS
The pathogenesis of CD is best understood as the development of an autoimmune condition
precipitated by an environmental allergen in a genetically predisposed individual. CD is seen
in subjects with specific HLA-DQ2 and DQ8 genotype, but everyone with this genotype does
not develop CD. Multiple other genes contribute to the disease, each having a weak effect.
Recent genome-wide studies have shown that after the HLA, the second strongest association
is for single nucleotide polymorphism (SNP) close to the interleukin (IL) 2 and IL 21 genes on
chromosome 4q27.14
The prolamines in the offending grain, i.e. wheat, rye and barley are absorbed into the
lamina propria and then presented to sensitized T cells expressing α/β T cell receptor by antigen
presenting cells in conjunction with HLA DQ-2/DQ-8 antigens. Tissue transglutaminase (TTG)
deamidates the gliadin and generates negatively charged residues of glutamic acid which
further stimulates the lymphocytes. Activated lymphocytes generate interferon g, IL 4, tumor
necrosis factor α and other cytokines resulting in enterocyte damage.15 The target epitope of
antiendomysial antibody in CD is actually TTG. Anti-TTG antibody adds to the villous atrophy
as TTG is essential for epithelial differentiation. In the long term, the chronic stimulation of T
cells in CD, sometimes results in T cell lymphoma of the gut. The pathogenesis of extra-intestinal
malignancy in CD is an area under research.
Clinical Presentation
The clinical features can be divided into 2 groups: gastrointestinal (GI) and non-GI (Table 7.1).
Symptoms usually appear around 6–24 months of age, after weaning with wheat products.
Age of gluten introduction, amount of wheat eaten and duration of breastfeeding account for
variability in age of onset of symptoms. Stunting (100%), anemia (90-100%) and chronic diarrhea
(88-94%) are the most common symptoms in Indian children.16, 17 The long lag period between
symptom onset and diagnosis due to lack of awareness and incorrect diagnosis of tuberculosis
or intestinal infections leads to severe growth failure and malnutrition in our country.8, 16, 17
The non-GI presentation is now more common than the classic presentation with diarrhea
in the West. Atypical presentation has been shown to occur in 30–40% of all adults and children
diagnosed with CD in India.18, 19 It has been documented that children with atypical presentation
are older in comparison to those with classical presentation (10.4 vs. 5.5 years).18 In 2 other
pediatric studies, 37% cases of difficult to treat anemia and 14% cases of short stature were due
to CD.20, 21
76
Celiac Disease
Associated Conditions
The prevalence of CD is increased in some autoimmune and genetic conditions as shown in
Table 7.2 and these subjects should be screened for CD even in the absence of symptoms of CD.
First-degree relatives of CD patients are at an increased risk of developing CD. In an Indian study,
4.4% of the first-degree relatives had CD and only 15% of first-degree relatives were negative for
HLA DQ2 and DQ8.22
Diagnosis
The diagnosis of CD should always be on firm grounds as it is a life-time commitment to a strict
GFD which has significant compliance issues affecting the patient’s quality of life. At the same
time, missing the diagnosis can be life threatening. The testing for CD should always be done
when the subject is eating a normal (gluten containing) diet.
Testing for CD is recommended in the following two groups of patients:
Group 1: Children and adolescents with GI or non-GI symptoms and signs suggestive of CD (Table 7.1)
Group 2: Asymptomatic children and adolescents with an increased risk of CD (Table 7.2).
Apart from the suggestive clinical scenario, the diagnosis of CD rests on three main
investigations, i.e. serology, HLA testing and small bowel histology.
Celiac Serology
Anti-tissue transglutaminase (TTG) antibody, anti-endomysial antibody (EMA) and anti- deamidated
gluten peptide antibody (anti-DGP) are the CD specific antibodies. TTG and EMA are typically of IgA
type. TTG is a simple, accurate, ELISA based test for initial testing of CD. It has a high sensitivity
(92–100%) and specificity (91–100%) in both children and adults. Several studies have shown that
high serum concentration of anti-TTG antibody (> 10 ULN) predicts villous atrophy better than low/
borderline values.23 Low level of anti-TTG antibody may be present in other autoimmune diseases,
liver disorders, psoriasis and myocardial damage but these antibodies are not associated with
EMA positivity.1 EMA estimation is done by an immunofluorescence method which is expensive,
operator dependent and not available universally. Therefore, despite being the “gold standard”24 of
serology (specificity 98–100%) it is not recommended as a first line of CD testing.
For the correct interpretation of results of serology, the patient’s age, total serum IgA level,
pattern of gluten consumption and intake of any immunosuppressant drug should be taken
into consideration. It is important to measure the serum IgA level as selective IgA deficiency is
more common amongst CD patients than in general population. For IgA competent individuals,
conclusions should be drawn from the results of IgA class antibody tests. In patients with IgA
deficiency, one needs to ask for IgG TTG or IgG EMA. The sensitivity of TTG or EMA test is low
in children <2 years of age. In these patients, i.e. age < 2 years or with IgA deficiency anti-DGP
antibodies may be used as additional tests especially if the suspicion of CD is strong. Antigliadin
(IgA and IgG) and antireticulin antibodies have high false positivity and thus not recommended
as a test of choice now. Serology plays a very important role in making a diagnosis of CD in
77
developing countries as there are many other causes of villous atrophy like cow’s milk protein
allergy, giardiasis, bacterial overgrowth, etc.
HLA Testing
Testing for HLA DQ2 and DQ8 is useful to exclude CD as absence of HLA DQ2/DQ8 makes the
diagnosis of CD unlikely. The negative predictive value of this test is utilized to screen the “high-
risk” patients. HLA testing has a role in diagnosis of “doubtful” cases like symptomatic individuals
with mild infiltrative changes on histology. HLA DQ testing should be done by appropriate
methods and in expert labs.25
Histology
Small bowel biopsies are taken at upper GI endoscopy. The duodenum may be normal or show
findings like absent/scalloped duodenal folds, or mosaic pattern of mucosa but these are not
specific for CD.26 Biopsies need to be taken in all patients irrespective of mucosal appearance
at endoscopy. The “recognition” of these findings at endoscopy should lead to duodenal biopsy
even if the patient was subjected to endoscopy for other reasons.
Multiple biopsies should be taken from the duodenum; minimum of one from bulb and 4
from the second or third part of duodenum, as the histological changes in CD are patchy and of
variable severity.1 The histology should be evaluated and reported according to Marsh Oberhuber
criteria27 described below:
• Grade 0: normal
• Grade 1: infiltrative [normal architecture with increased intraepithelial lymphocytes (> 25–
30/100 epithelial cells)]
• Grade 2: hyperplastic (grade 1 + hyperplastic crypts)
• Grade 3: destructive (varying degrees of villous atrophy associated with crypt hyperplasia
and increased IELs along with reduced surface enterocyte height, irregular brush border and
sometimes cytoplasmic vacuoles [grade 2 + villous atrophy]). Grade 3 can be subdivided into-
– 3a: partial villous atrophy (shortened villi, crypt : villi ratio 1:1)
– 3b: subtotal villous atrophy (atrophic but recognizable villi)
– 3c: total villous atrophy (absent villi)
Marsh 3 changes are considered characteristic of CD. Marsh 2 is suggestive of CD but requires
serological positivity for supporting the diagnosis whereas grade 1 changes are considered non-
specific for CD in children.28
Other investigations: Hematological investigations show presence of iron deficiency or dimorphic
anemia with thrombocytosis and sometimes Howell Jolly bodies due to hyposplenism.
Coagulopathy (prolonged prothrombin time) due to vitamin K deficiency which gets corrected
by parenteral vitamin K administration and hypoalbuminemia may be present. Bone mineral
density may be reduced in some patients. Transaminase elevation to 1.5 to 3 times of normal is
seen in 9-40% of CD cases. The role of small bowel contrast studies is restricted to the diagnosis
of other conditions with similar presentation.
Diagnostic Criteria
The revision of the Interlaken statement by European Society for Pediatric Gastroenterology,
78 Hepatology and Nutrition (ESPGHAN) in 1990 recommended that a diagnosis of CD is made in
a patient with clinical features and small intestinal mucosal histology consistent with CD who
shows an unequivocal clinical response to GFD.29 The serology may or may not be positive. The
Celiac Disease
recommendations had done away with the need to demonstrate a histological response to GFD
by a repeat biopsy or the need to give a gluten challenge to all patients.
ESPGHAN experts recently evaluated the possibility of making a diagnosis of CD without
histology and gave the recommendations1 that a diagnosis of CD can be made without a small
bowel biopsy only in a patient who meets the following criteria:
• Symptomatic patient
• IgA anti-TTG level of >10 ULN
• Positive EMA
• Positive HLA DQ2/DQ8.
These patients should show symptomatic improvement with normalization of celiac serology
in follow-up on a gluten free diet.
In our country, serology and biopsy is a simpler, cheaper, widely available and more reliable
method of diagnosing CD as the restricted availability, reliability of reporting and high cost of
HLA DQ2/DQ8 and EMA testing limits its universal use. Moreover, these recommendations needs
to be validated by studies and affirmed by other gastroenterological societies before they can be
put into clinical practice. Thus, as of today, small bowel biopsy remains on essential component
for diagnosis of CD in own country.
The recommendation for the patients in group 2 (asymptomatic, high risk group) is to use
HLA testing as the first line test. Absence of DQ2 and DQ8 makes a diagnosis of CD highly unlikely
warranting no further follow-up or testing. In patients > 2 years of age with positive HLA testing,
serology is recommended. In patients with positive serology, duodenal biopsy is required to
confirm the diagnosis. If serology is negative, it is repeated at 2–3 years intervals or if symptoms
appear.
Gluten challenge is reserved for patients in whom the diagnosis remains doubtful after a period
of GFD consumption. It should not be done in children < 6 years of age and during pubertal
growth spurt. A gluten challenge is to be done with the utmost care as patients may respond
with serious symptoms during gluten re-introduction. In contrast, some patients may take a long
time to exhibit symptoms. HLA testing should be done if not done earlier as a negative HLA DQ2/
DQ8 makes a diagnosis of CD unlikely. Baseline serology and biopsy are taken. An abnormal
baseline biopsy obviates the need for challenge. The patient is started on one slice of bread and
if tolerated, it is increased gradually over 2 weeks to a minimum of 4 slices per day or equivalent.
It should be continued until the patient is symptomatic or for 2–3 months, when serology and
biopsy is repeated. If the patient is asymptomatic and both serology and biopsy are negative,
the patient is followed on a normal diet for at least 2 years when the challenge is considered
complete. Patients need to be on long-term follow-up as many late relapses are known.
Treatment
The treatment of CD is lifelong gluten free diet (GFD), i.e. no intake of wheat, barley and rye in
any form. Although consumption of moderate amounts (50–100 gm) of oat for 6–12 months has
been shown to be non-toxic,30 the ingestion of oats should also be avoided. This is due to high
rates of contamination of commercial oats with wheat. 79
GFD is initiated only after completion of the diagnostic process and when a definitive
diagnosis of CD has been made. Milk may be avoided initially during the period of lactose
intolerance when the villi are still regenerating. Combined iron and folate deficiency is a typical
consequence of proximal small bowel enteropathy which needs correction by supplementation.

Similarly zinc, vitamin D and calcium supplementation are important. Usually GFD is a low fiber
diet which needs to be addressed.
Repeated counseling by dieticians in patients native language regarding food items “to
be” and “not to be” consumed is very helpful in sustaining compliance (Table 7.3). Adequate
time should be given for answering queries of parents and patients. Celiac support groups help
patients by providing them with adequate dietary information including gluten free recipes.
Homemade food is preferred. Home grinding is advised to avoid contamination. Occasional
consumption of GFD by other family members also helps the child. Although in India there is no
current regulation advising all packaged food to declare the presence or absence of gluten but
the child/parent should be advised to read all ingredients in commercial food and it is best to
avoid when in doubt.
Celiac crisis is a rare but serious complication of CD, reported both in children and adults.
Jamma et al31 defined it as acute onset or rapidly progressing symptoms of CD associated with
metabolic abnormalities (hypoproteinemia, acidosis, and electrolyte abnormalities like hyper/
hyponatremia, hypocalcemia, hypokalemia or hypomagnesemia) and/or signs of shock and
renal dysfunction, requiring hospitalization and parenteral nutrition. The mainstay of treatment
is GFD with correction of fluid and electrolyte disturbances and steroids (in selected cases). It is
important to differentiate this entity from re-feeding syndrome which has similar manifestations
and occurs when rapid and aggressive nutritional rehabilitation is done in patients with severe
malnutrition.32
After initiation of GFD, there is a prompt symptomatic response with weight and height gain
in the first few months. Periodic visits for assessment of symptoms, adequacy of diet (gluten free
and adequate calories), and growth monitoring is essential. Serology is repeated after 6 months
1
of GFD to show a decrease in titers as an evidence of dietary compliance.
Table 7.3: Model gluten free diet (Taken from Department of Pediatric Gastroenterology, SGPGIMS,
Lucknow, India)
Not to be given Can be given
Cereals: Wheat flour (atta, maida)—roti, paratha, Rice (pulav, biryani),
naan; Semolina (sooji), Vermicelli (sewain), Broken Rice/maize/bajra/jowar roties
wheat (dalia), Noodles, Pasta Arrowroot flour, Gram flour, Water chestnut (Singhara)
flour
Bakery foods: Bread, burger, biscuits, cookies, nan Homemade biscuits or cakes made with rice, maize or
khatai, pizza, cake, pie arrowroot
Sweets and confectionary: Chocolates, toffee, Sugar candy, homemade sweets or ice-cream, fruit jam
chewing gum, ice-cream, most sweetmeats,
custard
Beverages: Commercial nutritional drinks, barley Milk and buttermilk, coffee, tea, squashes, fruit juices,
water, canned soups, broth thickened by barley, Home made clear soups (only stock, no flour)
stew thickened by refined floor
Other processed foods: Sauces, puree, instant curry Cottage cheese (homemade), homemade sauces,
80 mixes, white vinegar, mayonnaise, commercial pickles
salad dressing
Celiac Disease
In subjects who do not respond to a gluten-free diet, non-compliance or inadvertent

ingestion of gluten should be considered. Rising/persistent high titers of anti-TTG antibodies are
helpful in this setting. Adherence to GFD is a major issue with compliance rates varying between
45-81% in various studies. If compliance to GFD is ensured and diagnosis of CD is definite,
other conditions like lactose intolerance, irritable bowel syndrome, small intestinal bacterial
overgrowth and microscopic colitis should be considered and treated. Refractory disease is a
diagnosis of exclusion in these patients and is largely described in adults.
In CD, the overall risk of cancer is only mildly increased, i.e. 1.3 fold but it is much higher for
non Hodgkin’s lymphoma (3–6 fold) and small intestinal carcinoma (10 fold). Strict GFD has a
protective effect with the risk of malignancy being equal to that in normal population after 5–10
years of therapy.33
Due to the difficulties in compliance with lifelong GFD, various newer therapeutic approaches
are being evaluated. These include detoxification of gluten by use of prolyl endopeptidases. Two
drugs in this class, ALV003 and AN-PEP are undergoing clinical trials. Reduction of intestinal
permeability by using zonulin antagonist (AT-1001 lorazatide) or induction of tolerance to gluten
by peptide based desensitization are also being evaluated.34 Another approach is to develop
genetically modified wheat which does not have the “toxic” gluten.
Prevention
The timing of dietary gluten introduction and pattern of breastfeeding during infancy is crucial
for the future onset of CD. The optimal window for gluten introduction is between 4–7 months of
life and breastfeeding should be continued during this period as it may help in developing gluten
tolerance.35 The other dimension to this problem is that not all wheat is alike when it comes
to inducing celiac disease. The ancient or diploid wheats (e.g. Triticum monococcum) are poorly
antigenic, while the modern hexaploid wheats (e.g. Triticum aestivum) have highly antigenic
glutens, more capable of inducing celiac disease.36 Thus, the preferred use of diploid wheat may
be helpful, especially for the “at-risk” population. Also, as not all genetically susceptible subjects
develop CD, additional factors like GI infections as well as composition of intestinal microflora
are important for determining the risk. Preventions of GI infections like rotavirus in early life by
use of vaccines may play a role in prevention of CD.37
Key Messages
1. Celiac disease is the commonest cause of chronic diarrhea in children in North India.
2. Subjects with GI or non-GI symptoms suggestive of CD and those belonging to the “high-risk” groups need
evaluation for CD.
3. Serology (anti-TTG/anti-EMA), HLA DQ2/DQ8 testing and small bowel biopsy are the main investigations for
diagnosis.
4. Treatment is with lifelong GFD along with correction of micronutrient/vitamin deficiencies and should be initiated
only after a definitive diagnosis is made.
5. Repeated counseling by expert dieticians and guidance from “celiac support group” helps in sustaining life-long
compliance to GFD.
81
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gastroenterology, Hepatology, and nutrition guidelines on the diagnosis of celiac disease. J Pediatr
Gastroenterol Nutr. 2012; 54:136–60.
2. Yachha SK, Misra S, Malik AK, Nagi B, Mehta S. Spectrum of malabsorption syndrome in North Indian
children. Indian J Gastroenterology. 1993;12:120–5.
3. Thakur B, Mishra P, Desai N, et al. Profile of chronic diarrhea in adults in western India: a hospital based
study. Trop Gastroenterol. 2006;27:84–6.
4. Yadav P, Das P, Mirdha BR, et al. Current spectrum of malabsorption syndrome in adults in India. Indian
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5. Kochhar R, Sachdev S, Kochhar R, et al. Prevalence of coeliac disease in healthy blood donors: A study
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6. Makharia GK, Verma AK, Amarchand R, et al. Prevalence of celiac disease in the northern part of India:
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7. Bhattacharya M, Dubey AP, Mathur NB. Prevalence of celiac disease in north Indian children. Indian
Pediatr. 2009;46:415–7.
8. Yachha SK, Poddar U. Celiac disease in India. Ind J Gastroenterol. 2007; 26: 230–7.
9. Rewers M. Epidemiology of celiac disease: what are the prevalence, incidence, and progression of
celiac disease? Gastroenterol. 2005;128 (4Suppl 1): S47–51.
10. Ludvigsson JF, Leffler DA, Bai JC, et al. The Oslo definitions for coeliac disease and related terms. Gut
(2012). doi:10.1136/gutjnl-2011;301–46.
11. Biesiekierski JR, Newnham ED, Irving PM, et al. Gluten causes gastrointestinal symptoms in subjects
without celiac disease: a double-blind randomized placebo-controlled trial. Am J Gastroenterol. 2011;
106:508–14.
12. Bolotin D, Petronic-Rosic V. Dermatitis herpetiformis. Part I. Epidemiology, pathogenesis, and clinical
presentation. J Am Acad Dermatol 2011; 64:1017–24.
13. Fasano A. Clinical presentation of celiac disease in the pediatric population. Gastroenterology. 2005;
128 (4 Suppl 1): S68-73.
14. Freeman HJ, Chopra A, Clandinin MT, Thomson ABR. Recent advances in celiac disease. World J
15. Farrel RJ, Kelly CP. Celiac sprue. NEJM. 2002;346:180–8.
16. Poddar U, Thapa BR, Singh K. Clinical features of celiac disease in Indian children: are they different
from the West? J Pediatr Gastroenterol Nutr. 2006;43:313–7.
17. Mohindra S, Yachha SK, Srivastava A, et al. Coeliac disease in Indian children: assessment of clinical,
nutritional and pathologic characteristics. J Health Popul Nutr. 2001; 9:204–8.
18. Sharma A, Poddar U, Yachha SK. Time to recognize atypical celiac disease in Indian children. Indian J
19. Agarwal N, Puri AS, Grover R. Non-diarrheal celiac disease: a report of 31 cases from northern India.
Indian J Gastroenterol. 2007;26:122–6.
20. Bansal D, Trehan A, Gupta MK, Varma N, Marwaha RK. Serodiagnosis of celiac disease in children
referred for evaluation of anemia: a pediatric hematology unit’s experience. Indian J Pathol Microbiol.
2011;54:756–60.
21. Bhadada SK, Bhansali A, Ravikumar P, et al. Changing scenario in aetiological profile of short stature in
India-growing importance of celiac disease: a study from tertiary care centre. Indian J Pediatr. 2011;78:
41–4.
22. Srivastava A, Yachha SK, Mathias A, Parveen F, Poddar U, Agrawal S. Prevalence, human leukocyte
antigen typing and strategy for screening among Asian first-degree relatives of children with celiac
82 disease. J Gastroenterol Hepatol. 2010;25:319–24.
23. Dahlbom I, Korponay-Szabo IR, Kovacs JB et al. Prediction of clinical and mucosal severity of celiac
disease and dermatitis herpetiformes by quantification of IgA/IgG serum antibodies to tissue
transglutaminase. J Pediatr Gastroenterol Nutr. 2010;50:140–6.
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24. Lewis NR, Scott BB. Systematic review: the use of serology to exclude or diagnose celiac disease: a
comparison of the endomysial and tissue transglutaminase antibody tests. Aliment Pharmacol Ther.
2006;24:47–54.
25. American Gastroenterological Association (AGA) Institute technical review on the diagnosis and
management of celiac disease. Gastroenterol. 2006;131:1981–2002.
26. Shah VH, Rotterdam H, Kotler DP, Fasano A, Green TH. All that scallops is not celiac disease.
Gastrointestinal Endosc. 2000;51:717–20.
27. Oberhuber G, Granditsch G, Vogelsang H. The histopathology of coeliac disease: time for a standardized
report scheme for pathologists. Eur J Gastroenterol Hepatol. 1999;11:1185–94.
28. Hill ID, Dirks MH, Liptak GS, Colletti RB, Fasano A, Guandalini S, et al. North American Society for Pediatric
Gastroenterology, Hepatology and Nutrition Guideline for the diagnosis and treatment of celiac
disease in children: recommendations of the North American Society for Pediatric Gastroenterology,
Hepatology and Nutrition. J Pediatr Gastroenterol Nutr. 2005;40:1–19.
29. Walker Smith JA. For working group of European Society of Paediatric Gastroenterology and Nutrition.
Revised criteria for diagnosis of celiac disease. Report of Working Group of European Society of
Paediatric Gastroenterology and Nutrition. Arch Dis Child. 1990;65:909–11.
30. Hoffenberg EJ, Haas J, Drescher A et al. A trial of oats in children with newly diagnosed celiac disease. J
Pediatr. 2000;137:361–6.
31. Jamma S, Rubio-Tapia A, Kelly, CP et al. Celiac crisis is a rare but serious complication of celiac disease
in adults. Clin Gastroenterol Hepatol. 2010;8:587–90.
32. Agarwal J, Poddar U, Yachha SK, Srivastava A. Refeeding syndrome in children in developing countries
who have celiac disease. J Pediatr Gastroenterol Nutr. 2012;54:521–4.
33. Verkarre V, Romana SP, Cerf-Bensussan N. Gluten free diet, chromosomal abnormalities and cancer
risks in celiac disease. J Pediatr Gastroenterol Nutr. 2004;38:140–2.
34. Sallid LM, Khosla C. Novel therapies for celiac disease. J Intern Med. 2011;269:604–13.
35. Norris JM, Barriga K, Hoffenberg EJ et al. Risk of celiac disease autoimmunity and timing of gluten
introduction in the diet of infants at increased risk of disease. JAMA. 2005;293:2343–51.
36. Molberg O, Uhlen AK, Jensen T, Flaete NS, Fleckenstein B, Arentz-Hansen H, et al. Mapping of gluten
T-cell epitopes in the bread wheat ancestors: implications for celiac disease. Gastroenterology. 2005;
128:393–401.
37. Discepolo V, Troncone R. What’s new in celiac disease? J Pediatr Gastroenterol Nutr. 2012;54 (supp1):
S3–S6.
83
8
Abdominal Tuberculosis
A Riyaz
Mycobacterium tuberculosis infects one-third of the world’s population and kills 3 million people
each year and hence, it is the single most important infectious cause of death on earth.1 It has
been estimated that between 2000–2020, one billion people will be infected, 200 million will
become sick , and 35 million will die, if control measures are not strengthened.
Abdominal tuberculosis (abdominal TB) is a major health problem in the developing
countries. A recent significant increase has occurred in developed countries also, especially in
association with HIV infection. It can affect almost any part of the gastrointestinal tract from
the mouth to the anus, the peritoneum and the pancreatobiliary system. It is the sixth most
frequent site of extra pulmonary TB.2 The presentation can be quite varied, and the pediatrician
must always consider the possibility of TB and confirm or exclude this treatable malady in any
child who presents with prolonged gastrointestinal symptoms.
The term “abdominal TB” refers to disease of the gastrointestinal tract, peritoneum and
abdominal lymph nodes. Genitourinary TB is usually classified into a separate entity, even though
kidneys and a major portion of the genital system in the female are intra-abdominal organs.3
CLASSIFICATION OF ABDOMINAL TB
1. Intestinal TB—65%
2. Peritoneal TB—30%
3. Glandular (lymph nodal) TB—5%.
ETIOPATHOGENESIS
In India, TB is caused mainly by Mycobacterium tuberculosis. However, in a study of 26 children
from Chile, Mycobacterium bovis was isolated in 80% of the 71 culture positive cases.4 Some of the
other species implicated are Mycobacterium avium and Mycobacterium intracellulare,5 especially
in HIV infected children.
The routes of GI infection include the following:
1. Hematogenous spread from the primary lung focus in childhood.
2. Ingestion of infected sputum, in patients with sputum positive, cavitary TB.
3. Direct spread from adjacent organs with primary tuberculous infection as in renal TB affecting
the duodenum.
4. Lymphatic spread from mediastinal tuberculous lymph nodes to the esophagus.
The most common site of involvement is the ileocecal region, possibly because of the
increased physiologic stasis, increased rate of fluid and electrolyte absorption, minimal
digestive activity and an abundance of lymphoid tissue at this site. It has been shown that the
M cells associated with Peyer’s patches can phagocytose BCG bacilli.6 The frequency of bowel
involvement decreases as one proceeds both proximally and distally from the ileocecal region.7
Peritoneal involvement may be due to spread from lymph nodes, intestinal lesions, or from
tuberculous salpingitis in adolescent girls. Abdominal lymph nodal and peritoneal TB may also
occur without gastrointestinal involvement in 30%.8
PATHOLOGY
Intestinal TB is of three types:
Ulcerative (60%)
It is seen more in the small intestine, especially in patients with malnutrition. This is considered a
highly active form of the disease.
It is characterized by inflammation and fibrosis of the bowel wall and the regional lymph
nodes. The serosal surface may show nodular masses of tubercles. The initial lesion is an
infiltration of the intestinal mucosa and Peyer’s patches. The infected areas soon ulcerate and
become necrotic. Inflammatory cells, epithelioid cell granulomas and Langhans giant cells may
be seen. The pathognomonic feature is the presence of caseation, which however, may not be
always present.9 The ulcers are shallow, and they often have a raised granulomatous edge. At this
stage of the disease, changes are reversible and healing without scar formation is possible. As
the disease progresses, ulceration becomes confluent and extensive fibrosis leads to bowel wall
thickening and pseudotumoral mass lesions, strictures and fistulae.
As tuberculous ulcers are superficial, they usually do not penetrate beyond the muscularis
mucosa.10 They may be single or multiple, and the intervening mucosa is usually uninvolved. The
long axis of the ulcer lies transversely as it follows the lymphatics, unlike Crohn’s disease, in which
the ulcers are superficial or serpiginous.11 Endarteritis may produce ischemia and contribute
to the development of strictures.12 This is also responsible for the rarity of massive bleeding in
intestinal TB.
Hypertrophic (10%)
This is seen in patients who are relatively well nourished. It is characterized by thickening of the
bowel wall with scarring, fibrosis and a rigid mass like appearance that may mimic carcinoma.
Ulcerohypertrophic (30%)
This is seen in the ileocecal region and colon. These patients have features of both the ulcerative
85
and hypertrophic types. They usually present with a lump in the right iliac fossa. Both sides of
the ileocecal valve are affected leading to incompetence of the valve, which is another point of
distinction from Crohn’s disease.
Peritoneal TB
• Ascitic
• Encysted
• Fibrous
• Purulent
Lymph nodal TB
• Mesenteric
• Other local nodes
• Retroperitoneal
CLINICAL FEATURES
Abdominal TB is seen mainly in young adults in the age group of 20–40 years. It is rare in children
compared to adults. In a study from Chennai, out of 1028 hospitalized children, 3.6% had
abdominal TB.13 Children above 5 years coming from poor socioeconomic status are affected
more. The spectrum of disease in the pediatric population is different from adults as peritoneal
and lymph node involvement is more common.14 Abdominal TB is reported in 10–20% of patients
with pulmonary TB, whereas associated pulmonary TB is seen in 20–75% of patients with
abdominal TB. Increasing severity of pulmonary TB increases both the incidence and severity
of abdominal TB.15 It is more common in immunocompromised people. In HIV- infected people,
tuberculosis tends to occur earlier than the other AIDS-defining opportunistic infections when
the CD4 cell count is in the range of 150–300 cells per microliter.
Oral TB
This is seen in children with severe malnutrition, who have long standing TB of one or more
internal organs. Lesions are seen mainly on the tongue. Small edematous red nodules rapidly
break down to form painful shallow ulcers with undermined bluish edges. The ulcers are less
than 2 cm in diameter and do not heal spontaneously.16
Esophageal TB
This is the least common site of tuberculosis (0.2%). A 14-year-old boy with typical features has
been reported by Sathiyasekaran recently.17 It occurs due to spread from the mediastinal lymph
nodes, lungs or spine. The patient may present with dysphagia and retrosternal pain.
Gastric and Duodenal TB

TB of the stomach and duodenum is rare (1%) due to the following facts:
1. Scarcity of lymphoid tissue in the upper GI tract
2. High acidity
3. Rapid passage of ingested organisms into the small bowel.
These patients present with dyspepsia, which is usually mistaken for peptic ulcer. It may lead
86 on to complications like perforation, fistulae, excavating ulcers extending into the pancreas and
obstructive jaundice by compression of the common bile duct.
Endoscopy and barium studies reveal multiple large and deep ulcers in the lesser curvature
of the antrum or in the pyloric area. It may result in gastric outlet obstruction and duodenal
strictures.
Small Bowel TB
TB is the second commonest cause of intestinal perforation in India, the first being typhoid.18
Tuberculous perforations are usually single and proximal to a stricture.
TB is a common cause of malabsorption in India. A history of recurrent abdominal pain in
a patient with malabsorption is suggestive of TB.19 Malabsorption may be caused by bacterial
overgrowth in a stagnant loop, bile salt deconjugation and diminished absorptive area due to
ulceration. Involvement of the mesenteric lymphatic system, known as tabes mesenterica, retards
chylomicron removal because of lymphatic obstruction, and contributes to malabsorption.
The ileum is more commonly affected than jejunum. Ileocecal involvement is seen in 80–
90% of patients with GI tuberculosis. These patients present with abdominal pain, weight loss,
anemia, bilious vomiting and irregular fever. There may be a doughy feel on palpation. A firm
mass may be palpable in the right iliac fossa. The most common complication is obstruction due
to stricture.
TB of Vermiform Appendix
The vermiform appendix may be involved secondary to extension of ileocecal disease or by
retrograde lymphatic spread, and may present as acute appendicitis. Tuberculous appendicitis
is extremely rare in children, but recently a case has been reported in a 2-year-old girl by Sinha.20
Segmental Colonic TB
Segmental or isolated colonic TB refers to the involvement of the colon sparing the ileocecal
region, and constitutes 9% of all cases of abdominal TB. The common sites are the sigmoid colon,
ascending colon and transverse colon. Colonic TB is most often associated with ileal TB.21
The common symptoms are irregular fever, diarrhea, weight loss, abdominal pain and a firm
lump in the right iliac fossa. Hematochezia is seen in 30%. The bleeding is frequently minor and
massive bleeding is rare. The diagnosis is suggested by barium enema or colonoscopy.
Rectal and Anal TB

Rectal TB is very rare in children. The commonest symptom is hematochezia, followed by
constitutional symptoms and constipation. Rectal examination reveals a tight annular stricture
with deep ulceration.
Anal TB is also very rare in children but a few cases have been described by Widhwa et al.22
Tuberculous Peritonitis
There are four varieties of tuberculous peritonitis: ascitic, encysted, fibrous and purulent.23
1. Ascitic form: The onset is insidious with malaise, irregular fever, loss of weight and abdominal 87
distension. Abdominal pain is usually minimal but the child may have abdominal discomfort
which may be associated with diarrhea or constipation. Shifting dullness and even fluid
thrill may be elicited, if the child has massive ascites. In the male child, congenital hydrocele
may sometimes appear, due to the patent processi vaginales becoming filled with ascitic
fluid from the peritoneal cavity. An umbilical hernia may appear due to the increased intra-
abdominal pressure. On palpation, a transverse solid mass can be detected, due to rolled-up
greater omentum infiltrated with tubercles.
The peritoneal cavity is filled with straw colored fluid and the peritoneum is studded
with tubercles.
2. Encysted (loculated) form: This is similar to the above, but only one part of the bowel is
involved. Thus, a localized intra-abdominal swelling is produced, which results in considerable
diagnostic difficulties. It is usually mistaken for mesenteric cysts in children. It may result in
late intestinal obstruction.
3. Fibrous (plastic) form: This is characterized by wide spread adhesions, which cause coils of
intestine, especially the ileum, to become matted together and distended. The distended
coils act as ‘blind loops’ and hence, the child develops colicky pain, steatorrhea and wasting.
They may develop subacute or acute intestinal obstruction. Examination reveals a palpable
mass due to the adherent omentum and intestine, and thickened mesentery.
4. Purulent form: This is usually secondary to tuberculous salpingitis, and is hence, rare in
children.
Lymph Nodal TB
This may present as a firm lump in the abdomen due to enlarged lymph nodes, loculated
ascites, matted omentum or intestine. The lymph nodes may obstruct bile duct, pancreatic duct,
duodenum, inferior vena cava and ureter.23
DIFFERENTIAL DIAGNOSIS
Abdominal TB should always be considered in the differential diagnosis of children with obscure
abdominal symptoms or physical findings, especially those who are immunocompromised or living
in areas where TB is endemic.
It may be extremely difficult to differentiate Crohn’s disease from TB as it gives virtually all
of the changes of intestinal TB. Severe active Crohn’s disease is usually not found in patients with
advanced HIV infection. The demonstration of M. tuberculosis helps to clinch the diagnosis of TB,
but it may be very difficult. The importance of differentiating Crohn’s disease from TB is more
critical today because of the potential to do harm with steroids and immunomodulatory agents.
The combination of these agents would have adverse consequences in cases of intestinal TB
misdiagnosed as Crohn’s disease (Table 8.1).
Yersinia enterocolitica can produce mesenteric adenopathy, ulcerations and thickening
of the bowel mucosa. Usually, this infection has a shorter history and resolves spontaneously.
Involvement of the cecum with carcinoma or amebiasis can be confused with TB in adults , but
these are very rare in children.
Immunoproliferative small intestinal disease (IPSID, α heavy chain disease, Mediterranean
88 lymphoma) is very rare in children. It is confined to certain regions of the world, especially
North Africa, Mediterranean countries, India and East Asia. Symptoms include fever, anorexia,
colicky abdominal pain, malabsorption and significant weight loss. Physical examination
Table 8.1: Differences between intestinal TB and Crohn’s disease24

Intestinal TB Crohn’s disease
Clinical Features
Fever +++ +
Diarrhea ++ +++
Hematochezia + ++
Perianal sinus/fistula – ++
Duration of symptoms Relatively short Prolonged
Endoscopy
Cobblestone appearance + +++
Aphthous ulcers + ++
Longitudinal ulcers + +++
Pseudopolyps + ++
Histology
Caseation necrosis ++ –
Large granulomas +++ +
Confluent granulomas ++ –
AFB + –
reveals emaciation, clubbing, and peripheral edema. Late physical manifestations are ascites,
hepatosplenomegaly, abdominal mass and peripheral lymphadenopathy.
DIAGNOSIS AND INVESTIGATIONS

Paustian’s Criteria25
At least one of the following criteria must be present to diagnose abdominal TB:
• A typical gross description of operative findings with biopsy of mesenteric nodes showing
histologic evidence consistent with tuberculosis
• Histologic demonstration of typical acid-fast staining rods of M. tuberculosis in the lesion
• Histologic evidence of tubercles with caseation necrosis
• Animal inoculation or culture of suspected enteric (exclusive of mucosal layer), mesenteric, or
regional lymph node tissue resulting in growth of the tubercle bacillus.
These are rather rigid criteria which may be considered and the diagnosis should be
substantiated by newer techniques like endoscopy, radiologic studies, USG, CT scan, PCR, etc.
Non-specific findings include raised ESR, anemia, and hypoalbuminemia. Total lymphocyte
count is raised in 50% of patients.26 Mantoux test is positive in about 50%.27
It may be noted that abdominal TB is a paucibacillary disease and microbiological proof
may not be always possible. Characteristic histological findings in a malnourished child with
prolonged gastrointestinal symptoms are sufficient to start treatment in endemic areas.
RADIOLOGICAL STUDIES
Chest Radiograph 89
Evidence of TB in a chest radiograph is seen in only about 25% and hence a normal chest
radiograph does not exclude abdominal TB.
Plain Radiograph of Abdomen

Plain radiograph of abdomen may show enteroliths, features of obstruction, i.e. dilated bowel
loops with multiple air fluid levels, and evidence of ascites, perforation or intussusception. In
addition, there may be calcified lymph nodes, calcified granulomas and hepatosplenomegaly.
Small Bowel Barium Meal

The following findings may be seen:
• Accelerated intestinal transit.
• Hypersegmentation of the barium column (chicken intestine).
• Precipitation, flocculation and dilution of barium.
• Nodular thickening of mucosal folds with loss of symmetry in fold pattern.
• Deep fissures, sinus tracts, enterocutaneous fistulae, and perforation can occur, although less
commonly, compared to Crohn’s disease.
• Luminal stenosis with smooth but stiff contours (hour glass stenosis).
• Multiple strictures with segmental dilatation of bowel loops.
• Typical ulcers may be demonstrated by double-contrast examination.
Barium Enema
The following features may be seen:
• Early involvement of the ileocecal region manifesting as spasm and edema of the ileocecal
valve. Thickening of the lips of the ileocecal valve and/or wide gaping of the valve with
narrowing of the terminal ileum (“Fleischner” or “inverted umbrella sign”) are characteristic.
• Fold thickening and contour irregularity of the terminal ileum, better appreciated on double
contrast study.
• “Conical cecum”, shrunken in size and pulled out of the iliac fossa due to contraction and
fibrosis of the mesocolon. The hepatic flexure may also be pulled down.
• Loss of normal ileocecal angle, and a dilated terminal ileum appearing suspended from a
retracted, fibrosed cecum (goose neck deformity).
• “Purse string stenosis”—localized stenosis opposite the ileocecal valve with a rounded off
smooth cecum and a dilated terminal ileum.
• “Stierlin’s sign” is a manifestation of persistent irritability from inflammation of the terminal
ileum. It is characterized by lack of barium retention in the inflamed segments of the ileum,
cecum and variable length of the ascending colon, with a normal configured column of
barium on either side. It appears as a narrowing of the terminal ileum with rapid emptying
into a shortened, rigid or obliterated cecum.
• “String sign of Kantor” —persistent narrow stream of barium indicating stenosis.
Both Stierlin’s sign and Kantor’s string sign can also be seen in Crohn’s disease and hence are not
specific for TB.
Enteroclysis followed by a barium enema may be the best protocol for evaluation of intestinal
TB.
Ultrasonography
90
Barium studies though accurate for intrinsic bowel abnormalities, do not detect lesions in the
peritoneum. Ultrasound is very useful for diagnosing peritoneal TB.
The following features may be seen, usually in combination.28

• Intra-abdominal fluid, which may be free or loculated
• “Club sandwich” or “sliced bread” sign is caused by localized fluid between the radially
oriented bowel loops, due to local exudation from the inflamed bowel (interloop ascites).
• Lymphadenopathy may be discrete or matted. The echotexture is mixed heterogenous, in
contrast to the homogenously hypoechoic nodes of lymphoma. Small discrete anechoic areas
representing zones of caseation may be seen within the nodes. With treatment the nodes
show a transient increase in size for 3–4 weeks and then gradually reduce in size. Calcification
in healing lesions is seen as discrete reflective lines. Both caseation and calcification are
highly suggestive of a tuberculous etiology and are rare in lymphoma.
• Bowel wall thickening is best appreciated in the ileocecal region. The thickening is uniform
and concentric as opposed to the eccentric thickening at the mesenteric border found in
Crohn’s disease and the variegated appearance of malignancy.
• Pseudokidney sign—involvement of the ileocecal region which is pulled up to a subhepatic
position.
CT Scan
The most common findings on CT that are highly suggestive of abdominal TB are high density
ascites, lymphadenopathy, bowel wall thickening, and irregular soft tissue densities in the
omental area.
Initially there is slight symmetric circumferential thickening of the cecum and terminal ileum.
Subsequently, the ileocecal valve and adjacent medial wall of the cecum are asymmetrically
thickened. In more advanced disease gross wall thickening, adherent loops, large regional
nodes and mesenteric thickening can together form a soft tissue mass centered on the ileocecal
junction. CT scan can also pick up ulceration or nodularity within the terminal ileum, along with
narrowing and proximal dilatation. Complications like perforation, abscess, and obstruction can
be visualized.
Mesenteric disease on CT scan is seen as a patchy or diffuse increase in density, strands
within the mesentery, and a stellate appearance. Lymph nodes may be interspersed. Omental
thickening is well seen often as an omental cake appearance.
Caseating lymph nodes are seen as having hypo dense centers and peripheral rim enhance-
ment. Along with calcification, these findings are highly suggestive of TB. In tuberculosis the
mesenteric, mesenteric root, celiac, porta hepatis and peripancreatic nodes are characteristically
involved, reflecting the lymphatic drainage of the small bowel. The retroperitoneal nodes (i.e.
the periaortic and pericaval) are relatively spared, and are almost never seen in isolation, unlike
lymphoma.29
Endoscopy
Endoscopy of the upper GI tract is useful in the diagnosis of lesions in the esophagus, stomach
and duodenum.
The availability of single and double-balloon enteroscopy and video capsule endoscopy has
made the diagnosis of small bowel TB easier. The ulcers in small bowel TB are characteristically 91
shallow with an extensive irregular “geographic” border, are usually not larger than 1–2 cm in
length and are transverse rather than the typical longitudinal ulcers seen in CD.
Colonoscopy is an excellent tool to diagnose colonic and terminal ileal involvement. Mucosal
nodules and ulcers are pathognomonic. The nodules have a pink surface without friability and
are most often found in the cecum especially near the ileocecal valve. Ulcers are usually seen
between the nodules. The intervening mucosa may be hyperemic or normal. Areas of strictures
with nodular and ulcerated mucosa may be seen. Other findings are pseudopolypoid edematous
folds, and a deformed and edematous ileocecal valve.
Biopsies should be taken from the edge of the ulcers. Granulomas and caseation may be
noted in positive cases.30
The yield of acid-fast bacilli is variable. A combination of histology and culture of the biopsy
material can be expected to establish the diagnosis in over 60% of cases.
Immunological Tests
The value of immunological tests remains undefined in clinical practice. ELISA and SAFA (soluble
antigen fluorescent antibody) tests for detection of circulating antibodies cannot distinguish
between past and present infections. However, a study by Bhargava et al showed that ELISA has
a diagnostic accuracy of 84% in abdominal TB.31
Ascitic Fluid Examination

In tuberculous ascites, the fluid is typically straw colored. The protein content is more than
3 g% and the cell count 150–4000, more than 70% being lymphocytes. The serum ascites albumin
gradient (SAAG) is less than 1.1. This is a much better guide to diagnose tuberculous peritonitis,
than ascitic fluid protein alone.32 AFB staining is positive only in 3%. A positive culture is obtained
in about 20% of cases, but it takes 6–8 weeks for the mycobacterial colonies to appear.
Adenosine deaminase is increased in tuberculous ascitic fluid due to the stimulation of T-cells
by mycobacterial antigens. However, in co-infection with HIV, the ADA values can be normal
or low. Interferon-γ levels are high in tuberculous ascites. Combining both ADA and interferon
estimations may further increase sensitivity and specificity. 33
Polymerase chain reaction may help to diagnose TB quickly by identifying DNA from
M. tuberculosis in clinical samples that are negative by microscopic examination. The most
commonly used target for detection of M. tuberculosis is the insertion sequence IS6110. PCR has
a limited role in evaluating children with TB. A negative PCR never eliminates the possibility of
TB, and a positive result is not always confirmatory. Besides, it is very expensive.34
Laparoscopic Findings
The laparoscopic findings in peritoneal TB can be grouped into 3 categories35
i. Thickened peritoneum with tubercles. The omentum, liver and spleen may also be studded
with tubercles.
ii. Thickened peritoneum without tubercles.
iii. Fibroadhesive peritonitis with markedly thickened peritoneum and multiple thick adhesions
fixing the viscera.
92
Laparotomy
Laparotomy is indicated only when the other methods fail. An experienced surgeon can easily
recognize tuberculous lesions, which can be confirmed by AFB staining, culture , histopathology
or PCR.36
MANAGEMENT
It may sometimes be very difficult to diagnose abdominal TB in children. If there is a strong
clinical suspicion of abdominal TB in a child with malnutrition in endemic areas, a therapeutic
trial of anti-TB treatment may be justified.37 The Revised National Tuberculosis Control Program
(RNTCP) was started in 1993 and by now it covers over 740 million people. Of the children treated
under RNTCP, both the cure and completion rates were above 90%. Abdominal TB comes under
category I, in which INH, rifampicin, pyrazinamide and ethambutol are given thrice weekly for
two months. In the continuation phase, INH and rifampicin are continued in the same dose for
four months.38 Antituberculous treatment may result in healing with fibrosis which may cause
adhesions and strictures. The role of corticosteroids in the prevention of strictures and adhesions
is not defined. Anand et al showed that clinical and radiologic resolution of tuberculous strictures
may occur with ATT, even in patients presenting with subacute intestinal obstruction.39
All children should be carefully monitored for hepatitis. A baseline SGPT may be done and
repeated periodically in the first 8 weeks of therapy, as the chance of hepatitis is high in this
period. If hepatitis occurs, INH, pyrazinamide and rifampicin should be stopped immediately. If
hepatitis is missed and ATT continued, the child may develop fulminant hepatitis. Ethambutol is
given in the dose of 15 mg/kg, until hepatitis resolves, and then INH, rifampicin and pyrazinamide
may be restarted. If hepatitis recurs, INH and ethambutol may be given. Ethambutol may rarely
cause optic atrophy and blindness. Hence, periodic ophthalmic evaluation is necessary in all
patients on ethambutol.
All children on ATT should be given hepatitis B vaccine, if they have not already received
it. Hepatitis A is endemic in our country. Hence, if the parents can afford, they may be given
hepatitis A vaccine also.
Family members, especially grandparents, must be screened for TB.
Surgery may be occasionally required. Tuberculous perforations are usually ileal and are
associated with distal strictures. The preferred treatment is usually resection and anastomosis,
as simple closure of the lesion is associated with a high incidence of leak and fistula formation.
Strictures which reduce the lumen by half or more are treated by stricturoplasty..40 For ileocecal
lesions, previously a right hemicolectomy used to be done. However, it has been shown that a
limited resection of the ileocecal area is sufficient as it involves lesser dissection which minimizes
risk of injury to the duodenum and ureter. 41
SUMMARY
Abdominal TB is a vexing problem in children in the developing countries. It is common in HIV
infected people in the West. It is defined as infection of the gastrointestinal tract, peritoneum or
93
lymph nodes. There is a paucity of literature of this condition in children. Peritoneal and lymph
node involvements are more common in children than in adults. The commonest site in the
intestine is the ileocecal area.
It may be acquired by the hematogenous route, swallowing of infected sputum or from
neighboring organs. The child may present with irregular fever, failure to thrive, abdominal pain,
alternating diarrhea and constipation, or a lump in the abdomen. A diagnosis may be made by
a combination of radiologic, endoscopic, microbiologic, histologic and molecular techniques. A
high index of suspicion is essential as the clinical manifestations may be non-specific. In all cases
of unexplained exudative ascites, tuberculous peritonitis should be excluded.
Abdominal TB comes under category I of RNTCP. Patients should be carefully monitored for
drug toxicities, especially hepatitis. Surgery may be occasionally required.
Key Messages
Abdominal TB is a rare condition in children. A definitive diagnosis may not be possible always. Hence, a high index of
suspicion is essential. If treated adequately, the prognosis is good. It is important to identify and treat contacts.
REFERENCES
1. Bloom BR, Murray CJL: Tuberculosis: commentary on a reemergent killer. Science 257;1055,1992.
2. Sharma MP, Bhatia V. Abdominal tuberculosis. Indian J Med Res. 2004;120:305–25.
3. Wig KL, Tandon BN. Abdominal tuberculosis. In. Rao KN, Viswanathan R. Textbook of tuberculosis 2nd
ed Vikas publishing house PVT limited, New Delhi.1981,462–71
4. Veeragandham RS, Lynch FP, Canty TG, Collins DL, Danker WL. Abdominal tuberculosis in children:
review of 26 cases. J Pediatr Surg. 1996;13:170–5.
5. Vij JC, Malhotra V, Choudhary V, Jain NK, Prasad G, Choudhary A et al. A clinicopathological study of
abdominal tuberculosis. Indian J Tuberc. 1992;39:213–20.
6. Bhansali SK. Abdominal tuberculosis. Experience with 300 cases. Am J Gastroenterol. 1977;67:324–37.
7. Prakash A. Ulcero-constrictive tuberculosis of the bowel. Int Surg. 1978;63:23–9.
8. Hoon JR, Dockerty MB, Peberton J. Ileocecal tuberculosis including a comparison of this disease with
non-specific regional enterocolitis and noncaseous tuberculous enterocolitis. Int Abstr Surg. 1950:91:
417–40.
9. Tandon H. The pathology of intestinal tuberculosis. Trop Gastroenterol. 1981;2:77–93.
10. Tandon HD, Prakash A. Pathology of intestinal tuberculosis and its distinction from Crohn’s disease.
Gut. 1972;13:260–9.
11. Anand BS. Distinguishing Crohn’s disease from intestinal tuberculosis. Natl Med J India. 1989;2:170–5.
12. Kapoor VK. Abdominal tuberculosis. Postgrad Med J. 1998;74:459–6.
13. Parthasarathy A, Sumathi N, Manoharan R, et al. Controversies in tuberculosis. Indian J Pediatr. 1987;
54:779–884.
14. Gupta DK, Rohtagi M, Mishra D. Abdominal tuberculosis. Ind Pediatr. 1991;188–94.
15. Pettengell KE, Larsen C, Garb M, Mayet FG, Singee AE, Pirie D. Gastrointestinal tuberculosis in patients
with pulmonary tuberculosis Q J Med. 1990;74:303–6.
16. Gawkrodger DJ. Mycoabcterial infections. In. Champion RH, Burton JL,Burns DA, Breathnach SM. Rook
textbook of dermatology vol 2 ed 6, Blackwell Science, London.1998;1181–1214.
17. Sathiyasekaran M, Shivbalu B. Esophageal tuberculosis. Indian J Pediatr. 2004;71:457-8.
18. Kapoor VK. Abdominal tuberculosis: the Indian contribution. Indian J Gastroenterol. 1998; 17:141–7.
94 19. Ranjan P, Ghoshal UC, Aggarwal R, Pandey R, Misra A, Naik S. Etiological spectrum of sporadic
malabsorption syndrome in Northern Indian adults at a tertiary hospital. Indian J Gastroenterol. 2004;
23:94–8.
20. Sinha S, Sarin YK. Tuberculous appendicitis. Indian J Pediatr. 2005;72:712.

21. Arya TVS. Jain AK, Kumar M, Agarwal AK, Gupta JP. Colonic tuberculosis: a clinical and colonoscopic
profile. Indian J Gastroenterol. 1994;13 (Suppl) A 116.
22. Widhwa N, Agarwal S, Mishra K. Reappraisal of abdominal tuberculosis. J Indian Med Asso. 2004;102:
31–2.
23. Thompson J. The peritoneum, omentum, mesentery and retroperitoneal space. In. Russel RCG, Williams
NS, Bulstrode JK (Eds) Bailey & Love’s Short Practice of Surgery, 24th ed Arnold, London. 2004;1133–52.
24. Almadi MA, Ghosh S, Aljebreen AM. Differentiating intestinal tuberculosis from Crohn’s disease: A
diagnostic challenge. Am J Gastroenterol. 2009;104:1003–12.
25. Paustian FF, Marshall JB. Intestinal tuberculosis. In Berk EJ (Ed). Bockus textbook of gastroenterology,
Vol 3. 4th ed, Philadelphia, WB Saunders. 1985;2018–36.
26. Thapa BR, Yaccha SK, Mehta S. Abdominal tuberculosis. Indian Pediatr. 1991;28:1093–1100.
27. Manohar A, Simjee AE, Haffagee AA, Pettengell KE. Symptoms and investigative findings in 145
patients with tuberculous peritonitis diagnosed by peritoneoscopy and biopsy over a five year period.
Gut. 1990;31:1130–2.
28. Sharma AK. Aggarwal LD, Sharma CS, Sarin YK. Abdominal tuberculosis in children: experience over a
decade. Indian Pediatr. 1993;30:1149–53.
29. Gulati MS, Sarma D, Paul SB. CT appearances in abdominal tuberculosis. A pictorial assay. Clin Imaging.
1999;23:51–9.
30. Singh V, Kumar P, Kamal J, Prakash V, Vaiphei K, Singh K. Clinicocolonoscopic profile of colonic
tuberculosis. Am J Gastroenterol. 1996;91.
31. Bhargava DK, Dasarathy S, Shrinivas. Evaluation of enzyme linked immunosorbent assay using
mycobacterial saline-extracted antigen for the sero diagnosis of abdominal tuberculosis. Am J
32. Murshall JB,Vogele KA. Serum-ascites albumin difference in tuberculous peritonitis. Am J Gastroenterol.
1988;83:59–61.
33. Dwivedi M, Misra SP, Misra V, Kumar R. Value of adenosine deaminase estimation in the diagnosis of
tuberculous ascites. Am J Gastroenterol. 1990; 85:1123–5. 565–8.
34. Delacourt C, Doveda JD. Use of polymerase chain reaction for improved diagnosis of tuberculosis in
children. J Pediatr. 1995;126:703–9.
35. Bhargava DK, Shrinivas, Chopra P, Nijhawan S, Dasarathy S, Kushvaha AK. Peritoneal tuberculosis:
laparoscopic patterns and their diagnostic accuracy. Am J Gastroenterol. 1992;87:109–12.
36. Riyaz A. Abdominal tuberculosis. In: Riyaz A. Pediatric Gastroenterology and hepatology 3rd edition
Paras publishers, Hyderabad. 2008:183–95.
37. Bajpai M, Gupta DK. Abdominal tuberculosis. In Seth V and Kabra SK (Ed) Essentials of tuberculosis in
children, Jaypee Bros, New Delhi. 2001,108–17.
38. Management of pediatric tuberculosis under the revised National Tuberculosis Control Program.
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39. Anand BS, Nanda R, Sachdev GK. Response of tuberculous stricture to antitubercular treatment. Gut
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40. Pujari BD. Modified surgical procedures in intestinal tuberculosis. Br J Surg. 1979;66:180–3.
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95
9
Inflammatory Bowel Disease in
Children and Adolescents
Malathi Sathiyasekaran, So Shivbalan
INTRODUCTION
Inflammatory bowel disease (IBD) is a chronic inflammatory disease of the gastrointestinal (GI)
tract and is an important cause of morbidity in children and adolescents. Ulcerative colitis (UC)
and Crohn’s disease (CD) are the two important entities classified under IBD. In 10% of cases
the findings are less definite and therefore this group is termed as indeterminate colitis (IC).1
The clinical presentation of IBD is varied with relapses and remissions and it is imperative
that a pediatrician recognizes the problem and refers to the pediatric gastroenterologist for
appropriate investigation and management.
EPIDEMIOLOGY
The incidence of IBD in children is much less than that seen in adults. It is more prevalent in
Scandinavia, Western Europe and North America compared to Asia, Africa and South America.
The incidence rates of pediatric IBD range from 0.2 to 8.5 per 100,000 for CD and 0.5–4.3 per
100,000 for UC.2 The incidence of CD is on the rise in children similar to the trend seen in adults.3
Data of IBD in Indian adults is available whereas there are very few in pediatrics.4,5
Age
Pediatric IBD can manifest at any age. The distribution of IBD occurs mainly at two age peaks the
early and later adult life with a much smaller peak in infancy and early childhood. The proportion
of patients with IBD below the age of 20 years varies between 25–40% in CD and is about 15%
for UC.6 The median age of presentation in a Welsh study was 12.1 years and 12.7 years for CD
and UC respectively.7 The pediatric IBD consortium data has documented that the proportion
of children with IBD increases with age with the maximum being in the age group of 12 to 18
years.2 Early onset IBD (EOIBD), i.e. disease occurring before the age of 5 years is a unique subset
where it is difficult to differentiate between UC and CD.8
Sex
IBD is seen in both sexes. In North America there seems to be a preponderance of CD in boys2
whereas others have reported more prevalence in girls.4 UC affects both sexes equally.
Inflammatory Bowel Disease in Children and Adolescents
Other Diseases
CD occurs with a higher frequency in patients with Turner’s syndrome, Hermansky-Pudlak
syndrome, cystic fibrosis and glycogen storage disease type 1B. IBD occurs less frequently in
those with inherited disorders of coagulation probably as they are less prone to microvascular
thrombosis.9
Breastfeeding
Children who receive formula feeding during infancy do not have a greater risk for developing
UC than those who receive breast milk. The negative association between breastfeeding and CD
remains controversial.10
Smoking: Passive smoking may increase the risk of developing CD in a child.10
ETIOPATHOGENESIS
Infections
Infection with various organisms such as measles virus, chlamydia, pseudomonas maltophilia,
mycobacterium (paratuberculosis and kansassi) have been associated in the etiology of IBD but
none have been implicated. The theory that IBD could represent a persistent infection with a
fastidious organism or an abnormal and prolonged response to a common pathogen has not
been proved. In the “infection theory” individuals who are genetically susceptible acquire micro-
vascular injury resulting in a granulomatous vasculitis of the mesenteric vessels, which leads to
microvascular thrombosis, multifocal gastrointestinal infarction, and eventually chronic sequelae
of CD such as ulcerations, fistulas, fibrosis, and strictures.The recent surge in the incidence of CD
in several countries including India could be due to a“hygiene hypothesis”,11 since disappearance
of helminthic infestations has coincided with the appearance of IBD in developed countries.11
Genetics
UC and CD are related polygenic inflammatory bowel diseases with distinct loci about 21 specific
to UC and 23 to CD and 20 overlapping susceptibility loci.12 Genome-wide association (GWA)
studies have revolutionized the complex IBD genetics to achieve the optimal prediction of
both clinical behavior and response to therapy. In UC the most consistent association is with
the HLA DRB1*0103 allele. Genes implicated in mucosal barrier function (ECM1, CDH1, HNF4a,
and laminin B1) confer risk of UC.13 Impaired IL10 signaling has reemerged as a key pathway in
intestinal inflammation. The most strong and replicated associations with Crohn’s disease have
been noted with NOD2, IL23R, CARD15 (Cathapse Activation Recruitment Domain) and ATG16L1
genes. CARD15 seems not only a susceptibility gene, but also a disease-modifier gene for CD.14
Immunologic Factors
IBD may represent an aberration in the normal balance between physiologic inflammation
and pro-inflammatory cytokines resulting in a conversion of a physiological response to
97
a pathological one and thereby causing tissue destruction. The defect may be at several
sites, including increased antigen uptake through a leaky gut epithelium, defective antigen
processing, abnormal vascular endothelial cell function and abnormalities in the production
of interleukins and eicosanoids. The theory of CD as a Th1 disease has been re-evaluated and
with the discovery of the Th17 lineage, driven by IL23 (as well as IL6 and transforming growth
factor β) and characterized by IL17 production it could probably also be Th17 dependent.15 UC is
characterized by a Th2 atypical immune response, with high levels of IL-6, IL-10, and IL-13, beside
the classical pro-inflammatory cytokines.
Pathophysiology
The hypothesis regarding the pathogenesis of IBD seems to be a interplay of three factors namely
environment, altered immunologic response and a genetically predisposed child16 (Fig. 9.1).
The active mucosal inflammation of the intestine results in the various presentations such as
diarrhea, protein-losing enteropathy, bleeding, abdominal pain, and stricture formation. Pro-
inflammatory cytokines and eicosanoids increase vascular permeability and cause electrolyte
secretion, and augment smooth muscle contraction. Several other cytokines promote the
recruitment and activity of collagen forming cells leading to fibrous tissue proliferation resulting
in bowel wall thickening and stricture formation.16
PATHOLOGY AND DISTRIBUTION

Crohn’s Disease
The transmural inflammation and discontinuous lesions involving the entire GIT extending from
the oral cavity to the colon are characteristic features of CD. The majority 50–70% have colonic
and ileal disease, isolated colonic involvement or diffuse small bowel disease involving the
proximal ileum or jejunum is seen in 10–15%.6 Isolated gastroduodenal disease may be seen in
98
Fig. 9.1: Pathophysiology of IBD

less than 5%17 and perirectal disease in 20% of patients. Noncaseating granuloma is the hallmark
feature. CD is subcategorized as predominantly inflammatory, fistulizing or stricturing disease
based on the clinical phenotype.
Ulcerative Colitis
The inflammatory process in UC is limited to the mucosa and there is no small bowel involvement.
UC is classified as distal colitis (proctitis, proctosigmoiditis), left sided colitis (extending beyond
the rectosigmoid junction and involving up to the splenic flexure) and pancolitis (involving the
whole colon or beyond the splenic flexure). In the evolution of the disease proximal extension of
proctosigmoiditis is around 25% within 3 years of diagnosis and could increase over years.18 The
histopathological features are cryptitis, crypt abscess and depletion of goblet cells.
CLINICAL PRESENTATION
Gastrointestinal Manifestation
Ulcerative Colitis
Children with UC most commonly present with diarrhea, rectal bleeding, and abdominal pain.
UC is classified as mild, moderate and severe depending on the clinical presentation. 40–50%
have mild symptoms with fewer than four stools per day with only intermittent hematochezia,
and minimal (if any) systemic symptoms or weight loss. About 30–40% are moderately ill with
weight loss, frequent diarrhea, and systemic symptoms. Acute fulminant disease with fever,
copious rectal bleeding more than 6 diarrheal stools and systemic symptoms is seen in 10–15%
of patients.19 Toxic megacolon is rare in children.
Crohn’s Disease
The mode of presentation in CD depends on the site of involvement. Abdominal pain and systemic
symptoms are generally more severe in CD than in UC. Diarrhea is a common symptom. Gross
blood in the stools is more common when the colon is involved. Fever occurs in approximately
50% and may be low grade or spiking. Fatigue, anorexia, weight loss and diminution in growth
velocity are seen in 20–60% of children. Perirectal involvement fistulae, fissure and skin tags
are seen in 25–30% of children.10 CD is classified as mild, moderate, and severe based on the
clinical presentation.20
Mild-Moderate Disease
Mild-moderate Crohn’s disease applies to ambulatory patients who are able to tolerate oral
alimentation without manifestations of dehydration, toxicity (high fevers, rigors, prostration),
abdominal tenderness, painful mass, obstruction, or >10% weight loss.
Moderate-Severe Disease
Moderate-severe disease applies to patients who have failed to respond to treatment for mild-
moderate disease or those with more prominent symptoms of fevers, significant weight loss,
99
abdominal pain or tenderness, intermittent nausea or vomiting (without obstructive findings),
or significant anemia.
Severe-Fulminant Disease
Severe-fulminant disease refers to patients with persisting symptoms despite the introduction of
steroids as outpatients, or individuals presenting with high fever, persistent vomiting, evidence
of intestinal obstruction, rebound tenderness, cachexia, or evidence of an abscess.
The popular scoring system for pediatric CD is the Pediatric Crohn’s disease activity index
(PCDAI). The parameters in PCDAI include subjective patient historical information (abdominal
pain, number and consistency of stools and general well being), physical examination findings
(abdominal mass, tenderness or perirectal disease), presence of extraintestinal manifestation
(such as arthritis, fever, rash, uveitis), laboratory data (hematocrit, ESR, serum albumin) and
weight, height velocity. PCDAI score ranges from 0 (no disease activity) to 100 (severe disease
activity).21 An abbrevited PCDAI score without the laboratory evaluations or calculated height
velocity of PCDAI has been found practical.22
Gastrointestinal Complications
Several complications have been reported in patients with IBD. Hemorrhage, obstruction,
perforation, abscess and fistula formation are well known complications of CD. The major
intestinal complications of UC are massive bleeding, toxic megacolon and cancer.6 Carcinoma of
the colon is a long-term complication of IBD and the two well accepted risk factors are duration
and severity of the disease. 23
Extraintestinal manifestations
These may be seen in 25–30% of patients with IBD and may have some prognostic significance.6
They may occur before, concurrently with the disease or even after the diseased colon is resected.
Skin manifestations include erythema nodosum and pyoderma gangrenosum. Aphthous
ulceration is the most common oral manifestation of IBD. Oral manifestation of CD as the initial
presentation has also been reported from South India.4 Ocular manifestations such as episcleritis
and anterior uveitis are also less common and occur when the disease is active. Arthritis is
another co-manifestation and occurs in 7–25%.24 Hepatobiliary problems such as chronic
hepatitis, sclerosing cholangitis and cholelithiasis may occur. The renal manifestations of IBD
include nephrolithiasis (5% of CD), hydronephrosis and enterovesical fistula. Thromboembolic
manifestations, vasculitis pancreatitis, interstitial pneumonitis and pericarditis have also been
reported.
Malnutrition
The nutritional status is compromised more in CD (50%) than in UC and failure to thrive is a
common presentation of CD. The cause of malnutrition may be due to suboptimal dietary intake,
increased gastrointestinal loss, malabsorption, increased demand associated with marked
inflammatory activity, delayed gastric emptying leading to early satiety and higher resting
expenditure.9 The gross mucosal inflammation leads to the loss of cellular constituents and
hematochezia, resulting in protein-losing enteropathy and iron-deficiency anemia. Deficiency
100 states for iron, folic acid, vitamin B12, nicotinic acid, vitamin D, vitamin K, calcium, magnesium,
and zinc may occur.
Growth Failure
Decrease in growth velocity may precede gastrointestinal symptoms in more than 50% of
children with CD25 compared to 10% in UC probably due to the different cytokine profiles.
Permanent growth failure can also occur due to chronic undernutrition or administration of
corticosteroids.8 Low serum levels of insulin-like growth factor (IGF 1) have been documented
in growth retarded children with CD. If the adolescent with IBD has developed secondary sexual
characteristics before remission the growth potential may be irreversibly lost whereas if they
achieve remission before puberty there is good catch up growth and height velocity.2
Bone Disease
Bone disease is a common problem in children with IBD since the disease occurs during the
critical period of peak bone mass formation. The other reasons include malnutrition, effect of
cytokines and glucocorticoid therapy.5 Despite the potential for IBD to develop osteoporosis, the
bone mineral density in adulthood can be normal if the disease is managed properly.
DIAGNOSIS
Initial Evaluation
The diagnosis of IBD is considered by a combination of clinical observations and confirmed
by laboratory, radiologic, endoscopic, and histologic findings. The initial evaluation includes a
detailed clinical, family and treatment history. Any child or adolescent presenting with recurrent
abdominal pain associated with or without fever, chronic diarrhea, bleeding per rectum or
growth failure is a possible candidate for IBD and needs a complete assessment. A careful
monitoring of the growth and development of the child is important. Abdominal examination
may not be contributory however if a mass is palpable in the right iliac fossa one should
consider CD or tuberculosis (TB). A perianal and rectal examination is necessary to detect skin
tags, fissures and fistulae. Laboratory tests such as complete blood count, C reactive protein,
motion for occult blood and total protein albumin/globulin ratio should be included. The assay
of fecal calprotectin helps in differentiating diarrhea due to IBD from irritable bowel syndrome.
Calprotectin concentration in stool correlates with the intensity of neutrophil infiltration of the
intestinal mucosa and with the severity of inflammation.26
Ultrasound (US) of Abdomen

US may detect thickened bowel loops, pseudokidney sign and enlarged lymph nodes in CD. The
findings of free fluid, lymph nodes, thickened mesentery or omentum are more suggestive of
abdominal tuberculosis than CD.
Endoscopic Evaluation
Ileocolonoscopy: plays a significant role in the diagnosis of IBD. In UC the mucosal changes are
continuous involving the rectum and extending proximally.The inflammation is confined to the
mucosa and the macroscopic changes include granularity, loss of vascular pattern, easy contact 101
bleed and ulcerations (Fig. 9.2). Multiple pseudopolyps and complete loss of haustrations may
be an additional finding in long standing disease. The intervening mucosa is not normal, there is
no rectal sparing and the terminal ileum is usually not involved except in back wash ileitis. Biopsy
of the involved mucosa shows cryptitis, loss of goblet cells and crypt abscesses with chronic
inflammatory cells in the lamina propria.
In CD the characteristic features are the skip lesions, cobble stoning of mucosa, apthous
ulcers or deep irregular ulcers of varying sizes with normal intervening mucosa (Fig. 9.3). The
rectum is usually spared. Strictures may be present which may interfere with completion of the
procedure. Involvement of the terminal ileum is a feature of CD. The transmural distribution of
the inflammation and the fissuring ulcers involving the muscularis propria in addition to the
noncaseating granuloma are highly characteristic of CD. Normal appearing colonic mucosa
isalso biopsied since microscopic inflammation is a feature of CD.
In India it is not uncommon to misdiagnose CD as TB though there are some differentiating
features. The ulcers seen in CD are longitudinal whereas they are more transverse in TB. Perianal
involvement is a feature of CD and not TB. The granulomas are smaller, ill formed, numerous
and noncaseating in CD whereas they are larger, well formed, confluent and caseating in TB.
Significant lymph node enlargement can occur without bowel involvement in TB but not in CD.27
Esophago gastroduodenoscopy is performed in all children suspected as CD. Gastric antral biopsy
and identification of focal active gastritis or microgranuloma increases the diagnostic yield.28
Enteroscopy: Isolated small bowel CD may pose a problem in diagnosis. The double balloon
enteroscopy or an intraoperative endoscopy helps in visualizing and obtaining biopsy of the
lesions if present.
Fig. 9.2: Colonoscopic appearance of ulcerative colitis showing loss of vascular pattern, and ulcers without
normal intervening mucosa
102 Fig. 9.3: Colonoscopic appearance of Crohn’s disease showing irregular ulcers with normal intervening mucosa
Capsule endoscopy: The wireless capsule endoscopy is useful in children more than 5 years of
age with isolated small bowel CD.29 In children with suspected stricture the capsule may result
in bowel obstruction.
Radiological Investigations
Barium Meal Series
Barium meal series may help to detect small bowel involvement such as strictures, fistulae and
ulcerations in CD. This study has largely been replaced by computerized tomography
Contrast Enhanced Computerized Tomography (CECT)

Contrast enhanced computerized tomography (CECT) is more sensitive than barium studies to
identify bowel wall thickening and also to assess the length and site of small bowel strictures.
Magnetic Resonance Imaging (MRI) Scan30

MRI with oral contrast enhancement is used in combination with CT or small bowel contrast
series for diagnosing CD related complications including pelvic fistulae.
Other Investigations
Serological Markers
A combination of perinuclear anti-neutrophil cytoplasmic antibody (pANCA) and anti-
saccharomyces cerevisiae antibody (ASCA) in older children has shown good specificity but low
sensitivity both for UC and CD.31 They are not recommended as screening tests for IBD.
DIFFERENCES BETWEEN UC AND CD AND DIFFERENTIAL DIAGNOSIS

Difference Between UC and CD
Though there are several distinctive features between CD and UC it may be difficult at times
to differentiate them. Some differentiating clinical, endoscopic and histologic features are
summarized in Table 9.1.
The differential diagnosis of IBD depends on the age and clinical presentation. In infants
Meckel’s diverticulum, allergic enterocolitis, Hirschsprung’s enterocolitis and intussusception
are included whereas in older children tuberculosis, lymphoma, yersinia enterocolitica, amebic
colitis, intestinal polyps, diarrhea predominant IBS and Henoch Schonlein purpura. should be
considered
THERAPY
The goals of therapy in IBD include clinical and laboratory control of inflammation, endoscopic
mucosal healing, achievement of proper growth and ensuring good quality of life.6 The treatment
regimen should be directed towards relief of symptoms and improving quality of life and
not necessarily normalization of all laboratory studies. The various aspects of therapy include 103
pharmacological, nutritional, surgical and psychosocial.
Table 9.1: Comparison between ulcerative colitis and Crohn’s disease

Features Ulcerative colitis Crohn’s disease
Bloody diarrhea Common Unusual
Abdominal pain Unusual Common
Abdominal mass Not present May be present
Growth failure Unusual Present
Failure to thrive Unusual Present
Oral ulcers Not present May be present
Perianal disease Not present Present
Rectal mucosal involvement Present Usually spared
Distribution of lesions Continuous Skip lesions
Ileum involvement Not involved May be involved
Depth of inflammation Involves only mucosa Submucosa, transmural
Ulcers Microulcers common Aphthous ulcers, linear ulcers
Complications Toxic megacolon Strictures, fistula
Histopathology Cryptitis, crypt abscess Granuloma
Pharmacological Therapy
The drugs used in IBD are 5-aminosalicylates, corticosteroids, antibiotics, immunomodulators
and biologicals. The “step-up” therapy where immune modulators are introduced later during
treatment is now less preferred than the “top down” regime where these drugs are introduced
early in the regime resulting in better and longer remissions in CD.
5 Aminosalicylates: The 5-ASA drugs (mesalamine, balsalazide) exert local anti-inflammatory
effects through a number of mechanisms which includes inhibition of 5 lipoxygenase with a
result in decreased production of leukotriene B4, scavenging of reactive oxygen metabolites,
prevention of the upregulation of leukocyte adhesion molecules and inhibition of interleukin
1 synthesis. 5-ASA is rapidly absorbed from the upper intestinal tract and various drug delivery
systems have been employed so that it reaches the distal small bowel or colon. Uncoated
mesalamine is also available as enema for use in left sided colitis. The dose of mesalamine is
40–60 mg/kg/day and it is used as the first line drug in mild and moderate UC and in mild CD. It
can also be used as maintenance in UC and CD.6
Steroids: Prednisolone is started at a dose of 1–2 mg/kg/day in moderate CD and also in moderate
or severe UC and tapered before stopping within 6–8 weeks. Oral budesonide 6–9 mg/day may
be prescribed to avoid the systemic side effects of steroids.
Immunomodulators: 6-Mercaptopurine (1–1.5 mg/kg/day) and azathioprine (2–2.5 mg/kg/
day) are effective in patients with active disease when added to corticosteroid therapy.32 They
facilitate the development of remission and promote tapering of the corticosteroid dosage.
104 Azathioprine and 6-MP are used as steroid sparing agents and administered along with or while
steroids is being tapered. Cyclosporine has also been used to treat fulminant ulcerative colitis
and methotrexate in CD with beneficial results.
Antibiotics: Metronidazole alone or in combination with ciprofloxacillin may be effective in the

management of perianal fistulae and rarely even in small bowel CD.6
Probiotics have been used as a supplement therapy in IBD specially in children with pouchitis.
Biological therapy: Biological agents selectively target specific sites in the complex cascade of
cytokine and chemokine effector molecules that comprise the end effect of immune system
activation. Biologic treatments can be divided into three categories namely inflammatory
cytokine inhibitors, the anti-inflammatory cytokines and selective inhibition of adhesion
molecules. Tumor necrosis factor-α is an important proinflammatory molecule in the
pathogenesis of IBD especially Crohn’s disease. Infliximab anti-TNF-α is probably the most widely
used biological agent though there are several agents such as natalizumab, interleukin10, IL11
and thalidomide.33 Infliximab has also been used in pediatric CD and has proved effective as
short-term therapy in moderate to severe CD and in active draining external fistulae.Infliximab
has also been used in severe UC in those who arenot willing for surgery. Complications such as
formation of antibodies, malignancies and lymphoproliferative disorders are risks which should
be considered when infliximab is prescribed.34
Nutritional Therapy
Children with IBD should be supported with proper nutrition to ensure better therapeutic results.
Caloric supplementation is very essential in children with growth delay or under nutrition.
Enteral nutrition with an oligopeptide formula or amino acid based formula have shown lesser
relapses.35 Calcium supplementation is an important adjuvant to prevent bone disease.
Psychological Therapy
IBD may have a profound influence on the lives of affected children, adolescents and their family
members. Every effort should be made to facilitate normal age appropriate activities and early
intervention by psychologists or psychiatrists should be sought.
Surgical Therapy
The indications for surgery in IBD include intractability, uncontrolled hemorrhage, perforation,
obstruction, stricture, fistulae, growth retardation, and carcinoma.
Multidisciplinary Approach
The care of the child with IBD involves a multidisciplinary approach involving the pediatrician,
pediatric gastroenterologist, nutritionist, psychologist, surgeon, social worker and nurse. The
team should also include the parents, sibling and teachers who should be well informed about
the child’s problem. This concept in care ensures an ideal, comprehensive management of the
IBD patient and helps in achieving appropriate levels of physical, mental and social well being.
PROGNOSIS
The outcome of IBD is variable with disease activity remaining high in some individuals in spite
105
of aggressive treatment. The prognosis of IBD depends greatly on the age of onset, extent, and
severity of the disease
SUMMARY
IBD is a chronic inflammatory disease of the gastrointestinal tract and occurs due to interplay
of an altered immune response and environmental factors in individuals with a genetic
predisposition. It can occur in any age group but more often in pre-adolescents and adolescents.
The two important entities are ulcerative colitis and Crohn’s disease. The clinical presentation
includes common symptoms such as anemia, fever, growth retardation, intestinal symptoms
such as abdominal pain, bleeding per rectum, diarrhea and extra intestinal such as oral ulcers,
arthritis or ocular manifestations. Gastrointestinal endoscopy and histopathology help in
diagnosis. Early recognition by the primary pediatrician and prompt referral to the pediatric
gastroenterologist for appropriate investigation and therapy is very essential. The management
involves a multidisciplinary approach and the key drugs used in practice are 5 ASA, steroids and
azathioprine. Novel drugs such as biologicals are beneficial to a select subset of children with
IBD.
Key Messages
1. Inflammatory bowel disease is a chronic inflammatory disease of the gastrointestinal tract and is an important
cause of morbidity in children and adolescents.
2. An increasing incidence of IBD, especially Crohn’s disease has been reported in several pediatric centers.
3. IBD occurs due to interplay of environmental factors and altered immune response in a genetically predisposed
individual.
4. IBD can occur in all age groups. Abdominal pain, fever, diarrhea, failure to thrive and growth retardation are the
characteristic features in Crohn’s disease whereas bleeding per rectum and abdominal pain is a manifestation of
ulcerative colitis. Ileo colonoscopy and histopathology help in diagnosis.
5. The drugs used in the management of IBD include 5 amino salicylic acid, steroids and immunomodulators.
6. Novel biologic interventions aid in the management of severe disease and its associated complications. Surgery
is recommended in certain specific situations.
7. More research is necessary to identify the actual triggering factor and prevent the occurrence of this morbid
disease in childhood and adolescence.
REFERENCES
1. Kirschner BS Inflammatory Bowel Disease in Children. Pediatr. Clin North Am.1988;1:189–208.
2. Mamula P, Markowitz JE, Baldassano RN. Inflammatory bowel disease in early childhood and
adolescence: Special considerations. Gastroenterol Clin North Am. 2003;32:967–95.
3. Heyman MB, Kirschner BS, Gold BD, Ferry G, Baldassano R, Cohen SA, Winter HS, Fain P, King C, Smith
T, El-Serag HB. Children with early-onset inflammatory bowel disease (IBD): Analysis of a pediatric IBD
consortium registry. J Pediatr. 2005;146:35–40.
4. Sathiyasekaran M, Raju BB, Shivbalan S, Rajarajan K. Pediatric Crohns disease in South India. Indian
Pediatr. 2005;42:459–63.
5. Mehta S. Inflammatory bowel disease in children: Indian perspective. Indian J Pediatr. 1999;66:587–8.
6. Baldassano RN, Piccoli DA. Inflammatory bowel disease in Pediatric and Adolescent patients.
Gastroenterol clin North Am. 1999;28:445–55.
7. Cosgrove M, Al-Atia RF; Jenkins HR. The epidemiology of pediatric inflammatory bowel disease. Arch
106 Dis child. 1996;74:460.
8. Mamula P, Telega GW, Markowitz JE, Brown KA, Russo PA, Piccoli DA, Baldassano RN. Inflammatory
bowel disease in children 5 years of age and younger.Am J Gastroenterol. 2002;97:2005–10.
9. Cuffari C, Darbari A. Inflammatory bowel disease in the pediatric and adolescent patients. Gastroenterol
Clin North Am. 2002;31:275–91.
10. Hyams JS. Crohn’s Disease. In:Wyllie R, Hyams JS, Eds. Pediatric Gastrointestinal Disease:
Pathophysiology, Diagnosis, Management. Philadelphia: WB Saunders. 1999;401–18.
11. Desai HG, Gupte PA. Increasing incidence of Crohn’s disease in India; Is it related to improved sanitation?
Indian J Gastroenterol. 2005;24:23–4.
12. Thompson AI, Lees CW.Genetics of Ulcerative Colitis. Inflamm Bowel Dis. 2011;17:831–48.
13. Cassinotti A, Birindelli S, Clerici M, et al. HLA and autoimmune digestive disease: a clinically oriented
review for gastroenterologists.Am J Gastroenterol. 2009;104:195–217.
14. Tsianos EV, Katsanos KH, Tsianos VE. Role of genetics in the diagnosis and prognosis of Crohn’s disease.
World J Gastroenterol. 2012; 18(2):105–18.
16. Matthew Shale, Subrata Ghosh Beyond TNF, Th1 and Th2 in inflammatory bowel disease. Gut
2008;57:1349–51.
17. Lenaerts C, Roy CC, Vaillancourt M, Weber AM, Morin CL et al. High incidence of upper gastrointestinal
tract involvement in children with Crohn disease. Pediatrics. 1989;83:777–81.
18. Mir-Madjlessi SH, Michener WM, Farmer RG. Course and prognosis of idiopathic ulcerative
proctosigmoiditis in young patients. J Pediatr Gastroenterol Nutr. 1986;5:571–5.
19. Markowitz JF. Ulcerative Colitis. In: Wyllie R, Hyams JS, Eds Pediatric Gastrointestinal Disease:
Pathophysiology, Diagnosis, Management. Philadelphia: WB Saunders,1999;419–32.
20. Hanauer SB, Sandborn W. Practice Parameters Committee of the American College of Gastroenterology.
Management of Crohn’s disease in adults. Am J Gastroenterol. 2001;96:635–43.
21. Hyams JS, Ferry GD, Mandel FS, Gryboski JD, Kibort PM, Kirschner BS, Griffiths AM, Katz AJ, Grand
RJ, Boyle JT, et al. Development and validation of a pediatric Crohn’s disease activity index. J Pediatr
22. Shepanski MA, Markowitz JE, Mamula P, Hurd LB, Baldassano RN. Is an abbreviated Pediatric Crohn’s
Disease Activity Index better than the original? J Pediatr Gastroenterol Nutr. 2004;39:68–72.
23. Gillen CD, Walmsley RS, Prior P, Andrews HA, Allan RN. Ulcerative colitis and Crohn’s disease: A
comparison of the colorectal cancer risk in extensive colitis. Gut. 1994;35:1590–2.
24. Burbrige EJ, Huang S, Bayless TM. Clinical manifestations of Crohn’s disease in children and adolescents.
Pediatrics. 1975;55:866–71.
25. Kanof ME, Lake AM, Bayless TM. Decreased height velocity in children and adolescents before the
diagnosis of Crohn’s disease. Gastroenterology. 1988;95:1523–7.
26. Carroccio A, Iacono G, Cottone M, Di Prima L, Cartabellotta F, Cavataio F, Scalici C, Montalto G, Di Fede
G, Rini G, Notarbartolo A, Averna MR. Diagnostic accuracy of fecal calprotectin assay in distinguishing
organic causes of chronic diarrhea from irritable bowel syndrome: A prospective study in adults and
children. Clin Chem. 2003;49:861–7.
27. Pulimood AB, Ramakrishna BS, Kurian G, Peter S, Patra S, Mathan VI. Endoscopic mucosal biopsies
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29. Reddy DN, Kaffes AJ, Sriram PVJ, Venkat Rao G. Capsule endoscopic features of crohns disease. Digestive
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33. Mamula P, Mascarenhas MR, Baldassano RN. Biological and novel therapies for inflammatory bowel
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108
10
Intestinal Parasites in Children
Pankaj Vohra
“Choose something common and you will find little is known about it”
—Sir Henry Head
INTRODUCTION
Infestation with intestinal parasites is a worldwide phenomenon but much more so in developing
nations especially in children of the urban poor and the rural population. In many cases, the
parasite infestation is asymptomatic and multiple organisms may be found in a single individual.
In some, especially who have a high worm burden or other co-morbidities, parasitemia can
result in a multitude of disorders including poor growth—both physical and mental. Treatment
of most infections in immunocompetent children is easy provided it is suspected. Cheap, non-
toxic, broad spectrum anti-helminths and anti-protozoals are available and these provide good
short-term benefits. In closed communities where infection rate exceeds 50%, there is a role
of preventive therapy at regular intervals. Long-term prevention of disease would require
committed government policies of providing adequate sanitation and potable water supply
along with mass education.
A parasite is an organism that grows, feeds and is sheltered by or within a different organism
while contributing nothing to the survival of its host. In the 1993 World Development Report,
intestinal helminthiasis was ranked first as the main cause of disease burden in children aged
5–14 years. However, it was also ranked highly as a disease that could be effectively controlled by
cost effective measures.1 Mortality in several parts of the world is also increased due to intestinal
parasites.2 It has been estimated that about 3.5 billion persons are affected by intestinal parasites,
of which 450 million are actually ill from the infestation. This is contributing to about 200,000
deaths per annum primarily from roundworm, hookworm and ameba. Dual or multi-infections
are common and more harmful due to co-existing malnutrition, micronutrient deficiency and
secondary immunodeficiency. It can also be expected that with increasing urbanization in
the future, and increase in urban slums in large parts of the developing world, incidence and
consequences of intestinal parasitemia may increase.3
EPIDEMIOLOGY
In India, studies have been carried out to see the disease burden in the community and between
urban and rural areas and in the lower socio-economic strata.4 Studies from Africa have clearly
shown the incidence of intestinal parasitemia to be higher in children having pica.5 It is also found
to be higher in children where the mothers’ education level was less than primary level and in
children who used hands for washing anal area after defecation.6 In some areas the incidence of
malnutrition and parasitemia are both high and probably not as a result of the presence of one.7
Studies in India have been conducted to estimate the incidence of intestinal parasitemia.
Some of these have been carried out in the population and hence includes symptomatic and
asymptomatic patients while some have been carried out in hospitals, i.e. symptomatic patients
and both have shown a high incidence of parasitemia.8-10 Recently a study has shown that
school children from rural areas had an infection rate of 91% while that from urban area had a
parasitemia rate of 33%.11 In different reports from Delhi, several helminths include Trichura and
Hymenolepis have been found to be responsible for diarrhea.12,13 Presence of infection in more
than one member of the family is common.14
As most helminths (unlike protozoa) do not multiply within the human body except
Strongyloides, this would suggest that each adult worm is a result from an invasion of a single
larva either orally or penetration through the skin.
Classification of Intestinal Parasites

A simple classification of the various types of intestinal parasites found in children of India is
shown in Table 10.1.
Table 10.1: Classification of intestinal parasites
A. Helminths
Nematodes (Roundworms)
1. Ascaris lumbricoides (Roundworm)
2. Ancylostoma duodenale (Hookworm)
3. Necator americanus (Hookworm)
4. Enterobius vermicularis (Pinworm)
5. Strongyloides stercoralis (Threadworm)
6. Trichuris trichiura (Whipworm) (Fig. 10.1)
Cestodes (Tapeworms)
1. Taenia solium (pork tapeworm)*
2. Taenia saginata (beef tapeworm)
3. Hymenolepis nana (dwarf tapeworm)
4. Diphyllobothrium latum (fish tapeworm)
B. Protozoa
1. Entamoeba histolytica
2. Giardia lamblia
3. Cryptosporidium parvum
4. Cyclospora
110 5. Isospora belli

6. Balantidium coli
* Cysticercosis-common Fig. 10.1: Trichuris trichiura (Whipworm)
Characteristics of Intestinal Parasites

Table 10.2 shows the medically important microbiological characteristics of some of the
common helminths affecting children while Table 10.3 shows their clinical aspects.
Table 10.2: Characteristics of helminths

Parasite and its diagnosis Usual infective form Usual form found Comments
and route of infectionin humans
Ascaris (Figs 10.2 and 10.3) Ingestion of eggs Adult worm in • Larvae penetrate intestinal epithe-
Stool examination for typi- containing larva jejunum; lium, reaches mesenteric lymphat-
cal eggs, rarely decorticate (freshly passed eggs 15–40 cm ics and portal circulation, reach pul-
eggs or an ejected adult are not infective) monary bed, molt in alveolar space
worm itself (usually dead) and travel up the respiratory tract
before being swallowed
Ancylostoma/Necator Larvae penetrate skin Adult worms in • Larvae enter capillaries and reach
Stool examination for typi- usually between toes small intestine; lungs where they rupture into alve-
cal eggs, rarely skin lesions 1 cm long oli and ascent the respiratory tract
similar to Strongyloides may and are swallowed
be seen
Enterobius Ingestion of eggs Adult females are • Ubiquitous and unrelated to
Adult worm visualized at often carried under 8–13 mm long sanitary conditions
perianal area at time of finger nails (eggs are • Re-infection due to hand-to-mouth
itching; reversed cellophane infective at the time transmission and hence nail biters
tape swab of perianal area of laying) are difficult to treat
to detect eggs; ova rarely • Person to person spread easy as
seen in stool the eggs are infective at the time
of laying and common to find more
than one family member infected
Strongyloides Filariform larvae Duodenum; adult • Larvae enter capillaries and reach
Larva in stool; duodenal penetrate skin usu- female measures lungs where they rupture into alve-
aspirate, or jejunal biopsy. ally between toes 2–2.5 mm oli and ascend the respiratory tract
Serodiagnosis for screening and are swallowed
available • Hatched eggs can develop into
larva within the intestine and pen-
etrate intestinal mucosa (internal
auto-infection) or perianal skin (ex-
ternal autoinfection), hence start-
ing another parasitic cycle
• Immunocompromised individuals
are most at risk to get heavy burden
Trichuris Ingestion of eggs Cecum; • No visceral migration occurs
Characteristic eggs in stool 3–5 cm long • Eosinophilia not common though
part of the worm is embedded in
the mucosa
• Adult worm sucks approximately
0.005 ml blood per day
Taenia Ingestion of under- Small intestine; • Cysticercosis more important
Eggs in stool; perianal swabs cooked pork or beef 3–5 meters long disease than that caused by adult
useful; segments required to worms
identify type of tapeworm
Hymenolepsis Ingestion of infective Jejunum; • Immunosuppressed hosts get 111
Eggs in stool egg; external auto- 2.5–9 cm heavy infection load
infection may occur;
Table 10.3: Pathological and clinical aspects of intestinal parasites

Parasite Development stages Adult stage
Ascaris Invasion of respiratory system may Usually asymptomatic; recurrent abdominal pain,
result in pneumonia (Loeffler’s nausea, anorexia and vomiting may occur; heavy
pneumonia) leading to cough, infestation can result in obstruction; worms may
dyspnea, fever, urticaria, hemopty- migrate into CBD to cause biliary colic, acute
sis, crepitations, high eosinophilic pancreatitis, act as a nidus for stone formation;
counts, X-ray consolidation; larvae adult worm may migrate out via rectum or in
may reach other organs like eye, vomitus
CNS and kidney to produce lesions
Ancylostoma and Local skin lesion; cough, low grade Usually asymptomatic unless heavy load leading
Necator fever, eosinophilia to iron deficiency anemia and hypoproteinemia;
retarded growth, pica
Enterobius None Nocturnal perianal itching – can wake child up at
night crying due to intense itching; perineal ex-
coriations; rarely worms may be seen peri-rectal;
urinary tract infection, vaginitis,
Strongyloides ‘Larva currens’—rapidly migrat- Diarrhea, malabsorption, protein losing enter-
ing urticaria on buttock, thigh and opathy, anorexia, pedal edema, bloody diarrhea
trunk as a result of external autoin- may occur if the worm load is high along with
fection; wheezy cough, eosinophil- Gram negative sepsis, peritonitis;
ia, Loeffler’s pneumonia
Trichuris None Light infections are asymptomatic; heavy infec-
tions can lead to diarrhea with blood; anemia,
clubbing, rectal prolapse, ?acute appendicitis
Taenia None; Man may become intermedi- Usually asymptomatic, abdominal pain, bloating,
ate host to T. solium nausea, passage of proglottids is painful or itchy
Hymenolepsis None Usually asymptomatic; in heavy loads–diarrhea
with malabsorption
Protozoa
Protozoa as a group are very common in children. They are identified all over the world, but
most infected persons remain asymptomatic or have self-limiting diseases. Some of the common
protozoa affecting Indian children have been discussed below.
Entameba Histolytica
Entameba is responsible for amebiasis—a common term used to describe the various clinical
manifestations of this organism. E. dispar is a non-pathogenic ameba that is indistinguishable
from E. histolytica when the cyst is examined. In presence of diarrhea, commensal ameba are
often seen in the stool. The trophozoites are differentiated by the presence of erythrocytes in E.
histolytica in invasive disease and their lack of in E. dispar. The latter are also somewhat smaller
with sluggish movements as compared to trophozoites of E. histolytica. E. dispar results only in
112 an asymptomatic carrier state.15 It is estimated that E. dispar is 10 times more common than E.
histolytica and only 10% of those infected with the latter are symptomatic.16,17
Fig. 10.2: Ascaris detected on barium meal
Fig. 10.3: Ascaris in common bile duct (arrows)
Infection occurs by ingestion of cysts that contaminate food and water or by direct fecal-
oral contamination. Cysts can remain viable for up to 2 months outside the human body and is
resistant to standard concentration of chlorine used to kill bacteria in the drinking water supply.
They are easily killed by heating to 55°C. Asymptomatic or convalescent carriers are the main
source of infection as they pass cysts while patients with dysentery often pass only trophozoites.
Trophozoites are non-infectious as they don’t survive for long outside the body and if ingested
are killed by the low gastric pH. Trophozoites establish in the cecum and ascending colon most
113
commonly. Though steroids, cytotoxic drugs and malnutrition increase susceptibility of disease,
HIV infection does not seem to.
E. histolytica clinically also involves the rectosigmoid and cecum. The edge of the pathological
lesion contains the trophozoites but the cysts are never seen here. Typically, the lesions extend
through the mucosa, muscularis mucosa, into the sub-mucosa where they expand laterally
making it into a flask-shaped lesion. If these lesions coalesce, denudation of the overlying
mucosa can occur. The parasite causes cytolysis and hence there is limited inflammation and
resultant few leukocytes are seen in the stool examination. Amebomas are areas of tissue edema,
areas of healing and tissue loss and can appear as tumors; annular amebomas have known to
cause intussusception and stricture. Amebomas may be multiple.
E. histolytica infection though usually asymptomatic, can cause merely changes in bowel
habits of the child or cause dysentery. If infection is detected with E. histolytica, it should be
treated as it can become invasive and result in dysentery and liver abscess—the latter being
its most dreaded complication. Invasive disease in young infants has a high mortality rate.
However, it must be kept in mind that E. histolytica causes less than 5% of all cases of dysentery
in children in India.18,19 Diarrhea usually begins insidiously while, dysentery may begin acutely
or insidiously; colicky pain, tenesmus, low grade fever and tenderness over both iliac fossa are
common. Fulminant colitis with perforation is very rare. In children rectal bleeding may be the
sole manifestation. Bacillary dysentery and in the chronic form of the disease, inflammatory
bowel disease are the important differential diagnosis. It is possible for a child with chronic
amebic infection to have diarrhea with only occult blood positive stools.20,21
Diagnosis is made on microscopy of fresh stool–presence of trophozoites with erythrocytes
within their cytoplasm (erythrophagocytic trophozoites) clinches the diagnosis. Finding
trophozoites without red blood cells or cysts may not be adequate to make a positive diagnosis of
ameba as the cause of diarrhea. As mentioned earlier, E. dispar trophozoites may also be released
during diarrhea of any cause—these never have erythrocytes within the cytoplasm. E. histolytica
II stool antigen test (TechLab, Blackburn, VA) has been approved by WHO to help distinguish
between E. histolytica and E. dispar.22 Stool examination usually reveals few leukocytes.
Proctosigmoidoscopy is useful to identify amebiasis especially if it is chronic–typically ulcers
are seen with normal intervening mucosa. Acute infections appear more non-specific with
ulcerations, friability and hyperemia. Amebic serology for gut limited infections is often negative.
However in invasive disease, negative serology makes likelihood of an amebic etiology unlikely.23
E. dispar infection does not result in antibody production.
Therapy of E. histolytica is by metronidazole, tinidazole or ornidazole. Diloxanide furoate,
iodoquinol or paramomycin is used as a cysticidal drug that is effective in the gut lumen. The
cysticidal drugs alone are useful for convalescent carriers. The standard recommendation is to
treat the invasive disease first followed by eradication of the intestinal carriage of the organism
(Table 10.8). The stool should be re-examined after a course of anti-amebic therapy.
Giardia
Giardia lamblia is present worldwide and endemic in India. It is the most common parasite
identified around the world.24 It is acquired by ingesting infective cysts in food and more
114 commonly water including from swimming pools. These cysts are infective at the time of
expulsion and hence can spread via the feco-oral route within the family. It is estimated that 10
cysts are adequate for initiating an infection. Infections are common in institutions and day-care
centers. Outbreaks have been recorded.
Incubation period varies from 5–20 days. The parasite inhabits the upper small intestine. The
parasite adheres to the enterocyte by its ventral sucker. The infection can remain asymptomatic
or may present as an acute infection, recurrent or chronic disease. The various manifestations
include watery diarrhea, anorexia, nausea, bloating, malaise, abdominal discomfort or cramps and
in heavy infections, failure to thrive as the organism coats the intestine leading to malabsorption.
Secondary lactose intolerance is common while fever, colitis and eosinophilia are not. Rarely,
it may be a cause of urticaria. In children with hypogammaglobulinemia, giardiasis may be
severe and recurrent suggesting that humoral immunity plays an important role. Giardiasis is
not significantly different in children with HIV disease nor has it been found to be so selective IgA
deficiency. Recurrent infections lead to development of partial immunity. Asymptomatic carrier
infection may persist for months.
The diagnosis is made on stool examination. Grossly, the stools are watery or appear pale and
greasy if there is any element of steatorrhea. There is no blood, mucus or significant number of
leukocytes seen. Trophozoites (in fresh and diarrheal stool) or more commonly cysts of giardia
may be seen on direct stool examination or in duodenal aspirates. Antigen detection with ELISA
is available in select laboratories. The morphology of the duodenal biopsy in a child affected
with giardia may vary from being normal to flattened villi. Giardia may also be seen in biopsy
specimens. Barium studies may reveal some non-specific changes.
Treatment of giardia infection includes use of several drugs as shown in the Table 10.8.
Refractory cases need to be treated with combination of metronidazole and quinarcine.25
Giardia infection can be prevented by providing good sanitation facilities. Hand-washing
after cleaning fecal matter or diapers and before preparing and eating food can reduce rate of
infection. Infective cysts resist levels of chlorination used in piped water supply and can survive
for 3 months at 4°C. Cysts can be eliminated by boiling or filtering the water through pore size less
than 1 um. Cysts can’t survive heating or dessication. In countries where large populations get
piped water supply, contamination at the source can result in epidemics. Avoiding swallowing
of swimming pool water and avoiding ingesting uncooked food that has not been adequately
washed should be recommended.
Cryptosporidium
Cryptosporidium is clinically the most important spore-forming intestinal protozoa—the others
being Isospora, Cyclospora, and Microsporidia—the last being found only in patients with HIV
infection. Cryptosporidium though discovered in 1912, was found to be a human pathogen
only in 1976 and has gained much importance once its disease potential was realized in
immunocompromised individuals.26 C. parvum is the clinically significant species and though
found in several animals can complete its life-cycle in humans alone. There are at least 2 distinct
genotypes. Cryptosporidium is an important cause of non-bloody diarrhea in infants and
children.27
Infection occurs with ingestion of the oocysts. Oocysts are infective at the time of release 115
and hence cluster infections could occur in a family, institution or day-care centers and result in
auto-infection. Contaminated water has been a source of epidemics or from close contact with
infected animals. As the parasite multiplies within the human body, few cysts are required to
initiate infection. Infection is common in children especially those under the age of 2 years.
The organism has a preference for the lower ileum and it resides in the intracellular extra-
cytoplasmic protoplasm of the enterocyte producing a characteristic bulge into the small bowel.
The incubation period is estimated as 5–7 days though it could range upto 14 days. The protozoa
attaches to the enterocyte resulting in fluid loss and malabsorption. In otherwise healthy
individuals, the disease may be asymptomatic or could result in a self-limiting watery diarrhea
that could be severe and may be accompanied by abdominal cramps, nausea and vomiting.
Some children may have a viral flu-like syndrome while others could manifest lactose intolerance.
The infection lasts about 7–14 days. Though the clinical disease may last only 2 weeks, lethargy
and weakness can persist for a month. In addition, the child may continue to discharge oocysts
for several more weeks.28
In children with HIV infection, SCID, agammaglobulinemia, leukemia or post measles with
malnutrition, the disease is more severe and long lasting. The diarrhea is watery and severe and
often associated with weight loss and worsening nutritional status leading to severe morbidity
and mortality. Cryptosporidium has been implicated in persistent diarrhea.29 It might also involve
extra-intestinal organs including cholecystitis, sclerosing cholangitis, pancreatitis and hepatitis
in immunocompromised children.
The diagnosis is made by finding small oocysts in the stool by using the modified Kinyoun acid-
fast stain technique. An indirect immunofluorescent stain for identifying oocysts and enzyme-
linked immunoassay for detecting antigen in the stool is also available in some laboratories. The
parasite may be visualized in duodenal biopsies as well with the villi revealing blunting and mild
inflammation. The stool itself is watery with few if any leukocytes.
Treatment for cryptosporidosis is supportive in immunocompetent children and by and
large ineffective in immunocompromised children.30 In children with HIV, effective anti-retroviral
therapy is found to be most useful. Trials with nitazoxanide, bovine immunoglobulin and
azithromycin with paramomycin have been all found to be partially successful.31
Prevention is the key especially in immunocompromised hosts. The oocyst can survive for
many months in a cool humid environment but is very susceptible to heat and drying. Chlorination
of water is not useful and hence provision of proper sanitation facilities is extremely important.
Handwashing after cleaning fecal matter and while preparing and eating food are useful.
Balantidium
Balantidium coli is a widely distributed protozoa that results in illness similar to amebiasis.32 The
organism infects pigs and the disease is believed to be more prevalent in populations in close
contact with pigs. Infection occurs by ingestion of infective cysts.
Most patients remain asymptomatic while in others it can lead to intermittent diarrhea as
well as a fulminant colitis.
The diagnosis is made by a stool examination. The characteristic large ciliated trophozoites or
cysts are detected.
116 Treatment is with metronidazole, iodoquinol and in older children tetracycline. Prevention is
by avoiding contact with pig excreta.
Isospora
Isospora belli is similar to Cryptosporidium in most respects including the type of clinical disease
it causes though eosinophilia has been reported more commonly. Diagnosis is made on the
modified acid-fast Kinyuon stain.
Isospora responds well to either sulphamethoxazole-trimethoprim or ciprofloxacin.
Cyclospora
Cyclospora is similar to cryptosporidium and isospora in most respects. The diarrhea however
can be longer and include systemic features like fever and chills. Diagnosis is made on identifying
the oocyst on a modified acid fast Kinyoun stain.
Cyclospora is treated with sulphamethoxazole-trimethoprim or ciprofloxacin.
When to Suspect Intestinal Parasites?
Intestinal parasites are often asymptomatic.33 This is probably related to adaptation of man with
the parasite. As the inflammatory response is limited against helminths, serodiagnosis is usually
not useful plus the body does not expel the parasite. Hence, a carrier state is quite common.
However, in many children, symptoms caused by intestinal parasites depends upon several
factors the most important implicated being the parasite load, stage of the life cycle of the
parasite and the immune competence of the host. In many situations, it is considered after high
eosinophil counts are found on a routine blood examination. It however must be kept in mind
that protozoa (other than Isospora), enterobius and trichura usually do not cause eosinophilia.
Some of the common symptoms associated with intestinal parasites are shown in Table
10.4.
Diagnosis of Intestinal Parasites

The mainstay of diagnosis of intestinal parasites is a stool examination.34 A good stool sample
is the one that is more liquid and fresh (hot stool). Well-trained and dedicated personnel must
examine the stool as it is the morphology of the ova and parasite that makes the diagnosis.
Pictures of various parasites, ova and cysts must be available in every laboratory to make the
correct identification. Artifacts are common and include white blood cells or macrophages that
may look like ameba, yeast may look like protozoal cysts, plant fibers (banana) may resemble
worms, vegetable pieces may resemble proglottids. Laboratories should also have ocular
micrometers to help measure suspected organisms and try to differentiate from non-pathogenic
organisms.
Due to the variable release of ova and parasites, it is recommended to have 3 fresh stool
examinations performed on 3 different days though it is worthwhile to get the 2nd and 3rd
stool test done only after the results of the first has come negative. Studies have used upto
15 stool samples with the highest yield being in the first 6 samples.34 Urine, toilet bowl water
or contamination with other disinfectants, stool mixed with water or mineral oil, barium are
unacceptable as they can kill trophozoites. Anti-microbials, anti-diarrheals, enemas, and laxatives
can all alter the morphology and make diagnosis difficult. Sometimes it is easier to collect stool 117
by passing an 8–10 French Nasogastric tube 5 inches into the rectum and gently suctioning using
a 20 ml syringe. Rectal swabs and samples brought to the laboratory in diapers are unacceptable.
Table 10.4: Common symptoms caused/associated with parasites

Allergy/urticaria All helminths
Anal pruritus Enterobius, Taenia
Anemia Hookworm, Trichura
Anorexia, nausea, diarrhea All parasites
Appendicitis Ascaris, Enterobius
Bloody diarrhea Trichura, Strongyloides, Entameba
Cough Larval stages of migratory helminthes, Strongyloides
Diarrhea All protozoa, Trichuria, Strongyloides
Eosinophilia Hookworm, Ascaris, Strongyloides, Taenia
Growth failure Ascaris, Giardia,
Malabsorption Giardia, Cryptosporidium, Strongyloides
Obstruction Ascaris
Obstructive jaundice Ascaris
Pancreatitis Ascaris
Pica Hookworm, Ascaris
Rectal prolapse Trichura
Recurrent abdominal pain All parasites
Recurrent urinary tract infection Enterobius
Skin lesions Hookworm, Strongyloides
The stool may be collected in formalin or polyvinyl alcohol as the diagnosis is based on the
morphology of the parasite or egg and stool cultures are not important. This kills the bacteria
which if continue to ferment carbohydrates, will increase the acid production and alter the
structure and finally destroy the wall of the parasite. Stool may be refrigerated up to 48 hours.
One part stool mixed with 3 parts polyvinyl alcohol preserves the trophozoites.
Liquid parts of the stool are good for seeing trophozoites while the solid component may
contain the cysts and ova and parts of the worm. T. saginata segments are motile. For Enterobius,
(and rarely Taenia) reversed cellophane technique (NIH swab) needs to be used to collect
specimens. Duodenal aspirate is useful for looking for Giardia, Cryptosporidium and Strongyloides.
Sigmoidoscopy is useful in diagnosing amebiasis, Trichiura and Balantidium coli.
The stool must be examined as a wet smear first, and then after concentration and a permanent
stain applied on the fresh as well as concentrated stool. Wet smear examination is fruitful if the
intestinal parasite burden is high or when active motile trophozoites are being sought. The wet
smear has to be examined with normal saline solution as well as dilute iodine (protozoal cysts
and ova are better delineated). Iodine will immediately kill the trophozoites. Concentration
procedures can be performed on fresh as well as preserved specimens. Concentration procedures
are recommended as they decrease the background material and increase the sensitivity of the
118 test. Concentration of stool can be performed by either the formol-ether sedimentation or zinc
sulfate floatation technique. Permanent staining can be done with trichrome or preferably iron-
hemotoxylin. This helps preserve the stool specimen that can be later analyzed if necessary.
Permanent stains are more sensitive for detecting protozoal infections. Unfortunately most
laboratories are not able to match standard recommendations as mentioned above (personal
communication).
In suspected cases of Cryptosporidosis, modified acid-fast Kinyuon stain35 should be used
to identify the cysts. Cysts of Cryptosporidium are easily mistaken for yeast cells in the absence
of using the modified acid-fast stain. Size of the oocyst seen on the modified acid-fast stain
provides clues to the etiology as shown below:
Oocyst size – 2–6 mm – Cryptosporidium
Oocyst size – 8–10 mm – Cyclospora
Oocyst size – ~25 mm – Isospora belli
Antigen testing in the stool is available for Entameba, Giardia and Cryptosporidium.
Treatment of Intestinal Parasitic Infections

Principles of therapy include:
1. Use easily available, cheap and short course medications (the currently available drugs are
mostly ineffective for pulmonary phase of disease)
2. Preferably treat the whole family together
3. Remember that no one drug works on all forms of parasites
4. Post therapy laxative may be needed in some situations
5. In immunocompromised hosts, re-infection with the same organism may occur
6. In children with repeated infections and no evidence of immune deficiency and compliance,
re-infection by close family members or contacts must be kept in mind.
7. As usually ‘large burden’ of parasites results in symptoms, reduction of worm load may be
adequate in a large number of children.36
Adverse-effects are rarely encountered when anti-helminths are taken in therapeutic doses.37
Some drugs, like thiabendazole, which is absorbed and then excreted have more adverse effects
and in the presence of other equally effective and safer drugs available, are used less often.
Levamisole is also no longer used as an anti-helminth. Albendazole has been found to be useful
not only as an anti-helminth but as an effective drug against Giardia.38 Another relatively new
broad-spectrum anti-helminth and anti-protozoal drug with a good safety profile is nitazoxanide
and ivermectin.39,40 Iodoquinol or its derivatives are generally avoided in children in India.41 With
niclosamide, purgatives need to be given after the drug to avoid liberation of the ova within the
gut after the disintegration of the adult worm segment to avoid the possibility of autoinfection.
Fortunately, drug resistance is not a major concern at this time.
Some of commonly used anti-helminths and anti-protozoals are shown in Tables 10.5 and
10.6 respectively while the drug of choice and alternatives for treating various parasites is given
in Table 10.7.
Prevention of Intestinal Parasites

Short-term but effective strategy for controlling parasites in anti-parasitic therapy including 119
periodic anti-helminthic (6 monthly single dose) therapy in areas of high infestation or children at
Table 10.5: Characteristics of commonly used anti-helminths

Drug Dose Mechanism of action Common adverse affects and comments
Albendazole 400 mg single dose (For Inhibits polymerization • Rarely nausea, vomiting, abdominal
Giardia infection 400 of tubulin and uptake pain, headache, elevated transaminases,
mg daily for 5 days) of glucose rash and bone marrow toxicity with pro-
longed administration
• Not recommended less than 2 years
• Poorly absorbed from GI (absorption
increases when taken with a fatty meal)
Ivermectin 150–200 mcg/kg single Activates glutamate de- • Pruritus, fever, myalgia, headache,
dose; For Strongyloides pendent chloride chan- hypotension
2 days therapy and in nels
hyperinfection 7–10 days
Mebendazole 100 mg twice daily for Same as albendazole • Not recommended less than 2 years
3 days or 500 mg once. • Rarely nausea, vomiting, abdominal
For Enterobius pain, headache, elevated transaminas-
100 mg/dose to be es, rash and bone marrow toxicity
repeated after 14 days
Niclosamide Taenia – 50 mg/kg Inhibits oxidative phos- • Nausea, vomiting, dizziness, pruritus
single dose followed by phorylation in parasite • Purgative needed to prevent auto-
a saline purgative; mitochondria infection that can occur by liberation of
Hymenolepis – Treat for 1 eggs from the dead worm
week with doses of 1 gm
for 5–15 kg, 1.5 gm for
more than 15 kg weight
Nitazoxanide Taenia – 50 mg/kg Blocks pyruvate: ferre- • Abdominal pain, diarrhea, vomiting
single dose followed by doxin oxidoreductase • Avoid in children less than 1 year of age
a saline purgative; enzyme dependent
Hymenolepis – Treat for 1 electron transfer essen-
week with doses of 1 gm tial for anaerobic me-
for 5–15 kg, 1.5 gm for tabolism
more than 15 kg weight
Piperazine 75 mg/kg dose for 2 Hyperpolarization of • Useful in heavy worm load of Ascaris as
days neuromuscular junction it kills the worm and prevents migration
• Useful in intestinal or biliary obstruction
• Should not be used in conjunction with
pyrantel pamoate
Praziquantel For Taenia – 5–10 mg/kg Alters intracellular • Malaise, abdominal discomfort,
single dose calcium levels headache, dizziness, urticaria
For Hymenolepis 25 mg/
kg single dose
Pyrantel 11 mg/kg single dose; Irreversible depolariza • To be used with caution in children
pamoate to be repeated after tion of neuromuscular with hepatic dysfunction
2 weeks in Enterobius junction • GI disturbances, headache, dizziness rare
and given for 3 days in • Not recommended less than 12 months
hookworm age
Thiabendazole 50 mg/kg/d in 2 doses Similar to albendazole • More adverse effects noted than with
for 2 days other benzimidazoles and hence not
used commonly
120 • GI disturbances, headache, dizziness,
drowsiness, elevated transaminases,
Steven-Johnson syndrome
Table 10.6: Characteristics of commonly used anti-protozoals

Drug Dose Common adverse effect and comments
Diloxanide 20 mg/kg/day for 10 days • Nausea, vomiting and flatulence, pruritus
furoate • Avoid in children less than 2 years age
Furazolidone 6 mg/kg/day in 4 divided • Luminally active drug
doses for 7–10 days • Nausea, vomiting, diarrhea, brown color urine
• Avoid in G6PD deficient patients and neonates
Iodoquinol 30–40 mg/kg/day in 3 divided • Luminally active for ameba, balantidium
doses for 20 days • Headache, rash, pruritus, very rarely optic neuritis
and seizures
• Use with caution in patients with thyroid disorders
and liver disease
• Serious side-effects are seen with prolonged high
dose therapy
Metronidazole 15 mg/kg/day in 3 divided • Nausea, vomiting, diarrhea, metallic taste, irritabil-
doses for 5–7 days ity, headache, vertigo, parasthesias
35–50 mg/kg/day in 3 divided
doses in severe ameba infection
Nitazoxanide 1–3 y–100 mg twice daily for 3 d • Abdominal pain, diarrhea, vomiting
4–11y–200 mg twice daily for 3 d • Avoid in children less than 1 year of age
Ornidazole 40 mg/kg single dose for Giardia • Nausea, vomiting, diarrhea, metallic taste, irritabil-
40 mg/kg/day for 3 days for ity, headache, vertigo, parasthesias but less than
Amebiasis metronidazole
Paramomycin 25–35 mg/kg/d in 3 divided • Diarrhea and GI upset, rare nephrotoxicity
doses for 7 days
Tinidazole 50 mg/kg single dose for Giardia • Nausea, vomiting, diarrhea, metallic taste, irritabil-
50 mg/kg single dose for 3 days ity, headache, vertigo, parasthesias but less than
for amebiasis metronidazole
Table 10.7: Drug of choice and alternative for various intestinal parasites
Drug of choice Alternatives

Helminths
Ancylostoma/Necator Albendazole Mebendazole, Pyrantel pamoate$, provide iron therapy as well
Ascaris Albendazole Mebendazole, Pyrantel pamoate, Ivermectin, piperazine (if
evidence of obstruction or migration)
Enterobius@ Pyrantelpalmoate Albendazole, mebendazole, ivermectin
Hymenolepis Praziquantel Niclosamide
Strongyloides Albendazole# Ivermectin, Thiabendazole
Taenia Niclosamide Praziquantel
Trichura Mebendazole Albendazole, Ivermectin*
Protozoa
Cryptosporidium Nitazoxanide Paromomycin
121
Contd...
Contd...
Drug of choice Alternatives

Entameba% Metronidazole Tinidazole, ornidazole
Giardia Metronidazole Nitazoxanide, furazolidone, tinidazole, albendazole#
$ Once daily dose for 3 days.

@ All drugs for Enterobius should be repeated after 2 weeks; all family members must be treated together, care of clothes and
linen important.
# Albendazole for Strongyloides twice daily for 2 days; Giardia needs single daily dose for 5 days.
* Ivermectin with albendazole together have better cure rate than either drug alone48
% for asymptomatic cyst passers–use diloxanidefuroate alone; in active infection use diloxanidefuroate after or along with
metronidazole
Table 10.8: Prevention strategies for individual parasites

Ameba • Filteration of water as chlorination does not eliminate infective cysts
• Boiling water for 5 minutes kills cysts
• Chemoprophylaxis for asymptomatic cyst passers
• Thorough washing of fruit and vegetables with an effective disinfectant
Cryptosporidium • Handwashing
• Prevention of sewage reaching water supply
• Immunosuppressed individuals should either boil water or drink bottled water
Giardia • Boil water
• Filter water
Hookworm • Avoid walking barefoot in areas where feces may have been used as fertilizer
• Improved sanitation
• ASP-2 antigen derived from infective larva being studied as a possible vaccine
candidate
Pinworm • Therapy to whole family
• Careful hand-washing
• Wearing of underpants under the pyjama at night so that the hand does not reach
the peri-anal area.
• Regular de-worming in closed communities
Roundworm • Improved sanitation
• Thorough cleaning of vegetables and fruits and it is preferred to peel skin
• Periodic anti-helminthic therapy in high risk individuals or communities
Strongyloides • Wearing shoes
• Avoiding fecal contamination of surroundings
• Screening of patients prior to immunosuppression
Tapeworm • Proper cooking of pork or beef (above 56°C)
Whipworm • Elimination of use of human feces as fertilizer
• Sanitation
high risk of developing disease is useful.42,43 This has been ratified by World Health Organization.44
122 Recently a study from India has shown remarkable improvement in weight and reduction in
stunting with 6 monthly deworming.45 Mass therapy has also been recommended.46 In the past
school children have been targeted but it is now evident that pre-school children (along with
pregnant women) will also benefit though infection rates peak between ages of 5 to 14.47
For preventing disease in the community, education of the people about the disease and
its mode of spread and hence prevention along with provision of potable water is paramount.
Personal hygiene needs to be talked about to parents and children themselves at every
opportunity. These would include hand-washing after defecation and before preparing, handling
and eating any food. Nails need to be cut and kept short and cleaned. Parents need to look
out for any irritation or itchiness in peri-anal area and ensure daily bathing. Regular plotting of
weights and heights of children on a graph will go a long way in picking up early failure to thrive
of which parasites may be one of the reasons.
Some strategies for preventing specific organism is shown in Table 10.8.
SUMMARY
Intestinal parasites are common in children in our country especially in rural areas and in the poor.
Most often infected children remain asymptomatic, however there could be varied presentations
of parasitemia including abdominal pain, diarrhea, malnutrition, anemia and limited intellectual
capability. Drug therapy is cheap, safe, effective, widely available and very useful to eliminate
parasites in the short term. Preventive strategies like regular deworming is useful in communities
where the parasitemia rate is over 50%. For long-term prevention, education, improved sanitation
and potable water are needed. However, several questions remain unanswered, e.g. do all
children need to be de-wormed; if yes then how often; when should an asymptomatic child be
dewormed if at all; do we need to make a stool test for all children prior to de-worming; is there
a risk of over-treating? Perhaps some of these questions will be answered in the coming years.
REFERENCES
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2. Murray CJ, Lopez AD. Mortality by cause for eight regions of the world: Global burden of Disease study.
Lancet. 1997;349(9061):1269–76.
3. Jong E. Intestinal parasites. Prim Care. 2002;29:857–77.
4. Ramesh GN, Malla N, Raju GS, et al. Epidemiological study of parasitic infestations in lower socio-
economic group in Chandigarh (north India). Indian J Med Res. 1991;93:47–50.
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Guinea, Africa: prevalence and relationship to geophagia. Int J Epidemiol. 1999;28:169–74.
6. Okyay P, Ertug S, Gultekin B, Onen O, Beser E. Intestinal parasites prevalence and related factors in
school children, a western city sample-Turkey. BMC Public Health. 2004;4:64–9
7. Awasthi S, Pande VK. Prevalence of malnutrition and intestinal parasites in pre-school slum children in
Lucknow. Ind Pediatr. 1997;34:599–605.
8. Patel JC. Ten year study of stool samples with particular reference to intestinal parasites. J Postgrad
Med. 1986;32:219–24.
9. Gadgil SD, Kulkarni SS, Apte VV, Nanivadekar AS. Intestinal nematode infection in India: a cross-
sectional survey. J Postgrad Med. 1984;30:137–43.
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11. Fernandez MC, Verghese S, Bhuvaneswari R, Elizabeth SJ, Mathew T, Anitha A, Chitra AK. A comparative
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around Chennai. J Commun Dis. 2002;34:35–9.
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dwellers in India. J Trop Pediatr. 2002;48:331–4.
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economic area of Chandigarh (North India). Nepal Med Coll J 2004;6:28-31.
15. Stauffer W, Ravdin JI. Entamoebahistolytica: an update. CurrOpin Infect Dis 2003;16:479–85.
16. Parija SC, Khairnar K. Entamoebamoshkovskii and Entamoebadispar-associated infection in
Pondicherry, India. J Health Popul Nutr. 2005;23:292–5.
17. Haque R, Huston CD, Hughes M, Houtp E, Petri WA. Amebiasis. N Engl J Med 2003;348:1565-73.
18. Bhan MK, Kumar R, Khoshoo V, Arora NK, Raj P, Stintzing G, Sood D, Srivastava R. Etiologic role of
enterotoxigenic Escherichia coli & rotavirus in acute diarrhea in Delhi children. Indian J Med Res.
1987;85:604–7.
19. Guidelines for management of diarrhoea in children. Bhan MK, Bhatnagar S, eds. Bhumica, New Delhi
2000.
20. Abd-Alla MD, Ravdin JI. Diagnosis of amoebic colitis by antigen capture ELISA in patients presenting
with acute diarrhoea in Cairo, Egypt. Trop Med Int Health. 2002;7:365–70.
21. Bardhan PK, Beltinger J, Beltinger RW, Hossain A, Mahalanabis D, Gyr K. Screening of patients with
acute infectious diarrhoea: evaluation of clinical features, faecal microsopcy, and faecal occult blood
testing. Scand J Gastroenterol. 2000;35:54–60.
22. Haque R, Mollah NU, Ali IK, et al. Diagnosis of amebic liver abscess and intestinal infection with the
TechLabEntamoebahistolytica II antigen detection and antibody tests. J ClinMicrobiol. 2000;38:3235–9.
23. Krupp IM. Antibody response in intestinal and extraintestinalamebiasis.Am J Trop Med Hyg. 1970;
19:57–62.
24. Ortega YR, Adam RD. Giardia: Overview and update. Clin Infect Dis. 1997;25:545–9.
25. Nash TE, Ohl CA, Thomas E, Subramanian G, Keiser P, Moore TA. Treatment of patients with refractory
giardiasis.Clin Infect Dis. 2001;33:22–8.
26. Kaur N, Diwan N. Cryptosporidosis in north Indian children. Indian J Med Sci. 1991;45:143–5.
27. Chen XM, Keithly JS, Paya CV, LaRusso NF. Cryptosporidiosis. N Engl J Med. 2002;346:1723–31.
28. Flynn PM. Spore-forming intestinal protozoa. In Behrman RE, Kliegman RM, Jenson HB (Eds): Nelson
Textbook of Pediatrics. 17th Edition, Elsevier, New Delhi, 1128.
29. Ochoa TJ, Salazar-Lindo E, Cleary TG. Management of children with infection-associated persistent
diarrhea.SeminPediatr Infect Die. 2004;15:229–36.
30. Smith HV, Corcoran GD. New drugs and treatment for cryptosporidiosis.CurrOpin Infect Dis. 2004;
17:557–64.
31. Cohen SA. Use of nitazoxanide as a new therapeutic option for persistent diarrhea: a pediatric
perspective. Curr Med Res Opin. 2005;21:999–1004.
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India. Parasitology. 1981;83(Pt 2):373–80.
33. Brunser O, Espinoza J, Brunser AM. Etiology of diarrhea: Bacteria and Parasites. In Gracey M, Walker-
Smith JA (Eds). Diarrheal Diseases, Nestle Nutrition Services, Nestle Nutrition Workshop Series. 1997;38.
34. Kang G, Mathew MS, Rajan DP et al. Prevalence of intestinal parasites in rural Southern Indians. Tropical
Medicine and International Health. 1998; 3:70–5.
35. Fritsche TR, Smith JW. Medical Parasitology.In Henry JB (Ed).Clinical Diagnosis and Management by
Laboratory Methods. 20th Edition, SaudersElsevier.
36. Moon TD, Oberhelman RA. Antiparasite therapy in Children.PediatrClin N Am 2005;52:917–48.
37. Liu Lx, Weller PF. Anti-parasitic drugs. N Engl J Med. 1996;334:1178–84.
38. Hall A, Nahar Q. Albendazole as a treatment for infections with Giardiaduodenalis in children in
Bangladesh. Trans R Soc Trop Med Hyg. 1993;87:84–6.
124 39. Stephenson LS. Optimising the benefits of anti-helminthic treatment in children. Pediatr Drugs. 2001;
3:495–508
40. Parashar A, Arya R. Nitazoxanide. Indian Pediatr. 2005;42:1161–5.

41. Gupta Y, Gupta M, Aneja S, Kohli K. Current drug therapy of protozoal diseases. Indian J Pediatr.
2004;71:55–8.
42. Sur D, Saha DR, Manna B, Rajendran K, Bhattacharya SK. Periodic de-worming with albendazole and its
impact on growth status and diarrheal incidence among children in an urban slum of India. Trans R Soc
Trop Med Hyg. 2005;99:261–7.
43. Awasthi S, Pande VK. Six monthly deworming in infants to study effects on growth.Ind J Pediatr.
2001;68:823–7.
44. Report of the third global meeting of partners for parasite control.Deworming for Health and
Development. 1993. Who.int/wormcontrol
45. Awasthi S, Pande VK, Fletcher RH. Effectivness and cost-effectiveness of albendazole in improving
nutritional status of pre-school children in urban slums. Ind Pediatr. 2000;37:19–29.
46. Mass therapy is cost effective for controlling intestinal nematodes. Drug Ther Perspect 1995;6:14-6.
47. The Millennium Development Goals. WHO 2005.
48. Bulletin WHO; 81:35–42.
125
11
Constipation in Children
BR Thapa
INTRODUCTION
Constipation is a symptom of underlying disorder and is more common in males as compared
to female children. It is a very common problem in pediatric age group. 10–25% of all patients
attending pediatric gastroenterology clinics are constituted by various fecal elimination
disorders. About 1.3–5% of children suffering from chronic constipation have problem of
encopresis. Chronic constipation is a real challenge to the parents, children as well as for the
pediatricians to understand and to treat it effectively. The presence of encopresis adds to the
parental anxiety and has a great impact on the overall development of the child in the society.
This warrants a meticulous and well planned approach to manage a child with constipation.1,2
DEFINITIONS
Constipation
Constipation is defined subjectively a feeling of unsatisfactory evacuation. The other
accompaniments could be passage of too small stool, too hard stool, too difficult to expel,
too frequent and incomplete evacuation, but the objective and well accepted definition of
constipation is passage of stools twice or less per week.
Based upon the symptomatology certain criteria have been used in literature to define
constipation. The guidelines of the North American Society of Pediatric Gastroenterology,
Hepatology and Nutrtition defines constipation as a delay or difficulty in defecation present
for 2 or more weeks and sufficient to cause significant distress to the patient. Loening Baucke
criteria also called as Iowa criteria (given in Table 11.1 to define constipation) has been used
widely in various randomized controlled studies. According to this constipation is labeled
when two out of the following symptoms are present in last three months: (1) less than 3 bowel
movements per week, (2) encopresis more than once per week, (3) large amounts of stool every
7-30 days (large enough to clog the toilet) and (4) palpable abdominal or rectal mass on physical
examination.3-5 Recently an attempt has been made to define the functional gastrointestinal
disorders in children called Rome II criteria (Table 11.2).6 But these criteria are too cumbersome
and are difficult to follow and in general practice are not of much help. Very recently the Paris
consensus on childhood constipation terminology (PCCT) group has offered working definition
of chronic constipation in children. The chronic constipation is defined based upon the defecation
characteristics during last 8 weeks as given in Table 11.3.7
Table 11.1: The Loening-Baucke criteria of pediatric constipation

At least two of the following criteria:
1. Defecation frequency less than 3 times a week
2. Two or more encopresis episodes per week
3. *Periodic passage of very large amounts of stool once every 7–30 days
4. A palpable abdominal or rectal mass at physical examination
* The criteria of a large amount of stool is satisfied if it is estimated to be twice the standard amount of stool, shown in a clay
model , or if stools are so large that they clog the toilet
Table 11.2: Childhood functional defecation disorders: ROME:II criteria
Infant dyschezia
At least 10 minutes of straining and crying before successful passage of soft stools in an otherwise healthy
child
Functional constipation
In infants and pre-school children at least 2 weeks of:
1. Scybalous, pebble like, hard stools for a majority of stools;or
2. Firm stools two or less times/week; and
3. No evidence of structural, endocrine, or metabolic disease
Functional fecal retention
From infancy to 16 years old , a history of at least 12 weeks of :
1. Passage of huge diameter stools at intervals < 2 times/week
2. Retentive posturing, avoiding defecation by contracting pelvic floor and gluteal muscles
Functional non-retentive fecal soiling
In children older than 4 years a history of once a week or more for the preceding 12 weeks of
1. Defecation into places and at times inappropriate to the social context,
2. In the absence of structural or inflammatory disease, and
3. In the absence of signs of fecal retention
Table 11.3: The PCCT definition of chronic constipation

When 2 or more of the following characteristics during last 8 weeks:
• Frequency of bowel movements less than three per week
• More than one episode of fecal incontinence per week
• Large stools in the rectum or palpable on abdominal examination
• Passing of stools so large that they obstruct the toilet
• Retentive posturing and withholding behavior
• Painful defecation
Encopresis
Encopresis is the involuntary passage of formed, semiformed or liquid stool in the child’s
underwear. Largely this is considered to be functional when there is no organic or anatomic
127
cause or medication responsible for it after the age of 4 years. This is equivalent to enuresis in
children and is also called overflow incontinence when there is chronic constipation. Before this
age it is very difficult to recognize because, diapers are used and moreover, voluntary control on
the act of defecation may not be achieved. This emphasizes the fact that encopresis could be
functional or overflow incontinence.1,2,8
Fecal Soiling
Fecal soiling is any amount of stool deposited in the underwear, independent of whether
functional or organic or anatomic lesion is present.
Fecal Incontinence
Fecal incontinence is fecal soiling in the presence of an organic or anatomic lesion such as anal
malformation, anal surgery, anal trauma, meningomyelocele and other neurological and muscle
diseases affecting the anorectal area and perineum. There is no retaining capacity due to lack of
reflexes involved in retention of stool and act of defecation. But some authors have used these
terms interchangingly in the literature.1
CLASSIFICATION
This is not clear from the literature. For better understanding of the problem the suggested
classification in given in Table 11.4. There is no ambiguity to understand the congenital and
acquired constipation. Congenital constipation is usually since birth and is associated with
Hirschsprung’s disease (HD) and congenital anorectal anomalies. Acquired constipation occurs
any time after birth, but there are no neurological and anatomical abnormalities of anorectal
region. Acute constipation is defined when it is of shorter duration possibly less than 8 weeks.
On the other hand when the
Table 11.4: Classification of constipation
duration of constipation is more
than 8 weeks and is labeled I. Depending upon the age of onset
chronic constipation. This may a. Congenital constipation (Since birth)
or may not be associated with b. Acquired constipation
megarectum and megacolon II. Depending upon the duration
or impaction and encopresis. a. Acute or simple constipation (2 weeks to 3 months)
Chronic constipation is mild b. Chronic constipation (> 2 months)
when there is no encopresis or • Mild
megarectum and megacolon – No megarectum/megacolon or impaction
or impaction whereas when it – No encopresis
is complicated by presence of • Severe (complicated)
encopresis, megarectum and – Associated with megarectum and megacolon or impaction
megacolon or impaction is – Associated with encopresis
termed as severe constipation.9,10
Pathophysiology of Constipation
Normal Bowel Habits
128
The normal frequency of stools varies from 3 times per day to 3 times per week. But this may be
as high as 4–10 times during breastfeeding period in infancy. Toddlers may pass stools 3–5 times
per day but as the age advances the transit time increases and normal adulthood frequency of
1–2 times per day is achieved after 4 years of age.
Physiology of Defecation
Infants have involuntary passage of stools and there is no control on defecation. They may cry
or make some movements while passing stools. Mostly they pass stool while feeding due to
exaggerated gastrocolic reflex. After the age of one year the voluntary control starts developing
and by the age of 1½ to 2 years they have the control and tell about the act of defecation. This is
achieved earlier in girls as compared to boys. By the age of one year the mother starts training
the child to follow one word to pass stool. The good and early control depends upon the training
by mother and the positive response by the child.
Normally the mass movements occur 3–4 times a day but only 1–2 times it matures for
defecation. The sigmoid colon acts as store house, once stool pass into the rectum then urge
to defecate is generated. There are two types of nervous systems involved, the autonomic and
the sensory. The autonomic is stimulated by contact of the stool to the mucosa of rectum and
afferent impulses move to central nervous system to stimulate efferent so that internal sphincter
relaxes. The internal anal sphincter is formed by thickening of the terminal inner layer of smooth
muscles of rectum. Below this, there is anal canal and external anal sphincter. The striated muscles
form the pelvic floor and external anal sphincter. These are innervated by pudendal nerve and
4th sacral nerve. The puborectalis muscle is the part of levatorani and at the level of internal
sphincter it makes a sling around the lower part of rectum and gets inserted into symphysis
pubis. This is very important muscle to form the anorcetal angle to maintain the continence.
Normally this angle is right angle (85 to 110°) and during the act of defecation the angle becomes
straight or obtuse in squating position to ensure smooth passage of the stool during defecation
as shown in Figures 11.1A and B. Once the fecal matter descends from sigmoid colon to rectum
the mere distension of rectum initiates the urge for defecation. There is relaxation of internal
sphincter but contraction of external sphincter. The external sphincter can be contracted or
relaxed voluntarily. If there is no conducive atmosphere the contraction leads to postponement
of urge hence, more accumulation of fecal matter. If individual wishes to pass stool and sits in
squatting position, the anorectal angle gets straightened, the puborectalis muscle and external
sphincter relax to fire the stool in the toilet. The rectosphincteric reflex is generated by rectal
distension only. The pelvic floor also descends by 1 to 3.5 cm to facilitate the passage of stools.
At the same time the abdominal muscles contract, the glottis is closed to generate the intra-
abdominal pressure to push the stool in a smooth fashion. The abnormality at any of the levels
of act of defecation results to dysfunctional fecal elimination disorders. The constipation is the
most important problem to develop.9,11
Bowel Training
Normal bowel training should be started at the age of one year when infant starts walking.
Regular timing and passage of at least one stool per day are essential for the normal function of
the bowel. For this use of appropriate potty or toilet where a child can sit in squatting position is 129
required. Mother should ensure child sits comfortably on the lavatory seat without fear.
A B
Figs 11.1A and B: Shows anorectal anatomy in the cross section of pelvis. (A) Shows the 90-degree anorectal
angle formed by the puborectalis muscle, which forms a sling between lower part of rectum and symphysis pubis
to maintain the continence. (B) Shows that during the act of defecation the puborectalis muscle relaxes and at the
same time the internal sphincter followed by external sphincter relaxation and descent of pelvic floor to facilitate
the smooth flow of stool. The anorectal angle as shown becomes obtuse in squatting position for easy passage
of feces
Mother should use one word for defecation training and if baby repeats this is a good
sign. Child should be made to sit for 5–10 minutes. Normally children start attending toilet
independently by the age of 2–3 years. Problems in the bowel training can arise because of
dietary changes, low fiber diet, formula feeds, anal fissure, intercurrent illnesses, travel, moving to
new home, family dysfunction, birth of sibling, erroneous parents expectation, family problems,
failed toilet training, unresolved stress in school, changing of school, privacy, drugs and various
neurological disorders. Most of the times these precipitating factors are responsible for onset of
constipation with some functional overlay.12–15
Pathogenesis of Constipation
Constipation during childhood is confluence of variations in physiological tendencies like
development transitions, environment factors and parental response. Most of the times
constipation is a problem in toddlers and this may become passive if tackled in time. There is
always a precipitating cause.
Infancy
During infancy the constipation is mostly pathological due to Hirschsprung’s disease, anorectal
problems, mental retardation or anatomical abnormalities of anorectal area. This may also be
due to formula feeding and lack of cereal supplementation after 6 months of life. Infants largely
on animal or formula milk feeds and on low fiber diet are prone to develop constipation. Lack of
breast feeding predisposes the infants to develop constipation due to top milk feeds. Sometimes
janamgutti and opiate like drugs given by parents may be responsible for constipation in
infants.16,17
130
Toddlers/Preschool Children
In toddlers the most important factor is the painful act of defecation due to anal fissure. The head
of the stools is always hard and can injure the anal canal leading to fissure formation. The anal
fissure is very painful. Child tries to defer next act of defecation, so the child goes on withholding
the stool as there is fear of pain to the next act of defecation. The anal injury occurs due to
passage of hard stool and later on this gives rise to retention and pain cycle (Fig. 11.2). This goes
on and results into chronic constipation. Children start adopting different postures to evacuate.
This leads further injury to anal canal. As they start going to school other confounding factors
come in operation. The most important confounding factors are low fiber diet in form of junk
foods, soft drink beverages and bakery products available in ready made form in the market. The
children have more liking for these foods and they
dislike fiber rich home made diet. Parents have no
time to feed their children with home made stuff.
Moreover the media is highlighting junk foods
in a big way to exploit the children. This results
into stool impaction and leads to megacolon
and megarectum to accommodate large volume
of stool. The retention of large volume of stool is
responsible for pain abdomen and encopresis or Fig. 11.2: Pain a common factor in constipation
soiling in the underwear subsequently. in toddlers
School Children
The lack of privacy and positive reinforcement leads to problem of chronic constipation.
Psychologically children are withdrawn and develop other functional problems also.2,3 This is
more common in female children who don’t find appropriate hygienic toilets and bath rooms in
the school. Various other causes of acute and chronic constipation in children are given in Tables
11.5 and 11.6 respectively.18–20
Table 11.5: Etiology of acute constipation in infants and children

Infants Toddlers and older children
Lack of breast milk Change of diet
Formula feeds Change of place
Cow milk based diet Traveling
Change of diet Anal fissure
Low fiber diet Boil
Anal fissure Abscess
Inflammation in perianal area Infected hemorrhoids
Boil Dermatitis
Dermatitis Low fiber diet
Drugs: Opiates, Janamgutti, etc. Drugs 131
Table 11.6: Etiology of chronic constipation with or without megarectum, megacolon or encopresis
Congenital Acquired constipation
• Anorectal defects • Idiopathic or functional 90-95%
– Anal stenosis • Anal lesions
– Anal atresia – Anal fissures
– Imperforate anus – Abscess
– Anterior displaced anus – Strictures due to IBD, TB
• Neurogenic – Anal surgery or trauma
– Myelomeningocele • Neurological conditions
– Spina bifida – Cerebral palsy
– Hypotonia
• Colonic neuropathies
– Mental retardation
– Hirschsprung’s disease
– Tumor of spinal cord
– Intestinal neuronal dysplasia
– Tethered cord
• Colonic defects • Metabolic
– Colonic atresia – Hypokalemia
– Short colon – Hypomagnesemia
– Hypophosphatemia
– Hypercalcemia
– Cystic fibrosis
– Celiac disease
• Endocrine
– Hypothyroidism
– Multiple endocrine neoplasia IIB (MEN)
– Diabetes mellitus
– Hyperparathyroidism
• Drug induced
– Antimotility drugs
– Anticholinergics
– Antidepressants
– Antihypertensives
– Anticonvulsants
– Opiates
– Codeine
– Antacids
– Phenothiazines
– Methylphenidate
• Low fiber diet
• Psychiatric problems
Association of Chronic Constipation

Children suffering from recurrent abdominal pain (RAP), 50% may be constipated and 20%
of them may show psychiatric problems. With the impaction of stools other associations are
enuresis, UTI, palpable mass, soiling/encopresis/overflow incontinence, finger evacuation,
132 solitary rectal ulcer, rectal prolapse, irritability, scissoring of legs, passage of stool while standing
(unphysiological way to pass stools). Usually there is loss of appetite and poor weight gain.4,5,21
The main complaint of the parents is the longer interval between bowel movements in the
child. The clinical picture associated with chronic constipation include pain abdomen, vomiting,
abdominal distension, excessive flatulence, fecal soiling, prolapse and blood streaked stools. The
infants and toddlers become more irritable and cranky. They are in the habit of withholding the
stools and pass stool at irregular intervals. The stools may be hard and come out in form of casts,
balls, or ribbon like. The amount may be small but at times large. They have to strain a lot to pass
stools. Infants squeeze their buttocks and flex the legs and cry a lot while passing stools. The
toddlers develop scissoring and cross their legs, squeeze their buttocks and strain a lot. They
can’t sit and pass stool in standing posture behind the curtain or door or sofa in a isolated place.
They are afraid of pain and don’t allow to touch the abdomen and perineum.
Constant withholding of stools, leads to impaction of fecal matter and is responsible for
development of encopresis. This is also called soiling in the underwears. The frequency of soiling
may vary depending upon the severity of constipation. These children may have enuresis, UTI
and behavioral problem. Children with constipation may appear quiet, withdrawn, embarrassed,
agitated, clinging to mother and angry on examination as compared to children with other
gastrointestinal disorders. The history of functional bowel disorder may be positive in parents at
times.22
Approach to Constipation
While taking history special attention should be paid towards the toilet habits, which include
character of stools in the toilet, in the underwear and stool withholding maneuvers. Age of
onset of constipation is also important. Constipation starting from neonatal life gives clue
towards developmental anomalies of anorectal area or colon. Delayed passage of meconium
gives clue of Hirschsprung’s disease. Associated abdominal pain may be the sole symptom of
constipation in 50% children with RAP. It is important to enquire about dietary habits of the
child. Consumption of excess of milk, juices and/or other drinks, junk foods and bakery products
may lead to constipation. In the modern era children largely depend upon low fiber diet and
this becomes important factor for onset of constipation. Less consumption of cereals, pulses,
vegetables and fruits can result into constipation. Inadequate and low fiberdiet are responsible
for less production of stool. One must also enquire about the associated conditions like enuresis,
UTI or any psychiatric problems. There is loss of appetite due to delayed stomach emptying and
slow transit time due to colo-gastric reflex. There may be poor weight gain.5-9,23
Patients should be thoroughly examined especially abdomen and anal region. Abdominal
examination may reveal a lump in the left iliac fossa or suprapubic area due to retention of fecal
matter in the sigmoid and descending colon. Sometimes whole of the colon may be palpable.
Rectal digital examination should be carried out. In case of acquired constipation hard fecal
matter is felt just at the entry of the finger in the anal canal on digital rectal examination. In case
of HD the rectum is empty whereas the fecal matter is felt high up and on withdrawal of finger
fecal matter may gush out. In presence of active anal fissure digital rectal examination should be
avoided because this can enhance the anal injury. Neurological examination including perianal 133
sensation testing should be done. Investigations in case of simple constipation are not required.
Plain X-ray abdomen can give idea about the impacted fecal matter or fecoliths in whole of
colon and rectum (Figs 11.3A and B). Barium enema is mandatory when the constipation is
since birth. To rule out the diagnosis of Hirschsprung’s disease (Figs 11.4A and B) investigations
like anorectalmanometry, surface perianal electromyography, intestinal transit determination,
defecography and defecation stimulation are not commonly required. These are needed in
intractable situations when rectoanal dyssynergia is suspected. Full thickness rectal biopsy
to demonstrate the absence of ganglion cells is required for the diagnosis of Hirschsprung’s
disease.24-27
Figs 11.3A and B: (A) Plain X-ray abdomen showing impacted stools and dilated rectum and colon. (B) Plain
X-ray abdomen showing fecoliths in the rectum and dilated colon
134 Figs 11.4A and B: (A) Barium enema showing narrow lower part of rectum with proximal dilation in ultrashort
segment Hirschsprung’s disease in a child. (B) Barium enema showing narrowing of rectum with proximal dilation
in short segment Hirschsprung’s disease in a child
The points to differentiate acquired constipation and Hirschsprung’s disease are given in
Table 11.7. The childhood constipation differs from that of adolescent/adulthood constipation
and the differences are given in Table 11.8. A meticulous practical approach in management of
chronic constipation is shown in Figure 11.5. This algorithmic approach is based upon clinical
presentation, investigations and treatment.
Treatment
Treatment of constipation is aimed at:
1. Treating the cause,
2. Evacuation/disimpaction
3. Maintenance therapy
The treatment of underlying precipitation factor and evacuation should start simultaneously.
After evacuation, the passage of normal stools should be maintained.4 The treatment protocol is
summarized in Figure 11.6.
Acute Simple Constipation

Acute constipation is usually mild and easy to treat proper diary should be maintained by the
parents. Enough fluids and carbohydrate rich diet takes care of constipation in infants. At the same
Table 11.7: Difference between acquired constipation and Hirschsprung’s disease in children
Features Acquired constipation Hirschsprung’s disease
• History
Onset at birth Never Common
Retentive posturing Common Unusual
Encopresis Common Rare
Large caliber stools Common Unusual
History of obstruction Rare Common
• Physical examination
Failure to thrive Unusual Common
Distended abdomen Occasional Common
Stool in ampulla Common Rare
Rectal ampulla Dilated Narrow
• Investigations
X-ray abdomen Fecal impaction, dilated rectum and Hugely dilated colon with fecal
colon matter
Barium enema No narrow segment, rather dilated Narrow segment with proximal
rectum and colon dilatation
Rectal biopsy Normal ganglioncells and ACHE* Absent ganglion cells and
increased ACHE*
Rectal manometry Normal Abnormal contraction 135
* ACHE: Acetylcholinesterase
Table 11.8: Difference between childhood and adolescent/adulthood with constipation

Features Children Adolescents/adults
Occurrence More common in male More common in female
To begin with Toilet training and school entrance Adolescence, young adulthood
Defecation behavior Withholding Straining
Scissoring and to pass Common Sit in squatting position and strain lot
stool in standing posture
Encopresis Common Rare
Use of medications or due Rare Common
to systemic disease
Barium enema Rule out Hirschsprung’s disease To rule out intrahuminal pathology
High fiber diet Rarely helpful Helpful
Role of biofeedback Controversial Beneficial in pelvic floor dyssynergia
Role of surgery Only in HD* and in anorectal anoma- May be helpful in slow transit constipa-
lies but not in functional constipation tion
* HD: Hirschsprung’s disease
136 Fig. 11.5: Practical approach to constipation

Fig. 11.6: Management of constipation summarized
time the toilet training should also be imparted. This is very common in children. Parents must be
educated and reassured that it is not pathological. One has to eliminate the precipitating factor.
Treat local causes like anal fissure, boil or dermatitis effectively. Procedures like enemas, finger
evacuation/disimpaction, finger dilatation and frequent use of suppositories should be avoided.
But encourage use of high fiber diet in terms of cereals, pulses, vegetables and fruits. Adequate
fluid intake is advised to keep proper hydration. Initially laxatives can be used. Encourage toilet
training simultaneously. Laxatives can be given for 7–10 days but prolonged use should be
discouraged. If this is not properly treated can result into chronic constipation.11
Chronic Constipation
Treatment of chronic constipation is possible by multimodality approach1 as described on 137
next page.
Initial Education and Counseling

The parents and child should be educated regarding normal feeding, normal anatomy,
bowel functions and transitions, process of stooling, definitions of medical terms, model for
development of bowel dysfunction and the purpose of each intervention. Parents should also
be explained about the problem to be encountered, to read the literature, develop caring
relationships, resolve issues of blame, guilt or punishment, etc. Stress the need for behavioral
modification techniques and need for long follow-up.2,11
Mild Chronic Constipation

The uncomplicated chronic constipation without palpable fecal masses, megarectum or
megacolon and encopresis is treated as the management protocol given under maintenance
phase of treatment. There is no need of evacuation with enema or bowel wash.
Chronic Constipation with Impaction and Encopresis

Bowel Disimpaction/Evacuation
This is very important to have clean bowel free of retained/impacted stools. This will also take
care of overflow incontinence/soiling. If initial disimpaction is not done, the treatment with oral
laxatives result into paradoxically increase in overflow incontinence, increase in abdominal pain
and bloating. These cases may land in the emergency ward with acute abdomen. So disimpaction
is mandatory before starting the laxatives in maintenance phase of treatment of constipation.
The disimpaction can be done by oral route, rectal route, combination of oral and rectal routes
and surgical methods.11
Oral Route
Total bowel wash is very effective to clear whole of colon. This can be done with normal saline
or polyethylene glycol electrolyte solution in the dose of 14–40 ml/kg/hour till the returns are
clear. Metoclopramide (5–10 mg) should be given ½ hour before the lavage to avoid vomiting.
Sodium phosphate solution can be used. In case child is not able to take enough fluids orally,
can be given through nasogastric tube. Clearance of colon can be ascertained by examination of
abdomen for fecal masses, per rectal digital examination and X-ray abdomen.28–34
Recently it has been shown that polyethylene glycol (PEG) a non-electrolyte substance is
very effective in disimpaction of the fecal mass in children. This is an osmotic agent. The dose of
PEG is 1.5 gm/kg/day for 3–4 days. This can be dissolved in 240 ml water and given orally. This is
quite effective, safe and easy to use orally without much side effects. In case loose stools occur,
the dose of PEG can be lowered and adjusted accordingly. The results are better with PEG as
compared to lactulose.35
Rectal Route
Enemas
138 Three hypertonic phosphate enemas 12 hourly can clear the rectum effectively. The dose
recommended is 6 ml/kg/day. When the weight of the child is above 20 kg the adult size
enema (4.5 oz) can be given. Occasionally hypernatremia, hyperphosphatemia, hypocalcemia,
hypokalemia and dehydration have occurred with hypertonic enema. Saline enema is less
effective but can be used. This takes longer time to clean the colon. Plain tap water and soap
water enemas are not to be used in children.1,11
Suppository
Glycerine or bisacodyl suppositories can be tried in younger infants and may evacuate rectum
effectively. But this is required repeatedly.
Purgation
Large dose of mineral oil (liquid paraffin) or castor oil or other osmotic agents can effectively
eavacuate rectum. Usually repeated doses are required. These are not used in children.28
Surgery
Surgical disimpaction is required rarely in severe constipation, failed medical treatment, mental
retardation and fearful situation with poor compliance. Surgery is the definite treatment of
Hirschsprung’s disease (HD) and other anorectal congenital anomalies in children.36,37
Maintenance Therapy
The goals of maintenance therapy are (1) to maintain adequate frequency, (2) to avoid continued
passage of large stools and (3) to prevent withholding/retention of stools. Retraining medications
include stool softeners or bulk-forming agents or osmotic agents. The laxatives used are milk of
magnesia, liquid paraffin, lactulose, lactitol, etc. in the dosage of 1–3 ml/kg body weight. These
should always be given twice a day. Recently reported PEG for maintenance phase in the dose
of 0.26–0.8 gm/kg/day has been shown to be very effective and safe even for long-term use. The
maintenance therapy has to continue for 4–6 months depending upon the response. Routine
use of bisacodyl, castor oil, senna and phenolphthalein is not recommended in children. These
stimulate the peristalsis, active electrolyte transport and fluid movements.11,38–41
Cisapride a prokinetic agent can be used in paraplegics, pseudo-obstruction, diabetics,
chronic constipation etc.42 Prebiotics and probiotics have been shown to be effective but
more studies are required. Combination of various agents is effective to avoid recurrence of
constipation. The most commonly used drugs/agents alongwith dosage and side effects are
given in Table 11.9.
Dietary Modification
Encourage breastfeeding during early infancy and cereal supplementation should be started
after 4 months of life. Diets rich in high fiber are bran based cereals, pulses, fruits, vegetables, etc.
For older children and adults daily intake of 20 gm of bran is quite effective to avoid constipation.
In younger children the fiber requirement can be calculated as age in years plus 5. This gives
the daily requirement of fiber in grams for that particular age (e.g. for 5 years + 5 = 10 gm).8
Intake of plenty of fluids is encouraged. Excess of drinks in form of milk, sugar, water, juices and
cold drinks to be avoided. Bakery products and junk foods to be discouraged.43-45 Mechanism by
139
which dietary unabsorbed carbohydrates known as prebiotics increase the stool bulk is given in
Figure 11.7.
Table 11.9: Commonly used oral laxatives in childhood constipation

Agents Dosages Side effects
Osmotic
Lactulose/Lactitol/ Maintenance Bloating, cramps, diarrhea
Sorbitol/Mannitol 1–3 ml/kg/day in 2 doses
Magnesium citrate Maintenance Hypermagnesemia,
1–3 ml/kg/ day in 2 doses hypophosphatemia and
Magnesium hydroxide Maintenance secondary hypocalcemia
1–3 ml/kg/ day in 2 doses
Polyeythylene glycol Disimpaction: 1.5 g/kg 1 day in 240 ml Nausea, vomiting, cramps and
(PEG) 3350 water x 3–4 days diarrhea
Disimpaction:14–50 ml/kg/h till clearance
Polyethylene glycol Maintenance: 5–10 ml/kg/day

Electrolyte solution
Lubricant
Mineral oil (liquid paraffin) Disimpaction: 15–30 ml/ year of age Aspiration risk
Maintenance: 1–3 ml/kg/ day in 2 doses Lipoid pneumonia, nausea
Sodium docusate Oral 100 mg twice a day, can be used as

enema.
Stimulants (given for short
course)
Sodium pecosulfate 5–10 mg daily Cramps, diarrhea
Bisacodyl oral and enema 5–10 mg daily oral Cramps, pain abdomen and
5 mg per rectally irritation anal irritation
Glycerine suppository Pediatric suppository up to 6 years, adult Anal irritation
suppository >6 years.
Disimpaction: 6 ml/kg
12 hourly 3 times
Sodium biphosphate enema 2.5–7.5 ml/day (2–6 years)
Senna 5–15 ml/day (6–12 years) Melanosis coli, hepatitis
Castor oil Disimpaction: 15–30 ml/day Cramps, severe diarrhea
Bulk laxatives
Psyllium (Isbagol), Maintenance dose: Bloating
Methylcellulose, Daily requirement
Polycarbophil Age in years + 5 = gm/day
Titrate up to 20 gm/day
Prokinetic drugs
Cisapride 0.5 to 1 mg/kg body weight in diabetes, Diarrhea
chronic intestinal pseudo-obstruction
Retraining/Toilet Training
There should be positive reinforcement for toilet sitting and defecation. Toilet timing should be
140 regular. Child should sit in squatting position for 5–10 minutes once or twice a day after the meals
to take advantage of gastrocolic reflex. For proper sitting in the English type of latrines adequate
Fig. 11.7: Mechanism of action of fiber and CHO
foot rest should be provided to the children, so that the flexion of knee joints and hip joints is
possible. Idea is to straighten the anorectal angle, so that stools can flow out easily. Positive
reinforcement at home and by the physician is very important. Parents should be prepared to
have verbal acclaim and selective awards for desired behavior, initiation of toileting, use of toilet,
production of stool, acknowledging the cleaning after defecation and for repeated successes.5
Biofeedback
Biofeedback is required when other measures are not working and there is anorectal dyssynergia.
This helps in relaxation of EAS and levatorani muscles. This is only possible above 5 years of age
because cooperation of patient is very important. It is effective in 50–80% patients. Take the
benefit of conditioning reflex in morning and evening like to move in front of toilet, to drink
water, put the tap on and sitz bath. Multidisciplinary behavioral treatment is effective in chronic
constipation and defecation process in HD in children.9,46-49
Follow-up
Long follow-up is required. In case the progress is very good the treatment can be weaned
off after 6 months, but rest of the protocol is term of high fiber diet and toilet training should
continue for 2–3 years to avoid relapse (Fig. 11.5). Appropriate psychiatric consultation should
be taken when required. If there is atypical presentation or poor response pathological cause 141
must be ruled out.
Outcome and Prognosis

Outcome with appropriate above mentioned therapeutic modalities is excellent in 45–100%
of individuals. Moderate response may be seen in 20–30% whereas 25–35% may have failure.
Good prognostic indicators are better compliance, adequate intake of high roughage diet
and self-confidence to achieve the success. Poor prognostic indicators are hearing disabilities,
disobedience, fearlessness, school time soiling, teenage occurrence, mental retardation, severe
motor disability, associated disorders and neurogenic cause. In a recent study this has been
shown that 30% of children suffering from constipation continue to be constipated during
puberty.50
Prevention
Prevention of colonic dysfunctions have received much less attention but attending pediatrician
can play important role by providing anticipatory counseling in terms of appropriate feeding
advice, high fiber diet, interpretation of normal bowel habits, counseling life issues of the child
and early detection of problem and intervention.
SUMMARY
Constipation is a common problem in children and occurs more oftenly in boys as compared
to girls. Functional constipation occurs in 90–95% children whereas secondary causes are
uncommon. In toddlers and school going children the anal fissure and painful act of defecation
are important triggering factors to develop constipation. The low fiber diet inform of junk foods,
soft beverages and bakery products have contributed lot in perpetuation of constipation. In case
of functional chronic constipation there is no need to do many investigations. On examination
detection of fecal mass per-abdomen or per-rectally is enough, at times plain X-ray abdomen
may be required and will show impacted fecal matter and dilated rectum and colon. The acute
constipation is simple and easy to treat. On the contrary the chronic constipation is usually
associated with complications and is difficult to treat. The chronic constipation with impaction
and encopresis requires evacuation followed by maintenance laxative therapy for 6 months in
order to avoid further retention. The initial counseling, dietary advice to take fiber rich diet and
toilet training are also very important components of treatment. The uncomplicated chronic
constipation can be managed with maintenance therapy. The regular follow-up and adequate
laxative treatment to ensure passage of soft stool without straining have key role in the success.
After 6 months of vigorous therapy the fiber rich diet, toilet training and reinforcement should
continue for 2–3 years to avoid relapse of constipation later.
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of chronic constipation in children. Clin Pediatr (Phila). 2002;41:225–9.
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44. Williams CL, Bollella M, Wynder EL. A new recommendation for dietary fibre in childhood. Pediatrics.
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144
12
Childhood Pancreatitis
Neelam Mohan
ANATOMY
The pancreas is a retroperitoneal organ and is positioned in the anterior para renal space. It is
posterior to the stomach and lesser sac and anterior to the abdominal aorta and upper lumbar
vertebrae. The pancreas is divided descriptively into 4 parts: (1) head (which includes the uncinate
process), (2) neck, (3) body, and (4) tail. The head of the pancreas is nestled in the duodenal
C-loop. The uncinate process curves around the superior mesenteric vein. The neck, body, and
tail extend obliquely and superiorly where the tail is associated closely with the splenic hilum.
The splenic vein is applied to the posterior border of the pancreas. The splenic vein merges with
the superior mesenteric vein behind the pancreatic neck to form the portal vein confluence.
The splenic artery and the gastroduodenal artery run along the superior and anterior surface
of the pancreas, respectively. The common bile duct extends inferiorly through or behind the
pancreatic head on its course to the duodenum. The pancreas also may have an ectopic location
within the duodenal or gastric wall that can become inflamed as well.
PHYSIOLOGY
The pancreatic exocrine secretions/enzymes primarily are drained by the duct of Wirsung,
which extends the length of the gland. The duct of Wirsung may empty into the duodenal
papilla separately or be joined by the common bile duct to form a common channel, which then
empties into the duodenal papilla. An accessory duct of Santorini, located in the pancreatic head
and neck, also is present and normally drains into the duodenum (just proximal to the duct of
Wirsung).
PANCREATITIS
Pancreatitis is a disease process with multiple triggers that may cause activation of proteases
within the pancreas.
International symposium in Marselle in 1984 classified pancreatitis as:
a. Acute pancreatitis—Where there is clinical and pathological reversibility. Acute pancreatitis
is classified further into mild and severe forms. Mild acute pancreatitis is associated with
minimal organ dysfunction and uneventful recovery. Severe acute pancreatitis is associated
with pancreatic necrosis and may lead to organ failure and/or local complications.
b. Chronic pancreatitis—Where permanent morphological changes are seen in the pancreas,

either the glands or duct.
c. Recurrent pancreatitis may be familial as a result of inherited biochemical or anatomic
abnormalities. Hereditary pancreatitis present as recurrent pancreatitis and these patients
are at high risk for pancreatic cancer.
ACUTE PANCREATITIS
Acute pancreatitis represents a diagnostic challenge in the pediatric age group. Although
it occurs less frequently in children than in adults it is probably more common in childhood
than has previously been appreciated and may have significant morbidity and mortality. It
has numerous causes, an obscure pathogenesis, few effective remedies, and sometimes an
unpredictable outcome.
Although the majority of adult cases of acute pancreatitis can be attributed to alcohol or
gallstone disease, the causes of acute pancreatitis in childhood are more numerous and include
trauma, infection medications, anatomic variants and systemic metabolic disorders.
Classification
The original clinical classification of pancreatic inflammation, established at the Marseilles
symposium in 1963, comprised acute pancreatitis, relapsing acute, chronic relapsing and
chronic pancreatits.1 Acute pancreatitis was characterized by clinical and pathologic reversibility,
whereas chronic pancreatitis was characterized by permanent morphologic changes in the
pancreas. Neither etiology nor severity was included in the classification, and it often proved
difficult to clinically distinguish between the relapsing acute and chronic relapsing categories.
The classification was redefined at the Second International Symposium in Marsielle in 1984.
Both these intermediate categories were eliminated and pancreatitis was as acute or chronic
pancreatitis.2
In Atlanta in 1992, a clinically based classification system for acute pancreatitis was proposed.
According to this group, acute pancreatitis is defined as an acute inflammatory process of the
pancreas, with variable involvement of the peri-pancreatic tissues or remote organ systems.
Illness severity is assessed using the APACHE II system (Acute Physiologic and Chronic Health
Evaluation)3 or Ranson Criteria4 and also information is obtained by contrast enhanced
computerized tomography (CT) regarding the extent of the injury, and the process is divided
into mild and severe forms. This system allows for reclassification of the patients diagnosis based
on additional information obtained during hospitalization.5
Pathogenesis (Fig. 12.1)

The primary initiating event, whether traumatic, infectious or metabolic, is damage to the
pancreatic acinar cell by premature activation of digestive enzymes within the cell. The damaged
acinar cell then attracts inflammatory cells and activates platelets and the complement system,
which leads to the release of cytokines (such as tumor necrosis factor alpha, interleukin, nitric
146 oxide and platelet activating factor), free radicals, and other vasoactive substances. These
substances damage the gland directly causing pancreatic edema, ischemic necrosis, and
eventual loss of glandular tissue.
Fig. 12.1: Pathogenesis of acute pancreatitis
It remains unclear what constitutes the primary event leading to intrapancreatic proteolytic
enzyme activation. Most speculation has entered around two hypotheses: (1) Reflux of duodenal
contents into the pancreatic duct, where enterokinase may activate trypsinogen or (2) pancreatic
ductal hypertension, resulting from continued secretion into an obstructed duct leading to
rupture of small ducts, extravasation of juices into the gland, and subsequent intraparenchymal
activation of enzymes. Recent findings cast doubt on this concept and propose that enzymes
become activated by lysosomal hydrolases within the pancreatic acinar cell itself.6 Several studies
have shown that oxygen free radicals play an important role in the development of inflammation
in acute pancreatitis.7, 8
Two additional factors suggested as potentially contributing to the pathogenesis of pancreatitis
include abnormalities in pancreatic microcirculation with resultant ischemia9,10 and emotional cases.11
Etiologies
There is a wide variety of causes of acute pancreatitis in the pediatric age group. In adults,
biliary tract disease and alcoholism are two commonest causes. In contrast, the causes of acute
pancreatitis in childhood are quite different, and the commonest etiologic factors are trauma,
multisystem disease, and drugs.12–14 Multisystem disease includes patients with wide varieties
of systemic conditions or disorders affecting multiple organs, such as sepsis, shock, systemic
infections, collagen-vascular disease, inflammatory bowel disease and Reye’s syndrome. In recent
years more patients with acute pancreatitis in association with Kawasaki disease, hemolytic-
uremia syndrome and Henoch-Schonlein purpura have been reported. Viral infections,
congenital structural anomalies and metabolic diseases are also considered as common causes
of acute pancreatitis in childhood. In a large number of cases, no particular cause is identified.
Infections could result from measles, mumps, Epstein-Barr virus, Coxsackie’s B, rubella,
hepatitis A and B, influenza, echovirus, mycoplasma, typhoid, malaria and ascaris lumbricoides 147
(leads to duct obstruction).
As for congenital pancreatic anomalies, the commonest and most controversial entity has
been pancreas divisum (dominant dorsal duct syndrome). Pancreas divisum occurs when the
dorsal and ventral pancreatic ducts fail to fuse during embryogenesis. As a result, most of the
pancreatic parenchyma is drained by the dorsal duct, with a relative obstruction to flow. Most
experts consider this anatomic variant to be a significant cause of relapsing pancreatitis that
should be treated by papillotomy.15 However, other authors consider pancreas divisum a normal
anatomic variant that is, at most, an infrequent cause of pancreatic pain.
In a large number of cases no particular cause is identified. A list of causes is given in Tables
12.1 and 12.2.
Clinical Spectrum
Acute pancreatitis can present with a wide spectrum of symptoms and complications (Table
12.3);16,17 the clinical course is presently unpredictable. The diagnosis is difficult to establish
unless a high index of suspicion is maintained. A combination of clinical signs and symptoms,
along with supportive biochemical abnormalities and imaging techniques, is usually necessary
to provide a certain diagnosis.
Abdominal pain, as in adults, is the outstanding symptom, but on rare occasions pain may be
absent especially in younger patients. Typically, the pain is sudden in onset increases gradually
Table 12.1: Causes of pancreatitis in pediatric age group

Trauma Systemic Disease Drugs Toxin
Abdominal trauma Infections Chlorthalidone Ethyl alcohol
Child abuse Sepsis L- Asparaginase Methyl alcohol Metabolic
Burns Shock Azathioprine Heroin Disorders
Surgical trauma Collagen vascular 6-Mercaptopurine Amphetamines Diabetes mellitus
disease Sulfonamides Organophosphate Hyperlipidemia
Henoch-Schonlein Sulfasalazine insecticides (Type I, IV, and V)
purpura Nitrofurantoin Acetaminophen Hyper
DVS Furosemide Yellow scorpion bite parathyroidism
Kawasaki disease Metronidazole Wilson’s disease
Inflammatory bowel Estrogens Renal failure
disease Tetracycline Hypercalcemia
Reye’s syndrome Valproic acid Hyperlipidemia
Corticosteroids Uremia
NSAIDS Alpha
Methyldopa 1-antitrypsin
Procainamide deficiency
Iatrogenic
hypercalcemia
Pancreatic Gastrointestine Transplantation Miscellaneous
Disorders Disorders Renal Hereditary
Cystic fibrosis Duodenal ulcer, transplantation Idiopathic
Diarrhea Penetrating Graft-versus-host Postoperative
Pancreatic divisum duplications disease
148 Duplication
Abnormalities of
duct
Table 12.2: Causes of acute pancreatitis in 272 children

Cause Incidence (%)
Idiopathic causes 22
Trauma 20
Infections 15
Biliary tract disease 14
Drugs 13
Miscellaneous 11
Congenital anomalies 05
Table 12.3: The important clinical features of acute pancreatitis

Symptoms Signs
• Abdominal pain • Localized epigastric tenderness
• Anorexia • Abdominal wall rigidity
• Nausea • Rebound tenderness
• Vomiting • Abdominal distention
• Coma (rare) • Diminished or absent bowel sounds
• Dyspnea (rare) • Hypotension or shock
• Low-grade fever
• Pleural effusion
• Ascites
• Oliguria/anuria
• Respiratory distress
• Grey-Turner sign (Bluish discoloration of periumbilical area)
• Cullen’s sign (Bluish discoloration of flanks)
in severity and reaches maximal intensity after a few hours. It is located most commonly in the
epigastrium, other sites include right upper quadrant, periumbilical area, back or lower chest
and occasionally patients complain of diffuse pain over the abdomen. Quality of pain is usually
difficult to determine in children. Radiation of the pain is less frequent in children than adults
and is seen in approximately 30% of cases. Pain could radiate to back, middle/lower part of
abdomen, right upper quadrant and the anterior aspect of chest wall. Eating usually triggers a
worsening of pain and vomiting. The patient may experience some pain relief when the knees
are drawn up to flexed trunks. The emesis may be bilious. Fever, if present, is usually low grade.
A family history of pancreatitis should prompt the clinician to ask about symptoms of hereditary
and systemic/metabolic disorders, such as diarrhea, vasculitis, joint pain, rashes, and pulmonary
disease. Pain was associated with vomiting in 70% of the cases. On examination, there may be 149
localized (epigastric) or diffuse tenderness of abdomen; rebound tenderness and guarding may
be present and is usually localized to the epigastrium or upper abdomen.
Abdominal distention may be observed. In severe cases of hemorrhagic or necrotizing

disease, Grey Turner’s sign (blue discoloration around the umbilicus), Dr. Cullen’s sign (bluish
discoloration around the flanks) may be noted. Both signs are due to ecchymosis with entrance
of blood into the fascial planes and are not pathognomic of acute pancreatitis. Hypotension or
circulatory shock or coma may be seen in patients with severe pancreatitits. Other less common
findings may include pleural effusion, respiratory distress, abdominal ascites, icterus, abdominal
mass, melena and hematemesis.
Complications of Acute Pancreatitis

Systemic Complications
• Hypocalcemia
• Hyperglycemia
• Hyperlipidemia
• Acidosis
• Hyperkalemia.
Organ System Complications

• Circulatory failure
• Renal failure
• Respiratory failure
• Gastrointestinal
• Hematological
• Neurological (psychosis or coma)
• Hepatobiliary.
Diagnosis
There is no single diagnostic test of acute pancreatitis. The clinical diagnosis rests on a gestalt of
quite variable nonspecific clinical finding, supportive laboratory tests, and imaging techniques.
Occasionally the diagnosis is made with certainty at laparotomy or at biopsy. A careful history is
required to determine the presence of any etiologic factors, such as a family history, associated
inherited or acquired conditions, medications and trauma, previous history of unexplained
episodes of pain, if any, should also be looked into.
Laboratory Investigations
Nonspecific Laboratory Tests
Leukocytosis with bandemia, hyperglycemia, hypocalcemia, and elevated alkaline phosphatase,
aspartate amino transferase and total bilirubin are frequent findings. Other nonspecific laboratory
abnormalities include metabolic alkalosis, albuminuria, glycosuria and coagulopathies.
Hypoxemia with hypoalbuminemia, hypocalcemia and azotemia with elevated glucose and
lactate dehydrogenase levels reflect more progressive disease and hemorrhagic pancreatic
150 damage.
Specific Laboratory Tests

The lack of a “gold standard” diagnostic test for acute pancreatitits creates substantial problems
in clinical practice, and in interpretation published report. The available laboratory tests and
imaging techniques are summarized in Table 12.4.
Serum Amylase
Although it has a relatively low sensitivity and specificity (75–92% and 20–60% respectively)
serum amylase remains the most frequently utilized biochemical test for acute pancreatitis. Its
serum level rises within 2 to 12 hours, and in uncomplicated cases, remains elevated for 2–5
days. A protracted elevation raises the suspicion of a pseudocyst or macroamylasemia. Serum
amylase levels greater than three times normal are considered significant for the diagnosis.
Because amylase is cleared by the kidneys, elevated urinary amylase levels may exist 24 hours
after normalization of serum levels. The level of serum amylase bears no relationship with the
severity of pancreatitis or its clinical course. Although serial determination with a gradual decline
usually can indicate improvement, clinical deterioration can parallel amylase level normalization.
The sensitivity of amylase in pediatric acute pancreatitis is less than in adults.
Lipemia may interfere with amylase determination,18 and total acinar destruction may result
in normal serum amylase during acute pancreatitis. It is also well known that there are many
nonpancreatic causes of hyperamylasemia. By raising the cut off level from three to six times
the upper limit of normal, specificity increases for pancreatitis, but at the expense of sensitivity.
There are several GI conditions where serum amylase may be elevate such as appendicitis, biliary
tract disease, choledocholithiasis, endoscopic retrograde cholangiopancreatography, intestinal
infarction, obstruction, perforation, peritonitis, ovarian tumors/cyst, pneumonia, alcoholism,
cirrhosis, head trauma, hepatitis, etc.
Amylase Isoenzymes
Normally, 60% of serum amylase is salivary and the rest is pancreatic. Although in acute
pancreatitis, the majority of serum amylase is of pancreatic origin, other abdominal conditions
also increase pancreatic isoamylase.19 Fractionation of isoamylase isoenzymes to pancreatic
amylase is more discriminatory than amylase levels, but not superior to lipase assay.20
Table 12.4: Laboratory investigations and imaging procedures in acute pancreatitis

Laboratory tests Imaging techniques
Serum amylase Plain film of abdomen
Urine amylase Plain film of chest
Amylase creatinine clearance ratio Upper gastrointestinal barium
Amylase isoenzymes Pancreatic ultrasonography
Serum lipase Abdominal computed tomography
Serum proteases Magnetic resonance imaging
Serum ribonuclease Endoscopic retrograde cholangiopancreatography 151
Amylase Creatinine Clearance Ratio

The higher ratio in pancreatitis is due to increased renal clearance of amylase in relation
to creatinine due to decreased renal tubular reabsorption of amylase in acute pancreatitis.
Subsequently, this test is not specific, and in many other conditions of hyperamylasemia, the ratio
is high. It is agreed that the clearance ratio does not add any important diagnostic information to
that provided by serum amylase determination.20, 21
Serum Lipase
Serum lipase levels have a reported clinical sensitivity of 86 to 100% and clinical specificity of
50 to 99%. By increasing the cut-off level to greater than three times the upper limit of normal,
sensitivity can be increased to 100% and specificity to 99%. Lipase levels remain elevated for a
longer period of time in the plasma than do amylase levels, beginning to increase within 4 to 8
hours after systems, peaking at 24 hours, and decreasing over 8 to 14 days. It should be noted,
however, that the degree of elevation of amylase and lipase in the plasma does not reflect the
severity of the pancreatic disease. By using serum amylase and lipase determination together,
clinical sensitivity for the diagnosis of pancreatitis increases to 94%.
Considerable controversy exists concerning lipase superiority compared with amylase
determination.19 Lipase is also found in intestinal mucosa, stomach, adipose tissue, leukocytes,
and breast milk and can be elevated in the serum of patients with other abdominal conditions.
Serum Immunoreactive Trypsin

The only source of trypsin in the human body is the pancreas. Total immunoreactive trypsin
increases in acute pancreatitis earlier as compared with amylase.22 Its sensitivity is higher than
lipase and pancreatic isoamylase with similar specificity19 and correlates with disease severity.
Unfortunately, it’s not readily available in most centers.
Ribonulcease
The concentration of serum ribonuclease is low in serum, and pancreatic ribonuclease can
be distinguished immunologically from other sources of ribonulcease. Elevated pancreatic
ribonuclease levels in serum have been suggested to be indicative of pancreatic necrosis.23
Imaging Procedures
The most useful and frequently used imaging procedures in evaluating acute pancreatitis are
abdominal ultrasonography and CT scan.
Conventional Radiology
It’s of limited value in evaluating acute pancreatitis. However, a plain film of abdomen and
chest are done to rule out local complications and other abdominal catastrophies such as a
perforated viscus or appendicolith suggesting acute pancreatitis. The findings are summarized
152 in Table 12.5.
Table 12.5: Conventional radiology in acute pancreatitis

Chest radiograph Abdominal plain film
Atelectasis Regional small bowel ileus (sentinel loop)
Basilar infiltrates Dilatation of transverse colon (colon cut-off sign)
Elevation(s) of hemidiaphragm(s) Absence of air in descending colon
Left pleural effusion Generalized ileus
Pericardial effusion Blurring of the left psoas margin
Pulmonary edema Pancreatic calcifications
Diffuse abdominal haziness
Peripancreatic extra luminal gas bubbles
Pancreatic pseudocyst
Accumulation of fluid within the pleural space is indicative of severe pancreatitis since high
concentrations of amylase are generally present within pleural collections, this measurement
can be helpful in confirming the diagnosis in difficult case.
Contrast studies of upper gastric intestinal tract rarely provide useful information. The
duodenal loop may appear widened and the inverted 3 appearance (Frostberg sign), with the
middle apex of 3 being the origin of the duct and the curves of the 3 indicating swelling of
the pancreatic head. The stomach may be displaced forward or medially by retroperitoneal
swelling or a pseudocyst. Barium enema examination may show extrinsic compression and/or
displacement of the midtransverse colon.
Ultrasonography
Abdominal ultrasound is the most frequently used and useful imaging investigation performed
in patients with suspected acute pancreatitis. The two major sonographic findings are increased
pancreatic size and decreased pancreatic echogenicity.21,24 The echogenicity marker seems to be
more reliable than pancreatic size alterations.
In “normal” children, the pancreatic echodensity is equal to that of the left lobe of the liver.
In children, sonography has a positive predictive value of 0.93 and negative one of 0.78 in acute
pancreatitis.24 Hypoechogenicity was reported in 44% of incidences of acute pancreatitis in
children. Overlying gas due to ileus may present a technical problem but water can be given to fill
the stomach and act as an acoustic window. Beside size, contour and echogenicity, sonography
can provide information on pancreatic duct, any calcification, pseudocyst, fluid in abdomen and
pleural space.
Abdominal Computed Tomography

Abdominal computed tomography is usually reserved for situations where sonography is
technically unsatisfactory or where better anatomic definition is required. Contrast-enhanced
CT is the imaging method of choice in delineating the pancreas, evaluating the severity of and 153
detecting the complications of acute pancreatitis. In mild pancreatitis, the CT scan demonstrates
a normal pancreas in 15 to 30% of patients.25 In more severe instances, however, nearly always
the scan is abnormal. Computed tomographic scan signs include changes in size and texture of
the inflamed pancreas, pseudocyst, abscesses, calcifications, duct enlargement, peripancreatic
edema, peritoneal exudate, and bowel distention.25,26 Dynamic CT pancreatography, in which
large doses of intravenous contrast medium are given rapidly and the pancreas is analyzed by
thin tomographic cuts, is now used to identify pancreatic perfusion defects that correlate with
pancreatic necrosis.27
Balthazar et al further constructed a CT severity index (CTSI) for acute pancreatitis that
combines the grade of pancreatitis with the extent of pancreatic necrosis.25 The CTSI assigns
points to patients according to their grade of acute pancreatitis as well as the degree of pancreatic
necrosis. More points are given for a higher grade of pancreatitis and for more extensive necrosis.
Patients with a CTSI of 0-3 had a mortality of 3% and a complication rate of 8%. Patients with a
CTSI of 4-6 had a mortality rate of 6% and a complication rate of 35%. Patients with a CTSI of 7-10
had a 17% mortality rate and a 92% complication rate.
Grade of acute pancreatitis and the points assigned per grade are as follows:
• Grade A - 0 points
• Grade B - 1 point
• Grade C - 2 points
• Grade D - 3 points
• Grade E - 4 points
Grade of necrosis and the points assigned per grade are as follows:
• None - 0 points
• Grade 0.33–2 points
• Grade 0.5–4 points
• Grade higher than 0.5–6 points
Degree of Confidence
In a prospective study of 202 patients, Clavien et al reported 92% sensitivity and 100% specificity
in diagnosing acute pancreatitis via CECT. Balthazar et al reported an overall accuracy of 80–
90% in the detection of pancreatic necrosis. Small areas of necrosis involving less than 30% of
the pancreas can be missed. Nevertheless, the extent of pancreatic necrosis has been found to
correlate well with operative findings and clinical severity. In a study by Block et al, the positive
predictive value of CECT for pancreatic necrosis was found to be 92%.
False Positives/Negatives
The pancreas may appear normal in approximately 25% of patients with mild pancreatitis. In the
acute phase of pancreatitis a small number of patients will have a false-positive diagnosis for
necrosis due to massive interstitial edema and vasoconstriction of the vascular arcades. Repeat
CT within a few days may show normal pancreatic enhancement.
154 Endoscopic Retrograde Cholangiopancreatography

With the development of a smaller pediatric side-viewing endoscopy, endoscopic retrograde
cholangiopancreatography examination can be successfully performed in small children. In
acute pancreatitis, the pediatric indications are evaluation of post-traumatic or post-pancreatitis

complications, detection of anatomic abnormalities associated with acute pancreatitis, and
study of the pancreatic ducts in chronic relapsing pancreatitis or hereditary pancreatitis.28,29 In
the largest series done, mild pancreatitis was reported after the procedure in 12% of children,
but in all it was self-limited.28 In the most recent report, only 5% of children developed transient
pancreatitis owing to the test.29 Endoscopy nowadays is also used for therapeutic drainage
of pseudocyst (resulting as a complication of acute pancreatitis). The cyst is drained into the
stomach or occasionally into the duodenum, depending on the site of maximum bulge of the
cyst. Endoultrasound may be used as a guide prior to this procedure.
Clinical Course and Complications

There is considerable variation in the clinical course of acute pancreatitis.16,30 The patient may
have a mild illness, appearing only moderately ill with transient abdominal discomfort, or there
may be a fulminating, rapidly progressive course, with the patient developing severe pain, renal
failure, circulatory collapse, and a fatal outcome within hours or days. There are no accurate data
regarding mortality in children. In adults, the overall mortality rate per attack is estimated to be
approximately 9%, but in severe, hemorrhagic pancreatitis the mortality is higher, ranging from
15 to 50% in large case reports.30,31 However severe pancreatitis and associated mortality is much
less in children. Clinical symptoms associated with a poor prognosis include the presence of
shock, renal failure, and severe hypocalcemia; these secondary complications almost certainly
occur as a result of severe hemorrhagic pancreatitis. Similarly, late complications, including
hemorrhage or rupture of a pancreatic pseudoaneurysm or development of pancreatic abscess,
carry a high mortality rate.
Attempts have been made to develop clinically useful prognostic scores of disease severity
in adults with acute pancreatitis by statistically analyzing early clinical features and biochemical
measurements. A prognostic scoring system has not been developed for children, and most
of those established for adults cannot be applied to the younger patient. For example, in the
system developed by Ranson and Pasternak,4 prognostic factors such as age (over 55 years) and
volume of fluid sequestration are not applicable to children. Since large numbers of patients are
required for multivariate analysis of prognostic criteria, a useful scoring system in the pediatric
age group will be difficult to establish. It must be emphasized, however, that certain clinical
features of pancreatitis are clear indicators of severe disease, being frequent in patients with
pancreatic hemorrhage or necrosis. These include disorders of body homeostasis, such as coma,
hypotension, renal failure, pulmonary edema, shock, and hemorrhage. Similarly, laboratory
indicators of severe disease include hyperglycemia, hypocalcemia, hypoxemia, hypoproteinemia,
raised blood urea nitrogen, leukocytosis, and a drop in hematocrit. The quantity of necrotic
tissue appears to be directly correlated with the development of systemic complications and
with the risk of infection, so the use of “dynamic pancreatography” has been suggested for early
identification of patients most at risk.32–34
Acute phase proteins, fibrinogen, a1 antiproteins and C-reactive protein (CRP) have all been
examined as potential indicators of disease severity. CRP is probably the more useful marker
of severe acute pancreatitis. In a multicentric study from Italy on 50 patients, it was seen that
155
patients with severe pancreatitis had serum concentration of C-reactive protein significantly
higher on the 1st day and on the 3rd day than in patients with mild acute pancreatitis.35 Other
markers which appear to be predictive of the severity of the attack with high reliability include
urinary trypsinogen activation peptide (TAP)34 and blood levels of leukocyte elastase (PMN
elastase).36
Complications
Local Complications
• Fluid collection
• Pancreatic necrosis
– Sterile
– Infected
• Hemorrhage
• Pancreatic abscess
• Duct rupture
• Duct stricture
• Pseudocyst.
Systemic Complication
• Shock
• Pleural effusion
• ARDs
• DIC
• Acute renal failure
• Distal fat necrosis
• Multiorgan system failure
• Septicemia
• Hypocalcemia.
Treatment
Medical Therapy
The treatment of acute pancreatitis is largely supportive, and the intensity of therapy is decided by
the severity of inflammation. Several specific clinical aims are followed during the treatment like.
1. Removal of the initiating offender (i.e. drugs or toxins).
2. Reducing the self-perpetuating autodigestive process in the pancreas.
3. Removal of digestive enzymes or toxins from the circulation or peritoneal cavity.
4. Treatment of local and systemic complications.
1. Removal of the initiating process: If the underlying cause is recognized such as drugs/toxins/
hypercalcemia they should be eliminated. However, frequently the autodigestive and
inflammatory response within the pancreas is well advanced at the time of diagnosis.
2. Interruption of autodigestion (Table 12.6): Various nonspecific and specific clinical measures
have been proposed to achieve this objective, but the therapeutic benefit of most of the
156 strategies has not been validated in clinical trials.
3. Inhibition or removal of pancreatic enzymes: Enzyme inhibitors, such as aprotinin and gabexate,
given intravenously or intraperitoneally did not improve the outcome in instances of severe
Table 12.6: Proposed methods of interrupting autodigestion
Objective Treatment(s) Efficacy

Putting pancreas to rest Nil per oral Questionable
Nasogastric suction -do-
Antacids -do-
Histamine antagonists -do-
Inhibition/reduction of secretions Anticholinergics None
Glucagon -do-
Somatostatin -do-
Vasopressin -do-
Hypothermia -do-
Calcitonin -do-
Cell wall stabilizers Prostaglandins Questionable
Inhibition of proteases Aprotinin None
Epsilon-aminocaproic acid None
Leupeptin Animal studies only
disease.18 Supportive measures, such as total parenteral nutrition or fresh frozen plasma, also
have not proved to be effective. Antibiotic coverage to prevent septic complications using
ampicillin did not change the course of acute pancreatitis.18 A recent study using imipenem
was successful in reducing the incidence of pancreatic sepsis in patients with necrotizing
pancreatitis.37
4. Treatment of local and systemic complication: Symptomatic and supportive management
is the key step in the management of acute pancreatitis. Shock, acute renal failure, ARDS,
multiorgan system failure need to be managed in an ICU setting.
Surgical Management of Acute Pancreatitis

The role of surgery in the management of acute pancreatitis is limited to debridement of infected
pancreatic necrosis and cholecystectomy to prevent recurrent gallstone pancreatitis. Diagnosis
of infected pancreatic necrosis is based on fine-needle aspiration for bacteriology.
CHRONIC PANCREATITIS
It’s a syndrome of destructive inflammatory condition that encompasses the many sequelae
of longstanding pancreatic injury.38 Thus, acute pancreatitis is an event, whereas chronic
pancreatitis is a process.
Categories of Chronic Pancreatitis

Chronic pancreatitis can be classified into three categories:
1. Chronic calcifying pancreatitis, 157
2. Chronic obstructive pancreatitis,
3. Chronic inflammatory pancreatitis.
Chronic calcifying pancreatitis is invariably related to alcoholism. The earliest finding is

precipitation of proteinaceous material in the pancreatic ducts that forms protein plugs that
subsequently calcify. The ducts and lobules are initially involved in a random manner, and they
are surrounded by normal parenchymal tissue. However, as the disease progresses, these normal
areas become more diffuse. The pancreatic ductal epithelium undergoes atrophy, hyperplasia,
and metaplasia at the site of the protein plugs. Many of the small pancreatic ductules dilate,
while others are obliterated by fibrosis.
The main pancreatic duct shows a chain-of-lakes appearance due to alternating stenosis
and dilatation. In approximately one half of patients with chronic calcific pancreatitis, the
pancreatic parenchyma contains cysts of varying sizes (several millimeters to 5 cm). These cysts
are lined by cuboidal epithelium and contain pancreatic enzymes. Peripancreatic fibrosis is
usually a late finding that involves the portal and/or splenic veins. Peripancreatic fibrosis causes
stenosis or occlusion of retroperitoneal lymph channels. Ascites may complicate chronic calcific
pancreatitis as a result of portal hypertension or lymphatic obstruction in 1–2% patients. In
chronic obstructive pancreatitis, the prominent histologic changes are periductal fibrosis and
subsequent ductal dilatation. These changes are much more focal than those in the other forms,
and in most patients, the changes involve only the portion of the pancreas in which ductal
drainage is impaired. Diffuse changes may occur, in which the main pancreatic duct or ampulla
is obstructed. Although protein inspissation may occur, histologic changes in the ductal mucosa
are less common, and calcification is unusual. Moreover, the pancreatic duct is dilated, and the
pancreas is normal in size, atrophic, or focally and/or globally enlarged. A variety of factors are
implicated in chronic obstructive pancreatitis; these include ductal obstruction due to ampullary
stenosis, inflammatory or neoplastic causes, surgical ductal ligation, and fibrosis due to a
pseudocyst as a complication an episode of acute pancreatitis.
Chronic inflammatory pancreatitis is rare and can affect elderly persons without a previous
history of alcohol excess.
Etiology of Chronic Pancreatitis

In adults chronic pancreatitis is usually associated with alcoholism (70%) or is idiopathic. In
children chronic pancreatitis is usually associated with genetic conditions such as typical or
atypical cystic fibrosis or hereditary pancreatitis or is idiopathic.
Current therapy38 regarding chronic pancreatitis is that it begins as acute pancreatitis and
progresses to end stage fibrosis. Both genetic and environmental factors influence on the rate
of progression. The genetic susceptibility factors include PRSSI, SPINKI and CFRT mutations.
Hereditary pancreatitis carries a high risk of malignancy in future. The anatomic variants
predisposing to chronic pancreatitis are thought to be post-traumatic pancreatic duct scars,
preampullary duodenal wall cysts, sphincter of Oddi disorders (controversial), pancreatic
divisum (controversial) and autoimmune pancreatitis. Chronic pancreatitis either in isolation or
associated with other syndromes such as Sjogiren’s, inflammatory bowel disease has also been
described. The etiological factors described for acute pancreatitis such as toxins, drugs and
metabolic disorders such a hypercalcemia hyperparathyroidism, etc. Hyperlipidemia could also
158 lead to chronic pancreatitis. The causes of chronic calcific and non-calcific chronic pancreatitis
are given in Table 12.7.
Table 12.7: Causes of chronic pancreatitis

Calcific Non-calcific
• Juvenile tropical pancreatitis • Traumatic stricture
• Pancreatic divisum
• Hereditary pancreatitis • Sphincter of Oddi dysfunction (SOD)
• Hypercalcemia • Gallstone pancreatitis
• Hyperparathyroidism • Fibrosing pancreatitis
• Hyperlipidemia • Sclerosing cholangitis
• Cystic fibrosis • Autoimmune pancreatitis
• Hemachromatosis • Misc
• Idiopathic – Inflammatory bowel disease, Coeliac disease
– Alpha 1 trypsin deficiency
– Radiation
– Henoch-Schonlein purpura (HSP)
– Systemic lupus erythematosis, Sjogren’s
Diagnosis
Diagnosis of chronic pancreatitis is based on clinical presentation, pancreatic function tests
and imaging studies showing characterising pancreatic morphology, rarely histologic features.
Classical presentation is with characteristic pain with or without exocrine (maldigestion) and
endocrine (diabetes) insufficiency. The patient experiences intermittent attacks of severe pain,
often in the mid or left upper abdomen and occasionally radiating in a band like fashion or
localized to the mid back. The pain may occur either after meals or independently of meals, but
it is not fleeting or transient and tends to last at least several hours. Unfortunately, patients often
are symptomatic for years before the diagnosis is established; the average time from the onset
of symptoms until a diagnosis of chronic pancreatitis is 62 months, add or subtract 4 months.
The delay in diagnosis is even longer in people without alcoholism, in whom the average time is
81 months from onset of symptoms to diagnosis.
• The natural history of pain in chronic pancreatitis is highly variable. Most patients experience
intermittent attacks of pain at unpredictable intervals, while a minority of patients experience
chronic pain. In most patients, pain severity either decreases or resolves over 5–25 years.
Nevertheless, ignoring pain relief with the expectation that the disease eventually will resolve
itself is inappropriate. In alcohol-induced disease, eventual cessation of alcohol intake may
reduce the severity of pain. Variability in the pain pattern contributes to the delay in diagnosis
and makes determining the effect of any therapeutic intervention difficult.
Pancreatic function tests alone are not diagnostic of chronic pancreatitis because these
tests do not differentiate chronic pancreatitis from pancreatic insufficiency. Pancreatic
insufficiency should be considered as an end stage of destructive chronic pancreatitis or condition 159
like cystic fibrosis, Shwachman–Diamond syndrome. Morphological or histological changes
help in confirming chronic pancreatitis. Histological confirmation of chronic pancreatitis is not
popular and thus morphological changes are relied on. The morphological changes include
calcification in gland or duct and duct abnormalities like irregularity, dilation or stricture. It is
difficult to diagnose patients with early mild or minimal change chronic pancreatitis.
Pancreatic Function Tests

Pancreatic function tests (PFT) diagnose chronic pancreatic insufficiency. The pancreas has
marked functional reserve, so it must be damaged severely before functional loss is clinically
recognized. These tests do not distinguish chronic pancreatitis from pancreatic insufficiency.
Commonly used PFT are shown in Table 12.8.
Table 12.8: Commonly used pancreatic function tests

Non-specific tests Specific tests
• 72 hr stool fat • Stool trypsin and chymotrypsin and fecal elastase–1
• Stool smear for fat • Pancreolauryl test
• Steatocrit • Bentiromide test
• Oral tolerance tests • Stable isotope-labeled breath tests
Pancreatic function tests are invasive or non-invasive. Invasive tests of pancreatic function
(e.g. the tube secretin tests) are the gold standard for determining exocrine pancreatic function.
However, very few centers perform direct testing of pancreatic exocrine secretion. Currently,
there are two noninvasive pancreatic tests available at many centers: fecalelastase 1 (FE1) and
functional MRCP.
Imaging Studies
Four imaging procedures are commonly used for the evaluation of pancreatic disease:
1. CT (Computerized tomography),
2. ERP (Endoscopic retrograde pancreatography),
3. EUS (Endoultrasound), and
4. MRI (Magnetic resonance imaging).
1. Computerized tomography (CT): The CT should be the first test in the evaluation of possible
chronic pancreatitis because it is noninvasive, widely available, and has relatively good
sensitivity for diagnosing moderate to severe chronic pancreatitis.39–41 Pancreatitis is
diagnosed by CT with the identification of pathognomic calcification within the pancreatic
ducts or parenchyma, and/or dilated main pancreatic ducts combined with parenchymal
atrophy. A helical CT scan is preferred. In early chronic pancreatitis the role of CT is limited.
2. Endoscopic retrograde pancreatography (ERP): In the absence of tissue confirmation, ERP
is considered most sensitive and specific test for diagnosis of chronic pancreatitis, with
sensitivity and specificity in earlier reports approaching 90–100% respectively.42 In mild or
early disease finding include dilations and irregularity of the smaller ducts and branches
160 of pancreatic duct (Fig. 12.2). In more moderate disease, these changes are found in main
pancreatic duct as well (Fig. 12.3).
Fig. 12.2: Abnormal pancreaticobiliary junction (APBJ)
Fig. 12.3: ERP—Grossly dilated PD with multiple calculi
Tortuosity, stricture, calcification and cysts may also be seen as disease becomes more
severe (Fig. 12.4). There are a few studies of ERP in Indian children.43 In our study44 on 70
children with pancreatitis ERP was done in 24 showed that in 17 ERP has the advantage of
therapeutic potential like removing stones, dilating ductal strictures and placing stents for
pancreatic secondary drainage and relieving pain.
3. Magnetic resonance imaging (MRI): Use of MRI to perform magnetic resonance cholangio-
pancreatography (MRCP) is gaining popularity particularly in children. It does not routinely 161
require sedation, is noninvasive and avoids ionizing radiation and contrast administration. It
Fig. 12.4: Irregular PD
Fig. 12.5: Endoscopic ultrasonography (EUS)
has a resolution that approaches 1 mm and the newer machines like the 1.5 T field strength
are gaining popularity in providing more information on pancreas and peripancreatic
tissues.
4. Endoscopic ultrasonography (EUS) (Fig. 12.5): EUS is likely to play an important role in
162 diagnosis and management of patients with chronic pancreatitis. High resolution (<1 mm)
images of pancreatic parenchyma and duct structure can be generated without the use of
ionizing radiation.
Presently EUS is very popular in adult population. However, pediatric EUS is available only in
limited centers and will gradually gain popularity; with the development of smaller probes and
experience in children.
Endoscopic Ultrasonography Criteria for Chronic Pancreatitis

Ductal
• Stones
• Echogenic duct walls
• Irregular duct walls
• Strictures
• Visible side branches cyst
• Ductal dilatation.
Parenchymal
• Echogenic strands
• Echogenic foci
• Calcification
• Lobular contour.
Management
Three components are essential to the optimal management of CP: (1) control of pain,
(2) improvement of maldigestion, and (3) management of complications.
Abdominal Pain
The management of chronic pancreatic pain is challenging. The American Gastroenterological
Association (AGA) has published an evidence-based technical review on the management of
pain in CP.45
Supportive therapy for abdominal pain on the premise that fibrosis and scarring
ultimately progress to pancreatic burnout and spontaneous relief of pain. Although long-term
improvement in pain is observed in some patients with CP, a significant subset continues to
experience debilitating pain for decades.46 The AGA technical review states, “a strategy of waiting
for spontaneous pain relief is not reliable and may be unreasonable advice for the patient with
persistent, severe pain.”45
The AGA technical review discusses several medical options for pain relief, including
abstinence from alcohol, analgesics, and pancreatic enzymes. Abstinence from alcohol is critical
because continued use may hasten disease progression, aggravate chronic pain, and increase
mortality. Non-narcotic analgesics (nonsteroidal anti-inflammatory agents, acetaminophen,
and tramadol) are the next step in management of painful CP. If pain persists, low doses of mild
narcotics may be added. Severe or recalcitrant pain may warrant the use of stronger opiates
in select cases. Pancreatic enzymes are presumed to improve pain by suppressing CCK release
from the duodenum, leading to decreased pancreatic stimulation. The AGA review critically 163
appraises the literature regarding the controversial use of enzymes for pain.45 A meta-analysis
of six randomized placebo-controlled trials did not reveal a statistically significant benefit
for supplemental pancreatic enzyme therapy for pain relief; however, there was substantial
methodologic variability among the included trials.47 Uncoated preparations may work better
by enhancing delivery to the proximal small bowel. Uncoated pancreatic enzymes may be
worth trying in all patients because of their safety and minimal side effects; however, the AGA
technical review cautions that “additional studies are required to establish the effectiveness of
this modality of treatment and to define whether certain subsets are more likely to benefit from
enzyme therapy.”45
Many patients with CP have nonvisceral pain (central or somatosensory in origin).48
A differential nerve blockade (DNB) is helpful in determining whether there is a central or
somatosensory component to the pain syndrome. A differential nerve blockade is indicated for
any patient with pancreatic pain that does not respond to simple medical therapeutic measures
such as non-narcotic analgesics and enzymes. Antidepressants, anticonvulsants (gabapentin),
topical therapy, and psychiatric counseling may be of use for patients with nonvisceral pain.
Nerve blockade may be used for select patients with visceral pancreatic pain. Limited studies
suggest that a subset of patients obtain significant short-term pain relief from CT-guided celiac
plexus blockade. EUS-guided celiac plexus blockade has recently emerged as an effective
alternative, with a more prolonged duration of effect.49
It is generally accepted that pain in CP may result in part from obstruction of the main
pancreatic duct from stones and strictures, leading to increased ductal and parenchymal
pressure. Because obstruction contributes to pain, patients with “large-duct” CP may benefit from
endoscopic or surgical duct-decompression therapy. Endoscopic techniques include biliary and/
or pancreatic sphincterotomy, removal of pancreatic duct stones, and placement of pancreatic
stents.
Several surgical options exist for select patients with pain resulting from CP. In patients with
a dilated main pancreatic duct, a side-to-side pancreaticojejunostomy (Puestow procedure)
may be performed. Most studies of surgical and endoscopic decompressive therapy in CP have
revealed good short-term but poor long-term pain control. The AGA technical review states that
these procedures are best performed based on “need for long-term narcotic therapy, marked
diminution of the quality of life because of intractable pain, or major nutritional consequences
of pain.”45
Pancreatic resection is reserved for patients with small-duct disease and pain unresponsive to
medical therapy. The Whipple procedure and distal pancreatectomy have been used in the past
for treatment of patients with small-duct CP. Newer resection techniques offer substantial relief
of pain related to an inflamed and scarred gland, with preservation of surrounding structures.
For example, the Beger procedure involves resection of the inflamed pancreatic head with
careful sparing of the duodenum; the Frey procedure adds a longitudinal duct decompression
to the pancreatic head resection. The AGA technical review cites several potential drawbacks
of resection procedures, including: (1) paucity of randomized trials, (2) loss of exocrine and
endocrine function including diabetes (3) technical expertise required for organ-sparing
methods, and (4) lack of pain relief in some patients, even after total pancreatectomy.45 In spite
of these drawbacks, resection may offer significant relief to a subset of carefully chosen patients,
164 particularly if performed in high-volume centers.
The AGA medical position statement for treatment of pain in CP provides a stepwise algorithm
for use of the above-stated therapeutic modalities45 (Fig. 12.6).
Maldigestion
Pancreatic enzymes are used for treatment of maldigestion in CP. Exogenous pancreatic enzymes
are safe, well tolerated, and produce few side effects. There are a multitude of available pancreatic
enzyme preparations; they differ based on enzyme content, the use of microspheres versus
microtablets, and the presence of a coating for delayed release. Lipase is the most important
determinant of the effectiveness of individual preparations. A minimum of 30,000 USP units of
lipase per meal allows adequate intraluminal digestion of fat and protein in most patients. The
dose may need to be titrated to as much as 60,000 to 80,000 USP units lipase per meal because
not all the lipase may reach the proximal small intestine in active form. Enzymes may be taken
entirely at the onset of each meal; however, dosing is more physiologic if one-half the amount is
taken at the onset and one-half approximately 15 minutes into the meal.
Because the enzyme “microspheres” contained in most coated preparations are typically
released too distally in the small bowel, uncoated preparations are optimal for management
of maldigestion. Alternatively, patients may break open coated capsules and sprinkle the
microspheres over food to ensure proper delivery to the proximal bowel. Because uncoated
preparations are more easily denatured by gastric acid, acid suppression with either a proton-
pump inhibitor (e.g. omeprazole 20 mg once daily) or histamine-receptor antagonist (e.g.
famotidine 20 mg twice daily) is required.
Response to enzyme therapy may be monitored through an assessment of symptoms or,
more objectively, through 72-hour stool fat quantification.
A poor response to pancreatic enzymes may suggest one of several possibilities:
• Denaturation of enzymes by gastric acid
• Improper timing of enzymes
• Coexisting small intestinal mucosa disease
• Loss of enzyme potency
• Rapid intestinal transit (try uncoated preparation)
• Noncompliance
• Alternate diagnosis (e.g. pancreatic cancer).
A daily proton-pump inhibitor may be added for those refractory to therapy because gastric
acid may denature exogenous enzymes (Fig. 12.7).
Management of Complications
Large or symptomatic pseudocysts may be drained endoscopically through transmural or
transpapillary approaches.
Large pseudocysts may also be definitively drained surgically through cystgastrostomy and
cystjejunostomy.
Biliary and gastric outlet obstructions are best managed through surgical decompression.
Complications of pancreatic duct disruption or fistulae (pancreatic ascites or pleural effusions)
165
are managed by prolonged pancreatic rest (parenteral nutrition) and endoscopic placement of
pancreatic duct stents.
Fig. 12.6: Approach to management of chronic pancreatitis
166
Fig. 12.7: A general approach to treatment of maldigestion in CP
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168
13
Symptoms and Signs of Liver
Disease in Childhood
S Srinivas, V S Sankaranarayanan
INTRODUCTION
Children with liver disease present in a variety of ways and have a multiplicity of symptoms
and signs of varying severity. At one end of the spectrum is a child who is found incidentally to
have an abnormal liver test but no clinical features of liver disease; at the other end is the child
who has obvious symptoms and signs of acute or chronic hepatocellular failure. Some of these
symptoms are quite specific for liver disease; Others are suggestive but may reflect disease or
dysfunction in any system.
SYMPTOMS OF LIVER DISEASE

Symptoms of liver disease are general ill health, gastrointestinal symptoms, jaundice and
associated symptoms, circulatory, cardiopulmonary and hematologic symptoms, nervous
system and endocrine system disorders. Past medical history, family history, drug history and
social history are relevant in history diagnosis.
General Ill Health

Nonspecific symptoms of both acute and chronic liver disease upto 60% of patients include
weakness, increased fatigability and general malaise. Lethargy is often seen in chronic viral
hepatitis and primary biliary cirrhosis depending upon severity of underlying liver disease and
they may last long and may follow acute hepatitis like presentation. With specific treatment the
symptoms may improve. Altered manganese homeostasis in the central nervous system may be
a contributing factor.
Gastrointestinal Symptoms
Gastrointestinal symptoms are frequently noted and are nonspecific. Loss of appetite in icteric
patients is typical of acute viral hepatitis due to Hepatitis A virus as part of prodrome. Long-
term anorexia leads to weight loss and often seen in end stage chronic liver disease associated
with growth retardation and muscle wasting and ascites and edema. Nausea and vomiting
and other dyspeptic symptoms are common with gallstones and many forms of liver disease.
Prodrome of acute viral hepatitis, drug toxicity (acetaminophen overdose), alcohol abuse need
to be considered. GI bleed, a dreadful complication of portal hypertension due to esophageal
or gastric variceal bleed necessitates endoscopy. Erosive gastritis may be seen in acute liver
failure. Abdominal pain commonly seen in hepatobiliary disease, often present across the upper
abdomen or right quadrant of the abdomen even in acute hepatitis. Dull ache is often due to
stretching of the capsule of the liver. Tender liver is seen in acute hepatitis, hepatic abscess or
hepatic malignancy. Severe colic suggests biliary disease and/or cholangitis. Very large and firm
splenomegaly can cause dragging pain over left upper quadrant of the abdomen. Diffuse painful
discomfort is seen in tense ascites particularly in spontaneous bacterial peritonitis or Budd-Chiari
syndrome. Altered bowel habits or stool appearance in liver disease includes mild diarrhea, pale
stool (cholestasis, biliary obstruction, pancreatic insufficiency), severe diarrhea (ulcerative colitis
or celiac disease) and melena (portal hypertension) with or without hematemesis. Melena and
constipation are often seen and may precipitate hepatic encephalopathy.
Jaundice (Fig. 13.2)

Presence of jaundice indicates hepatobiliary disease, a most striking symptom noted even by
lay people. Clinical jaundice is seen when serum bilirubin level exceeds 2 mg/dL and is first seen
in the sclera. Higher levels (>5 mg/dL) suggests significant hepatocellular injury or extrahepatic
cholestasis. Prodromal symptoms of fever, nausea, anorexia, malaise, dull activity and upper
abdominal pain suggest acute hepatitis especially hepatitis A. Yellow urine associated with pale
stool denotes severe hepatocellular or cholestatic disease. Urine staining the diaper yellow in a
young neonate, should create an yellow alert not to miss an underlying biliary atresia. Symptoms
of infection or severe colic suggest cholangitis or cholelithiasis or biliary ascariasis or sludge
in biliary passage. Progressive pruritis is notably seen in biliary obstruction, intrahepatic or
extrahepatic and needs thorough evaluation.
Hematologic and Circulatory Symptoms

Spontaneous or trivial bleeding in patients with liver disease is seen in both acute and chronic liver
failure. Petechiae and ecchymosis occur in chronic liver disease. Subconjunctival hemorrhage
in acute liver failure should raise the possibility of acetaminophen induced acute liver failure
and sometimes there may be uncontrollable bleeding tendency. Presence of ascites with
fluid retention is characteristic of advanced cirrhosis with underlying portal hypertension and
denotes decompensation of liver disease. Many children have dependant edema. Right sided
pleural effusion, dyspnea due to severe ascites, pulmonary hypertension or hepato-pulmonary
syndrome with cyanosis and clubbing are indicators of poor prognosis in chronic advanced liver
disease. Oliguria and nocturia occur as fluid retention develops and increases the severity of liver
disease.
Nervous System Manifestations

The most striking feature of liver disease is encephalopathy which occurs in upto 80% of patients
with chronic liver disease with varying degree of severity and may need hospitalization in ICU. The
spectrum of hepatic encephalopathy includes grade I characterized by behavior and personality
170
Symptoms and Signs of Liver Disease in Childhood
changes, Grade II stage of somnolence, Grade III stupor and Grade IV coma. Rapidly increasing
severity with increasing INR warrants referral for liver transplantation. In severe acute liver failure
it is a bad prognostic feature. Hepatic encephalopathy is a complex neuropsychiatric syndrome
and may have a daily chronic course with symptoms of minimal hepatic encephalopathy.
They are reduced attention span, sleep disturbance, altered personality, loss of memory, poor
scholastic performance, confusion, reduced peer relationship and physical activity, increasing
drowsiness and in due course coma with fetor hepaticus and coarse flapping tremor. Specific
diseases can also lead to characteristic neurological symptoms such as extrapyramidal features
like choreoathetosis, dysarthria, gait disturbance in Wilson’s disease, cerebellar dysfunction in
alcoholic liver disease or night blindness due to Vitamin A deficiency in chronic cholestasis.
History of difficulty in getting up-climbing up (positive Gower’s sign ) from lying down posture in
an otherwise normal child without clinically obvious/symptomatic liver disease may be a cause
for incidental elevation of liver transaminases. Similarly obesity with fatty liver is associated with
elevated transaminases.
Endocrine Problems
Reduced sexual maturity rate and dysfunction and infertility, libido, impotence, sterility, painful
gynecomastia in boys (Fig. 13.7) or other signs of feminization or testicular atophy are reported
in liver disease. Bilateral parotidomegaly is seen in alcoholic liver disease, autoimmune liver
disease and cryptogenic cirrhosis and most of the above findings return to normal within few
days of successful liver transplantation.
History of Past Illness in Liver Disease

Past history in liver disease evaluation is important. History of neonatal cholestasis may be
positive in future chronic liver disease with portal hypertension.
History of blood transfusion, needle pricks, tattooing, ear boring, dental extraction, recurrent
blood transfusion could result in hepatitis B or C.
History of hepatotoxic drug usage such as paracetamol, methotrexate, anticonvulsants,
anticancer drugs, antipsychotics, anti-tuberculous drugs, nitrofuradantoin, ketoconazole,
dapsone etc. in induced liver disease.
History of ulcerative colitis in primary sclerosing colitis.
History of biliary surgery like Kasai in ascending cholangitis and stricture.
Family History
Family history, if positive, gives clue to the cause of liver disease in some of our patients such as
genetic/metabolic liver disease such as—Wilson’s disease, Glycogen storage disease, tyrosinemia,
urea cycle disorders, galactosemia, alpha-1 antitrypsin deficiency, Niemann-Picks and infantile
Gaucher’s diseases and PFICs.
A family history of diabetes in hemochromatoses or thyroid disease, rheumatoid disease,
erythema nodosum, dermatitis herpetiformis, etc. or early liver failure suggest autoimmune hepatitis.
171
Social History
Alcohol consumption, intravenous drug abuse, sexual nonmarital practices, exposure to
industrial chemicals and toxins may be a causal factor of newly presenting liver patient . History
of aversion for cigarette smoking may suggest hepatitis A infection.
POSITIVE PHYSICAL EXAMINATION SIGNS IN CHILDREN WITH LIVER DISEASE

A detailed history of the presenting complaint of the patient should help to offer the history
diagnosis with one or two differential diagnosis and this should be complemented by a
thorough and systematic and respective (hepatobiliary) system physical examination with
documentation of both the presence and absence of pertinent physical signs. The physical
findings may be disease-specific such as Kayser-Fleischer rings in Wilson disease, liver flap in
hepatic encephalopathy, visible tortuous epigastric veins with flow outwards from umbilicus of
intrahepatic portal hypertension often due to cirrhosis of liver.
To avoid inter- and intraobserver variation, pediatrician and medical postgraduates should expose
themselves frequently and practice regularly under the guidance of experienced faculty in giving
physical/clinical examination training.
Physical Signs in Liver Disease—General Examination

Orientation of the patient, sensorium whether alert or disoriented or unconscious (Glasgow
coma scale grading), bedridden or ambulant, nutrition of the patient, well looking or ill-looking
and if so, acutely ill (well nourished) or chronically ill, febrile/afebrile, should be documented
like any other system examination. Gross findings like anasarca, ascites, anemia, jaundice,
lymphadenopathy, dyspnea and facial dysmorphism, clubbing, cyanosis, skin bleeds (petechiae,
bruise) to be noted. Anthrapometric assessment of growth and muscle wasting are important.
Most of the physical signs found in both acute and chronic liver disease are summarized in
Table 13.1, which will give clue to the clinical diagnosis.
Fetor hepaticus (sweet, slightly faecal smelling of breath) suggests severe hepatocellular
disease with portal hypertension and encephalopathy.
Abdominal Examination in Liver Disease

Inspection
Distension especially in the flanks suggests ascites. Abdominal wall movement may be less.
Diffuse abdominal tenderness and pain occur in massive ascites and spontaneous bacterial
peritonitis whereas upper abdominal pain occurs in hepatitis, cholangitis, acute gastritis and
acute Budd-Chiari syndrome. Abdominal skin may show petechiae, scratch marks or striae and
very shiny in massive ascites. Dilated and tortuous epigastric veins in portal hypertension due to
intrahepatic cause especially chronic liver disease (cirrhosis). An everted umbilicus indicates gross
ascites. Caput medusa and umbilical cavernoma in severe cirrhotic portal hypertension. Dilated
veins due to obstructed inferior vena cava are often seen more laterally in the sides of abdomen
172 and back and the flow is below upwards in contrast to cirrhotic portal hypertension where the
flow is away from umbilicus. Hernia orifices open up with contents of intra-abdominal organs in
Table 13.1: Physical signs in liver disease

Skin signs in liver disease Disease
Jaundice with dark urine Hepatobiliary disease
Hyperpigmentation PBC, Hemochromatosis (melonin deposition) Hyperbilirubinemia
(S. Bil > 25–30 mg/dL)
Vitiligo Autoimmune disease (PBC, Ch. hepatitis)
Pruritus–intense PFIC (Fig. 13.2) EHBO, Hepatitis B/C with cholestasis Alagille
syndrome, PBC, Autoimmune disease, PSC
Scratch marks with polished nails Cholestatic pruritus sparing the back
Lichen planus, Xanthomata PBC, Ch cholestasis like PFIC
Purpura, bruising, bleeding Coagulopathy, low platelet state
Tatoo marks, erythema multiforme Hepatitis B and C
Skin rashes, seborrheic dermatitis Histiocytosis (Langerhans, Sea blue)
Vascular spiders (spider nevi) (Fig. 13.6) Cirrhosis; rare in younger children
Limb signs: proximal myopathy Alcohol abuse, vit D def., osteopenia (CLD)
Arthritis PBC, Autoimmune d, Hemochromatosis
Pitting edema, legs Chronic liver disease with ascites
Hand and nails: Palmar erythema Acute and chronic liver disease, rheumatoid arthritis thyrotoxico-
(Fig. 13.5) sis, fever, pregnancy
Polished nails Cholestatic pruritus
Leuconychia, Band leuconychia (Muehrcke Chronic liver disease (low serum albumin), nephritic syndrome,
line) (Fig. 13.4) diabetes mellitus, pulmonary tuberculosis, rheumatoid arthritis
and multiple sclerosis
Blue lunulae Wilson’s disease, Argyria
Finger clubbing Chronic liver disease, regresses after liver transplantation, hypoxia
and pulmonary hypertension, hypertrophic osteoarthropathy
CVS: congestive cardiac failure Advanced hemochromatosis, cardiomyopathy
Hyperdynamic circulation Acute liver failure and chronic liver disease
Pulmonary hypertension Hepatopulmonary syndrome
Respiratory: cyanosis Chronic liver disease (30%), hepatopulmonary syndrome
Pleural effusions Decompensated cirrhosis (6%)
Right sided pleural effusion Decompensated cirrhosis, post-liver transplantation
Fibrosing alveolitis and Sjögren syndrome Autoimmune conditions
Emphysema lung Alpha 1 antitrypsin deficiency, cystic fibrosis, chronic suppurative
lung disease
Other clinical clues:
Dysmorphic facies Alagille syndrome, (Fig. 13.1) Zell Weiger syndrome, Cretinism
Normal birth weight, early conj. hyperbili- EHBA (Fig. 13.3)
rubinemia
Rickets Tyrosinemia, Wilson disease
Cataract Galactosemia, Wilson disease
Microcephaly Intrauterine infections (e.g. Rubella)
173
Tremors, dysarthria, KF Ring Wilson disease
Mental retardation Galactosemia, Lipid storage disease
Fig. 13.1: Alagelle syndrome Fig. 13.2: PFIC
Fig. 13.3: EHBA Fig. 13.4: Leuconychia in cirrhosis liver

174
Fig. 13.5: Palmar erythema
Fig. 13.6: Spider nevi
175
Fig. 13.7: Gynecomastia with visible veins in cirrhosis liver
chronic liver disease. Abdomino-scrotal edema suggests underlying severe hypoalbuminemia.

Rectal examination may reveal protruding hemorrhoids.
Palpation
Palpation of the abdomen should be done in anticlockwise manner from left iliac fossa, left
lumbar, palpation of spleen for its size, firm consistency with notch and tenderness, liver for size in
midline and right midclavicular line, edge, firm or hard consistency, surface and tenderness, right
lumbar region for kidney and right iliac fossa and hypochondrium. Palpation of the abdomen
includes genitalia, aorta, femoral vessels and hernial orifices. True hepatomegaly, especially
palpable left lobe suggests chronic liver disease. Tender liver may be part of right ventricular
failure, viral hepatitis, cholangitis, abscess or malignancy. Massive splenomegaly may be seen
in portal hypertension with hypersplenism or many other conditions. Palpable kidney is seen in
adult renal polycystic disease.
176
Liver Span is the distance between the upper border of liver (By percussion) and the lower
border of liver (By palpation) at the right midclavicular line.
Normal Liver Span: Infants : 5–7cm
5 years : 7–10 cm
10 years : 10 cm
Clinical Significance of Liver Span

Liver span of more than 7 cm at two years of age is an indication for evaluation of liver disease;
an abnormally short liver span is of poor prognosis in acute liver cell failure and also seen in
cirrhosis liver.
Percussion
Percussion of abdomen is useful in assessing the size of the liver, liver span and in the presence
of ascites-shifting dullness. Fluid thrill and Puddle sign indicate moderate to severe and mild
ascites respectively.
Auscultation
Atrial bruit (malignancy, AV malformation and alcoholic hepatitis), venous hums (portal
hypertension-Cruveilhier-Baumgarten syndrome) and friction rubs (inflammation or infiltration)
can be appreciated.
Examination for Endocrinologic Abnormalities in Liver Disease

Often seen in alcoholics with cirrhosis such as hypogonadism, testicular atrophy, gynecomastia,
gonadal atrophy and pseudo-Cushing’s syndrome. Some of the above findings may also be seen
in hemochromatosis causing chronic liver disease.
Neurologic Findings in Liver Disease

Neurologic Wilson’s disease, Vit A and E deficiency, acute liver cell failure due to viral hepatitis
and alcohol abuse can cause hepatic encephalopathy varying from mild cognitive impairment
(minimal hepatic encephalopathy to coma), flapping tremor, convulsions are of poor prognostic
signs. Poor prognostic markers of chronic liver disease include persistent jaundice, intractable
ascites, spontaneous bacterial peritonitis, progressive encephalopathy, persistent hypotension,
coagulopathy bleeds with clinical features of low serum albumin, persistent hyponatremia and
prolonged prothrombin time.
Summary
Liver disease in infants and children can manifest from neonate to adolescence due to varied
etiology and can present as acute, chronic, acute on chronic and acute fulminant. A detailed
history evaluation of the dominant symptoms focussing on the cause, nature and severity of
presentation including the complications and assessment followed by a meticulous systematic 177
and system examination to arrive at a provisional diagnosis. Extrahepatic manifestations do give

valuable clues for the underlying liver disease. Pediatricians and postgraduates are expected to
have more and more practical exposures with the infants and children with liver disease and
devote adequate time to practice clinical medicine primarily rather than requesting for symptom
based laboratory investigations and reacting on the laboratory reports with bias. It is stressed
that a step by step clinical approach is not only rewarding but also cost effective and time saving
for successful management and early referral for further management whenever necessary.
FURTHER READING
1. Bacon BR, O’ Grady JG, Bisceglie AM, Lake JR, Comprehensive Clinical Hepatology. History and physical
examination; 2nd edition Peter D.Howdle. Mosby Elsevier. 2010;4:61–72.
2. Frederick J, Ronald J Sokol, William F. Balitreri. Liver Disease in Children. 3rd Edition: 2007.
3. Marcdante K, Kliegman RM, Jenson HB, Behrman RE. Liver disease. Nelson Essentials of Pediatrics (6th
edn). 2010;130:489–96.
4. Friedman LS, Keefe EB. Pediatric liver disease. Handbook of Liver Disease (2nd edn). 2004;23:203–305.
5. Michael Swash, Michael Glynn. Gastrointestinal system. Hutchison’s Clinical Methods—An Integrated
Approach to Clinical Practice (22nd edn). 2007;8:117–47.
6. Gupta P, Piyush Pediatrics Pearls—Clinical Methods in Pediatrics (1st edn). 2009;9:257–84.
7. Sherlock S, Dooley J. The liver in infancy and childhood. Diseases of the Liver and Biliary System (11th
edn). 2002;26:453–71.
178
14
Liver Function Tests
Saravanapandian, Sarah Paul, John Matthai
INTRODUCTION
Liver, the largest internal organ in the body has many complex functions. It acts as a filter of the
blood received from the GI tract through the portal vein. It synthesizes proteins that are involved
in vital functions and is an important site of carbohydrate, protein and lipid metabolism. It
detoxifies toxins, metabolizes drugs and hormones, conjugates bilirubin and excretes it through
the bile. Liver dysfunction, therefore, has catastrophic consequences on the body.
Liver function tests comprise of a battery of tests that are used:
a. as a tool for screening and documenting liver injury
b. to provide vital clues to the etiology of liver disease
c. to monitor the disease progression and response to treatment
d. to assess prognosis in children with liver failure.
PATTERNS OF LIVER INJURY

Appropriate utilization of the tests requires knowledge of the injury patterns in liver diseases.
There are three major patterns of liver injury – hepatocellular, cholestasis, and mixed pattern.
1. In hepatocellular pattern of injury, there is either structural damage and destruction of liver
cells (viral hepatitis, drug toxicity) or functional impairment (mitochondrial hepatopathies).
2. In cholestatic pattern, there is impaired bile transport, which may be due to Extrahepatic
obstruction (Biliary atresia), Intrahepatic duct narrowing or paucity (Alagille syndrome), Bile
duct damage (Sclerosing cholangitis), Failed transport at the canalicular level (Progressive
familial intrahepatic cholestasis).
3. In the mixed pattern, there is a combination of hepatocellular injury and cholestasis (drug-
induced liver disease).
These injury patterns are not mutually exclusive as there may be overlapping of more than
one pathologic process in common diseases affecting liver. However, the classification helps in
basic understanding of the usefulness of liver function tests.
The liver function tests can be categorized into five:
A. Tests to detect hepatocyte injury
B. Tests to detect cholestasis or impaired bile flow
C. Tests that assess synthetic function of liver

D. Tests that assess metabolic and excretory function of liver
E. Tests that assess liver fibrosis.
The conventional panel of liver function tests and their significance are given in Table 14.1.
Table 14.1: Conventional liver function tests
Tests Significance
Serum bilirubin – total and direct Cholestasis, impaired conjugation
Liver enzymes – AST and ALT Hepatocellular damage
Serum alkaline phosphatase (ALP) Cholestasis, infiltrative disease
Gamma-glutamyltransferase (GGT) Cholestasis
Serum Albumin Synthetic function
Prothrombin time (PT) Synthetic function
AST—Aspartate aminotransferase; ALT—Alanine aminotransferase
Apart from the above, estimation of Lactate dehydrogenase (LDH), 5’ nucleotidase, bile acids
and ammonia in the blood are some of the other tests that are useful in certain clinical situations
although they are not routinely employed. Serum ceruloplasmin, ferritin, alpha 1 antitrypsin
and alpha fetoprotein are also of diagnostic significance in select situations. Interpretation of
liver chemistry should always be done in conjunction with the clinical picture. Asymptomatic
children with mild abnormality in LFT can be kept under observation. However those with signs
and symptoms of liver disease or hepatic decompensation should be evaluated expeditiously
even though the LFT may be only mildly deranged.
TESTS OF LIVER CELL INJURY

Aminotransferases
Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT) are liver enzymes that
catalyze the transfer of amino group to α-keto glutaric acid to form oxaloacetate and pyruvate
respectively. Older terms like SGOT and SGPT are replaced by AST and ALT respectively to
correctly indicate their function. ALT is a cytosolic enzyme seen predominantly in liver. AST
exists in two isoforms – cytosolic and mitochondrial, and is seen in cardiac and skeletal muscles,
brain and RBCs apart from liver. These enzymes are normally present in small amounts in the
serum. Following hepatic injury, their serum levels rise due to release from the damaged and
dead hepatocytes or due to leakage secondary to altered membrane permeability.1,2 The levels
rise 12 hours after hepatic insult and peak in 24 to 48 hours. ALT is a more specific indicator of
liver cell injury as the highest concentration of this enzyme is in the liver.3 Markedly elevated
aminotransferases, with alkaline phosphatase levels less than 3 times the normal is indicative of
acute hepatic injury.4
180 The extent of elevation of liver enzymes can give a clue to the underlying etiology
(Table 14.2).
Table 14.2: Level of aminotransferases and their common etiologies

Common etiologies for symptomatic children with aminotransferase > 1000 IU/L
• Acute viral hepatitis
• Reye’s Syndrome
• Autoimmune hepatitis
• Ischemic injury
• Drug induced
Symptomatic children with aminotransferase level < 1000 IU/L
• Chronic hepatitis
• Infections like leptospirosis, dengue, malaria
• Storage disorders like Gaucher’s disease
• Inborn errors of metabolism
• Celiac disease
Asymptomatic children with liver enzyme elevation < 1000 IU/L
• Non-alcoholic fatty liver disease (NAFLD)
• Wilson’s disease
• α1 – antitrypsin deficiency
• Chronic hepatitis B, C
NAFLD is a common cause of elevated transaminases among obese children in the West.
However in our country, the possibility of Wilson’s disease and chronic hepatitis B and C infection
should not be overlooked, since these can also present in a similar fashion.
In most cases of acute hepatic injury, elevated transaminases is accompanied by raised
serum bilirubin. However in Reye’s syndrome and valproate-induced hepatotoxicity, where
the injury is predominantly mitochondrial, there is marked elevation of liver enzymes without
hyperbilirubinemia.
AST: ALT Ratio

Serum ALT is more specific than AST in hepatic injury. When the level of AST is disproportionately
elevated in comparison with ALT, extrahepatic causes such as muscular dystrophy,
cardiomyopathy, rhabdomyolysis and hemolysis should be excluded.5,6 However even in some
hepatic conditions, elevation in AST is greater than ALT. In adults, AST: ALT ratio > 2 occurs in
alcoholic hepatitis and chronic hepatitis C infection, while a ratio greater than 1 indicates the
presence of cirrhosis.7 This ratio has not been adequately studied in children and has limited
application. One study on infants with chronic liver disease demonstrated that increase in
AST/ALT ratio correlated with worse outcome.8 AST to ALT ratio > 4 has been reported to occur
in fulminant Wilson’s disease.9 AST has both cytoplasmic and mitochondrial isoforms. Since
mitochondrial injury is an important component of fulminant Wilson’s disease serum levels of
AST will be higher than ALT.
Role of Serial Monitoring

Serial measurements of liver enzymes useful in:
1. Follow up of clinical activity in acute viral hepatitis and autoimmune hepatitis. 181
2. Assessing effectiveness of immunosuppression in chronic hepatitis.
3. For diagnosing and monitoring drug-induced hepatotoxicity.
There is a poor correlation between the extent of liver cell necrosis and the serum transaminase
level.3,10 However, in acute liver failure, a rapid decline in the level especially if associated with
decrease in liver size, increase in bilirubin and coagulopathy indicates poor prognosis.3,11 The fall
in enzyme level in this situation is due to massive liver cell necrosis and decrease in the number
of viable hepatocytes.
Lactate Dehydrogenase
Lactate dehydrogenase is a cytoplasmic enzyme that exists in five isoforms. Since it is present
in other tissues as well, its elevation lacks specificity. The two clinical situations in which it is
diagnostically useful are ischemic hepatitis and malignant infiltration of the liver. In the former,
there is massive transient elevation of the enzyme, and in the latter, its sustained elevation is
accompanied by raised alkaline phosphatase.11
TESTS THAT DETECT IMPAIRED BILE FLOW OR CHOLESTASIS

Alkaline Phosphatase (ALP)
Alkaline phosphatase is a zinc metalloenzyme that is widely found in various tissues like
intestines, kidneys and placenta, but the major contribution of its serum activity is from liver and
bone osteoblasts.12 In the liver, it is seen in the microvilli of bile canaliculus. Serum level of alkaline
phosphatase varies with age, gender, postprandial state, blood group status and osteoblastic
activity of bone.13 Hence in a healthy growing child, the value is expectantly high.14,15 Since it is
synthesized by non-hepatic tissues as well, detection of elevated alkaline phosphatase in the
serum warrants checking for GGT and 5’ nucleotidase levels to confirm that it is of hepatic origin.
In cholestatic and infiltrative disorders of liver, the alkaline phosphatase level is elevated.
Cholestasis leads to accumulation of bile acids, which stimulates the synthesis of alkaline
phosphatase and its release into the circulation from the liver.16,17 Age appropriate reference values
are given in Table 14.3. Elevation of alkaline phosphatase in cholestasis is usually accompanied
by raised bilirubin. In focal infiltration of the liver due to conditions such as leukemia, lymphoma,
granuloma and metastasis, there can be an elevated ALP without an increase in serum bilirubin.18
Low ALP activity may be due to zinc deficiency, hypothyroidism or pernicious anemia. Zinc is
a cofactor of alkaline phosphatase hence in zinc deficient states the measured enzyme activity
in the serum is reduced. In fulminant Wilson’s disease, the alkaline phosphatase level can be
low and the ratio of alkaline phosphatase (in international units per liter) to total bilirubin (in
milligrams per deciliter) is often < 2.9
Table 14.3: Age appropriate reference range of alkaline phosphatase in boys and girls37
Age group Normal value (U/L) – male Normal value (U/L) – female
1–60 d 100–370 100–370
2 mo–8 yr 110–460 110–460
9–10 yr 110–350 110–350
11–12 yr 110–340 110–440
182 13–14 yr 130–400 90–340
15–16 yr 80–450 80–210
Gamma-Glutamyl Transpeptidase (GGT)

Gamma-glutamyl transpeptidase is a microsomal glycoprotein that exists in many tissues other
than liver, but is absent in bone. Newborns have very high levels of GGT, even five to eight times
the adult normal values.19 Normal GGT levels in children are given in Table 14.4. High level of
GGT is seen in cholestatic disorders, but hepatocellular injury also can lead to modest elevation.
Elevated GGT and alkaline phosphatase suggests Table 14.4: Normal GGT levels in children37
cholestasis, but cannot differentiate diffuse intrahepatic Age group Reference range (U/L)
cholestasis from extrahepatic cholestasis. Among the
1–30 d 16–450
cholestatic diseases, GGT is low or normal in progressive
1–3 mo 16–267
familial intrahepatic cholestasis type 1 and type 2 (PFIC)
and benign recurrent intrahepatic cholestasis (BRIC), 3–5 mo 16–267
whereas in PFIC type 3 it is elevated. BRIC presents with 5–8 mo 8–84

intermittent signs of cholestasis in the young infant and 9 mo–17 yr 5–55
has a good prognosis. 11
5’nucleotidase
Even though it is present in other tissues, its elevation in serum is almost specific for liver disease.
It is elevated in same conditions as that of an elevated alkaline phosphatase but unlike alkaline
phosphatase, they are not elevated in bone disorders.
TESTS OF SYNTHETIC FUNCTION

Albumin
Albumin is synthesized solely in the liver and has a half life of about 20 days. In a patient suspected
to have hepatic involvement, decrease in albumin level indicates chronic liver disease. Albumin
level is normal in diseases like acute viral hepatitis, drug-related hepatotoxicity and obstructive
jaundice so that, levels below 3 gm/dl in hepatitis should raise the suspicion of chronic liver
disease.20 Poor nutrition, chronic inflammation, nephrotic syndrome and protein losing enteropathy
are non-hepatic causes of hypoalbuminemia. When low albumin is accompanied by increased
total protein due to elevated gamma-globulin fraction, it may be an indication of chronic active
hepatitis. Among the causes of chronic active hepatitis, a strikingly high value of immunoglobulin
is seen in autoimmune hepatitis, which can be confirmed by the presence of autoantibodies like
antinuclear antibody, smooth muscle antibody and liver kidney microsomal antibody.21
Prothrombin Time (PT)

Liver synthesizes clotting factors like V, VII, IX, X, XI, prothrombin and fibrinogen. Coagulopathy
due to parenchymal liver disease occurs only when there is substantial impairment in the
synthesis of clotting factors.10 In addition, cholestasis can cause malabsorption of fat soluble
vitamins including vitamin K, thereby leading to decreased synthesis of vit K dependent factors.
Other than liver disease, prolonged PT may also be due to congenital or acquired clotting factor
deficiency. Prolonged PT indicates abnormality in the extrinsic pathway which may be secondary 183
to deficiency of one or more factors involved. Among the factors involved in extrinsic pathway,
factor VII has a half life of about 6 hours. Thus, when other causes are excluded, prolonged PT is
an indicator of recent liver synthetic function, making it useful in acute hepatic failure. On the
other hand, PT is not a sensitive indicator of chronic liver disease and even in patients with severe
cirrhosis, the level can be normal or only slightly prolonged. Curiously, there can be profound
prolongation of PT and PTT in some metabolic liver diseases like tyrosinemia presenting in the
newborn period.22 Similarly, in paracetamol poisoning, the elevation of prothrombin time can be
out of proportion to bilirubin.23
Assessment of prothrombin time is useful in:
1. Detecting patients at risk of bleeding before a planned diagnostic or therapeutic procedure.
2. Monitoring the progression of underlying chronic liver disease.
3. Early detection of fulminant failure in acute viral hepatitis.3
4. Prognostication of acute liver failure.
Prolongation of PT can be either due to vitamin K deficiency (e.g. cholestasis, fat malabsorption)
or clotting factor deficiency (e.g. liver failure, bleeding disorder). Parenteral vitamin K corrects
prolonged PT in cholestasis and fat malabsorption within 24 hours but not in severe intrinsic liver
disease.24 This can be utilized in clinical situations to differentiate between cholestasis and liver
failure. Prolonged PT due to DIC can be differentiated from liver disease by the measurement of
factor VIII level. Since factor VIII is synthesized by non-hepatic tissues, its level is low in DIC but
normal in liver disease.11
Lipids and Lipoproteins

Patients with acute liver disease have increased levels of plasma triglycerides, decreased
percentage of cholesterol esters, and abnormal electrophoretic lipoprotein patterns. This
is probably secondary to the deficiency of hepatic enzymes such as lecithin cholesterol acyl-
transferase (LCAT) and hepatic lipase.25 In non-cholestatic chronic liver disease, decreased
cholesterol level may be found. In particular, low level of high density lipoprotein is found to
be associated poor prognosis in chronic liver disease.26,27 Serum cholesterol level is increased
in chronic cholestatic liver disorders and they are carried in Lipoprotein X along with elevated
phospholipids.28 Lipoprotein pattern is not useful in differentiating the various causes of cholestasis.
TESTS THAT ASSESS METABOLIC AND EXCRETORY FUNCTION OF LIVER

Bilirubin
Bilirubin is the degradation product of heme contained in hemoglobin, myoglobin and other
proteins like cytochromes and catalases. The majority of bilirubin is derived from breakdown
of senescent RBCs in the reticuloendothelial system and ineffective erythropoiesis in the bone
marrow. Bilirubin thus formed in the peripheral tissues is bound to albumin and reaches the
liver, where it is taken up by hepatocytes, conjugated to bilirubin mono and di-glucuronides and
secreted into the bile.
Unconjugated bilirubin (indirect) is lipid soluble and cannot be excreted in urine. Conjugated
184 bilirubin (direct) is water soluble and is excreted through the urine. In the normal state more
than 90% of bilirubin is in unconjugated form. Serum levels reflect the equilibrium between rate
of production, efficiency of conjugation and hepatobiliary excretion. Therefore, high bilirubin

levels can occur with increased production (hemolysis), defective conjugation (deficiency of
UDP-glucuronosyl transferase) and decreased excretion (Biliary atresia, gallstones). Due to
the conjugative reserve of the liver, bilirubin levels do not usually exceed 6 mg/dL in cases of
hemolysis.4,29 Conjugated bilirubinemia is defined as direct fraction of bilirubin >20% of the
total. In conjugated bilirubinemia, bilirubin appears in urine before jaundice becomes clinically
detectable; thereby urine for bilirubin is a useful test for early diagnosis in viral hepatitis.30 It can
be due to hepatocellular necrosis or obstruction of the biliary tract. In case of obstructive etiology,
since renal excretion of bilirubin keeps pace with the hepatic production, serum concentration
seldom raises more than 25 mg/dL. Profound elevation of total bilirubin >25 mg/dL is mostly
due to massive hepatocellular necrosis, often complicated by accompanying renal failure or
hemolysis.10,18 Peak bilirubin level has some prognostic value only in chronic liver disease and
fulminant hepatic failure. In the latter, presence of deep jaundice is associated with increased
mortality.31,32
Bile Acids
Bile acid assay is not readily available and are not routinely included in the analysis of liver
function. Serum bile acids are disproportionately elevated in conditions such as PFIC and primary
sclerosing cholangitis.11 Measuring bile acids is a sensitive test to detect early cirrhosis in adults
but not in young children.
Ammonia
Liver plays a vital role in the clearance of ammonia from the blood. In chronic liver disease
hyperammonemia develops due to altered urea cycle as well as portosystemic shunting. In
patients with cirrhosis, hepatic encephalopathy may be precipitated by gastrointestinal bleeding
due to increased ammonia production secondary to bacterial action on the blood proteins in the
colon. In acute liver failure of any etiology hyperammonemia occurs but has no prognostic value.
Hyperammonemia may be associated with encephalopathy but there is very little correlation
between levels of encephalopathy and serum ammonia.33 Other causes of elevated ammonia
include urea cycle disorder, fatty acid oxidation defect and Reye’s syndrome.
TESTS THAT ASSESS LIVER FIBROSIS

Fibrosis accompanies any ongoing chronic liver damage. Currently histopathology is the only
means to assess fibrosis, but it suffers from serious drawbacks of sampling error. The focus is now
on developing blood investigations and imaging modalities to assess the extent and progression
of liver fibrosis. Validated biomarkers have already been approved in some countries as the first
line procedure for staging of liver fibrosis.34 Panel of biomarkers have better diagnostic accuracy
than isolated markers. Fibro Test, Fibro Spect, Hepa Score are some of the notable panels. Among
these, Fibro Test-ActiTest has been tested in children with liver disease.35,36 It is calculated from
the serum levels of α2-macroglobulin, haptoglobulin, apolipoproteinA1, gamma-glutamyl
transpeptidase, total bilirubin and alanine aminotransferase adjusted for age and gender. 185
Elastography is a non-invasive ultrasound based method to assess fibrosis in the liver. It allows
quantification of liver fibrosis based on analysis of the propagation of shear waves produced
by a vibrator. With progression of fibrosis, the rate of transmission increases. More studies are
required to validate their use in children.
TESTS IN SPECIFIC SITUATIONS

Ceruloplasmin
Ceruloplasmin is an acute phase reactant synthesized in the liver. Apoceruloplasmin combines
with copper facilitated by ATP7B protein to form ceruloplasmin. In Wilson’s disease (WD), there is
absent or reduced activity of ATP7B protein resulting in low serum ceruloplasmin level, usually
<20 mg/dL. Low ceruloplasmin per se is insufficient to diagnose Wilson’s disease since low
levels are seen in 20% of carriers of WD gene, protein losing enteropathy, aceruloplasminemia
and nephrotic syndrome. Oxidase assay technique is the preferred method for estimation
as it measures only the enzymatically active, copper containing ceruloplasmin and not
apoceruloplasmin. Basal 24-hour urinary excretion of copper should be obtained in all patients
in whom the diagnosis of Wilson’s disease is being considered. The amount of copper excreted
in the 24-hour period is typically >100 µg in symptomatic patients, but values >40 µg require
further investigation.
a1-antitrypsin
α1-antitrypsin is a protease inhibitor synthesized by the liver. It is present in more than 20
different co-dominant alleles, most common being M form. Others are F, S, Z forms. Z form is
associated with defective function. PiZZ homozygotes manifest as neonatal hepatitis and have
serum alpha1-antitrypsin levels < 2 mg/ml.
a-fetoprotein
α-fetoprotein is α1 globulin, present in high concentration in fetus. Its level falls rapidly minutes
after birth. High values are seen in hepatoblastoma and hepatocellular carcinoma (HCC). In
hepatoblastoma, values correlate with size of the tumor, and is therefore useful in monitoring for
recurrence. High levels may also occur in other liver diseases like tyrosinemia, acute and chronic
hepatitis, and in non hepatic conditions such as fanconi anemia, endodermal sinus tumors. Serial
estimation is useful in screening patients at high risk for developing HCC.
Key Messages
1. Liver function tests must be interpreted in the context of a clinical diagnosis.
2. These tests lack sensitivity and so normal results do not confirm absence of disease.
3. Liver function tests are useful in identifying the pattern of liver disease rather than arriving at an etiological
diagnosis.
4. Age specific normal values have to be employed when interpreting lab tests like alkaline phosphatase, GGT and
prothrombin time.
5. Gross elevation of transaminases occurs in primary hepatocellular diseases while ALP and GGT are very high in
cholestatic diseases.
186 6. Increasing bilirubin with falling transaminases denotes poor prognosis in acute severe failure.
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15
Acute Hepatitis
INTRODUCTION
Acute hepatitis refers to any inflammatory process of the liver that lasts for less than 6 months.
Infection due to hepatitis viruses and drugs are the most common etiology.
The clinical spectrum of acute hepatitis varies from a mild illness requiring no treatment; to
fulminant liver failure requiring liver transplantation. In the last decade, our understanding of
the pathogenesis of acute liver injury and molecular biology of hepatitis viruses has increased
significantly. Since the inflammation is self-limited, most children need only supportive care.
VIRAL HEPATITIS
The acute response of the liver to infection with all hepatotropic viruses is very similar.1 The
entire liver is edematous and congested. The lobular architecture remains intact but balloon
degeneration and necrosis of groups of hepatocytes is seen in the initial stages. A diffuse
mononuclear cell infiltration causes expansion of the portal tracts. There is no bile duct damage.
Diffuse Küpffer cell hyperplasia is seen in the sinusoids along with infiltration of polymorphs and
eosinophils.
Hepatic injury occurs by 3 mechanisms: 1. Direct cytopathic injury to the hepatocytes, 2.
Secondary to the retention of bile salts during the cholestatic phase, 3. Changes that occur
in carbohydrate, ammonia and drug metabolism.2 In all forms of acute hepatitis, there is a
rapid increase in serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST),
reflecting hepatocyte damage. ALT is more specific to the liver than AST. Peak values do not
correlate with the extent of hepatocellular necrosis and has little prognostic value. Rapidly
declining values in association with a rising bilirubin and prolonged prothrombin time predicts
a poor outcome, since it indicates massive hepatic necrosis. A normal bilirubin does not rule
out the presence of acute viral hepatitis, since many children have anicteric disease. Prolonged
prothrombin time reflects deranged synthesis of coagulation factors and is a sensitive indicator
of acute severe liver injury. Serum albumin has a long half life and therefore not useful in acute
liver damage. Low blood sugar in acute hepatitis reflects altered carbohydrate metabolism and
insulin degradation and indicates severe hepatocyte injury. Elevated ammonia indicates inability
of the liver to synthesize urea and reflects severe liver disease.
HEPATITIS A
Hepatitis A is an acute self-limited illness, with few complications in children. The hepatitis A
virus (HAV) is a small, spherical, non-enveloped 27–32 nm, RNA virus belonging to the group
Picornavirus. The virus is not sensitive to heat, cold and acidic conditions and is therefore relatively
resistant to disinfection. Food must be heated to more than 85°C for a minute for disinfection.
The only natural hosts for HAV are humans and primates. There is no known carrier state.3
Epidemiology
HAV infection is endemic in most developing countries. Over crowding, poor hygiene, improper
sanitation and contamination of food and water are predisposing factors.4 Transmission is by the
feco-oral route. Fecal excretion of the virus occurs from late in the incubation period, reaches
the peak during the prodromal phase and becomes negligible once jaundice has set in. Most
children develop a mild sub-clinical infection before 5 years of age. There is no chronicity and
no long-term carrier state. Relapsing disease lasting many months has been reported to occur,
but the ultimate prognosis is good.5 Among children seen in hospital with acute viral hepatitis,
38–58% are due to HAV.6,7 Around 50% of cases of acute liver failure (ALF) in children is due to
HAV. The risk of ALF due to HAV is more common in older children and adolescents and in those
with underlying chronic liver disease.
Clinical Features
Infection occurs in two major forms. Over 90% of young children in developing countries develop
an asymptomatic infection which is sub-clinical or inapparent. In older children and adolescents
the infection is usually symptomatic, with about 70% developing icterus and the remaining
anicteric. The incubation period is 2 to 6 weeks. In the prodromal phase which usually lasts about
3-7 days, children may have low grade fever, fatigue, anorexia, nausea and vomiting and right
upper abdominal discomfort. In children who develop the icteric form of the disease, darkening
of urine is followed by gradually increasing jaundice. Lightening of stool color as well as itching
occurs in the cholestatic phase. The liver is mildly enlarged, soft and tender at this stage and the
constitutional symptoms improve. Spleen is usually not enlarged. Some children may develop
ascites and pleural effusion. In uncomplicated cases, convalescent phase follows. The jaundice
gradually wanes after the first week, and disappears in about 2–6 weeks. The appetite improves
during the second week. The liver size returns to normal a week after the icterus disappears.
ALF is a dreaded complication of HAV infection.8 Progressive rise in bilirubin with uncorrected
prolonged prothrombin time and falling ALT and AST is characteristic.
Diagnosis
A specific diagnosis is based on the detection of the specific antibody response to HAV (Fig.
15.1). IgM anti-HAV peaks at 1 week after onset of symptoms and cannot be detected after 3–6
months. Anti-HAV of the IgG subclass is detected 1 week later than anti-HAV IgM. It is present in
high titre by 1 to 2 months and persists for years. In patients with biphasic or relapsing hepatitis
190 A, anti-HAV IgM persists at low titre for 12–24 months.9 HAV RNA is present in the stool from
2 weeks before to 1 week after the onset of symptoms.
Acute Hepatitis
Fig. 15.1: Natural course of hepatitis A infection in children
Management
There is no specific treatment for hepatitis A. Most children are only mildly symptomatic and
the infection is self limiting. A fat free, high carbohydrate diet can be recommended for children
with persistent vomiting in the early phase of illness. Intravenous hydration may be needed in
some children. All hepatotoxic drugs including paracetamol should be avoided. There is no role
for steroids.
Prevention
A. Hygiene and sanitation: Clean water supply, hand washing and care in the preparation of food
are important in preventing the spread of hepatitis A.
B. Immunoglobulin: Protection provided by immunoglobulin is only temporary. It must be
administered within two weeks after exposure to HAV and the efficacy is about 85%. It is
effective immediately and the dose is 0.02 ml/kg. It is indicated in Newborns of HAV infected
mothers and children with chronic liver disease who are exposed to HAV. Immunoglobulin
prophylaxis is not indicated for healthy household contacts.10
C. Hepatitis A vaccine: Hepatitis vaccine is a formalin inactivated suspension containing HM175
strain of the virus with aluminium hydroxide as the adjuvant. The vaccine is approved for
use in children above two years of age, and is administered intramuscularly. The pediatric
formulation contains not less than 720 ELISA units/80AV units in 0.5 ml and can be used till 18
years of age. Two dose schedule is recommended, with the second dose after 6–12 months.
Sero-conversion occurs in up to 90% of children after the first dose and close to 100% after
the second dose. HAV vaccine can be administered concurrently with other vaccines at
separate sites. It is an optional vaccine but all children with chronic liver disease and those on 191
long-term hepatotoxic drugs should receive the vaccine.
VIRAL HEPATITIS B
Hepatitis B infection occurs all over the world, with a higher incidence in developing countries.
India is an intermediate endemic region (2–5% of population is positive for HBsAg). However, the
prevalence may be higher, since almost 30% of individuals being positive for HBsAbs in some
parts of India.11
The true prevalence among Indian children is not known, with studies in different regions
reporting figures from 4.35–10.4%.12 In areas of high endemicity, perinatal transmission from
HBsAg positive mothers is believed to be the most important route of transmission. The risk
is much higher in mothers who are also HBeAg positive. In areas of low endemicity, horizontal
transmission from family contacts and use of unsterile syringes is important.13 Blood transfusion
is no more an important route of transmission.
Hepatitis B Virus
This partially double-stranded DNA virus is spherical (Dane particle), approximately 42 nm in
diameter and is double shelled. The outer component consists of the hepatitis B surface antigen
(HBsAg) and the inner core contains the hepatitis B core antigen (HBcAg). Within the core is
the genome of HBV, which is a single molecule of double stranded DNA, DNA polymerase and
hepatitis Be antigen (HBeAg). The HBeAg serves as a marker of active viral replication.
Natural Course of HBV Infection

Hepatitis B virus does not directly kill hepatocytes. Liver injury occurs when the hosts immune
system attacks the virus that is inside the hepatocytes. When the immune response is vigorous
and effective, there is acute severe hepatocyte injury but quick viral clearance. In those who
develop chronic infection, the immune response is ineffective lasting many years or decades,
resulting in chronic liver disease.
There are 4 stages in the natural history of HBV infection.14
1. Replicative phase with immune tolerance: This represents the incubation period of the disease
and lasts several weeks in healthy individuals.
2. Replicative phase with immune clearance: The immune system of the host responds to the
virus in this phase of the disease resulting in hepatic inflammation and direct cell lysis. In
those with acute hepatitis B, this is the period of symptomatic hepatitis and typically lasts 4–6
weeks. If the immune response is ineffective, this phase may persist for many years. Maximum
liver damage occurs in this phase.
3. Integrative phase with no replication: When the immune response of the host is successful,
active viral replication ends. HBV DNA becomes undetectable and antibodies against HBeAg
(HBeAbs) become positive.
4. Integrative phase with viral clearance: The viral replication completely stops and HBsAg
becomes negative. The person is completely cured of the disease. Patients who recover from
acute hepatitis B will achieve this phase, but those with chronic infection usually will never
192 reach this phase.
Acute Hepatitis
Clinical Features
The clinical presentation is similar to acute hepatitis A. The incubation period varies from 50 to
180 days. The typical clinical course of acute icteric hepatitis B shows three phases: (a) Prodromal
phase, (b) Symptomatic phase, (c) Convalescent phase. The prodromal phase lasts for 2 to 3
weeks and precedes the development of jaundice. The symptomatic phase is heralded by fever,
fatigue, myalgia, anorexia, nausea, vomiting, and abdominal pain. In the early stages, jaundice
may be associated with extra-hepatic manifestations like arthralgia and papular acrodermatitis of
childhood (Gianotti-Crosti syndrome). The extra-hepatic manifestations are related to circulating
immune complexes composed of HBsAg and anti-HBsAbs. Jaundice typically lasts for about 4
weeks. Unlike hepatitis A, the percentage of children who develop icteric disease is much higher.
Consequently, the percentage of children who develop ALF is also much higher. Deepening
jaundice and shrinking liver size with mental changes indicate acute liver failure. Acute liver
failure B may develop as early as 2 months of age in infants of HBsAg carrier mothers.15 Presence
of precore mutants does not increase risk of acute liver failure.16
Serology of Acute Hepatitis B Infection (Fig. 15.2)

In acute hepatitis B infection, HbsAg as well as the markers of active viral replication (HBe Ag
and HBV DNA) will be positive. This usually occurs about 6 weeks after inoculation, before the
onset of clinical symptoms. These tests remain positive throughout the prodromal phase and the
early part of the symptomatic phase. Anti-HB core antibodies (HBcAbs) initially of the IgM class
followed by the IgG class are the first Abs to appear and these occur during the symptomatic
phase. These IgM antibodies persist for months, and the IgG for many years. Anti-HBe antibodies
(HBeAbs) appear towards the end of the symptomatic phase, reach a peak in 4–6 weeks and
gradually decline. Anti-HBs antibodies are the last to appear, and is a marker of resolving infection
(Table 15.1). Most patients with acute infection clear the HBsAg by 6 to 8 months. Individual
193
Fig. 15.2: Natural history of acute hepatitis B infection
Table 15.1: Serological diagnosis in acute hepatitis B

HBV DNA HBsAg HBsAbs HBeAg HBeAbs HBcAbs
Early acute hepatitis B + + – + – –
Established acute hepatitis + + – + – +
Convalescent stage – – + – + +
Past-infection – – + – + –
Immunization – – + – – –
(HBV DNA: Hepatitis B Viral DNA, HBsAg: Hepatitis B surface antigen, HBsAbs: Hepatitis B surface antibodies, HBeAg: Hepatitis
B e antigen, HBeAbs: Hepatitis Be antibodies, HBcAbs: Hepatitis B core antibodies).
who are unable to clear the virus from the body within 6 months are deemed to have chronic
infection. The outcome of HBV infection depends on the age at infection, the immune status of
the host and virologic factors.17 95% of infected neonates develop chronic infection, compared
to 20% in older children.
Management of Acute Hepatitis B

Currently there is no evidence that treatment improves recovery from acute infection. Available
data does not warrant the use of alpha interferon in any form of acute hepatitis B in children.18
There is also no evidence to justify the use of oral drugs like lamivudine and Adefovir.
Hepatitis B vaccine is indicated for active immunization against hepatitis B infection. The
recombinant vaccine is widely used. 10 mcg dose is recommended up to 10 years of age. The
conventional 0, 1 and 6 months schedule takes longer to confer protection, but results in higher
antibody titres. The 0, 1, and 2 months schedule provide quicker protection and better patient
compliance but needs another dose at 12 months. Immunogenicity is over 95% after 3 dose
schedule. An adequate response is defined as an anti-HBsAb response greater than 10 mIU/ml.
Routine post-immunization testing for antibody levels is not necessary.
Hepatitis B immunoglobulin (HBIG) provides immediate passive immunity and should be
administered intramuscularly. Recommended dose in children is 32–48 IU/Kg body weight and
in neonates 100–200 IU. HBIG does not interfere with antibody response to hepatitis vaccine.
Babies born to mothers who are HBsAg positive should receive within 12 hours of birth the
first dose of vaccine and the HBIG given at a separate site. Subsequent doses of the vaccine
should be given at 1, 2 and 12 months. Even without concurrent HBIG, the vaccine offers 90–95%
protective efficacy. Failure of immunization in newborns occurs with high level of maternal HBV
DNA and low levels of maternal anti-HBcAbs.19
HEPATITIS E
Hepatitis E virus is a non-enveloped, single stranded RNA virus, classified within a separate
“Hepatitis E- like virus genus”, and is similar in structure to calicivirus. Transmission is by Feco -oral
route and contamination of water sources in urban areas may result in epidemics of hepatitis E.
194 The rate of person to person transmission, however, is relatively lower compared to HAV.
Acute Hepatitis
Clinical Features
The incubation period is 6 weeks and the mean duration of symptoms is about 1–2 weeks.
The pathology and clinical features are similar to HAV infection. In children, it is usually a self-
limited anicteric disease. The virus is excreted in the stool for about 2 weeks after the onset of
symptoms. Risk of acute liver failure is low in children except in those with a pre existing chronic
liver disease.20 Pregnant women, however, have a high mortality (20%).
Intrauterine infection with HEV has been reported. Unlike HAV, sub-clinical infection is less
common. In endemic areas, the prevalence of anti-HEV IgG among children is 25% compared to
90% for HAV. Data on co-infection of HEV and HAV is scant. Acute HEV infection does not result
in chronic liver disease.
Diagnosis
Anti-HEV IgM can be detected in the serum by enzyme immunoassay about 1 week after the
onset of illness. It remains positive for 2–3 months and then declines. IgG appears later but
persists for 2–6 years.21
Management
There is no specific treatment. Improved sanitation and water supply will prevent epidemics.
Efforts are on develop an effective vaccine. A candidate vaccine has been evaluated in clinical
trials.
OTHER VIRUSES
About 10% of acute viral hepatitis in the general population occurs due to viruses other than
hepatitis viruses–Cytomegalovirus (CMV), epsteinbarr virus (EBV), herpes virus, adenovirus and
parvovirus.
Immunocompetent children with primary CMV infection are asymptomatic.22 The incubation
period ranges from 3–12 weeks. In immunocompromised individuals, the disease is more severe.
In general, CMV infection leads to a life-long latent phase in the host, with reactivation when the
person’s immune status lowers. Acute CMV infection is suspected when anti-CMV IgM antibodies
are positive. The diagnosis is confirmed by detection of viral particles by PCR in the serum or by
culturing the organism from urine. In severe cases, therapy with Ganciclovir may be effective. A
recombinant CMV vaccine has completed phase I trials.
EBV is a double stranded DNA virus. Primary infection in young children is a systemic disease.
Mild anicteric hepatitis may occur. Rarely (1 in 3,000 cases) it may take a more fulminant course
with severe hepatitis, bone marrow failure and acute respiratory distress syndrome which may
be fatal.
DRUG-INDUCED HEPATITIS
The liver plays a very important role in the metabolism of many drugs. Since the liver in children
is immature, manifestations of drug-induced liver disease is varied. Hepatitis due to drugs is not 195
common in children either due to under-diagnosis or because children take far fewer drugs than
adults. Anti-TB drugs, anti-convulsants, and paracetamol are most commonly involved.
The liver has two important functions in drug metabolism namely, activation (Phase I) and
detoxification (Phase II). This balance is influenced by age, liver maturity, nutritional status and
concomitant drugs. Enzyme inducers enhance the enzyme cytochrome P-450, and can lead to
increased production of toxic metabolites. Barbiturates, alcohol, anesthetics, hypoglycaemic
drugs, anticonvulsant drugs, rifampicin, omeprazole are all enzyme inducers. Phase II reactions
inactivate such chemicals to some extent. A positive imbalance between toxic metabolites
produced (phase I) and the detoxification capacity (phase II) results in hepatotoxicity.
Acute liver injury occurs over a period of days to a week or two. It is usually associated with
complete recovery if the drug is promptly withdrawn. Hepatotoxic drugs are classified as intrinsic
and idiosyncratic hepatotoxins. Intrinsic hepatotoxins have dose-related toxicity. Idiosyncratic
reactions are unpredictable and are not dose related. Underlying liver disease, concomitant
therapy with multiple hepatotoxic drugs and malnutrition increase the risk of drug-induced
hepatitis.
The pattern of injury depends on the type of drug involved.23 In children it is mainly cytotoxic.
Hepatocyte damage may be zonal or may lead to massive hepatocellular necrosis. Hepatocytes
in zone 3 of the Rappoport acini have high levels of drug metabolizing enzymes and thus have
the highest potential for producing toxic metabolites. Cholestatic injuries are also common. It
is characterized by jaundice, pruritus, prominent elevation of ALP and mild elevation of serum
aminotransferases. Erythromycin, nitrofurantoin and cotrimoxazole may cause cholestasis.
Acetaminophen results in zonal liver cell necrosis. Valproic acid may cause microvesicular steatosis
leading to fatty liver similar to Reye’s syndrome. Phenytoin causes an acute hypersensitivity
reaction.
Diagnosis
Children on long-term hepatotoxic drugs must be carefully monitored. Underlying liver disease
should be ruled out before starting hepatotoxic drugs. In suspected cases, records of all drugs
ingested over the preceding three months, especially “over the counter drugs” must be carefully
evaluated.
Investigations have a limited role. When possible, drug levels must the checked. Peripheral
blood eosinophilia occurs only in hypersensitivity type reaction. Alkaline phosphatase,
transaminases and prothrombin time are used to monitor the extent of liver injury. Liver biopsy
may help in some cases to assess severity of damage and exclude other causes of liver disease.
Specific Drug Hepatotoxicity

Paracetamol
This commonly used antipyretic and analgesic drug is generally safe because it is rapidly
metabolized. However as a single large dose or in repeated doses, it causes acute hepatitis
and hepatocellular injury in zone 3 of the acinus. Sulfation and glucuronidation are important
196 pathways for metabolism of paracetamol. At high drug levels, these pathways get saturated and
the drug gets metabolized through a minor pathway of the cytochrome P-450 system. This leads
Acute Hepatitis
to the production of a toxic metabolite N-acetyl p-L benzoquinone imine (NAPQI) which oxidizes
cellular proteins and alters cellular calcium metabolism, leading to cell death.24 Paracetamol can,
however, be conjugated by glutathione. N-acetylcystiene, the specific antidote for paracetamol
over dose acts by providing substrate for more synthesis of glutathione.
A single dose of 120–150 mg/kg could be hepatotoxic.25 Young children are comparatively less
susceptible to paracetamol hepatotoxicity than adolescents and adults. Rectal administration of
acetaminophen can also cause hepatotoxicity, since absorption is unpredictable.
Paracetamol poisoning has a characteristic clinical picture. Nausea and persistent vomiting
lasts for about 24 hours. Tender hepatomegaly, jaundice and coagulopathy are noted after 1–2
days. In severe cases acute liver failure may occur. The best predictors of low risk of hepatotoxicity
are normal prothrombin time and ALT/AST at 48 hours.26
When ingestion in toxic doses is suspected, plasma level should be measured 4 or more hours
after ingestion. The Rumack–Mathew normogram can be used to determine if treatment with
antidote is indicated. N acetyl cystiene is the most effective antidote and must be given within
10 hours of ingestion for maximal benefit. Beyond 24 hours, it has very little benefit. The drug is
available in both oral and parenteral form. The initial oral loading dose of 140 mg/kg should be
followed up with 70 mg/kg every 4 hours for 3 days. It should be diluted to a 5% concentration
and given through a nasogastric tube. Continuous intravenous infusion is not superior to the
oral regimen.27 Early hemodialysis is better if the plasma paracetamol levels are very high. The
mortality rate in well managed cases is less than 1%. The hepatic dysfunction resolves in 2–3
weeks.
Valproic Acid
Valproate hepatotoxicity is unique in that it is much more common in young children than in
adults.28 Some children develop mild hepatomegaly and elevated transaminases within one or
two weeks of starting the drug. Values return to normal on decreasing the dose or stopping the
drug. Some children may develop an acute severe hepatitis which may rapidly progress to liver
cell failure. Children below 3 years, multiple anticonvulsants, and presence of associated medical
problems like mental retardation are more likely to develop hepatotoxicity with valproate.29
Valproate hepatotoxicity is more common in those with an abnormal metabolic pathway;
which results in the generation of a toxic metabolite, 4 en valproic acid (4en VPA). Conjugation
with carnitine is an efficient excretory pathway of valproate. Contrary to earlier reports, a recent
study showed that very early carnitine supplementation has a beneficial role.30
Phenytoin
Phenytoin-induced hepatitis is a “drug hypersensitivity reaction”.31 Phenytoin-induced hepatitis
may present as part of a systemic disease with fever, rash, Steven-Johnson syndrome and
lymphadenopathy. There may be jaundice with elevation of the serum aminotransferases.
Hypersensitivity reactions are thought to occur due to abnormal handling of the toxic metabolites
of phenytoin metabolism. Concurrent administration of phenobarbitone aggravates liver injury.
Intravenous methylprednisolone, 2 mg/kg/day has been effective in some patients. Intravenous 197
gamma globulin has shown some benefit in those with Steven-Johnson syndrome.32
Carbamazepine
Hepatotoxicity is uncommon with the use of carbamazepine in children. It may present as
an acute hepatitis, which may be severe and fatal. A drug hypersensitivity reaction similar to
that with phenytoin has also been reported. It has also been reported to present with rash,
lymphadenopathy, and hepatosplenomegaly mimicking a viral infection.33
Detoxification of carbamazepine involves the enzyme Epoxide hydrolase, which is involved
in the metabolism of phenobarbitone and phenytoin. Children susceptible to carbamazepine
hepatotoxicity may also be susceptible to phenytoin and phenobarbital hepatotoxicity.
Phenobarbitone
Phenobarbitone rarely causes hepatitis and when it occurs, is usually part of a multisystem drug
hypersensitivity reaction. The liver disease is usually self limited. An inherited enzyme defect
makes some individuals susceptible to hepatotoxicity with phenobarbitone, phenytoin and
carbamazepine. Intravenous methyl prednisolone has been used in the treatment of severe
phenobarbitone hepatitis.34
Lamotrigine
Hepatotoxicity with Lamotrigine can occur as a typical anticonvulsant hypersensitivity
syndrome. Metabolism of lamotrigine produces an arene oxide compound which mediates this
hypersensitivity. The hepatic involvement varies from an elevation of the liver enzymes to severe
acute hepatitis.
Antituberculous Drugs
Isoniazid rarely produces fatal hepatic necrosis in children. The incidence of symptomatic INH
hepatitis in children is 0.1 to 7.1%. The risk of hepatic dysfunction is more in children who are
also receiving Rifampicin and Pyrazinamide. Concurrent Carbamazepine may result in severe
hepatitis. Hepatotoxicity typically develops in the first 8 to 10 weeks of treatment. Children with
more severe forms of tuberculosis, such as tuberculous meningitis are at a greater risk.35
INH hepatotoxicity is due to a toxic metabolite, Acetylisoniazid. Susceptibility to hepatotoxicity
has been attributed to polymorphisms for N acetylation. Rapid acetylators are at greater risk.
Hepatotoxicity may also be dose related and newer low dose regimens eliminate this risk. Careful
monitoring is important in the first 10 to 12 weeks of treatment.
The hepatotoxicity of Rifampicin increases in combination with INH. It induces cytochrome
P-450 enzyme systems, and pre-existing liver disease as well as concomitant therapy with INAH
or anticonvulsants increases the risk of liver injury. Hepatotoxicity due to Pyrazinamide is dose
related and currently recommended doses are considered safe. Combination therapy with INH
increases the risk of hepatotoxicity.
Antibiotics
All forms of erythromycin are potentially hepatotoxic, but toxicity is uncommon in children
198 below 10 years of age. The clinical presentation includes anorexia, nausea, upper abdominal pain
Acute Hepatitis
and jaundice. Pruritus is seen only in adults. Investigations show eosinophilia in the peripheral
blood with elevated SGPT and bilirubin, but normal ALP and GGT. The hepatocellular damage is
either due to a toxic metabolite or the erythromycin molecule itself. Recovery occurs promptly
upon withdrawal of the drug.
Hepatotoxicity may occur with all sulfonamides – sulfanilamide, trimethoprim-sulfame-
thoxazole and pyrimethamine – sulfadoxine. Sulfasalazine has been associated with severe liver
disease in adolescents. Sulfonamide hepatotoxicity represents metabolic idiosyncrasy. It is due to
the production of an electrophilic toxic metabolite in the liver and slow acetylators are at higher
risk. The liver injury may present as an asymptomatic enzyme elevation, granulomatous hepatitis
or acute fulminant hepatic failure.
Management
Early recognition is important and the offending drug must be stopped immediately. Acute
hepatitis and cholestasis resolve in a few weeks. Treatment is mainly supportive. The role of
steroids is controversial. Liver transplantation may be life saving in those with fulminant hepatic
failure. Chronic hepatitis and fibrosis may not always resolve completely.
SUMMARY
Inflammation of the liver that begins acutely and lasts for less than 6 months is acute hepatitis.
Infection due to hepatitis viruses and drug-induced hepatitis are common causes. Irrespective
of the cause, acute hepatitis is anicteric in most children and therefore not always diagnosed. In
all forms of hepatitis, the ALT is elevated. Prolonged uncorrected prothrombin time is a useful
prognostic index. Hepatitis A, the most common cause is a mild self-limited disease of young
children. Complications like fulminant hepatic failure and relapsing hepatitis may occur in
older children. Even though the protective efficacy is close to 100%, HAV vaccine is currently an
optional vaccine in India, due to the high cost.
Perinatal transmission is the most important route of HBV infection in endemic areas.
Clinical features of acute HBV infection is similar to other viral hepatitis except that extra hepatic
manifestations may be noted during the early symptomatic phase. In acute hepatitis B infection,
HBsAg, HBeAg and HBV DNA will be positive. During recovery anti-HBcAbs are the first to appear
followed by anti-HBeAbs and finally anti-HBsAbs. Anti-viral treatment is not indicated in acute
HBV infection. Babies born to mothers with chronic HBV infection should receive the vaccine
and intramuscular HBIG at separate sites, as soon after birth as possible. Hepatitis E infection in
children is an icteric self-limited disease which occurs in epidemics due to contaminated water.
Drug-induced hepatitis is under diagnosed in children owing to lack of awareness. Underlying
liver disease, malnutrition and using multiple hepatotoxic drugs increases the risk. Paracetamol
is hepatotoxic in a single large dose or in repeated doses. N-acetyl cysteine administered
orally as early as possible is a specific antidote. Anticonvulsants and anti-TB drugs are also
hepatotoxic.
199
Key Messages
1. Acute hepatitis in children commonly occurs from either infection with one of the hepatitis viruses or secondary
to hepatotoxic drugs. Most children have anicteric disease.
2. Hepatitis A is usually a sub-clinical infection with few complications. Acute liver failure may occur only in older
children and in those with underlying chronic liver disease. The two dose schedule of hepatitis A vaccine, results
in seroconversion rate close to 100%.
3. In acute hepatitis B, HBsAg, HBeAg and HBV DNA are positive. During recovery, HBcAbs appear first, followed by
HBeAbs and finally HBsAbs.
4. Anti-viral drugs are not indicated in acute hepatitis B.
5. Perinatal transmission is the most important route by which children acquire hepatitis B. A baby born to a mother
who is HBsAg positive, should receive the vaccine and the HBIG (given at a separate site) at the earliest.
6. Hepatitis E is water borne infection which can result in massive epidemics. In children, it is usually an icteric self-
limited disease.
7. Drug-induced hepatitis is under diagnosed in children. It is predominantly a cytotoxic liver disease and drug
withdrawal results in prompt recovery.
8. Underlying liver disease, malnutrition and use of multiple hepatotoxic drugs increase the risk of drug-induced
liver disease. Paracetamol, anticonvulsant drugs and anti-TB drugs are commonly implicated.
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12. Quamer S, Shahab T, Alam S, et al. Age specific prevalence of hepatitis B surface antigen in Pediatric
population of Aligarh, North India. Ind J Pediatr. 2004;71:965–7.
13. Hsu SC, Chang MH, Ni YH, et al. Horizontal transmission of hepatitis B in children. J Pediatr Gastroenterol
Nutr. 1993;292:771–4.
14. Lee WM. Hepatitis B virus infection. N Eng J Med. 1997;337:1733–45.
200 15. Durand P, Debray d, Mandel R, et al. Acute liver failure in infancy: a 14 year experience of a pediatric
liver transplantation center J Pediatr. 2001;139:871–6.
Acute Hepatitis
16. Hsu HY, Chang MH, Lee CY, et al. Pre core mutant of hepatitis B virus in childhood hepatitis B: an
infrequent association J Infect Dis. 1995;171:776–81.
17. Chang MH, Sung JL, Lee Cy, et al. Factors affecting clearance of hepatitis B e antigen in hepatitis B
antigen carrier children. J Pediatr. 1989;115:385–90.
18. Tassoppoulos NC, Koutelou MG, Polychronaki H, et al. Recombinant interferon alpha therapy for acute
hepatitis B: a randomized double blind placebo controlled trial. J Viral Hepatitis. 1997;4:387–94.
19. Lin HH, Chang MH, Chen DS, et al. Early predictor of the efficacy of immunoprophylaxis against
perinatal hepatitis b transmission: analysis of prophylaxis failure. Vaccine. 1991;9:457–60.
20. Arora NK, Nanda SK, Gulati S, et al. Acute viral hepatitis types E, A&B singly and in combination in acute
liver failure in children in North India.J Med Virol. 1996;48:215–21.
21. Mathur P, Arora NK, Panda SK, et al. Sero epidemiology of Hepatitis E virus in urban and rural children
of north India. Ind Pediatr. 2001;38:461–75.
22. Davison S. Acute Hepatitis. In Kelly DA (Ed). Diseases of the liver and biliary system in children. Blackwell
Sciences Ltd, London. 1999;65–76.
23. Benichou C. Criteria of drug induced liver disorders: report of an international consensus meeting. J
Hepatol. 1990;11:272–6.
24. Heubi JE, Barbacci MB, Zimmerman HJ. Therapeutic misadventures with acetaminophen: hepatotoxicity
after multiple doses in children. J Pediatr. 1998;132:22–7.
25. Ward RM, Bates SA, Benitz WE et al. American academy of Pediatrics committee on drugs statement:
acetaminophen toxicity in children. Pediatrics. 2001;108.
26. James LP, Wells E, Beard RH, et al. Predictors of outcome after acetaminophen poisoning in children
and adolescents. J Paediatr. 2002;140:522–6.
27. Perry HE, Shannon MW. Efficacy of oral versus intravenous N–acetyl cystiene in acetaminophen
overdose: Result of an open label, clinical trial. J Pediatr. 1998;132:149–52.
28. Zafrani ES, Berthelot P. Sodium valproate in the induction of unusual hepatoxicity. Hepatology. 1982;
2:648–9.
29. Bryant AE III, Dreiffuss FE. Valproic acid hepatic fatalities. III. U.S. experience since 1986. Neurology.
1996;46:465–9.
30. Bohan TP, Helton E, McDonald I, et al. Effect of L-carnitine treatment for valproate-induced
hepatotoxicity. Neurology. 2001;56:1405–9.
31. Kahn HD, Faguet GB, Agee JF, Middleton HM. Drug-induced liver injury. In vitro demonstration of
hypersensitivity of both phenytoin and phenobarbital. Arch Intern Med. 1984;144;1677–9.
32. Scheuerman O, Nofech-Moses Y, Rachmel A, Ashkenazi S. Successful treatment of antiepileptic drug
hypersensitivity syndrome with intravenous immune globulin. Pediatrics. 2001;107e:14–5.
33. Brain C, MacArdle B, Levin S. Idiosyncratic reactions to carbamazepine mimicking viral infection in
children. BMJ. 1984;289:354.
34. Roberts EA, Spielberg SP, Goldbach M, Phillips MJ. Phenobarbital hepatotoxicity in an 8- month-old
infant. J Hepatol. 1990;10:235–9.
35. O’Brien RJ, Long MW, Cross FS, et al. hepatotoxicity from isoniazid and rifampin among children treated
for tuberculosis. Pediatrics. 1983;72:491–9.
201
16
Acute Liver Failure in
Children
Prashant Mathur, Narendra Kumar Arora
INTRODUCTION
Acute liver failure (ALF) is a clinical catastrophic syndrome rather than a specific disease entity. It
represents the consequences of severe hepatocyte dysfunction and alteration of their structure.
There are a multitude of causative factors, which differ between children and adults. Regardless of
the antecedent cause, acute liver failure is clinically characterized by multi-organ failure including
hepatic encephalopathy, a complex coagulopathy, raised intra-cranial tension, complications of
renal dysfunction, cerebral edema, susceptibility to infections and hemo-dynamic disturbances,
all potentially related to impairment of hepatic synthesis or degradation of important chemical
mediators in these processes. Though uncommon, this critical illness is mostly associated with
high mortality and resource costs. The outcomes of ALF are more favorable in children than
adults.
The definition of acute or fulminant liver failure given by Trey and Davidson in 1959 led
to the recognition of cerebral edema as the most common reason for death.1 Altered mental
status (hepatic encephalopathy, HE) and coagulopathy in the setting of an acute hepatic disease
defines acute liver failure.
The development of liver failure represents the final common outcome of a wide variety of
potential causes. The broad differential diagnosis suggests severe loss of hepatocyte function
which in turn sets in motion a multiorgan response, and death may occur even when the liver
has begun to recover.2 In most instances, massive necrosis of hepatocytes occurs; however,
hepatocellular failure without necrosis is characteristic of fatty liver of pregnancy and Reye’s
syndrome, suggesting that the actual death of cells is not a universal or essential feature.
Regardless of the inciting event, the typical pathologic picture is that of coagulative necrosis
throughout the hepatic lobule. Certain conditions, such as injury induced by organic solvents
or acetaminophen poisoning, affect the centrilobular region. In sub-acute hepatic failure (SAHF)
the liver histology shows the typical features of acute viral hepatitis with bridging necrosis, portal
to portal or portal to central bridging and absence of regenerative nodules.
Although the causative agent is frequently known, a full understanding of the pathogenesis
of acute liver failure still eludes us. A shock-like state and cerebral edema, shared by all forms
of acute liver failure, suggest a unified pathogenetic mechanism. Endotoxemia is common but
cannot entirely explain these complex metabolic changes. Likewise, levels of tumor necrosis
Acute Liver Failure in Children
factor alpha, an endogenous mediator of septic shock, are increased in many but not all patients
with acute liver failure, and the substance therefore cannot be the universal mediator of the
hemodynamic changes observed.
Prostaglandin metabolism is perturbed in acute liver failure and may be important in
producing or protecting against tissue hypoxia. One serum protein that is markedly diminished
in acute liver failure and may have pathogenetic importance is group-specific component (Gc)
protein, which binds and sequesters actin released during hepatic necrosis. It seems unlikely
that a single pathogenetic mechanism can explain all the abnormal events. Nevertheless, basic
studies are particularly necessary in acute liver failure, since intuitive treatment approaches have
thus far been of limited value.
In 1975 Trgstrup et al3 hypothesized three grades of the limit of hepatic function in acute
hepatic failure: coma, survival and regenerative. In cases where the regenerative capacity
exceeded the hepatic parenchymal necrosis, the failure was massive for any effective therapy. It
was also hypothesized that the prognosis for life in acute hepatic failure depends on the extent
of hepatocyte damage. Thus coma and prolongation of prothrombin time are signs that appear
even if liver shows no necrosis. They are thought to indicate the suddenness of hepatic failure
but not to correlate with the extent of hepatic necrosis. It is suggested that in Fulminant Hepatic
Failure (FHF) signs of hepatic failure appear at various histological stages from slight change,
such as hepato-cellular degeneration, to massive necrosis; whereas in subacute hepatitis the
liver has been massively necrosed when signs of hepatic failure such as coma appear.
Bianchi et al4 suggested that four histological stages are present in acute hepatic failure: early,
peak, late and residual stages. The liver size changes in FHF appear to be related to histological
stages. In acute hepatitis the clinical stage nearly corresponds to the histological stage whereas
in FHF they do not always correspond with each other. It is considered that in cases in which the
clinical course is acute, the clinical manifestations precede histological changes.
The mortality in absence of liver transplantation is reported to be up to 90% in adults and
74% in children. However, the pediatric liver transplantation centers in North America have
brought down the mortality rates to 62–80%.5
DEFINITIONS
The classical definitions of fulminant hepatic failure, sub-acute hepatic failure and chronic
hepatic failure have been modified as our knowledge of the natural course of liver failure has
improved. They are helpful in understanding the rate of evolution of illness, and are being used
to determine outcome of the event and thus help in instituting appropriate therapy.
• Acute liver failure (ALF): this term is used to describe patients without previous history of liver
disease and, those who develop a rapidly progressive liver failure. Based on the duration
between onset of jaundice and noticing of encephalopathy, O’Grady et al6 proposed three
subcategories of ALF.
– Hyperacute liver failure: The interval between onset of jaundice and noticing of
encephalopathy is less than 7 days. These patients have rapid development of coma but
their outcome for survival is the best.
– Acute liver failure: The interval between onset of jaundice and noticing of encephalopathy
203
is between 7 days to 28 days. There is high incidence of cerebral edema but their prognosis
is poor without a liver transplantation.
– Subacute liver failure: Also known as late onset hepatic failure (LOHF), subfulminant hepatic
failure (SFHF), protracted viral hepatitis with impaired regeneration, subchronic atrophy of
the liver and subacute hepatic necrosis. It is when the interval between onset of jaundice and
noticing of encephalopathy is between 4 weeks to 24 weeks. They have the least incidence of
cerebral edema and the prognosis is worst. Ascites is an important presentation.
– Chronic liver failure (CLF): Occurrence of signs of liver failure such as hepatic encephalopathy
and/or clinically detectable ascites at least six months after onset of hepatic illness.
It is generally agreed that individuals with a shorter time period between onset of jaundice
and noticing of encephalopathy have a better outcome than those with a longer interval.
Limitations of these Definitions in Relation to Pediatric Patients

These definitions are not much useful for pediatric acute liver failure as the occult hepatic
involvement may exist, particularly in conditions like autoimmune or metabolic liver disease.
Most investigators have not regarded the presence of HE as a pre-requisite for the diagnosis of
liver failure in neonates and young infants since it can be absent or late in the course of illness and
its detection in young children is difficult.7 Thus, coagulopathy is the only dependable symptom.
Hepatic Encephalopathy
The development of HE in patients with ALF signals a critical phase of the illness (also defined as
fulminant hepatic failure) and is associated with a reduced survival.8 In epidemiological studies
performed in the pre-transplant era, spontaneous recovery of liver function was 70% in stages I
and II encephalopathy and was reduced to < 20% in stages III and IV encephalopathy. Death in
hepatic coma is common in patients with cirrhosis and advanced liver failure, but a unique feature
of ALF is death from cerebral edema and intracranial hypertension. The clinical stages of HE are
dynamic and there is bi-directional movement of the patient. These stages guide the severity and
likely outcome of HE, and assists in evaluating response to treatment.
There are important factors which have been identified to precipitate HE in a patient with
acute liver injury: gastrointestinal hemorrhage, infections; fluid-electrolyte disturbances; seda-
tive drugs; uremia.
There is increasing realization that a disturbance in brain water regulation is central to the
process responsible for hepatic encephalopathy. Multiple elements point at the definitive role of
circulating toxins, in the development of HE. This phenomenon may be observed in the presence
of a relatively intact liver.
Etiology
The causes of acute liver failure vary with the age of the child. In neonates, infections or inborn
errors of metabolism are common, while viral hepatitis and metabolic causes are more likely in
older children.9 Table 16.1 summarizes causes of acute liver failure in infancy and childhood.
Based on the published data on ALF in children from India, the etiological proportions seen
are as hepatitis A infection (35%), hepatitis E infection (15%), mixed HEV and HAV infections
204 (15%), acute hepatitis B (10%), drug induced (5%), those with underlying chronic liver disease
(5%) and non-A to E infections (15%). Enterically transmitted hepatitis viruses (HAV and HEV)
were found to be associated with 60% of acute hepatic failure in children.10
Table 16.1: Factors associated with acute liver failure

Viral hepatitis (Isolated/mixed)
• Hepatitis A, B, C, D, E, G
• Herpes simplex
• Epstein-Barr virus
• Parvovirus B 19
• Varicella zoster
• CMV
• Adenovirus
• Echovirus
• Coxsackie virus
Drug induced
• Acetaminophen (Paracetamol)
• Isoniazid
• Halothane
• Sodium valproate
• Phenytoin
Metabolic causes
• Wilsons disease
• Neonatal hemochromatosis
• Tyrosinemia Type I
• Mitochondrial disorders
• Hereditary fructose intolerance
• Alpha–1 antitrypsin deficiency
• Niemann-Pick disease
• Indian childhood cirrhosis
• Glycogen storage disease Type IV
Hypoperfusion
• Budd-chiari syndrome
• Veno–occlusive disease
• Right sided congestive heart failure
• Cardiogenic shock
Autoimmune hepatitis
Mixed: viral infection on underlying chronic liver disease
Unknown causes
In about half to two-third of patients with ALF, the etiology is unknown. The possible reasons
include unavailability of all diagnostic facilities, rapidly deteriorating clinical condition, problems
with obtaining biological samples repeatedly and lack of understanding of the limitations of
205
some test in the setting of ALF, e.g. serum ceruloplasmin for Wilson’s disease.
Risk Factors
Acute liver failure is an uncommon complication of acute viral hepatitis, occurring in about
0.2–4% of cases depending on the underlying etiology.11 The clinical clues signifying an atypical
course of acute viral hepatitis and suggesting ‘at risk’ patients for developing acute liver failure
are persistent or deepening jaundice, persistent vomiting or anorexia, relapse of initial symptoms
or re-appearance of fever after onset of jaundice, mental status changes, rapidly shrinking liver
size, rising bilirubin levels in face of falling aminotransferases, development of ascites, persistent
hypoglycemia and vitamin K resistant prolongation of prothrombin time.
Hepatitis A is the most common form of hepatitis worldwide but it progresses to acute liver
failure only in 0.35% of cases12 and has a case fatality rate of 0.14% for hospitalized patients.13 In
endemic countries and regions for HAV, acute liver failure in children due to HAV is the commonest
cause. It is not related to more severity of the infection but, because of high frequency of HAV
associated acute hepatitis. Risk factors for the development of fulminant hepatitis A infection
include age over 40 years,12 and hepatitis A infection superimposed on underlying liver disease.14
It is not known at present whether there are differences in the risk of HAV related ALF in the
pediatric age group as compared to adults. Patients with fulminant hepatitis A have a better
prognosis than do those with acute liver failure due to any other cause; up to 70% of them may
survive without resorting to liver transplantation.15,16
Hepatitis B is the most common identifiable viral agent responsible for acute liver failure
worldwide12 with fulminant hepatitis occurring in approximately 1% of cases. Absence of HBeAg
and presence of anti-HBeAg seems to increase the risk of acute liver failure in newborns and
infants who have acquired the infection vertically from their mothers. Reactivation of latent
HBV infection may lead to fulminant disease, and this usually occurs in immunocompromised
patients. Risk of acute liver failure increases 7–8 times with co-infection or super-infection of
HDV and HBV.17 Super-infection with HDV may carry greater risk of fulminant hepatitis than
simultaneous infection.18 The emerging role of mutant hepatitis B virus infections in causing liver
failure needs to be explored in the pediatric age group. There is some evidence that presence of
core/pre-core mutants may be associated with liver failure.
Hepatitis C as a cause of acute liver failure is very uncommon. Hepatitis E is increasingly
being labeled as the causative agent responsible for acute liver failure.19 This is especially true
for hepatitis E endemic regions. The course of Hepatitis E virus infection in pregnant women
is associated with high mortality especially among those in third trimester ranging from 20 to
40%.20,21
Intake of hepatotoxic drugs in a child who is already suffering from liver disease whether due
to infectious, metabolic or any other cause might enhance the probability of precipitating acute
liver failure.
Precipitating Factors
The possible precipitating factors of acute liver failure include infections, sepsis, persistent fever,
persistent vomiting, hypovolemia, gastrointestinal bleeding, constipation, use of hepatotoxic
206 drugs (anti-tubercular, antipyretics and anti-convulsants, etc.), and zinc deficiency in established
acute hepatitis. These operate through one or more of the following mechanisms: increased
ammoniagenesis, increased diffusion of ammonia across blood-brain barrier, and impaired

hepatocellular function.
The pediatric age group experiences the most unique co-existence of underlying metabolic
liver diseases which at many times is first noticed when acute liver failure is precipitated due
to superimposed hepato-trophic viral infections. Similarly, infections or exposure to hepatoxic
drugs in chronic liver disease (autoimmune hepatitis) precipitates acute liver failure. Initial
studies suggested a poorer outcome in children with mixed HEV and HAV infection as compared
to single infections. However, more recent studies have not corroborated the same view.
Regardless of the cause, acute liver failure has a particular constellation of clinical features that
are distinct from those seen with chronic hepatic insufficiency. Typically, nonspecific symptoms,
such as malaise or nausea, develop in a previously healthy person, followed by jaundice, the
rapid onset of altered mental status, and coma; thus, the patient goes from being healthy to near
death within 2 to 10 days. The condition is often not suspected from physical examination alone
and may be mistaken for a drug overdose (in a teenager whose behavior is bizarre) or gram-
negative septicemia (which has similar clinical features). Patients with sub-acute hepatic failure
have a more gradual onset of hepatic insufficiency, accompanied by ascites, renal failure, and a
very poor prognosis. Cerebral edema is infrequent in such patients.
There is increased susceptibility for infections in patients with acute liver failure. Presence of
fever, leukocytosis, positive cultures, unexplained drop in BP, reducing urine output, worsening
encephalopathy, severe acidosis and DIC indicates sepsis and warrants aggressive investigations
as the probable causes. Vast majority of infections occur within 72 hours of admission. Most
often the infecting organism is a bacterial agent (Staphylococcal and gram-negative sepsis), but
fungal infections are not uncommon.
The clinical appearance of hepatic encephalopathy is variable, depending on the extent
and rapidity of hepatic damage, the degree of porto-systemic shunting, and the contribution
of precipitating factors. Initial symptoms of encephalopathy may be subtle and are likely to be
passed off for the behavioral aberration of the child. Change in personality is one of the earliest
signs of hepatic encephalopathy. Patients may pass through various stages of encephalopathy
so rapidly that the parents may not notice the early phases. A child with acute onset of combative
behavior or being irritable without reason should always be screened for hepatic encephalopathy.
Table 16.2 gives the early indicators
of hepatic encephalopathy. Every Table 16.2: Early clinical indicators of hepatic encephalopathy
clinician should carefully ask and/or • Confusion/euphoria
look for these early manifestations • Combative behavior/restlessness/irritability
of hepatic encephalopathy in all • Short attention span
children with acute hepatitis. • Disordered sleep or sleep inversion
Cerebral edema is a major cause • Changes in handwriting
of mortality in patients with acute • Tremors
liver failure. A sustained rise of ICP
• In-coordination or dropping objects 207
to 30 mmHg or more is taken as
• Headache/dizziness/nightmares
an indication of raised ICP. Fifty to
eighty percent of patients with acute liver failure have cerebral edema;22 most of grade IV patients
would have raised ICP. The intracranial pressure in a child with acute liver failure rises paroxysmally
initially and then remains constant. Paroxysmal or sustained systemic hypertension and increase
in the tone of the muscles of the arms and/or legs are probably the earliest signs of raised ICP.23
Impaired or absent pupillary reflexes, bradycardia, sustained severe hypertension and abnormal
reflexes are other signs of raised ICP. Increased tone of the muscles may ultimately give rise to
de-cerebrate posturing. Other features such as headache, vomiting, bradycardia and pupillary
changes occur rarely if at all. In final stages marked hyperventilation, trismus, ophisthotonus and
respiratory arrest occur.
Precipitating factors: Body movements, excessive and frequent handling of patients, frequent
suctioning or noxious stimuli contribute to the rise in ICP. If a child is kept in a horizontal decubitus
or if there is excessive coughing, sneezing or vomiting, the ICP rises transiently. Sustained severe
hypoxemia and/or hypercapnia also raise the ICP, as does seizure activity. Hence, all these factors
must be actively looked for and prevented in these patients.
Management
Acute liver failure is a medical emergency associated with an unpredictable and an often-fatal
course; survival depends not only on the capacity of the liver to regenerate, but also on the initial
intensive supportive medical care. Managing ALF is a team effort. Consultations in the areas of
intensive care, gastroenterology, infectious diseases, hematology, neurology, neurosurgery, and
transplantation surgery may be needed to address the myriad complex issues that can confront
the medical staff.
The essential components of hospital care are:
1. to assess the severity of disease and determine etiology.
2. to prevent complications such as encephalopathy, cerebral edema, sepsis, gastrointestinal
bleeding, renal failure and multiorgan failure.
3. to provide hepatic support.
4. to assess prognosis and evaluate for liver transplantation, where available.
Immediate Intensive Care

The child must be cared for preferably in an Intensive care unit (ICU) setting. It is imperative to
establish an adequate intravenous access in the form of intravenous and CVP lines as parenteral
drugs and fluids form a major component of the management efforts.
A child, who has tachycardia, cold extremities, signs of dehydration, poor pulses and
perfusion needs aggressive fluid resuscitation. Strict protocol based monitoring including
cardiac monitoring; input-output charting with an indwelling urinary catheter if required and
frequent clinical monitoring would ensure a better management of such critically ill patients.
A feeding tube may be used for the purpose of feeding. Appropriate care must also be taken
of bladder, bowel, skin, back and eyes. If the child is in grade III or IV hepatic encephalopathy or
208 rapidly progresses into it, elective mechanical ventilation is recommended. A suggested schema
of the steps involved in the immediate intensive care is presented in Table 16.3.
Table 16.3: Schemata for immediate intensive care

• Establish adequate IV access (two peripheral lines and a CVP line)
• Volume resuscitation
• Cardiac monitoring; pulse oximetry
• Nasogastric tube for feeding/drainage
• Urinary catheter
• Strict input/output charting
• Frequent clinical assessment
• Hepatic coma feeds (N2 content– 4% of total calories) or Parenteral feeding if ventilated
• Care of bowel, back, bladder, skin, eyes
• If grade 3 or 4 encephalopathy—ELECTIVE MECHANICAL VENTILATION
Initial Workup
Initial workup of the child should include identification of the stage of hepatic encephalopathy
and the presence of the precipitating factors as eluded to previously.
Investigations that are necessary in the immediate management of the child with acute liver
failure include those to assess hepatocyte function (liver function tests—fractionated serum
bilirubin, SGOT, SGPT, alkaline phosphatase, prothrombin time), blood chemistry (electrolytes,
urea, creatinine, sugar, calcium, phosphate), and evidence of infection (cultures, blood counts,
and X-rays).
After initial stabilization, further investigations are done to determine the etiological factors
associated with liver failure.
Ideally all these investigations must be ordered simultaneously because stepwise
investigation protocol causes unnecessary delay in arriving at a working diagnosis and line of
management to be followed.
Fluid and Metabolic Disturbances (Table 16.4)

Appropriate management of fluid and metabolic abnormalities can go a long way in the ultimate
outcome in patients with acute liver failure.
Infections
The presence of severe hepatic encephalopathy and cerebral edema tend to arise in systemic
inflammatory states, which may be precipitated by infections. Although the initial investigations
should be able to identify possible infections, prophylactic antibiotics form a major and important
part of any treatment regimen for acute liver failure because uncontrolled infections and subtle
infections worsen the prognosis.
Use of aseptic nursing techniques is the first line of defense against septic complications
in acute liver failure and should be strictly enforced. Change of intravenous catheters every 72 209
hours and routine culture of removed catheter tips is essential.
Table 16.4: Management of fluid and metabolic complications in acute liver failure
Total fluid intake: normal maintenance requirement (10% Dextrose in N/5 saline)
Hypotension
• Resuscitate with normal saline, Ringers lactate, plasma or blood
• Avoid overloading
• If mean arterial pressure (diastolic pressure + 1/3 pulse pressure) is less than 60 mmHg—start dobutamine
Metabolic acidosis
• Suspect fluid deficit
• Look for sepsis (if no fluid deficit)
Hypokalemia
• Frequent; associated with metabolic alkalosis
• Give KCL infusion/100 ml IV fluid
3 mEq (1.5 ml) if serum K+ > 3 mEq/L
4 mEq (2 ml) if serum K+ 2.5–3 mEq/L
5 mEq (2.5 ml) if serum K+ 2–2.5 mEq/L
6 mEq (3 ml) if serum K+ < 2 mEq/L
Metabolic alkalosis
• Increase IV KCL to next step
Hyponatremia (Na+ < 120 mEq/L)
• Restrict fluids to 2/3-3/4 maintenance
• Restrict Na+ infusion to less than 2 mEq/Kg/day
Hypernatremia (Na+ > 150 mEq/L)
• May be precipitated with lactulose administration: reduce/stop lactulose
• Give N/5 fluids including correction fluid
Hypoglycemia (Blood glucose < 40 mg/dl)
• Infuse 50% dextrose (@ 1 ml/Kg).
• Maintain blood sugar between 100–200 mg/dl
The choice of antibiotics would depend on the offending agent if identified but in general,
it should cover both gram-negative bacteria and staphylococci. The usual practice is to use a
combination of 3rd generation cephalosporins, cloxacillin and aminoglycosides. If there is no
improvement within 72 hours, it is prudent to step up antibiotics to cover Pseudomonas aeruginosa,
fungal sepsis and anaerobic organisms depending upon individual patient requirements.
Cerebral Edema (Table 16.5)

Appropriate management of cerebral edema and raised ICP would be to either prevent, treat
or to minimize the aforementioned factors. The head end of the bed should be raised to
210 20 degrees with the head in the neutral position.24 Nursing of the patient should be carried out
in an ICU setting, with a quiet comfortable atmosphere and minimum handling of the patient.
Table 16.5: Management of cerebral edema in acute liver failure
Cerebral Edema Indicators

• Paroxysmal or sustained severe hypertension
• Muscle tone changes
• Decerebrate posturing
• Bradycardia
• Pupillary changes
• Reflexes (brisk/sluggish)
Treatment of Raised ICP
• Raise head end of bed 30°-45°
• Place head in neutral position
• Minimum handling of the patient
• Elective ventilation (aim is to maintain pCO2 between 22–26 mmHg)
• Mannitol 20%: 3–5 ml/kg/dose by rapid IV push; max 6–8 doses can be given at 4–6 hourly interval
• If no recovery, thiopental infusion can be resorted to (for those who are on ventilator)
• No role of steroids
• ICP monitoring if feasible, goal to keep ICP < 20 mmHg and CPP > 50 mmHg
Factors that Increase ICP
• Body movement and handling
• Frequent suctioning/noxious stimuli
• Horizontal decubitus
• Severe hypoxemia/hypercapnia
• Coughing/sneezing/vomiting
• Seizures
Psychomotor agitation must be carefully and appropriately managed to avoid acute increase in
ICP. Correction of hypoxemia or hypercapnia are essential therapeutic steps for cerebral edema
since vasodilatation due to hypercapnia can lead to marked increase in ICP. Elective endotracheal
intubation, sedation, and use of mechanical ventilation with hyperventilation may be useful in
patients who are very agitated and combative.25 It has been seen that short-term hyperventilation
with the aim to maintain pCO2 between 22–26 mmHg may be helpful in reducing ICP.22
Mannitol, an osmotic diuretic, is used to lower the ICP. It is effective only in those patients
in whom initial ICP is less than 60 mmHg.25 Serum osmolality should be monitored in patients
being given mannitol. The drug is contraindicated if serum osmolality exceeds 320 mOsm/Kg.
In general intravenous mannitol in doses of 0.5–1 gm/Kg must be given as a bolus dose over
5 minutes. Repeated boluses may be necessary to maintain recurrent surges in ICP. The maximum
effect occurs 15–60 minutes after infusion. Once renal failure develops it should be used only in
combination with ultrafiltration.
The use of steroids in patients with cerebral edema due to acute liver failure has not been 211
found to be of any use, unlike its beneficial effects on patients with brain tumors.25,26
Monitoring the ICP using intracranial electrodes may improve selection of patients for liver
transplantation, but does not affect survival.27
Hepatic Encephalopathy (Table 16.6)

The actual treatment of hepatic encephalopathy is relatively simple and does not depend upon
the stage of encephalopathy except the nutritional advice.
Colonic cleansing reduces the luminal content of ammonia28 and decreases the bacterial
counts.29 To achieve adequate cleansing of the gut, bowel washes need to be given every 6–8
hourly with acidic fluid (1 teaspoon vinegar in 1/2 liter plain water). Various laxatives can be
used, but non-absorbable disaccharides like lactulose are preferred, because they result in the
additional effect of potentiating the elimination or reduction of the formation of nitrogenous
waste compounds. Lactulose may be administered either orally or with the help of a nasogastric
tube in doses of 0.5 ml/kg/dose (max. 30 ml/dose) four times a day adjusted to produce 2–4
loose acid stools per day. Side effects sometimes seen include dehydration and hypernatremia.
Contrary to the prevalent views, there is no need for restriction of proteins in the diet for
Grades I and II encephalopathy but vegetable proteins are preferred over animal sources.
Micronutrients, Vitamin C, Vitamin E and zinc also need to be given. Anticonvulsants may be
required if seizures are present. Phenytoin or phenobarbitone are the usually administered
anticonvulsant. No sedatives should be given as they interfere with the assessment of the status
of consciousness of the child.
Coagulopathy (Table 16.7)

The conventional approach to the treatment of severe coagulopathy associated with acute liver
failure includes administration of Vit K in doses of 5–10 mg intravenously or subcutaneously
per day to increase the concentration of Vit K dependent factors. Coagulation defects require
administration of fresh frozen plasma or blood (preferably fresh) if invasive procedures have to
be done or if there is active bleed. Prophylactic transfusion may be given if platelet count is less
Table 16.6: Management of hepatic encephalopathy
Bowel washes
• With acidic fluid (1 teaspoon vinegar in 1/2 liter plain water), 6–8 hrly
Lactulose
• Oral/NG tube - 0.5 ml/kg/dose (max. 30 ml/dose) four times/day at a rate adjusted to produce 2–4 loose
acid stools per day
• Side effects: Dehydration, hypernatremia
Enteral feedings
• No restriction of proteins for Grade I and II encephalopathy; vegetable proteins preferred (1–2 gm/day).
• Micronutrients, Vit. C, E, zinc
Anticonvulsants (if seizures present)
212 • Dilantin/phenobarbitone: 2–3 mg/kg/day
• No sedatives
Table 16.7: Management of coagulopathy

For GI bleeds
• Cold saline washes 4 hrly
• Inj. Ranitidine 3 mg/kg/day
• Sucralfate (2–4 gm/day)
• Antacids: 15–30 ml, 4 hrly after gastric lavage
Coagulation defects
• Fresh frozen plasma; blood (fresh)
(If invasive procedures to be done or active bleed)
• Vit K - 5–10 mg IV/day
• Prophylactic transfusion if platelet count <50,000 cells/cumm
DIC
• FFP or whole blood; antibiotics if infection
Prothrombin time
• Good monitoring tool
Table 16.8: Hepatorenal syndrome

Diagnosis
• Indicated by decreasing urine output with increasing blood urea and creatinine
• Urine Na+ <10 mEq/L (ATN urine Na + >20 mEq/L)
• Urinary creatinine: Plasma creatinine ratio >30
• Urinary osmolality 100 mosm. Higher than plasma osm.
Treatment
• Restrict Na+ and water intake to 2/3rd or less according to urinary output
• Hemodialysis, peritoneal dialysis
than 50,000. Disseminated intravascular coagulation is managed with fresh frozen plasma or
whole blood and antibiotics if there is evidence of infection. Gastrointestinal bleed may respond
to cold saline washes every 4 hourly, injection ranitidine in doses of 3 mg/kg/day and antacids
in doses of 15–30 ml 4 hourly after gastric lavage. Exchange plasmapheresis causes a rapid
improvement of coagulation abnormalities and has little or no risk of volume overload, and may
remove anticoagulant or fibrinolytic released during hepatocellular necrosis.
Renal Failure and Hepatorenal Syndrome (HRS) (Table 16.8)

Since there is sodium retention one should restrict sodium and water intake to 2/3 or less
depending on the urinary output of the child. Hemodialysis or peritoneal dialysis may be
required in unresponsive cases. However patients with HRS are usually hypotensive, hence
use of continuous arteriovenous hemofiltration (CAVH) or ultrafiltration (CAVU) rather than 213
conventional hemodialysis may be preferable.30 Use of CAVH to treat fluid overload and
pulmonary edema while awaiting liver transplantation may be useful for a critically ill patient
with HRS. Use of dopamine in doses of 2–5 ugm/kg/min, which causes renal vasodilatation, can
be used as adjunctive therapy. However, its role remains doubtful.
Systemic treatments such as corticosteroids, heparin, or insulin and glucagon have shown
no efficacy. Antiviral agents have not been used to any extent for this condition. Blood or plasma
exchange, hemodialysis, or other methods that seek to detoxify the blood may improve the
coma grade, but result in no long-term benefit when liver-cell mass is not reconstituted. Interest
in prostaglandin analogues based on studies in animals led to clinical trials that initially showed
some promise; however, efficacy could not be demonstrated in controlled studies.
Liver Transplantation
It is the definitive treatment for ALF, but a detailed discussion is beyond the scope of this chapter.
However, it accounts for 5–12% of all liver transplant activity. It is estimated that up to 25% of
patients have contraindications to transplantation and the remaining deteriorate before an
organ is available.
The poor prognosis and immediate referral for liver transplantation is indicated by:27
1. Prothrombin time > 60 seconds
2. Decreasing transaminases levels
3. Rising bilirubin levels > 300 mmol/l
4. Rapidly decreasing liver size
5. Acid-base pH <7.3
6. Hypoglycemia <4 mmol/l with increasing dextrose requirements
7. Hepatic encephalopathy grade 2 or 3.
Certain etiologies like paracetamol poisoning and hepatitis A have the best prognosis for
spontaneous recovery. In general, elective transplantation patients have a better outcome than
emergency cases. In the scenario of scarcity of donors, it is important to make an assessment
as to which patient requires urgent transplantation, who has passed the requirement and is on
way to recovery and in whom further delay would be catastrophic. Unfortunately, unlike for
adult patients with ALF, there are no good prognostic criteria which can predict survival without
transplantation. Hence, there is need to develop strategies for optimizing the indication and use
of liver transplantation in children.31
Liver Support Mechanisms

They have been developed to ‘bridge the gap to liver transplantation’. These are short-term
measures that only lead to survival if the liver spontaneously recovers or is replaced. They can
be divided into those based on bioartificial livers using cell-based therapies and those based on
albumin dialysis [methods molecular absorbent recirculating system (MARS)] or plasmapheresis.32
Hepatocyte transplantation involves attempts to inject hepatocytes which will home in the
liver and would rapidly replicate. The extracorporeal liver assist device (ELAD) consists of a
hemodialysis cartridge with the extracapillary spaces occupied by cultured cells that are derived
214 from a human hepatoblastoma cell line.
These support mechanisms are becoming available in some selected specialized centers in
the country and would see more usage as their effectiveness and availability are established and
costs become affordable.
Monitoring Protocols (Tables 16.9 to 16.11)

A carefully formulated monitoring protocol for patients with acute liver failure on intensive
medical management is a must for the management to be effective. Protocol based management
and monitoring has been time and again shown to be the most effective way of improving the
outcome in such patients. These protocols may be suitably modified according to individual
patient requirements, and availability of staff and resources.
Table 16.9: Intensive monitoring of a child with acute liver failure during the
stay in the intensive care unit
Clinical examination every 4 hourly
• Pulse rate, respiratory rate, blood pressure, and temperature
Fluid intake/output charting every 8 hourly
Neurological/coma grading every 12 hourly
Biochemical testing every 12 hourly
• Na+, K+, blood urea
• Blood sugar; ABG
Coagulopathy every 24 hourly
• Prothrombin time
Table 16.10: Parameters to be monitored in a child with acute liver failure

Parameters to be monitored once daily
• Weight
• Liver span
• Ascites
• Evidence of bleeding
• Infection
• Review prescription
• Biochemical: prothrombin time
Parameters to be monitored twice weekly
• LFT
• Urea, creatinine
• Calcium and phosphate
• Chest X-ray
Parameters to be monitored as required
• Evidence of infection: blood counts, blood cultures, urine cultures, ESR and CRP.
215
• Urinary electrolytes, creatinine and osmolality.
• Other investigations as required
Table 16.11: Typical prescription for a child with acute liver failure
• Inj. Cefotaxime/Cloxacillin/Amikacin
• IV fluids N/5 saline in 10% Dextrose
• KCl (to be added as per serum K+ conc.)
• Inj. Vit C-500 mg
• Bowel washes 6 hrly/lactulose through NG
• Mannitol 20%
• Inj. Ranitidine IV, 12 hourly
• Inj. Vitamin K
• Hepatic coma feeds (Nitrogen–4% of total calories)
• Raise head end (30°–45° )/head in neutral position
• Minimum handling, quiet room
• Input–output charting
Mortality/Morbidity in ALF
Several factors contribute to morbidity and mortality. The etiologic factor leading to hepatic
failure and the development of complications are the key parameters. In general, the best
prognoses occur in the absence of complications. Spontaneous bacterial peritonitis, adult
respiratory distress syndrome, hepatorenal syndrome, bleeding, cerebral edema, and sepsis
pose challenges that reduce the probability of survival. The determination of prognosis guides
the decisions on the need for transplantation and referral to a specialist center.
• Type of acute liver failure: Hyperacute liver failure has the best prognosis followed by acute
liver failure. Most patients with sub-acute liver failure succumb to the illness despite absence
of significant cerebral edema.
• Viral hepatitis: In patients with FHF due to hepatitis A virus (HAV), survival rates are greater
than 50–60%. These patients account for a substantial proportion (10–20%) of the pediatric
liver transplants in some countries despite the relatively mild infection that is observed in
many children infected with HAV. The outcome for patients with FHF as the result of other
causes of viral hepatitis is much less favorable.
• Non-acetaminophen-induced FHF: In non-acetaminophen-induced FHF, a PT of greater than
100 seconds and any 3 of the following 5 criteria are independent predictors: (1) age younger
than 10 years or older than 40 years, (2) FHF due to non-A, non-B, non-C hepatitis, halothane
hepatitis, or idiosyncratic drug reactions, (3) jaundice present more than 1 week before onset
of encephalopathy, (4) PT greater than 50 seconds, and (5) serum bilirubin greater than 300
mmol/L (17.5 mg/dL). Once these patients are identified, arrange appropriate preparations
for OLT. These criteria were developed at King’s College Hospital in London and have been
validated in other centers; however, significant variability occurs in terms of the patient
populations encountered at any center, and this heterogeneity may preclude widespread
applicability. Many other prognosticating tests are proposed. Reduced levels of group-
specific component (Gc)-globulin (a molecule that binds actin) are reported in FHF, and a
216 persistently increasing PT portends death. These and other parameters are not validated
widely yet.
• Age: Patients younger than 10 years and older than 40 years tend to fare relatively poorly.
• Rate of development and degree of encephalopathy: A short time from jaundice (usually the
first unequivocal sign of liver disease recognized by the patient or family) to encephalopathy
is associated paradoxically with improved survival. When this interval is less than 2 weeks,
patients have hyperacute liver failure. Although the grade of encephalopathy is a prognostic
factor in cases of acetaminophen overdose, it does not correlate with outcome in other
settings.
Sex: No data are available to suggest differences in frequency or susceptibility. One exception is
pregnancy-induced liver disease (including a unique predisposition to FHF from HEV) and the
development of hepatic adenomas (which may rupture or hemorrhage).
SUMMARY
Acute liver failure in children is associated with a high mortality. The prompt recognition and
control of the occurrence of cofactors which aggravate and precipitate liver failure are most
critical in determining the outcome.33 Most cases in our setup are due to water borne hepatotropic
viruses HAV and HEV, either singly or in combination. The clinician must be aware of the earliest
and the subtle signs of acute liver failure to identify cases early enough for appropriate referral
and institution of therapy. Despite good intensive care, only 20–30% children with liver failure
will survive. The liver support systems are yet to be validated in different settings and with time
their availability would improve. As and when liver transplantation becomes widely available in
India, it would be an attractive option.
Key Messages
1. Acute liver failure in children is a rare, yet catastrophic event during the course of liver disease with high mortality
outcomes.
2. The etiological profile differs from the western population, with preponderance of viral hepatitis as causative
agents.
3. Early recognition, institution of aggressive management and careful monitoring improves outcomes.
4. Liver transplantation offers definitive management option for acute liver failure. There is need to rationalize its
indications in view of limited expertise, costs and availability of donor livers.
5. The knowledge gap in acute liver failure to be addressed includes definitions, risk factors, management outcomes
and prognostication.
REFERENCES
1. Trey C, Davidson LS. The management of fulminant hepatic failure. In: Popper H, Schaffner F (Eds):
Progress in liver disease, New York: Grune and Stratton. 1970:282–98.
2. Lee WM. Acute Liver Failure. NEJM. 1993;329:1862–72.
3. Tygstrup N. Liver failure and quantitative liver function. In: Williams R, Murray-Lyon IM (Eds): Artificial
Liver Support, London: Pitman Medical. 1975:286.
4. Bianchi L, Simmerli- Ning M, Gudat F. Viral hepatitis. In: MacSween RNM, Authony PP, Sheuer PJ (Eds):
Pathology of the liver, Edinburgh: Chruchill Livingston. 1979:164–91.
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children: A regional experience. J Paediatr Child Health. 2003;39:107–11.
6. O’Grady JG, Schalm SW, Williams R. Acute liver failure: re-defining the syndromes. Lancet. 1993;342:
273–5.
7. Kelly DA. Fulminant hepatitis and acute liver failure. Management of Digestive and Liver Disorders in
Infants and Children. JP Buts and EM Sokal (Eds): Elsevier Science. 1993;577–93.
8. Vaquero J, Chung C, Cahill ME, Blei AT. Pathogenesis of Hepatic Encephalopathy in Acute Liver Failure.
Sem Liv Dis. 2003;23(3):259–69.
9. Devictor D, Tissieres P, Durand P, Chevret L, Debray D. Acute liver failure in neonates, infants and
children. Expert Rev Gastroenterol Hepatol. 2011: 5(6): 717–9.
10. Arora NK, Nanda SK, Gulati S, et al. Acute viral hepatitis types E, A and B singly and in combination in
acute liver failure in children in North India. J Med Virol. 1996: 48(3): 215–21.
11. O’Grady J. Acute liver failure. In: O’Grady J, Lake J, Howdle P (Eds): Comprehensive Clinical Hepatology
1st edn. London: Mosby. 2000;30:1–20.
12. Fagan EA, Williams R. Fulminant viral hepatitis. (Review) Br Med Bull. 1990;46:462–80.
13. Gusty ID. The epidemiology of viral hepatitis. In Vyas GN, Dienstag JL, Hoofnagle JH (Eds), Viral hepatitis
and liver disease. Orlando: Grune and Stratton. 1984;415–21.
14. Akriviadis EA, Redeker AG. Fulminant hepatitis A in intravenous drug users with chronic liver disease.
Ann Intern Med 1989;110:838-9.
15. Gimson AE, White YS, Eddleston AL et al. Clinical and prognostic differences in fulminant hepatitis type
A, B and non-A non-B. Gut. 1983;249:1194–8.
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17. Treem WR. Hepatic failure In Walker WA, Durie PR, Hamilton JR, Walker Smith JA, Watkins JB (Eds):
Pediatric Gastrointestinal Disease. BC Decker Inc, Philadelphia. 1991;146–92.
18. Maggiore G, Hadchouel M, Sessa F, Vinci M, et al. A retrospective study of the role of delta agent
infection in children with HBsAg positive chronic hepatitis. Hepatology. 1985;5:7–9.
19. Acharya SK, Dasarathy S, Kumer TL, et al. Fulminant hepatitis in tropical population: Clinical course,
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20. Krawcznski K. Hepatitis E. Hepatology. 1993;17:932–41.
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fulminant hepatic failure. J Hepatol. 1986;2:43–51.
23. Caranci P, Van Thiel DH. Acute liver failure. Lancet. 1995;345:163–9.
24. Keays R, Harrison PM, Wendon JA, et al. Intravenous acetylcysteine in paracetamol induced fulminant
hepatic failure: A prospective randomized controlled trial. Br. Med J. 1991;303:1026–9.
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failure. Gut. 1980:820–5.
26. Canalese J, Gimson AES, Davis C, Mellon PJ, Davis M, Williams R. Controlled trial of dexamethasone and
mannitol for the cerebral edema of fulminant hepatic failure. Gut. 1982;23:625–9.
27. Kelly DA. Managing acute liver failure. Postgrad Med J. 2002;78:660–7.
28. Wolpert E, Phillips SF, Summerskill WH. Ammonia production in human colon: effect of cleansing,
neomycin and acetohydroxamic acid. N Eng J Med. 1970;283:159–64.
29. Vince A, Bown R, O’Grady F, et al. The effect of perfusion on the flora of the excluded colon. Gut.
1973;14:178–82.
30. Golper TA. continuous arteriovenous hemofiltration in acute renal failure. Am J Kidney Dis. 1985;
6:373–86.
31. Sartorelli MR, Comparcola D, Nobili V. Acute liver failure and pediatric ALF: strategic help for pediatric
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32. O’Grady JG. Acute liver failure. Postgrad Med J. 2005;81:148–54.
33. Bernuau J. Acute liver failure: avoidance of deleterious cofactors and early specific medical therapy for
218 the liver are better than late intensive care for the brain (Editorial). J Hepatol. 2004;41:152–5.
17
Neonatal Cholestatic Jaundice
SK Yachha
Jaundice among neonates generally occurs due to unconjugated hyperbilirubinemia particularly

in early life. Common causes are physiologic (self-limiting), Rh and ABO incompatibility, G-6PD
deficiency and others. Diagnosis and management of unconjugated hyperbilirubinemia is
directed towards control of unconjugated jaundice by conservative treatment, phototherapy
or blood exchange transfusion. However liver related jaundice called neonatal cholestasis (NC)
has an onset in neonatal period to first three months of life wherein jaundice is conjugated. In
this write up practical approach and management of NC pertinent to Indian setting is given.
Neonatal cholestasis is defined as impaired canalicular biliary flow resulting in accumulation of
bilirubin, bile acids and cholesterol in blood and extrahepatic tissues. The incidence of NC is
around 1 in 2500 live births in the west1,2 and in India it constitutes 30% of all hepatobiliary
disorders.3 These babies present with cholestasis (prolonged conjugated hyperbilirubinemia,
passage of dark urine with or without pale stools). Conjugated hyperbilirubinemia is defined as
direct bilirubin level >1 mg/dL when the total bilirubin is <5 mg/dL or >20% of the total bilirubin
if >5 mg/dL. A subset of infants may present with signs of coagulopathy (deficiency of clotting
factors or vitamin K deficiency), neurological abnormalities in the form of irritability, lethargy,
seizures and poor feeding. Hepatomegaly is common. Other physical features may be growth
retardation seen in congenital infections and syndromic fetal dysmorphisms.
Any infant presenting beyond 2 weeks of age with jaundice and passage of dark urine that
stains the diapers should be immediately evaluated.
ETIOLOGY
A number of disorders are known to cause NC that may be due to infections, bile duct anomalies,
metabolic, endocrinopathies, chromosomal disorders, toxic, vascular and many others.1,2,4,5 However,
for the sake of simplified approach and causes mostly known at present in India needing prioritization
is highlighted. Combined data of medical centers is shown in Table 17.1. Surgical data of six Indian
centers showed a total number of biliary atresia (BA) cases 391 (types: 90% type III, 7.8% type II
and 1.7% type I). Cirrhosis was observed in 75–100% of cases at laparotomy, a reflection of the
delay in diagnosis, referral and surgery.3
Table 17.1: Etiology of 1008 cases of neonatal cholestasis (Combined data of 8 medical centers in India)3
Disease groups Causes in each subgroup

A. Hepatocellular 53% (n = 533)
Neonatal hepatitis • Idiopathic giant cell hepatitis 64%
47% (n = 468) • TORCH infections 22% (CMV 58%, toxoplasmosis 23%, hepatitis
10%, rubella 4.5%, syphilis 4% and herpes 1%)
• Sepsis 8%
• Other causes like malaria, UTI, etc. 6%
Metabolic Galactosemia, 35%, AIAT deficiency 33% (suspected)*, TPN related
4% (n = 43) 19%, tyrosinemia 7%, storage disorders 4%, hemochromatosis 2%
Other causes Inspissated bile plug syndrome (n = 9), recurrent intrahepatic
2% (n = 22) cholestasis (n = 2), progressive familial intrahepatic cholestasis
(n = 1), hypothyroidism (n = 4), associated Down’s syndrome (n =
3); and one case each of polycystic disease, postintestinal surgery
and immunodeficiency.
B. Obstructive 38% (n = 383) Biliary atresia 34%,Choledochal cyst 4%
C. Ductal Paucity 3% (n = 29) Syndromic variety 17%, Non-syndromic variety** 83%
D. Unknown 6% (n = 63)
* Recent studies using confirmatory test of isoelectric focussing reported 57/58 children of liver disease having normal PIMM
phenotype.25
** Mostly now considered secondary to other causes and not as a primary defect.
BILIARY ATRESIA
Biliary atresia (BA) is an idiopathic inflammatory process involving the bile ducts resulting in
obstruction of biliary tract, chronic cholestasis and progressive fibrosis and eventually to biliary
cirrhosis. Incidence of BA is 1:15,000 and the basic etiology is still not clear. Anatomically BA is of
three types: type I involving common bile duct and a patent proximal biliary system (5% cases);
type II atresia involving the hepatic duct with patent proximal ducts (3%); type III involving right
and left hepatic ducts at the porta hepatis (90%). BA may be associated with cystic dilatations in
8–18.9% of cases, a majority being extrahepatic and should not be confused with choledochal
cyst on imaging. Early diagnosis and treatment (Kasai procedure), before the age of 60 days, is
important for better prognosis. Pale stool documentation as shown in Figure 17.1 should be
done that indicates very high possibility of non-flow of bile into small intestine and thus urgency
to diagnose BA. Ultrasonography may be helpful to suggest BA. Hepatobiliary scintigraphy is of
benefit if it shows radioactivity in duodenum indicating patent biliary system that rules out BA.
Diagnosis of BA is not confirmed if no excretion of radioactivity in duodenum is seen. Patients
should be primed with ursodeoxycholic acid (30 mg/kg/day in 2–3 divided doses) for three
days before scintigraphy. Liver biopsy should be done at an earliest (not before 4 weeks of age)
and it provides diagnosis in 94–97% cases. Histopathological features are those of bile ductular
220 proliferation, fibrosis and widening of portal tracts.
Fig. 17.1: Approach to a case of neonatal cholestasis
In a study from our institute 55 cases of NC that fulfilled the selection criteria and had liver
biopsy available were analyzed. Validity of percutaneous liver biopsy diagnoses was compared
with confirmed cases by laparotomy findings and 1-year follow up. Ductular proliferation (P =
0.0002), bile duct and ductular bile plugs (P = 0.009), and portal fibrosis (P = 0.002) were the best
indicators of BA and among them ductular proliferation was the most important in distinguishing
BA from NH. Ductal plate malformation was observed in 17.9% cases of BA. Sensitivity and
specificity of percutaneous liver biopsy for diagnosing BA was 88.2% each. Thus in developing
countries liver biopsy should be done to decrease the frequency of negative laparotomy and to
achieve cost-benefit with reduced morbidity.6 Laparotomy and per-operative cholangiography
is performed wherever possible to have final confirmation of BA. Standard treatment of BA is
Kasai hepatoportoenterostomy. Success of the surgery is based on the anatomical findings, age
at surgery and the experience of the surgeon. The success of surgery is shown by the excretion
of bile and improvement of jaundice. Ascending cholangitis occurs in 50% cases following Kasai
surgery, mostly due to gram-negative rods. Portal hypertension develops if the disease takes a
221
progressive course. In a multicenter study, survival at 24 months without liver transplantation
was 84% if total serum bilirubin was <2 mg/dL and 16% if >2 mg/dL.7 The survival rate with native
liver is 32–60% after 5 years and between 22% and 53% after 10 years.8–11 On long-term follow
up, children with successful portoenterostomy by teenage require transplantation in 85% cases
and 15% have symptom-free survival with native liver. Despite this outcome, portoenterostomy
remains the first line treatment for BA as it allows children to escape immunosuppressive drug
treatment due to liver transplantation for a long time and a proportion can still survive without
transplantation.11
IDIOPATHIC NEONATAL HEPATITIS (GIANT CELL HEPATITIS)

These babies have no identifiable cause of cholestasis and have classical pathological
findings (lobular disarray with ballooning of hepatocytes, focal hepatic necrosis and giant cell
transformation with evidence of extramedullary hematopoiesis). Two forms are known sporadic
and familial that could possibly suggest an undiagnosed genetic or metabolic disease. A
subgroup of familial cases is also known. Management is supportive with nutritional support
and vitamin supplementation. Sporadic cases have an excellent prognosis, 90% resolution by
age 1 year.12 Familial form have relatively poor prognosis. Recently idiopathic group is reported
to be shrinking from the year 1974 towards more identifiable etiology in the year 2004.13
GALACTOSEMIA
Classical galactosemia is an autosomal recessive disorder of galactose metabolism, caused
by a deficiency of the enzyme galactose-1-phosphate uridyl transferase (GALT; EC 2.7.712).14
In this disorder there is accumulation of galactose and consequently production of toxic
metabolites causing damage to liver and central nervous system. The clinical spectrum of classic
galactosemia differs according to the type and number of mutations in the GALT gene. Mostly
these patients clinically manifest in the neonatal period, after ingestion of galactose that is
released from lactose (glucose and galactose) by intestinal lactase from ingested breast milk
and top milk. These children present with jaundice, hepatosplenomegaly, liver dysfunction,
hypoglycemia, renal tubular dysfunction, muscle hypotonia, cataract and commonly have E. coli
sepsis. If untreated galactosemia patients rapidly develop progressive liver disease leading to
liver cirrhosis and death. Diagnosis of classical galactosemia is confirmed by measurement of
GALT activity in red blood cells. The only therapy for patients with classical galactosemia is a
galactose-restricted diet, and initially all galactose must be removed from the diet as soon as the
diagnosis is suspected. Treatment is lifelong restriction of milk or milk products including breast
feeding. Restriction of galactose-containing fruit and vegetables is not currently recommended.
PROGRESSIVE FAMILIAL INTRAHEPATIC CHOLESTASIS (PFIC)

PFIC is a group of genetic disorders that show progressive intrahepatic cholestasis with autosomal
recessive inheritance. PFIC-1 (original Byler disease) is caused by mutations of the FIC 1 gene
encoding a P-type ATPase protein involved in aminophospholipid transport; FIC1 gene is located
on chromosome 18q 21–22. PFIC-2 is due to mutations of the SPGP (sister of P-glycoprotein)
222 gene encoding the ATP-dependent canalicular bile acid transporter (also called BSEP, bile salt
export pump) located on chromosome 2q 24. PFIC-3 is due to mutations of the MDR3 (multidrug
resistance-3) gene encoding the biliary phospholipid transporter and is located on chromosome
7q 21.15 Clinical features, investigations, treatment and outcome of each subtype are shown in
Table 17.2.
ALAGILLE SYNDROME
This is an autosomal dominant disorder wherein there is ‘paucity of interlobular bile ducts’.
Alagille syndrome has been linked to mutations in human JAG-1 gene mapped on chromosome
20p 12. This gene encodes a ligand for the Notch signalling pathway. These patients present
with: (a) chronic cholestasis, (b) characteristic facies, (broad forehead, small chins and saddle
nose with bulbous tip and hypertelorism), (c) skeletal abnormalities (butterfly vertebrae, curved
phalanges and short ulna), (d) cardiac anomalies, (e) ocular anomalies (posterior embryotoxon
and optic nerve drusen), and (f ) renal abnormalities. They may have developmental delay. Alagille
syndrome patients usually present as NC, characteristic facies may not be evident early period
of life and also liver biopsy may show bile ductular proliferation. Management is supportive and
pruritus affects the quality of life. Around 50% cases presenting with NC progress to cirrhosis by
the end of first decade and may require liver transplantation.
HEREDITARY TYROSINEMIA
Hereditary tyrosinemia type I (HT-I) is characterized by progressive hepatocellular damage,
renal tubular dysfunction, hypophosphatemic rickets and excretion of tyrosine metabolites. This
disease is caused by a mutation in the gene coding for fumaryl acetoacetate hydrolase an enzyme
involved in oxidative degradation pathway of phenylalanine and tyrosine; several mutations in
this gene have been identified. The liver is large. Hepatocytes show intense fatty infiltration and
Table 17.2: Clinical features, investigations, treatment and outcome of babies with Progressive familial
intrahepatic cholestasis13,15
Disease Clinical features Investigations Treatment and outcome
Common to all types: intense
pruritus, jaundice, nutritional
deficiencies especially fat and
fat soluble vitamins
Type 1 Systemic involvement: Liver, Normal GGT, liver biopsy- Supportive**, Cirrhosis in first
pancreas and diarrhea PILBD, granular bile* decade of life, LT in second decade
Type 2 Liver-specific involvement, over GGT not increased; liver bi- Supportive**, worse prognosis, LT
lap with type I opsy-giant cells hepatitis, in first decade
canalicular and hepatocel-
lular cholestasis, amor-
phous bile*
Type 3 Delayed until early adulthood Markedly elevated GGT; Supportive, UDCA, non-response
H/o cholestasis of pregnancy in Liver biopsy may mimic to UDCA need LT
the mother biliary atresia
GGT- gamma glutamyl transpeptidase, PILBD- paucity of interlobular bile ducts, LT- liver transplantation, UDCA-ursodeoxycholic
223
acid, * on electron microscopy, ** surgical biliary diversion may reduce pruritus
acute hepatocellular necrosis in acute stage. Progressive hepatic fibrosis results in cirrhosis with
formation of regenerating nodules. One-third of cases surviving above two years of age develop
hepatocellular carcinoma. Hepatocellular and renal damage occurs as a result of accumulation of
succinylacetone and its immediate precursors. Acute form of disease manifests in the first weeks
or months of life with vomiting, diarrhea, a cabbage-like odor, hepatomegaly, edema, ascites,
splenomegaly and coagulopathy. Jaundice is seen in one-third of cases. Hypoglycemia may also
occur. Mortality is due to liver failure usually by 8 months of age with 10% surviving beyond one
year. Laboratory evaluation shows coagulopathy, increased alpha-fetoprotein level 1-100 times
and the diagnosis is confirmed by the presence of succinylacetone in urine.
Treatment of HT-I: Dietary restriction of phenylalanine and tyrosine is the main stay of therapy.
Nutritional treatment should be designed to minimize the phenylalanine-tyrosine load to
only essential requirements. All children should be prescribed a low-phenylalanine low-
tyrosine diet designed to meet their needs for growth without providing excesses of these
amino acids. Supportive therapy is instituted. Pharmacotherapy with nitisinone (Orfadin;
Swedish Orphan International AB, of Stockholm, Sweden) is a highly potent reversible
inhibitor of 4-hydroxyphenylpyruvate dioxygenase.16 This drug prevents formation of catabolic
intermediates from tyrosine (i.e. maleylacetoacetate, fumarylacetoacetate) that are converted
to toxic metabolites (i.e. succinylacetone, succinyl acetoacetate) responsible for observed liver
and kidney toxicity. Succinylacetone can also inhibit the porphyrin synthesis pathway leading
to the accumulation of 5-aminolevulinate, a neurotoxin responsible for the porphyric crises
characteristic of HT-1. Nitisinone was studied in more than 180 children with a median age of
9 months at the start of therapy. When the drug was combined with a restricted diet, the four-
year survival rate of children under 2 months of age at the time of diagnosis was 88%. Historical
data for children treated with dietary restrictions alone indicates a survival rate of 29% for the
same time period. Pediatric dose is 1 mg/kg/d PO divided bid at least 1 h ac initially; adjust dose
to individual requirements; may increase to 1.5 mg/kg/d after 1 mo if biochemical parameters
not normalized; not to exceed 2 mg/kg/d. The most common side effects of the drug are mild
reductions in platelet and white blood cell counts. The drug is approved by FDA and at present
is available only on international study protocol. Liver transplantation is only indicated where
nitisinone fails or where the development of hepatocellular carcinoma is likely or suspected.17 A
summary of the disease is given in Tables 17.3 and 17.4.
NEONATAL HEMOCHROMATOSIS
Neonatal hemochromatosis is a newly recognized and rare syndrome in which congenital cirrhosis
or acute liver failure develops early in infancy and is associated with marked iron deposition in
the liver and extrahepatic tissues (acinar cells of the pancreas, minor salivary glands, proximal
renal tubule, adrenal cortex, thyroid, and myocardium) sparing reticuloendothelial system.18 This
condition is fatal if left untreated. Presentation of neonatal hemochromatosis with hepatic failure
is usually preceded by oligohydramnios, placental edema, and intrauterine growth retardation or
stillbirth. The syndrome affects the fetal liver in utero, the disorder also occurs both sporadically
224 and recurrently in sibs. Causation by a maternal factor is postulated. The liver is generally
shrunken and bile stained with extensive fibrosis and nodular regeneration; there is massive
Table 17.3: Clinical manifestations and diagnosis of conditions causing neonatal cholestasis and
neonatal liver failure
Commonest cause, onset of organ damage in utero, abnormal iron deposition
in liver (worst affected), pancreas, heart, CNS and salivary glands; end stage liver
disease present by birth, possible pathogenesis gestational alloimmune.
Clinical features:
Maternal: Stillbirths, previous sib deaths; antenatal period : IUGR, oligohydram-
nios, placental edema; small for date baby.
Presents usually few hours to sometimes weeks after birth as hypoglycemia,
coagulopathy, jaundice, anemia, ascites, anasarca, splenomegaly with shrunken
Neonatal
liver.
Hemochromatosis
Investigations: Low to normal transaminases, hypoalbuminemia, hypofibrino-
(NH)
genemia, thrombocytopenia.
Diagnosis:
• High serum ferritin median 2448 (415 -100,000) μg/l for screening, low serum
transferrin , high transferrin saturation (95% to 100% up to 157% vs. normal
newborn 80%)
• Lip biopsy: salivary gland biopsy showing iron deposition on staining (best
for Indian situations) or MRI pancreas with low signal intensity on T2 imaging
confirms the diagnosis.
• Aquired in utero, perinatal period (85%) or postnatal
• No history in 60% to 80% of mothers
• HSV 1, HSV 2 common
• Poor feeding, lethargy, vesicles, seizures, renal failure, ascites
• Very high ALT: median 9705 (908- 13,806) IU/L
Herpes simplex infection • Highest mortality if not treated on time.
(HSV) Suspect in a sick neonate presenting in first week of life especially if bacterial
cultures are not growing anything.
Diagnosis:
• Cultures of vesicles, oropharynx , conjunctiva, blood, CSF
• CSF—PCR
• Blood—PCR
Inborn error of tyrosine metabolism, inheritance: autosomal recessive; involves
liver, kidneys and peripheral nerves. Presents as acute hepatic crisis or chronic
liver disease. 60% present as ALF in first 2 years of life including neonatal period.
Presentation:
• Coagulopathy, mildly raised transaminases and no jaundice in the neonate
• Neonatal cholestasis with liver failure
Type 1 Tyrosinemia • “Boiled cabbage” or “rotten mushroom” odour
• Hypoglycemia, coagulopathy, hepatomegaly, ascites
• Rapid decompensation with death unless promptly treated
Diagnosis
• Screening: high alpha-fetoprotein: mean level: 160,000 µg/ml vs. normal full-
term baby 84,000 µg/ml
• Confirmation: Increased urinary succinylacetone
225
Table 17.4: Specific treatment of common causes resulting in neonatal cholestasis and neonatal liver
failure
Antioxidant Cocktail
• N-acetylcysteine 140 mg/kg orally, then 70 mg/kg 4 hourly for 19 doses
• Selenium 2–3 μg/kg/day intravenously over 24 h
• Alpha tocopheryl polyethylene glycol succinate 20–30 IU/kg/24 h orally
• Prostaglandin E1 0.4–0.6 μg/kg/h intravenously for 2–4 weeks
• Chelation: Desferrioxamine 30 mg/kg/24 h intravenously over 8 h until ferritin
<500 μg/l
(Cocktail therapy including chelation has varied effect on outcome ranging
from 0–40% survival without liver transplantation).
Comment: Of chelation-antioxidant regimen acetylcysteine and vitamin E are safe
and easy to administer and may have potential benefit. Use of deferoxamine can
Neonatal be potentially harmful because of its inhibitory effect on neutrophil function. PGE-1
Hemochromatosis (NH) and selenium have no proven benefit.
New regimen with better outcome

High-dose of intravenous immunoglobulin (IVIG) in combination with exchange
transfusion. (75% survival without liver transplantation vs. 17% in historical
controls)
Liver transplantation if no response
Reduction in NH: At-risk pregnancies administration of intravenous immuno-

globulin at 1 g/kg of body weight weekly from week 18 until the end of gesta-
tion6
Treatment
• High dose acyclovir 60 mg/kg/day for 21 days, but often continued till PCR is
Herpes Simplex Virus negative. Necessary to document negative CSF PCR at treatment end
(HSV) Infection • Foscarnet and cidofovir in resistance (0.3%)
High index of suspicion and early institution treatment are keys to success
• NTBC [2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione]
Dosage: 1 mg/kg/d PO divided bid, then increased further not exceeding > 2
mg/kg/d
Type 1 Tyrosinemia
• Drug therapy and dietary restrictions of phenylalanine and tyrosine
(preparation not marketed in India)
• Liver transplantation as emergency or elective if no response
loss of hepatocytes but surviving cells show giant cell or pseudoglandular transformation
with focal nodular regeneration and varying degrees of cholestasis. Diagnosis of neonatal
hemochromatosis should be suspected in newborn babies presenting with coagulopathy and
hyperbilirubinemia with hypoalbuminemia, ascites, or splenomegaly. It is one of the important
causes of acute liver failure in neonates. Investigations that help diagnosis are demonstration
of (a) complete or near complete saturation of iron binding capacity, (b) iron staining of buccal
mucosa/minor salivary gland biopsy tissue and (c) identification of the decreased intensity on T2-
226 weighted MRI (pancreas, heart) characteristic of iron. Serum ferritin level may be elevated. Brief
of neonatal hemochromatosis is summarized in Tables 17.3 and 17.4.
Treatment has to be instituted fast for this condition. A medical regimen consists of N-acetyl
cysteine, selenium, desferoxamine, d-α-tocopheryl polyethylene glycol 1000 succinate, vitamin
E, and prostaglandin E1α. Sepsis is an important complication that should be identified and
treated effectively. Liver transplantation is the only definitive therapy for this condition.
New hope for treatment has been reported recently by administration of weekly infusions
of intravenous immunoglobulin, starting at 18 weeks of gestation in women (n = 15, 16
pregnancies) affected by neonatal hemochromatosis during their most recent pregnancy. All
16 infants were born healthy. Laboratory evidence of neonatal hemochromatosis was found in
12, four had clinically and histologically significant liver disease. Seven babies required medical
treatment, none transplantation and all currently well,19 Neonatal hemochromatosis though a
severe metabolic disease is salvageable by early antioxidant treatment and liver transplantation
in addition to optimal medical care. Children with moderate liver failure can survive without liver
transplantation, but should be monitored closely for deterioration.20
MANAGEMENT
What steps should be adopted in evaluation are shown in Figure 17.1. Neonatal cholestasis
babies should be promptly managed without loss of time. The investigatory approach should
take into consideration the clinical condition and presentation of the child (Fig. 17.1). In a sick
baby with cholestatic jaundice possibilities of galactosemia, toxoplasmosis, herpes, tyrosinemia,
sepsis, etc. should be considered. In babies apparently looking healthy and passing pale stools,
serious consideration should be given to search for obstructive causes like BA or choledochal cyst
on priority. These babies may have other causes like ductal paucity or even neonatal hepatitis.
NC cases who are passing pigmented stools and do not look sick may be having neonatal
hepatitis, ductal paucity, rarely metabolic/storage disorders or hypothyroidism; this group of
children (passing pigmented stools) are unlikely to have biliary atresia. Work up of these cases
should be based on a rational approach and all unnecessary investigations should be avoided.3
Liver biopsies of babies with suspected BA are an emergency and should be reported on priority
basis.3 Disorders of importance as discussed above should be managed as per their specific
treatment.
Cholestasis results in a variety of distressing symptoms and consequences of severe
magnitude which forms an important aspect of management of these cases. Nutritional
support, vitamin supplementation and investigations at the earliest possible opportunity
(Fig. 17.1) should be instituted. Those unfortunate babies who are not diagnosed on
time consequently develop nutritional problems, pruritus, infection, portal hypertension,
ascites and hepatic encephalopathy which need treatment. In breastfed babies, continue
breastfeeding and supplement medium chain triglyceride (MCT) based feeds. Older children
should be offered a diet rich in calories (200 Kcal/kg/day), rich in MCT, and carbohydrate
supplement with glucose polymers, protein (1–2 g/kg /day) from vegetable source, vitamins,
trace elements and minerals. Almost 2–3% calories should come from essential fatty acids.
Anorexic babies should be offered nasogastric feeding. Table 17.5 shows supportive drug
therapy and treatment required to manage pruritus in NC. Pruritus can be reduced by giving 227
one or more than one drug in combination. Naloxone and terfenadine (1–3 mg/kg/day) can
also be tried to control pruritus.
Table 17.5: Supportive management of neonatal cholestasis

Drug Dose Side effects
Vitamin K (Phytonadione) 2.5–5 mg on alternate day None
Vitamin D3 Oral Hypercalcemia
• Cholecalciferol 2500–5000 IU/d Nephrocalcinosis
• 25-OH cholecalciferol 3–5 mcg/kg/d
• Alfacalcidol**
(1-hydroxycholecalciferol) 0.1 mcg /kg/day
Vitamin A Aquasol A: 2500–5000 IU/d Hepatotoxicity, Hypercalcemia,
or Pseudotumor cerebri*
Injectable: 30,000 IU IM at diagnosis Avoid hyper-vitaminosis as it can en-
and then 10,000 IU monthly till hance fibrosis
cholestasis resolve
Vitamin E Potentiation of vitamin K deficiency
coagulopathy
Aquasol E: 50–400 IU/d
TPGS: 15–25 IU/kg/d Diarrhea,

Hyperosmolality with TPGS
Water soluble vitamins Twice the recommended daily None
allowances
Pruritus
Ursodeoxycholic acid 10–20 mg/kg/d Diarrhea, hepatotoxicity
Rifampicin 10 mg/kg/d Hepatotoxicity, drug interactions
Phenobarbitone 3–10 mg/kg/d Sedative effect, behavioral changes
Cholestyramine 0.25–0.5 g/kg/d Constipation, steatorrhea, hyperchlo-
remic metabolic acidosis
* Observed at our center with a higher than 30,000 IU/ dose by Injectable route,
TPGS: d-a-tocopheryl polyethylene glycol 1000 succinate. Vitamins should be administered in all cases of NC cases irrespective
of etiology.
** Alfacalcidol is an analog of vitamin D3 and is considered to be a more useful form of vitamin D supplementation, mostly
due to much longer half-life and lower kidney load.
TPGS: d-α-tocopheryl polyethylene glycol 1000 succinate. Vitamins should be administered in all
cases of NC irrespective of etiology. @ Alfacalcidol is an analog of vitamin D3 and is considered
to be a more useful form of vitamin D supplementation, mostly due to much longer half-life and
lower kidney load.
CHOLESTASIS IN PREMATURE BABIES

Cholestasis is a common problem in very low birth weight babies due to structural, functional
and other pathological predisposing factors. Investigations (when BA is suspected, though
uncommon) should be deferred till infants corrected gestational age is term and the weight is
228 >2 kg. Liver biopsy should be done if pale stools persist beyond corrected gestational age of
2 months and non-excretion of hepatobiliary scan.
EFFORTS TO IMPROVE REFERRAL

There is considerable delay in presentation of NC cases both in India (average delay of 3 months
in referral, pooled data of 8 medical centers), 3 delay in referral results in missed opportunity
for treatment of BA in first 60 days of life. The only option of treatment thereafter is liver
transplantation, which is not presently feasible on a large scale in developing countries due to
several constraints. This delay contributes to increase in morbidity and mortality and also to
poor outcome of several other disorders (other than BA) grouped under NC. Why this delay in
referral? Babies with NC by and large look well, feed well, develop normal social smile giving a
false impression of well being to parents. Other contributory factors of delay in referral are those
of lack of awareness at primary and secondary levels of care to prioritize referral and also lack of
clarity in clinical approach to promptly diagnose the underlying cause. The “Consensus Report on
Neonatal Cholestasis Syndrome” held at Lucknow, India in 1999 recommended several corrective
measures including adoption of a uniform management protocol to improve the outcome of
NC cases in India.3 Subsequently in India more efforts to emphasize upon awareness and early
referral have been in place.21,22
At Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, we targeted our
awareness campaign in the state of Uttar Pradesh and adjoining states that form the referral
base of our patients. We compared our previous data (January 1992 to July 1995) that was
published before national consensus (period A)23 with the data after national consensus and
during our continued awareness campaign at two stages [May 1999 to August 2002 (period B),
and September 2002 to May 2004 (period C)]. NC constituted 60, 70, and 68 cases, during periods
A, B and C respectively. Number of NC cases per month steadily increased from 1.5 (period A) to
1.8 (period B) and then to 3.2 (period C). Mean age of presentation of BA to our center showed
a positive trend of earlier referral (132, 122 and 97 days during periods A, B and C respectively).
Thus, the delay of BA cases decreased from 121 days (period A) to 107 days (period B) and then
to 78 days (period C).24 This data emphasizes positive impact on earlier referral in BA apart from
increased frequency of NC referral.
Pediatric Gastroenterology subspecialty of IAP has launched “Neonatal Cholestasis Yellow
Alert” poster campaign for creating awareness among referring pediatricians throughout the
country. Awareness campaign and this book chapter devoted for young doctors will certainly
help salvage a number of infants and thus contribute in reducing infant mortality rates.
REFERENCES
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in Children (ed 2). Philadelphia, PA, Lippincott Williams & Wilkins. 2001:187–94.
2. McKierman PJ. Neonatal cholestasis. Semin Neonatol. 2002;7:153–65.
3. Consensus Report on Neonatal Cholestasis Syndrome (NCS). Pediatric Gastroenterology subspecialty
chapter of Indian Academy of Pediatrics document. Indian Pediatr. 2000; 37:845–51.
4. Roberts EA. Neonatal hepatitis syndrome. Semin Neonatol. 2003; 8: 357–74
5. Karpen SJ. Update on etiologies and management of neonatal cholestasis. Clin Perinatol. 2002;
29:180–200.
6. Rastogi A, Krishnan N, Yachha SK, Khanna V, Poddar U, Lal Richa. Histopathologic features and accuracy
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Hepatol. 2009;24:97–102.
7. Shneider BL, Brown MB, Haber B, Whitington PF, Schwarz K, Squires R, et al. Biliary Atresia Research
Consortium. J Pediatr. 2006;148:467–74.
8. Ohi R. biliary atresia. A surgical perspective. Clin Liver Dis. 2000;4(4):779–804.
9. Davenport M. biliary atresia. Semin Pediatr Surg. 2005;14(1):42–8.
10. Peterson C. Surgery in biliary atresia—futile or futuristic? Eur J Pediatr Surgery. 2004;14(4):226–9.
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12. Venigalla S and Gourley G R. Neonatal cholestasis. Semin in Perinatology. 2004;29:348–55.
13. Balistreri WF, Bezerra JA. Whatever happened to “Neonatal hepatitis”. Clin Liver Dis. 2006;10:27–53.
14. Bosch AM. Classical galactosaemia revisited. J Inherit Metab Dis. 2006;29:516–25.
15. Jansen PL, Strautnieks SS, Jacquemin E, et al. Hepatocanalicular bile salt export pump deficiency in
patients with progressive familial intrahepatic cholestasis. Gastroenterology. 1999;117:1370–9.
16. Nitisinone: new drug. Type 1 tyrosinemia: an effective drug. Prescrire Int. 2007;16:56–8.
17. McKiernan PJ. Nitisinone in the treatment of hereditary tyrosinemia type 1. Drugs. 2006;66:743–50.
18. Kelly AL, Lunt PW, Rodrigues F, Berry PJ, Flynn DM, McKiernan PJ, et al. Classification and genetic
features of neonatal haemochromatosis: a study of 27 affected pedigrees and molecular analysis of
genes implicated in iron metabolism. J Med Genet. 2001;38:599–610.
19. Gissen P, Kelly D. New hope for treatment of neonatal haemochromatosis. Lancet. 2004;364:1644–5.
20. Grabhorn E, Richter A, Burdelski M, Rogiers X, Ganschow R. Neonatal hemochromatosis: long-term
experience with favorable outcome. Pediatrics. 2006;118:2060–5.
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22. Yachha SK. Cholestatic jaundice during infancy. Indian J Gastroenterol. 2005; 24(2):47–8.
23. Yachha SK, Khanduri A, Kumar M, Saxena R, Sikora SS, Gupta RK. Neonatal cholestasis syndrome—an
appraisal at a tertiary centre. Indian Pediatri. 1996;33:729–34.
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230
18
Chronic Liver Disorders in
Children
Sheila Bhave
CONCEPT OF CHRONIC LIVER DISEASE1–3

Chronic liver disease (CLD) refers to a wide spectrum of disorders characterized by ongoing liver
damage with a potential for progression to cirrhosis or end stage liver disease (Table 18.1). As
against acute liver disease, which is usually associated with complete clinical and histological
recovery within 4 to 6 weeks, CLD implies long standing disease (usually more than 3 to
6 months), leading to various manifestations and complications of liver cell failure. However,
unlike in adults, ‘long’ duration of the disease should not be considered as a mandatory aspect
of the definition of CLD in children, as progressive irreversible changes can occur in children,
even with symptoms as ‘short’ as one week. CLD, of course may be superimposed by acute liver
disease which may eventually obscure the nature of the original insult.
Table 18.1: Spectrum of chronic liver disease
1. Neonatal cholestasis syndrome (NCS) 4. Copper and iron associated disorders

• Biliary atresia (BA) • Indian childhood cirrhosis (ICC)
• Neonatal hepatitis (Torch, Hep. B, C, drugs), • Wilson’s disease
parenteral nutrition • Other copper associated childhood
• Ductal paucity (Watson-Alagille syndrome) disorders
• Choledochal cyst (CC) • Hemochromatosis
• Progressive familial intrahepatic cholestasis (PFIC), 5. Venous congestion/vascular problems
etc. • Budd-Chiari syndrome, venocaval webs
2. Chronic hepatitis • Venoocclusive disease (VOD)
• Chronic viral hepatitis–B/C/D/others • Congestive heart failure, constrictive
• Autoimmune hepatitis pericarditis
• Chronic drug-induced hepatitis (e.g. paracetamol, • Non-cirrhotic portal fibrosis
isoniazide) 6. Miscellaneous
• Sclerosing cholangitis • Cystic fibrosis (CF)
3. Genetic/metabolic liver disease • Fibropolycystic disorders (polycystic
• Alpha 1 antitrypsin deficiency disease of liver, kidney)
• Galactosemia, fructosemia • Histiocytosis X
• Tyrosinemia, inherited urea cycle defects • Fatty liver, “NASH”
• Mucopolysaccharoidosis–Hurler’s • Chronic liver abscess
• Glycogen storage disease–type III, type IV • Idiopathic cirrhosis, nutritional cirrhosis
• Gaucher’s, Niemann-Pick disease, Wolman’s disease
• Peroxisomal (Zellweger) mitochondrial disorders
SPECTRUM AND PREVALENCE OF CLD IN INDIA3,4

Chronic liver disease accounts for at least 1 to 5% of pediatric ward admissions and upto 20%
of ward mortality in our country. Up until the 1970s, Indian childhood cirrhosis (ICC) was the
commonest cause of CLD in India. Today, ICC is a rarity, whereas, diseases like chronic hepatitis,
Wilson’s disease and biliary atresia are diagnosed with increasing frequency and have therefore
become relatively more important forms of pediatric liver disease. The changing pattern of CLD
as seen at the KEM Hospital, Pune during the last 30 years is depicted in Table 18. 2.
MANIFESTATIONS OF CHRONIC LIVER DISEASE5–7

The liver of a neonate or a child generally responds to injury in a limited and set pattern,
irrespective of the type of insult.
Clinical Manifestations
The following are the manifestations of liver cell failure/cirrhosis seen in varying degrees in
chronic liver disease.
• Hepatomegaly (especially enlarged left lobe) or alternately a ‘small’ liver or a ‘hard’ liver
• Firm splenomegaly
• Jaundice (usually prolonged/recurrent)
• Pruritus
• Ascites
• Bleeding manifestations: Nose bleeds, hematemesis, melena – (combination of vitamin K
deficiency, other clotting factor deficiency, platelet dysfunction and portal hypertension).
• Cutaneous portosystemic shunts (caput)
• Cutaneous features of CLD (spider angiomata, xanthomata, popular acrodermatitis
• Malnutrition, growth failure, muscle wasting
• Endocrine abnormalities (such as menstrual irregularities, gynecomastia)
• Encephalopathy
• Renal dysfunction–Hepatorenal syndrome (azotemia, oliguria in patients with cirrhosis)
• Bacterial infections, spontaneous bacterial peritonitis.
Table 18.2: Changing patterns of chronic liver disorders in India, KEM Hospital, Pune 1980–2010
Average annual incidence (cases/year)
Liver disease
1980–84 85–89 90–94 95–99 2000–04 05–09 09 +
Indian childhood cirrhosis 37 22 4 2 1 1 0
Neonatal cholestasis 9 10 28 34 44 40 51
Metabolic liver disease 2 5 6 10 14 22 32
Chronic hepatitis 9 6 6 7 8 6 5
Wilson’s disease 2 4 5 7 14 16 21
Miscellaneous 18 9 13 23 32 28 16
TOTAL 77 56 62 83 113 113 125
232 Acute hepatitis 52 48 56 68 84 82 64
Chronic Liver Disorders in Children
Presentation
i. Compensated liver disease may be asymptomatic, only indication of CLD being isolated
hepatosplenomegaly, splenomegaly alone or increased serum transaminases.
ii. CLD usually presents with vague ill health, irregular fever, anorexia, vomiting, abdominal
pain and abdominal distension with prolonged jaundice.
iii. Child may present with a respiratory or a gastrointestinal infection with findings typical of
CLD.
iv. Occasionally the presentation can be acute with complications of CLD such as bleeding
(hematemesis), ascites or encephalopathy.
Biochemical Features Suggesting Chronicity

• Persistently raised transaminases and alkaline phosphatase (especially in biliary disorders)
• Serum albumin <35 g/L, reversal of albumin globulin ratio
• Prolonged prothrombin time (in spite of vitamin K correction).
Histological Manifestations
A liver biopsy is usually mandatory in the specific diagnosis of CLD. The usual manifestations are:
• Inflammation or necrosis or both suggested by ‘activity’ leading to repair/chronic changes/
massive hepatic damage.
• Cholestasis: Concomitant response with or without bile duct obstruction.
• Cirrhosis: End stage of acute or chronic liver disease. This is characterized by broad bands
of fibrous tissue between central and portal areas with formation of regenerative nodules.
Cirrhosis implies progressive scarring with altered hepatic blood flow leading to further liver
cell dysfunction and portal hypertension.
Liver cirrhosis can be classified:
i. According to size of nodules–micronodular (diameter <1 cm)/macronodular (diameter
up to 5 cm/mixed
ii. Posthepatitic/postnecrotic/biliary cirrhosis (fibrosis starts within portal tracts and then
spreads into the parenchyma
iii. According to etiology
iv. According to function–compensated (inactive)/decompensated (progressive).
• Tumor formation: Occasionally seen after long standing insult, such as chronic hepatitis B or C
• Specific histological features of various diseases are usually superimposed on the above
‘general’ histological features of liver damage.
INVESTIGATIONS OF PATIENTS WITH SUSPECTED CHRONIC LIVER DISEASE 5,7,8

Definitive diagnosis of CLD is usually based on liver biopsy findings, however, a battery of lab and
imaging tests should be done before biopsy to gauge the severity and cause of liver affection.
General
LFTs–S.bilirubin, Transaminases, Full blood count, ESR 233
y-glutamyltransferase S.urea and electrolytes
Alkaline phosphatase Chest X-ray

S. proteins-albumin, S. immunoglobulins USG abdomen
Lipids, cholesterol Liver biopsy
Prothrombin time Endoscopy
Ammonia
Etiological Investigations in Selected Patients

• Radioisotopic imaging ( hepatobiliary scan)
• HBsAg, and other viral markers for Hepatitis A, B, C, E , TORCH
• Serum tissue autoantibodies ANA, SMA, LKM
• Ceruloplasmin, 24 hours urinary copper, liver copper
• Urinary reducing substances (non-glucose)
• Fasting blood sugar, pyruvate and lactate
• Alpha 1 antitrypsin phenotype
• Hemoglobin electrophoresis
• S. iron and total iron binding capacity
• S. amino acids, S. bile acids
• Urinary porphyrins
• Sweat electrolytes, CF mutation studies
• Intravenous pyelography, inferior veno cavogram
• Cardiac Doppler, hepatic venous blood flow Doppler.
MANAGEMENT OF CLD AND ITS COMPLICATIONS6,9

After making a diagnosis and confirming etiology (when possible), the aim of management should
be to minimize further liver damage by treating the cause (if possible) and preventing complications.
The principles of management are:
1. Assessment: Is it CLD? What stage? Any features requiring urgent critical care?
2. Look for treatable causes of CLD and aim for specific therapy:
– Specific therapies are available in a number of CLDs. For e.g. copper chelating drugs in Wilson’s
disease, Kasai surgery in biliary atresia, nitisinone for tyrosinemia type, anti viral agents for
chronic Hepatitis B and C and immunotherapy for autoimmune hepatitis.
3. Control of infections: (treatment and prevention)
4. Look for coagulopathies: Treatment and prevention
(Vitamin K, platelets, FFP, sclerotherapy)
5. Control of edema, ascites and complications, such as peritonitis
6. Prevention of hepatic encephalopathy
Monitor drugs, diet, metabolic disturbances and procedures
7. Nutritional support
Enteral/parenteral nutrition depending on stage of liver disease
Appropriate micronutrient and vitamin supplementation.
8. Management of portal hypertension
234 Medical/Surgical
9. Management of anemia and renal failure
10. Liver transplantation in appropriate cases: With the advent of liver transplantation as
a definitive therapy for many types of CLD, it is necessary to predict the outcome of the
ongoing disease and offer timely intervention. Prognostic factors have now been described
by many transplant services which can optimise timing of referrals.9
INDIAN CHILDHOOD CIRRHOSIS (ICC)4,10,11

Indian childhood cirrhosis (ICC), a progressively fatal liver disorder of young Indian children
was first described scientifically by BC Sen in Kolkata in 1887. It was estimated to be the fourth
commonest cause of death in preschool children in India. Many theories of its causation from
viruses to aflatoxins and genetics to autoimmunity were put forth and discarded. In 1978, a
finding almost by chance, revealed a striking association of greatly increased hepatic copper (Cu)
and ICC. The exciting finding (subsequently confirmed by many) led to a viable hypothesis of Cu
contaminated milk feeds as a cause of ICC and suggested means of treating and preventing the
disease. The subsequent dramatic reduction in the incidence of ICC all over the country during
the past two decades has been particularly gratifying.
ICC: Epidemiological and Clinical Features (Fig. 18.1)

The characteristic, clinical and epidemiological features of ICC are:
i. Specific age range of 6 months to 5 years.
ii. Male predominance.
iii. Upto 20% affection of siblings and high rates of parental
consanguinity.
iv. Restriction to the Indian sub-continent affecting rural ‘well
off’ Hindus.
v. Clinically, the disease begins insidiously with non-specific
symptoms such as abdominal distention, irregular fever,
excessive crying and altered appetite. In a few, the disease
may begin with jaundice, but by and large jaundice is a late
feature. The feel of the liver is characteristically firm to hard
with a sharp ‘leafy’ edge.
vi. Untreated, the progress is relentless with increasing
hepatosplenomegaly, ascites, edema and jaundice. Death
is usually due to bleeding, secondary infection or hepatic
coma.
vii. Standard liver function tests are usually deranged but not
diagnostic.
Fig. 18.1: Child with ICC
Histopathology (Figs 18.2A and B)
The two most discriminatory features of ICC are (i) typical widespread coarse dark brown orcein
(Cu stains) staining and (ii) intralobular pericellular fibrosis. Hepatocytic ballooning necrosis and
hyaline are also diagnostic though late features. Portal fibrosis, inflammation and disruption of 235
limiting plate are also seen. Parenchymal fat is usually absent and cholestasis a late feature.
Figs 18.2A and B: (A) Liver histology in ICC. (B) Orcein positive granules on liver biopsy
Differential Diagnosis
Clinically the disease may resemble nutritional liver disease, chronic hepatitis or metabolic liver
disease. Liver biopsy is usually diagnostic, though CAH and cryptogenic cirrhosis should be
differentiated with Cu studies.
Copper and Indian Childhood Cirrhosis

ICC is associated with greatly increased hepatic Cu. Whereas, liver Cu in normal children is less
than 50 µg/gm, the values in ICC are usually over 1000 µg/gm. Such high values are not seen in any
other liver disorder of this age group except Wilson’s Disease. However, levels of ceruloplasmin
which are characteristically lowered in Wilson’s disease, are normal or raised in ICC.
Though greatly increased hepatic Cu in ICC is well accepted, the source of this Cu is still
debated. Many epidemiological studies suggest the following combination of factors in the
etiopathogenesis of Cu accumulation in ICC namely:
i. Lack of sufficient maternal breast milk
ii. Leading to early introduction of large amounts of ‘top’ animal milk feeds and
iii. Use of brass/Cu vessels for boiling or storing milk.
Studies in siblings of children with ICC have suggested a variable period of Cu storage with minor
histological changes before the development of florid cirrhosis. It is as yet unclear about the
role of a second factor such as genetic predisposition, or another environmental insult or simply
continued Cu ingestion in the genesis of full blown ICC.
Prevention of ICC
The Cu ingestion hypothesis of ICC suggested the remarkable possibility of eradication of a fatal
liver disorder by a simple message of health education. This was demonstrated in Pune District
by an extensive interventional study which was associated with a significant fall in the number
236 of cases of ICC.10 Spontaneous reduction in use of brass vessels all over country appears to be the
most plausible reason for the drastic reduction in numbers of ICC in India.
Treatment of ICC
The Cu chelating drug D-penicillamine though ineffective in late cases shows a remission in
upto 60% of early (pre-icteric) ICC. Remission is associated with clinical recovery, reduction in
hepatic Cu to normal levels and striking histological reversal of cirrhosis within a couple of years
of therapy. D-penicillamine is initiated in a dose of 10 mg/kg and built upto 20 to 40 mg/kg and
continued till adequate clinical and histological recovery (usually 3 to 5 years). Side effects such as
rashes, proteinuria and bone marrow depression though rare must be monitored. Symptomatic
therapy such as adequate diet, blood transfusions and diuretics have to be given as indicated.
ICC Like Disorders: Cu Associated Childhood Cirrhosis

Scattered reports from western countries and Australia have described isolated cases of ICC like
cirrhosis with raised hepatic Cu and high mortality. Cu contaminated water (Cu pipes and low
pH of water) has been incriminated in some, whereas the Austrian Tyrolean cases had a clear
history of Cu vessels being used for boiling cow’s milk. The strong familial incidence in many, has
suggested that both genetic and environmental factors (or combinations) are probably involved.
Such cases of ‘idiopathic’ Cu toxicosis probably comprise the small number of atypical ICCs that
continue to be seen in India.
VENOUS OUTFLOW OBSTRUCTION DISORDERS12–14

These disorders are not uncommon in children in India:
1. Veno-occlusive disease of liver (VOD)
2. Budd-Chiari syndromes (BCS)
3. Chronic constrictive pericarditis and chronic CCF.
Veno-occlusive Disease of Liver (VOD)

This form of liver disorder was once common in preschool age (1–6 years) in Jamaica and in
other ethnic regions of South Africa, Columbia and in India. Clinically, the disease resembles
ICC, though the onset is usually sudden with abdominal distension, pain due to hepatomegaly
and ascites. The outcome is variable with acute liver failure and death in one-third of the
cases; development of CLD with cirrhosis and portal hypertension in 20 to 30% and the rest
recovering within 4 to 6 weeks. Diagnosis is established by liver biopsy. The histological features
are characterized by occlusion centrilobular venuoles, endothelial edema followed by marked
fibroblastic proliferation and hepatic necrosis leading ultimately to cirrhosis in some. The
condition is thought to arise from ingestion of hepatic toxins such as pyrrolizlidines and senecio
alkaloids contained in ‘bush’ teas or herbal medications.
There is no specific treatment. However, the prevalence of the disease has decreased
dramatically since awareness has linked the use of toxic medications to VOD.
Budd-Chiari Syndrome (BCS)

This syndrome occurs when the hepatic vein is obstructed anywhere between the efferent
237
veins upto the entry of inferior vena cava with the right atrium. The obstruction could be due
to a membrane (web), thrombus (complicating polycythemia, trauma, infection or drugs), or a

malignancy (e.g. leukemia or hypernephroma). In a number of cases, the obstruction is idiopathic.
Clinically, the acute form is characterized by severe abdominal pain, vomiting, marked
hepatomegaly and rapid onset of ascites leading to acute liver failure. In the more chronic form
patient presents with abdominal pain, hepatic enlargement, ascites and leg edema. Prognosis is
determined by the hepatic damage and complication of portal hypertension.
Investigations required include inferior venocavography, USG, 99Tcm liver scan and if possible
a liver biopsy. Appropriate investigations to exclude underlying causes and to differentiate from
constrictive pericarditis are required.
Treatment is generally symptomatic except when a surgically treatable cause such as a
venacaval web can be demonstrated. Liver transplantation is an option in the severe form of the
disorder.
Chronic Constrictive Pericarditis and Chronic CCF

These disorders also present with massive abdominal swelling due to hepatomegaly, splenomegaly
and ascites with nonspecific symptoms of fatigue, dyspnea on effort and weight loss. There may
be facial edema, raised JVP, poor pulses and low BP. Hepatic damage occurs due to increased
pressure in hepatic veins secondary to increase pressure on the right heart.
Diagnosis is suggested on the basis of USG, cardiac Doppler, ECG and if required liver biopsy.
Underlying diseases such as active tuberculosis should be ruled out by appropriate tests.
Treatment
Children with Koch’s should be treated with anti-tubercular regime and steroids. If the disease is
inactive or idiopathic pericardiectomy should be considered. If myocardial or hepatic damage is
not severe, improvement takes place over 6 to 12 months with a good return of cardiac efficiency.
NONALCOHOLIC STEATOHEPATITIS (NASH)15,16

Nonalcoholic steatohepatitis (NASH) is a well-known entity in adults and now increasingly
recognized in children and adolescents. The condition was so named because, histologically,
it resembled alcoholic hepatitis, though not associated with ethanol abuse. The condition is
now referred to as “Nonalcoholic fatty liver disease (NAFLD)” to include the entire spectrum of
hepatic steatosis with or without inflammation, fibrosis and resulting cirrhosis. The condition is
most prevalent in adolescent or prepubescent children with obesity and/or metabolic syndrome
and/or Type I or II diabetes mellitus. The characteristic clinical features range from isolated
hepatomegaly and slightly elevated transferases to active severe liver disease. Acanthosis
nigricans associated with insulin resistance is an important associated physical sign. NASH/
NAFLD is to be suspected in a clinical setting of a life style disorder with raised enzymes and
USG features of “fatty liver”. A liver biopsy is required for definitive diagnosis and its grading and
may show steatosis alone to inflammatory changes and mild fibrosis to probable cirrhosis and
progressive end stage cirrhosis.
238 The disease derives its importance due to the rapidly rising prevalence of obesity and lifestyle
disorders in children in India. At this stage therapy is limited to weight reduction and treatment
of insulin resistance. Prognosis is entirely dependent on response to intervention.
CONCLUSION
This chapter presents an overview of the concept, patterns, manifestations, management and
complications of chronic liver disease in children. The chapter also details Indian childhood
cirrhosis, venous outflow obstruction disorders and nonalcoholic steatohepatitis. Details of
other CLDs such biliary atresia and chronic hepatitis will be found in related chapters.
Key Messages
1. Chronic liver disease (CLD) refers to a wide spectrum of disorders characterized by ongoing liver damage with a
potential for progression to cirrhosis or end stage liver disease.
2. CLD accounts for upto 5% of pediatric admissions and upto 20% of mortality in our country. The commonest
cause of CLD in India is now neonatal cholestasis syndrome (NCS).
3. CLD usually manifests with signs and symptoms of liver cell failure or cirrhosis. Liver biopsy is mandatory for
definitive diagnosis. Prognosis depends entirely on etiological diagnosis and related management options.
4. Indian childhood cirrhosis (ICC), once a common and dreaded disease of young Indian children, is now a rarity.
The exciting discovery of the role of copper in the causation of ICC led to the eradication of the disease.
5. Venous outflow disorders such as VOD and Budd Chiari syndrome are occasionally encountered. Early diagnosis
and appropriate management are necessary for optimal outcome.
6. NASH/NAFLD is now emerging as an important cause of CLD in children with lifestyle disorders such as obesity
and diabetes (type I or II).
REFERENCES
1. Vegnente A, Larcher V, Mowat AP, et al. Duration of CAH and development of cirrhosis. Arch Dis Child.
1985;60:656–60.
2. Mieli-Vergani G, Vergani D. Autoimmune Hepatitis. In Kelly DA (Ed): Diseases of the liver and biliary
system in children. Blackwell Science Ltd., Oxford, UK. 2008;191–200.
3. Bhave SA, Bavdekar A, Pandit AN. Changing pattern of chronic liver disease in India. Indian J Pediatr.
1994;61:675–82.
4. Bhave SA. Indian childhood cirrhosis (Update). Recent advances in pediatrics. Gastroenterology,
hepatology and nutrition. Gupte S. Jaypee Brothers Medical Publishers. 2000;(6):322–31.
5. Kelly DA. Investigating the Liver. In Kelly DA (Ed): Diseases of liver and biliary system in children.
Blackwell Science Ltd., Oxford, UK. 2008;21–33.
6. Mowat AP. Chronic hepatitis in liver disorders in children (3rd edn). Butterworths & Co., Publishers.,
London. Oxford. 1999;317–29.
7. Satyasekharan M. Approach to a child with CLD. IJPP Hepatology. 2002;4:363.
8. Nelson Textbook of Pediatrics. Liver. 2004;1303–23.
9. Shepherd R. Complications and management of chronic liver disease. In Kelly DA (Eds): Diseases of the
liver and biliary system in children. Blackwell Science Ltd., Oxford, UK. 2008;351–61.
10. Bhave SA, Pandit AN, Singh S, et al. The prevention of Indian childhood cirrhosis. Ann Trop Pediatr.
1992;12:23–30.
11. Pandit A, Bhave S. Present interpretation of the role of copper in Indian childhood cirrhosis. Am J Clin
Nutr. 1996;63:830S–5S.
12. Tandon BN, Joshi YK, Sud R, et al. Follow-up of survivors of epidemic VOD in India. Lancet. 1984;2:730–3.
13. Rollins BJ. Hepatic veno occlusive disease. Am J Med. 1986;81:297–300.
14. Sherlock S, Dooley J. Budd-Chiari syndrome. Diseases of the liver and biliary system (11th edn). 2002;453–66.
15. Manton ND, Lipsett J, Moore DJ, Davidson GP, Bourne AJ. Non-alcoholic steatohepatitis in children and
adolescents. Med J Aust. 2000;173:476–9. 239
16. Roberts EA. “Non alcoholic steatotis.” In: Kelly DA (Ed): Diseases of the liver and biliary system in children.
Blackwell Science Ltd., Oxford, UK. 2008;253–69.
19
Portal Hypertension
Sutapa Ganguly
Portal hypertension (PH) is the commonest cause of gastrointestinal bleeding in children of

India.1,2 The mortality after index hematemesis in variceal bleeding is 30% and after recurrent
variceal bleeding is as high as 70%.3 Indian studies reveal that extrahepatic portal venous
obstruction (EHPVO) is the predominant cause of PH in children.4–8 In studies from developed
countries intrahepatic obstruction accounts for 55–60% of all PH in children.2,9,10 This article
covers the etiology, clinical profile, investigation and management of children with PH in India.
DEFINITION
PH is defined a clinical syndrome in which the pressure in the portal vein rises above 10–12 mmHg
(normal value being 7 mmHg).11
CLASSIFICATION OF PH
PH can be caused by obstruction to the portal blood flow anywhere along its course. It is
customary to classify PH into: (i) pre-sinusoidal (extra and intra-hepatic), (ii) sinusoidal and
(iii) post-sinusoidal causes though there are overlapping. In pre-sinusoidal causes of PH the
hepatocellular function is preserved and hence usually they stand well the bleeding episodes
in comparison to the children with chronic liver disease who succumb early or develop hepatic
failure.
EHPVO: The obstruction may be at any part in the course of the portal vein.
Etiology
Infections
Umbilical infection with or without catheterization in neonates is associated with 10 to 20%
of cases of EHPVO.12–15 However in prospective studies in children with umbilical sepsis and
cannulation, development of EHPVO is rarely documented.16,17 In a recent series in India such
history could be elicited in 6 of 160 children (3.7%).18 Intra-abdominal infection including acute
appendicitis and primary peritonitis in older children can lead to portal pyemia, pylephlebitis and
inflammatory masses around the portal vein leading to development of portal vein thrombosis.12
Dehydration and increased coagulability of blood associated with disseminated intravascular
Portal Hypertension
coagulation in systemic sepsis are other contributing factors. Recurrent episodes of diarrhea may
result in endophlebitis in portal circulation due to absorption of toxins and bacteria, this could
potentially lead to thrombosis and portal hypertension due to obstruction portal venous system.
This hypothesis, however, needs to be confirmed.19 Abdominal tuberculosis has been implicated
as a cause of PH in children.20 Thrombosis of portal vein has been associated with biliary tract
infection and primary sclerosing cholangitis.
Hypercoagulable States
Hypercoagulation secondary to acute dehydration, polycythemia, and inherited and acquired
deficiencies of anticoagulant proteins like protein C, protein S and antithrombin III has been
associated with EHPVO.21, 22 Association of conditions like Budd-Chiari syndrome23 or splenic
vein thrombosis24 with celiac disease suggested deficiency of protein C and S Other acquired
condition with deficiency of protein C and S include malnutrition, nephritic syndrome and
malignancy.
Congenital obstruction can be produced anywhere along the line of right and left vitelline
vein from which the portal vein develops. The portal vein may be absent with visceral venous
return passing to the systemic veins particularly inferior vena cava. Hilar collaterals are absent.25
Several congenital anomalies have been reported in association with EHPVO. They include
microcephaly, coloboma of iris, deformed pinna and cardiac anomalies like ASD, VSD and
PDA.26,27 These anomalies were found in 40% of children with EHPVO of unknown cause and 12%
with known cause.26
Trauma
Laceration of portal vein may rarely be associated with abdominal injury due to automobile
accident and ligation of the vein is required to control bleeding.
Invasion and Compression

Invasion of portal vein by hepatic tumor and thrombosis of splenic vein due to chronic
pancreatitis28 are reported causes of PH.
Intrahepatic Causes of PH
Cirrhosis and NCPF may be associated with EHPVO in children and adults. In adults with
cirrhosis a frequency of 0.6 to 16.6% has been reported in different series.29,30 Shunt surgery,
splenectomy and liver transplantation in these patients predispose to the development of
EHPVO. Development of hepatoma in a patient with cirrhosis is a prerunner of the occurrence of
EHPVO.31 Three percent of patients with NCPF may have portal vein thrombosis.29,32,33
Idiopathic
In some cases of EHPVO no etiology could be found. In earlier series majority of cases were
idiopathic.12 However, due to availability of different sensitive and sophisticated diagnostic
facilities, etiology can be revealed in as high as 90% of cases in recent series.19 But Yachha et al in
241
1996 reported 64 out of 65 cases (98%) of EHPVO to be idiopathic.34
At the time when occlusion of a portal vein by a thrombus develops, patient may remain
asymptomatic; the thrombus becomes organized and tortuous collaterals develop around the
blocked portal vein, a process known as cavernous transformation. However, sometimes, acute
portal vein thrombosis is associated with the development of progressive ascites, abdominal
pain secondary to small bowel ischemia and intestinal infarction leading to acute abdomen and
melena if thrombus extends to the superior mesenteric vein. This presentation may occur in
septicemia and dehydration associated with severe diarrhea and mortality is often high.
Intrahepatic Causes of PH
Noncirrhotic Portal Fibrosis
It is a distinct syndrome of obscure etiology characterized by obliterative portal venopathy
resulting in PH, well tolerated episodes of variceal bleeding and preserved liver function. It is a
well-established cause of PH in adults.35–38 In children its incidence varies in different series.39,40
However, in Eastern India, it is an important cause of PH in children.41
Though definite etiology of NCPF could not be pinpointed but based on clinical observations
and available information it is proposed that NCPF and EHPVO both are the portal venous
inflow tract diseases can develop in a genetically predisposed individual when infection or
a prothrombotic event could precipitate thrombosis in the portal vein or its radicals. If it is a
major thrombotic event occurring at an early age in life, the main portal vein become occluded,
leading to the development of EHPVO. However, in the case of repeated microthrombotic events
the small and medium sized branches of portal veins are affected leading to the development of
NCPF.
Chronic Liver Disease

Cirrhosis and chronic hepatitis are common intrahepatic causes of PH in children. The major
cause of cirrhosis in children are viral hepatitis, neonatal cholestasis syndrome and metabolic
liver diseases like Wilson’s disease, glycogen storage disease, a1 antitrypsin deficiency, etc. PH
was associated with 14% of CLD in our series,42 whereas it was detected in 13 out of 29 cases
subjected to upper GI endoscopy in a series of 40 cases of CLD reported by Dangwal et al.43
Postsinusoidal block: Veno-occlusive disease (VOD) or endophlebitis obliterans is a nonthromb-
otic obliterative process of the lumen of the small intrahepatic branches of the hepatic veins
by loose connective tissue. The luminal and perivenular regions show fibrosis in the later
stages. The resultant PH is characterized clinically by ascitis and later hepatic failure.44,45 There
are three major etiologic factors responsible for VOD (1) Plant alkaloids, (2) Irradition, (3) Drug-
immunosuppresants, antineoplastics and indigenous system of therapy.
Historically the earlier report on pyrrolizidine toxicity was from rural South Africa in 1920.46
Later following observation of Stuart et al44 several-epidemic and sporadic forms were reported
from all over the world. There were reports of 2 epidemics one in 1973 and another in 1975
in Sarguja district in Madhya Pradesh47 following contamination of millet fields with crotalaria
242 seeds. Death in adults is due to progressive liver failure, while in children the disease progresses
to chronicity and there is variceal bleed due to cirrhosis of liver. A continuous venous hum is
Portal Hypertension
often heard over the dilated anterior abdominal veins in this group of patients and peripheral
signs of liver cell failure are absent.
Budd-Chiari syndrome or hepatic venous outflow tract obstruction (HVOO) is defined as
obstruction to the veins, which carry blood out of the liver. The condition was first described
by George Budd48 from England in 1845, followed by Hans Chiari in 1899 from Austria.49 The
syndrome is classically described as a triad of right upper quadrant pain, hepatomegaly and
ascites. Splenomegaly is not a common feature but is an association when complicated by PH.
HVOO has many causes and the site of obstruction varies in the different regions of the world.
While thrombosis of hepatic vein (Type I) is more frequent in Western countries obstruction
of inferior vena cava at the level of diaphragm is common in India and other developing
countries.50,51 Variceal bleeding is more common in type II than in type I.51
Thrombosis of hepatic veins is caused by hematological disorders with increased clotting
tendency, e.g. Polycythemiarubravera, paroxysmal nocturnal hemoglobinuria, anticoagulant
protein C and S deficiency or a latent myeloproliferative state. A recent sensation is the discovery
of an abnormal factor V called factor V Leiden which leads to activated protein C resistance and
thrombosis.52
CLINICAL FEATURES OF PH
EHPVO: The mean age of presentation was reported to be 5 to 6 years.12,53 In India 83% of patients
with EHPVO present with upper gastrointestinal (UGI) bleed before the age of 20 years, compared
to the data of Western World where more than 43% may present after this age.12,14
Hematemesis with or without melena is the commonest mode of presentation; only 8 to 10%
patient may not bleed.12–14 UGI bleeding is massive and recurrent but risk of rebleeding after
major episode is less than cirrhosis54 but is fairly uniform and occurs once in every 2 years.55 The
average number of bleed is 2.5 to 5 episodes per patient.1,56
Hematemesis and melena occurs typically in a healthy child spontaneously or following a
febrile upper respiratory tract infection. Use of aspirin and other nonsteroid anti-inflammatory
drugs may predispose to UGI bleeding.57
Splenomegaly is almost universal in patient with EHPVO. It can be present as early as 1 month
of age and is usually seen before 3 years of age.58,59 Splenomegaly is mild (<6 cm) in 42%,
moderate (6–10 cm) in 40% and massive (>10 cm) in 18%.
Children with EHPVO do not grow as do their healthy sibs.60 Their mental function is normal.
They usually do not develop encephalopathy even after massive GI bleeding. They have normal
liver function. Patient with EHPVO may develop transient ascites following major bleeding
episode. Persistent or massive ascites in children with EHPVO should doubt about the diagnosis
or suggests the possibility of presence of coexistent cirrhosis. It has been observed that the
frequency and severity of upper GI bleeding in children with EHPVO decreases after puberty,
as if they grow out of their bleed. Periumbilical veins are not seen but there may be dilated
abdominal wall veins in left flank.
EHPVO is detected at times (10%) while investigating for unexplained splenomegaly, without
upper GI bleed. It is usually diagnosed by ultrasonography. 243
At the time, when occlusion of portal vein by a thrombus develops, patient may remain
asymptomatic; the thrombus become organized and tortuous collaterals develop around the
blocked portal vein, a process termed as cavernous transformation. However, sometimes acute
portal vein thrombosis is associated with development of progressive ascites, abdominal pain
secondary to small bowel ischemia and intestinal infarction leading to acute abdomen and
melena if thrombus extends into the superior mesenteric vein. This presentation may occur in
septicemia and dehydration associated with severe diarrhea. Mortality is often high.60
Chronic Liver Disease

In PH occurring secondary to CLD the presentation is usually dominated by manifestations of
primary disease. While nearly 80% of children with EHPVO experience at least one episode of
hemorrhage, only 30–40% of children with CLD do so.9 Sixty five percent of cirrhotic patients
with varices will not bleed within 2 years of diagnosis but 50% will die of the first hemorrhage.
Gastrointestinal bleeding in this group of children may precipitate hepatic encephalopahty.
In addition, presence of coagulation abnormalities may make the bleeding more severe and
increases the mortally rate.
There may be prominent veins in anterior abdomen wall while in post-sinusoidal block
prominent veins are seen in right flank and back.
Factors Predicting Rupture

There is a strong correlation between variceal size assessed endoscopically, and the probability
of bleeding.61 Intravariceal pressure is less important although a portal pressure above 12 mmHg
appears necessary for varices to form and subsequently bleed.62
‘Red spots’, danger sign seen at endoscopy are valuable predictors of imminent hemorrhage.63
The bleeding episodes in children may be initiated by a minor, febrile, intercurrent infection. The
mechanism is unclear.
INVESTIGATIVE APPROACH TO PH
This is directed towards (1) assessment of the current hematological status of the child, (2)
Concomitant information on the liver function and etiology of the liver disease, (3) demonstration
of the site of bleeding collaterals, patency or block of the portal vein.
1. Complete hemogram gives an idea of the degree of anemia and presence or absence of
hypersplenism.
2. If liver disease is suspected then liver function tests, prothrombin time and ultrasound is
done. Liver biopsy and special tests are required to pinpoint the exact etiology.
3. Esophagogastroduodenal endoscopy is the best method to demonstrate the varices and
pinpoint the exact site of bleeding (Table 19.1). It is far more sensitive than barium swallow
which demonstrate large varices and cannot tell whether varices are the cause of bleeding
or not. Barium swallow cannot be done during acute bleeding. Doppler ultrasound and
pressure transducer can be attached to endoscope to look for the flow or pressure in the
varices. The varices are present most often at the lower end of esophagus but they may be
seen in the stomach duodenum and jejunum and sometimes solely at these sites without
244 esophagealvarices causing massive GI bleed.64,65 Esophageal varices are considered the
source of bleeding if either they are found to be actively bleeding at endoscopy or show
evidence of recent bleeding in the form of adherent clot and white platelet nipple over the
Portal Hypertension
Table 19.1: Conn’s endoscopic classification of esophageal varices82
Grade–I On inspiration only Can be effaced Straight Red

Grade–II Both on inspiration and expiration Can be effaced Straight Red
Grade–III Projecting into lumen less than 50%, Wavy ± Cannot be effaced Straight Blue
Grade–IV Projecting into lumen more than 50% and Tense Tortuous Blue
coiled ±
Table 19.2: Modified Hosking’s classification of gastric varices89
Type 1 LCGV (lesser curve gastric varices)

Type 2 a. Subcardiac fundal varices
b. Diffuse fundal varices
Type 3 a. Isolated fundal varices with splenic vein thrombosis
b. Isolated fundal varices without splenic vein thrombosis
Type 4 LCGV + fundal varices
Type 5 Antral varices
varix. Varices are presumed to be the source of hemorrhage if no lesion other than the varices
are seen at endoscopy.
Gastric varices may be extension of esophageal varices across the squamocolumnar junction
(these are treatable by sclerotherapy) or at fundus (which if bleed, require devascularization or
shunt surgery) (Table 19.2). Portal hypertensive gastropathy is seen as mosaic like pattern with
small polygonal areas surrounded by whitish yellow depressed border.66
For demonstration of hepatic vasculature, collaterals and shunts various imaging techniques
are used. Noninvasive techniques are ultrasound with duplex Doppler, CT scan and MRI.
Invasive techniques include splenoportovenography (SPV), arterioportography, percutaneous
transhepatic portography and inferior venocavography.67–69
IMAGING
Noninvasive Investigations
Ultrasound Doppler
Demonstration of an echogenic thrombus within the portal veins is best evidence of EHPVO.
Other findings include dilation of the vessel proximal to the occlusion, lack of identifiable portal
vein, cavernoma formation around the site of block, lack of variation of portal vein diameter with
respiration.70–73 However, cavernoma formation may take up to 12 months to develop. Thickness
of the lesser omentum is never more than aorta but with PH it is moderately to markedly
increased in thickenss in 84% patients.9 Hepatic echo-texture can give an idea abuot the liver
pathology. USG is also a sensitive device to detect minimal ascites.
A recent study showed USG to be accurate in 80% of the patients. Collaterals in splenic hilum, 245
hepatomegaly, ascites and splenic infarct were independent markers to differentiate cirrhosis
from EHPVO.74 Doppler study is also useful and shows absence of portal venous signal in EHPVO.
Contrast enhanced CT scan shows the thrombus as non-enhancing filling defect within the
lumen of the portal vein and dilatation of may small veins at the hilum.
CT Angiography and MRI scan are increasingly used in the Budd-Chiari syndrome and
to identify liver lesions associated with portal hypertension like focal nodular regenerative
hyperplasia. MR angiography is recently used as a non-invasive alternative to conventional
angiography to delineate portomesenteric venous anatomy.
Angiography—Inferior vena cavography with pressure measurements is valuable in patients
with Budd-Chiari syndrome in whom hepatic venography can be used ot assess hepatic venous
patency. Balloon dilatation can be undertaken of inferior vena caval membrane or short segment
narrowing of the hepatic veins, which can prove therapeutic.
MEDICAL AND ENDOSCOPIC MANAGEMENT OF PH IN CHILDREN

Upper gastrointestinal bleeding is a dramatic event and is associated with loss of large volume of
blood. Variceal bleeding in children differs from adults in many respects:
i. Predominance of EHPVO (at least 50% more prevalent than IHPH)
ii. Difficulties to perform shunt surgery
iii. Apparent development of natural shunts with growth
Patients with EHPVO has food liver function treatment should be directed to control acute
bleeding and prevention of recurrent bleeding.
Steps of Management of Acute Bleeding

1. Resuscitation: Hemodynamic stability
2. To stop active bleeding
3. To prevent recurrent bleeding
4. To treat the underlying cause for bleeding
To resuscitate the patient–An intravenous line has to be established and a large size cannula
to be placed in a good size vein.
Blood samples to be collected for grouping, cross matching, hemogram, coagulogram and
blood biochemistry. Ideally a central venous line should be put separately to guide replacement
therapy.
Oxygen is given to counter hypoxia due to acute blood loss and fall in hemoglobin. Nasogastric
aspiration is done half hourly to check the ongoing or recurrent bleeding. Nasogastric lavage
is given to clear the stomach for endoscopy, to define bleeding lesions, to check ongoing or
recurrent bleeding and to prevent blood going down to intestine. This avoids rise in blood urea
nitrogen and prevents hepatic encephalopathy particularly if there is underlying liver disease.
Vitals to be monitored which include heart rate, respiratory rate, blood pressure intake-
output chart. It has to be done every 10 minutes till the child is stabilized and then hourly for
24 hours after stoppage of bleeding or stabilization. The child has to be catheterized in the shock
stage to monitor the urine output.
Over transfusion of the child should be avoided and hematocrit should not exceed 30%.
246
Portal Hypertension
MANAGEMENT OF VARICEAL BLEEDING

This can be done by:
i. Control of ongoing bleeding
ii. Prevention of 1st bleeding (Primary prophylaxis)
iii. Prevention of recurrent bleeding (Secondary prophylaxis).
Management of Acute Variceal Bleeding

Variceal bleeding can be controlled by the following modalities:
• Pharmacotherapy (PT)
• Balloon tamponade
• Endotherapy
• Transjugular intrahepatic portosystemic shunting (TIPS)
• Surgery.
Pharmacotherapy
PT has several advantages on other modes of therapy. It is used (i) to stop acute variceal bleeding,
(ii) to control recurrent bleeding by lowering portal pressure, and (iii) to prevent fresh episodes
of bleeding in unbled patients.
Theoretically the ideal PT is relatively inexpensive, not operator dependent and can be used
any time of the day.
Hemodynamics of PH
Drugs used in PHT exert their effect by reducing portal inflow or reducing intrahepatic or
collateral resistance (Fig. 19.1). Other less validated but readily available drugs may reduce
collateral blood flow by increasing lower esophageal sphincter tone or reducing circulating
plasma volume. Esophageal varices are formed when the portal venous pressure (PVP) exceeds
10 mmHg and varices tend to bleed when PVP exceeds 12 mmHg. Although the PVP cannot always
be normalized by pharmacologic means, it has been demonstrated that a 20% decrease in the
pressure gradient from the baseline value reduces the risk of variceal bleeding significantly.75,76
Pharmacologic therapy for acute variceal bleeding theoretically is an ideal approach as:
a. There is no delay in initiation of management
b. No equipment is required
247
Fig. 19.1: Hemodynamics of portal hypertension
c. Needs no expertise
d. It is totally non-invasive.
The most widely used agents to stop variceal bleeding are:
1. Intravenous vasopressin
2. Terlipresin–the synthetic analog of vasopressin
3. Nitroglycerine
4. Somatostatin
5. Octreotide–the synthetic analog of somatostatin.
Vasoconstrictors
• Vasopressin/terlipressin
• Somatostatin/Octreotide
• β adrenergic antagonist.
Vasodilators
• Nitroglycerine
• Isosorbidemononitrate
• Isosorbidedinitrate.
Vasopressin (VP)
It is potent but non-selective vasoconstrictor and has used for many years in the treatment of
variceal bleeding VP lowers the portal pressure by causing splanchnic arterial vasoconstriction
and reducing the splanchnic blood flow.
VP is given in a bolus dose of 1 unit per 3 kg of body weight diluted with 2 ml/kg of 5%
dextrose infusion over a period of 15–20 minutes. This can be repeated two to three times at 20
to 30 minutes interval closely monitoring the heart rate and rhythm.
However, this agent causes bleeding control in 50% of cases, vasospastic side effects in 50%
and treatment was discontinued in 20% of cases.77 Risk of myocardial infarction is of greatest
concern.
To reduce the risk and potentially lower the portal pressure further, nitroglycerine has been
used in combination with vasopressin.
Nitrovasodilators
The pharmacologic rationale for using nitroglycerin is that nitrates are believed to reduce the
collateral and possibly portahepatic resistance by increasing local concentrations of NO. It also
produces vasodilatation by decreasing venous return and thereby reducing cardiac output.
It also acts on arterial smooth muscle causing arterial dilatation, hypotension and splanchnic
vasoconstriction.
Three randomized controlled trials have compared VP alone with VP plus a NTG preparation
248 and in each study there was a trend towards improved control of hemorrhage with combination
therapy as well as fewer side effects, thereby rendering monotherapy of VP obsolete.77
Portal Hypertension
Terlipressin
Another approach is to use the synthetic analogue of VP–the triglycyl-lysine VP (Terlipressin)
which undergoes cleavage of glycyl residues to allow a slow release of lysine-vasopressin. It
acts by immediate intrinsic vasoconstriction and slow vasoconstriction after change to lysine-
vasopressin. Though there is limited experience in children the drug has shown to be more
effective in controlling bleeding (upto 79%) than VP without any adverse side effects. Terlipressin
was found to be as effective as balloon tamponade and somatostatin in terms of both control of
bleeding and mortality.
It may be administered as intravenous injections (2 mg) every four hours till a bleeding free
interval of 24–48 hours is achieved.
Somatostatin
It is a peptide having growth hormone inhibitory property. It has a variety of physiologic action
including inhibition of release of several vasodilatory hormones such as glucagon and direct effects
on vascular smooth muscle. The net pharmacologic action is to induce splanchnic vasoconstriction
selectively. The recommended dosage is one to thee bolus injections (250 µg/bolus) during first
hours of therapy followed by infusion of 250 µg/hour continuous infusion for 2–5 days.
Somatostatin has been compared to vasopressin in seven trials, with a trend towards lower rate
of failure to control bleeding with somatostatin (Pooled odds ratio 0.68%, 95% Cl. 0.45 to 1.04).
In addition, there were significantly fewer complications with somatostatin. Disadvantage
of somatostatin is its short half life, i.e. 1 to 3 minutes. The important adverse effects are
hyperglycemia and gallbladder stasis.
Octreotide is the synthetic analogue of somatostatins with longer half life (90 minutes. In
children the dose is 1–2 µg/kg as bolus to maximum of 50 µg followed by constant infusion of
0.4–2 µg/kg in for 5 days.
Three trials have suggested that somatostatin and octreotide are as effective as EST in
controlling acute variceal hemorrhage.77
Several trials that compared somatostatin or octreotide with terlipressin showed no
significant differences in either control of bleeding or mortality rate.77, 78
Effectiveness of somatostatin and octreotide for controlling acute variceal bleeding for 2 to
5 days is comparable to that of vasopressin and EST.79
In summary, vasopressin plus nitroglycerine, terlipressin, and somatostatin or octreotide
all appear to be useful in the treatment of acute variceal hemorrhage. Octreotide is the most
favored drug for its long half life and minimum side effects. Current opinion favors endoscopic
therapy as first-line therapy for acute variceal hemorrhage, with pharmacologic therapy of
particular value in patients who are too unstable for endoscopy, or who have bleeding that is
not immediately controlled by endoscopy and as a valuable adjunct to endoscopy therapy to
prevent early rebleeding.
Use of Antibiotics
Antibiotic prophylaxis is an integral part of therapy for patients presenting with variceal bleeding 249
for preventing bacterial infections or spontaneous bacterial prophylaxis.
Prevention of Hepatic Encephalopathy

In patients who present with or develop encephalopathy, should be treated with lactulose
but there is no strong evidence evaluating the usefulness of lactulose in prevention of hepatic
encephalopathy.
ENDOTHERAPY
Endoscopy should be performed as soon as possible after admission (within 12 hours) especially
in patients with clinically significant bleeding or in patients with features suggestive of cirrhosis.
• Presence or absence of esophageal varices
• Gastric varices
• Portal hypertensive gastropathy
• Gradation of varices
• Site of active bleeding if any.
Endoscopic Sclerotherapy
Preparation
An informed consent is taken from the parents. An overnight fasting is the only preparation
required in infants and children before the procedure.
Instruments
For most children except infants and neonates a standard endoscope with insertion tube outer
diameter of 9 mm is adequate. There are over a million bundles of optical fibers. When switched
on, a cold light source with halogen bulb allow intense illumination without generating heat.
Technological advances in improving fiber bundles further has allowed endoscopes with
5.9 mm and 3.6 mm of external diameters for use in small children and neonates.
Sedation
Although some people had recommended general anesthesia for children less than 10 years2,81
most pediatric endoscopists advocate the use of a combination of meperedine and diazepam
intravenously. However, the dosage of sedation is kept at the minimum as the use of excessive
force may not be appreciated by an obtunded child and complications become more.
At our center, for small children and infants intramuscular ketamine is used in dosage of 2
to 3 mg/kg. Ketamine induces dissociative anesthesia–profound analgesia, immobility, amnesia
with light sleep and feeling of dissociation from own body and surroundings. The primary site
of action is in the cortex and subcortical area. Respiration is not depressed, reflexes are not
abolished but there is small increase in muscle tone, heart rate and blood pressure. Hence
periodic assessment of cardiovascular function is required. However, children tolerate the drug
better than adults.
For older children talking to the child, explaining the procedure and taking him/her into
250 confidence about the procedure, yields better results than any sedative.
Portal Hypertension
Technique
The child is placed in the left lateral position with neck slightly flexed. An assistant should always
monitor the cordiorespiratory status, since tracheal compression and air distension of stomach
may compromise the airways and respiratory system. There should be proper arrangement for
cardiopulmonary resuscitation in the procedure room.
The scope should be advanced down the hypopharynx under direct vision keeping the tip in
the middle. The distal esophagus is identified by change from white to pinkish red mucosa.
The varices were graded from I-IV as per standard classification of Conn.82
The stomach is inspected including the fundus by complete retroflexion to see the gastric
varices. The scope is inserted through the pyloric canal into the duodenal bulb. The pyloric canal
is visualized slowly withdrawing the scope and rotating its tip. Second look of the esophagus is
made while withdrawing the scope.
The sclerosant may be injected into the varies (intravariceal), along the side of the varix
(paravariceal) or a combination of the two. Intravariceal sclerotherapy aims at obliteration of
varices by inducing thrombosis and a necro-inflammatory response. Paravariceal injections on
the other hand provide a proliferative fibro-inflammatory response in the submucosa without
actually obliterating the varices. With either technique EST is started at the cardiac end of
esophagus and continued for the lower 5–6 cm of the esophagus.
Sclerosant
A variety of sclerosants in varying combinations have been used by different authors. Five
percent ethanolamine is favored in UK, South Africa and Japan. 0.5 to 30% polydocanol is popular
in Germany and rest of the Europe; 5% Sodium Morrhuate and 0.5–1.5% of Sodium Tetradecyl
Sulphate (STS) are the sclerosants of choice in United States.83 Most authors agree that most
effective agents are the more damaging ones and these include STS and absolute alcohol and
recommend against their use. In our country due to high cost of these sclerosants and non-
availability, attempts have been made to evaluate economic, effective and locally available
sclerosants. In our center we use 3% polidocanol (Ethoxysclerol) for those who can afford it and
75% alcohol for the rest. 0.5 to 2 ml of the sclerosant injected per shot and total volume injected
in a sitting varies from 10–15 ml.
Two controlled trials have shown that injection at weekly interval till variceal obliteration
leads to early eradication of varices with decreased risk of rebleeding.84 We use injections at
weekly interval for first 3 sittings then at 3 weekly interval till the varices are obliterated. The
mean number of injection courses required for variceal obliteration has been reported to be
between 4 to 6.2,41,85
Subsequently the patients are called for follow-up every three months for next 2 years, there
after at yearly intervals. Any recurrent varies detected on follow-up are reinjected.
Complications
Minor complications are fortunately the most frequently noted complications in children. These
include fever, chest pain, dysphagia and superficial mucosal ulceration (6–70%). These should be 251
considered an accompaniment of EVS as they are of little clinical consequences.
Major complications which result in significant morbidity occur in 1–13% of patients and
include esophageal perforations (1.3–7%), bleeding from esophageal ulcer (1–13%) and
pulmonary complications (5–7%). In our series rebleeding was the only major complication
noted in 13% cases.
Esophageal stricture though a major complication does not lead to death and respond well
to 1-3 sittings of dilation by advanced Keymed dilator or Savary dilator.
Other serious complications are rarely seen and are reported as isolated case reports include
spinal cord paralysis, splenic venous thrombosis, splenic abscess, gastric perforation, etc.86
In conclusion EST is an accepted mode of treatment for both acute variceal bleeding and
prevention of variceal rebleeding in portal hypertension in children. Complete or near complete
obiliteration of varices was noted is more than 90% of cases in different series.41,87,88 Limitations of
the procedure are the need for lifelong follow-up and 10 to 20% risk of rebleeding during initial
period prior to variceal obliteration. It should not be recommended for patients referred from
remote areas where ready access to facilities for resuscitation is not available.
In 1988, Stiegmann et al90 introduced endoscopic band ligation as an alternative to endoscopic
sclerotherapy for esophageal varices. Subsequently, many studies have compared EVL with EST
and showed that EVL is as effective as EST. However, it (EVL) eradicates varices rapidly with a fewer
sessions and has lesser complications than EST.91,92 EVL produces superficial ulcers as a result of
which strictures occur rarely. In fact EVL has become the preferred mode of treatment for variceal
bleeding in adults. However, studies on EVL in children are on limited number of children only.
Initially it used to be single-band ligation technique (Stiegmann Goff band).90 After applying
a band, endoscope needed to be removed, reloaded and reinserted for each variceal ligation. To
overcome the trauma of repeated insertion of endoscope a plastic over-tube has been used to
facilitate repeated esophageal intubation in adults and older children. However, the use of the over-
tube itself has caused many complications including perforation. Subsequently multiband ligator
device has been introduced to overcome this difficulty.93 These new multiband ligator devices
allow the application of up to 10 bands during a single intubation. Both adult and pediatric studies
have demonstrated the speed and convenience of this technique compared with single-bander
technique. The technique is to ligate all visible variceal columns starting at gastroesophageal
junction in a spiral manner in a proximal direction within the lower 5-6 cm of the esophagus.
Although the first report of using band ligation in children came in the same year of its
introduction by Hall et al94 in 1988, but first pediatric series of 22 cases was published in 1996 by
Price et al.95 Subsequently there are a few small series of EVL in children, comprising of 6 to 15
cases only. In all these reports single band ligator was used. McKiernan et al96 from UK in 2002
reported for the first time the use of multiband ligator in children. Pediatric experience with this
technique remains limited but early experience is encouraging. Overall, varices were ablated in
81% of cases with a median of three treatment sessions compared to five sessions needed for
400 children treated with EST in published reports.97–102 Rebleeding rate was significantly higher
in EST group (25% vs 4%), as was the rate of major complications (25% vs 4%).
Therefore, even in children, EVL is safe and effective method of treatment of esophageal
varices. Compared to EST, it eradicates varices faster with fewer sessions and complications are
252 also less. Hence it should be the fist line of treatment in children with variceal bleeding. Despite
this clear benefit of EVL, when used alone, there is a higher risk of recurrence of varices as it is
Portal Hypertension
difficult to ligate smaller varices and perforators and paraesophageal collaterals remain patent
after EVL.103 To overcome this problem, recently it has been recommended to use low dose EST
after EVL to take the advantages of both methods.104
Balloon Tamponade
Balloon tamponade (BT) should be used in massive bleeding as a temporary bridge until definitive
treatment can be instituted. This procedure aims to stop the variceal bleeding by occluding the
gastroesophageal blood flow by compressing the esophageal varices and/or upper gastric veins
with air inflated balloons. Triple lumen pediatric Sangstaken Blackmore tube is used in children
where two lumens are for gastric and esophageal balloons and third lumen is for aspiration of
gastric contents. This technique is difficult to practice in children and is associated with severe
complications like aspiration pneumonia, rupture of esophagus, etc. particularly in the hands of
inexperienced persons. Efficacywise balloon tamponade and PT are equal but PT is non-invasive.
Surgical Management of EHPVO

Endoscopic sclerotherapy or banding is an effective primary treatment modality of bleeding
esophageal varices in majority of children with reasonable liver function. However, surgical
intervention is indicated for the following cases:
• Uncontrolled bleeding from the esophageal varices not responding to atleast 2 sessions of
banding or sclerotherapy
• Bleeding gastric or ectopic varices not responding to endoscopic treatment
• Hypersplenism or massive symptomatic splenomegaly
• Lack of access to endosopic treatment or rare blood group
• Symptomatic biliary obstruction due to choledocal varices
• Selected patients with Budd-Chiari syndrome
Surgical management depends on the site of block in the splenoportal venous system. Since
portal vein is the commonest site of block, splenic vein is available for anastomosis with the
low pressure systemic veins. In patients with isolated splenic vein thrombosis causing gastric
varices without esophageal varices, splenectomy cures the disease. However, in rare patients
with thrombosis of entire splenoportal axis shunt surgery is not possible.
Prevention of Variceal Bleeding

It can be categorized into (i) primary prophylaxis, i.e. prevention of initial bleeding and (ii)
secondary prophylaxis, i.e. prevention of recurrent bleeding.
Pharmacologic Therapy for Primary Prophylaxis105

a. Prevention of formation or growth of varices
Porto-systemic collaterals may develop before the appearance of varices, and can be
diagnosed non-invasively. However, their clinical importance is uncertain. HVPG is predictive
of varices formation.
All cirrhotic patients should be screened for vairces at diagnosis. There is no indication at this 253
time, to treat patients to prevent formation of varices.
b. Prevention of the first bleeding episode

Patients with small varices could be treated with nonzelsective beta-blockers to prevent
progression of varices and bleeding but further studies, especially as relates to prevention
of bleeding, are required before a formal recommendation can be made. Patients with small
varices with red wall signs or of child C class have an increased risk of bleeding and may
benefit from treatment.
Non-selective beta-blockers (propranolol and nadolol) and long acting nitrates have been
studied extensively to prevent initial bleeding form varices.75,77,78 By b1 blockade they reduce the
cardiac output and thereby lower the portal pressure and by b2 blocking action they produce
splanchnic vasoconstriction due to unopposed α adrenergic activity and therapy reduce portal
pressure and variceal flow. With β blocker therapy 25% reduction of sleeping pulse rate from
baseline is often used as a surrogate marker of efficacy.
Data available from 11 trials that compared β blockers with placebo in prevention of 1st
variceal bleeding. Propranolol was used in 8 of these trials and nadolol showed reduction in the
frequency of 1st bleed.77 In an earlier study where data of individual patients from four β blocker
trials were pooled and analyzed found that death from bleeding was reduced significantly by
β blocker therapy. It was also demonstrated that, although β blockers were most effective in
patients who had well-preserved liver function, they also had a protective effect in subjects with
ascites advanced liver disease.
A cost-effectiveness analysis in 1997, on the other hand, supports the use of propranolol as
the most effective therapy for primary prophylaxis of variceal bleeding in cirrhotic patients who
have esophageal varices regardless of their Child’s class and the risks of bleeding.80
Nadolol has a long half life and can be given in once daily dosage. It does not have expensive
hepatic metabolism.
It seems appropriate to perform screening endoscopy in patients with cirrhosis or
extrahepatic portal hypertension which presents at times with unexplained splenomegaly
without any episode of variceal bleeding to look for moderate to large varices and to treat them
prophylactically with β blockers.
Endoscopic Treatment
Prophylactic endoscopic band ligation (EVL) is useful in preventing variceal bleeding in patients
with medium and large esophageal varices.
EVL is more effective than non-selective betablockers in preventing 1st variceal bleeding
but does not improve survival. However, long term benefits of EVL are uncertain because of
short duration of follow up. EVL should be offered to patients with medium/large varices and
contraindications or intolerance to β-blockers.
Secondary Prophylaxis or Prevention of Recurrent Hemorrhage

Secondary prophylaxis should start as soon as possible preferably from day 6 of the index
bleeding episode.
β-blockers, band ligation or preferably both should be used for prevention of recurrent
254 bleeding in patients with cirrhosis and portal hypertension.
On patients with EHPVO, endoscopic therapy is effective for secondary prophylaxis. There is
yet insufficient evidence to recommended β-blockers.
Portal Hypertension
In those patients with a persistent documented prothrombotic state, anticoagulant therapy

can be considered.
There is insufficient evidence in favor of interventional therapy such as TIPS and local
thromolysis. Decompressive surgery should only be considered for patients with failure of
endscopic therapy. For portal biliopathy with obstructive jaundice, endoscopic therapy is
recommended. In case of failure shunt surgery may be considered.
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20
Metabolic Liver
Diseases
Ashish Bavdekar
Liver plays a central role in innumerable metabolic processes in the body, and hence is affected
primarily or secondarily in many inborn errors of metabolism—these are referred to as metabolic
liver disorders (MLDs). Understandably, MLDs are commoner in pediatric patients (than adults),
and are responsible for a great deal of liver related mortality and morbidity in children. They now
account for upto 40% of all chronic liver admissions to large medical centers in India. This is mainly
due to a dramatic decline of ICC in recent years and improved awareness of MLDs in the medical
community. However, lack of diagnostic facilities, even in most advanced liver referral centers is
a major impediment to early and accurate diagnosis. Lysosomal enzyme estimations, mutational
analyses, urine gas chromatography and other diagnostic tools are only now becoming available
in a few centers.
Early diagnosis is the key to the outcome as specific therapies are now available in some
of these disorders. A strong index of suspicion is the key to making a definitive diagnosis. The
commonest MLDs seen in India are Wilson’s disease, glycogen storage diseases (GSD) and
galactosemia and these are discussed in this chapter. Some disorders like GSD usually present
later in childhood and are relatively more easier to diagnose due to their characteristic clinical
features. However, Wilson’s disease has a more varied presentation. Management of MLDs is
always a challenge. Not all of them have a specific therapy but in some like Wilson’s disease, GSDs,
galactosemia, etc. medical therapy or dietary manipulations are important to sustain a normal life.
WILSON’S DISEASE
Wilson’s disease (WD) is an inborn error of metabolism characterized by toxic accumulation
of copper (Cu) in liver, brain, cornea and other tissues. It occurs worldwide with an estimated
prevalence of 1 in 30-50,000 and is one of the leading causes of chronic liver disease (CLD) in
Indian children.1 During the last 20 years, over 1,000 children with CLD have been assessed at
the Liver Unit, KEM Hospital, Pune. The copper associated disorder, Indian childhood cirrhosis
was the commonest CLD in the 1980s, but is now a rarity. WD is now commonly seen at our
center and till date 124 children with WD have been diagnosed. Selected clinical information of
these children with regard to type of presentation, age and outcome is presented in Table 20.1.
Younger the age at presentation, more acute were the manifestations and higher the mortality,
except in asymptomatic sibs.
Table 20.1: Clinical presentation and outcome of 124 children with Wilson’s disease seen at the
Pediatric Liver Unit, KEM Hospital, Pune (1980–2000)
Presentation No. Age at diagnosis Duration of illness Survival
(years)* (months)* n (%)
Neurological 28 11.5 (2.5) 16.5 (17.38) 23 (82)
Chronic liver disease 43 8.2 (3.4) 8.1 (15.45) 26 (61)
Acute hepatitis 13 7.1 (2.6) 1.1 (0.40) 5 (39)
Fulminant hepatic failure 11 5.96 (2.1) 0.7 (0.24) 1 (9)
Others (Rickets, hemolysis) 10 10.8 (3.4) 14.0 (19.57) 9 (90)
Asymptomatic sibs 19 7.3 (4.1) — 15 (79)
* Values expressed as sean (SD)
DIAGNOSTIC CHALLENGES
Variable Clinical Features
The age of presentation can vary from 4 to 60 years. The manifestations are more likely to be
hepatic in early childhood and neurological in adolescents; however, other forms of presentation
are also seen. Early symptoms can often be vague and non-specific such as lethargy, anorexia,
abdominal pain and epistaxis. The spectrum of hepatic manifestations include all forms of chronic
or acute liver disease–asymptomatic hepatomegaly, chronic hepatitis, portal hypertension,
cirrhosis, acute “viral hepatitis” and sometimes in fulminant hepatic failure with high mortality.
Neurological abnormalities can be equally varied and include clumsiness, speech difficulties,
scholastic deterioration, behavior problems and occasionally convulsions as also choreoathetoid
and dystonic movements. Most of these patients have past or concurrent history of biochemical
evidence of liver disease. Due to the slow and non-specific evolution of neurological signs, it
sometimes takes as many as 1–2 years from onset of symptoms till a diagnosis of WD is made.
Other presentations are “osseomuscular” with bony deformities (knock knees) suggestive of
resistant rickets, acute or recurrent hemolysis, etc. With such diverse presenting features, the key
to diagnosis is a high index of suspicion.
No Single Diagnostic Test

Once suspected, it should be easy to confirm or exclude WD by appropriate tests of Cu
metabolism. However, no single test is diagnostic by itself, and a group of tests need to be done
in order to make the diagnosis. Interpretation of these tests is also not easy in many situations.
Serum ceruloplasmin is reduced in most patients with WD. However, 5–40% of WD may have
a normal ceruloplasmin.2,3 Radial immunodiffusion assays (as used in most laboratories) may
overestimate ceruloplasmin levels.4 Normal ceruloplasmin levels in WD may also be found in
hepatic inflammation, pregnancy or women on estrogen therapy. On the other hand, even a low
ceruloplasmin level is not diagnostic of WD as such values are also found in normal newborns,
severe malnutrition and protein losing states, acute liver failure of any etiology and 20% of
260 WD carriers. Ceruloplasmin is a good screening test but cannot be solely relied on to make a
diagnosis. Many physicians order a total serum Cu in suspected WD, but it offers minimal aid in
diagnosis. The levels may be low, normal or high in WD.
Metabolic Liver Diseases
In symptomatic patients with WD, the 24 hour urinary Cu excretion is more than 100 ug/day.
However, similar high values have also been documented in non-WD chronic hepatitis, Indian
childhood cirrhosis, chronic cholestatic liver disease, acute liver failure of any etiology and Cu
contaminated urine samples. Estimation of urinary Cu after a penicillamine challenge has been
suggested as a test to differentiate WD from other causes of raised urinary Cu.5 Similar high post-
penicillamine urinary Cu in children with acute hepatitis A infection has cast doubts on the value
of this test.6
A complete Kayser-Fleischer (KF) ring indicates long-standing disease and severe Cu
overload. In our series of 124 children, KF rings were present in 78% of children in whom they
could be evaluated—96% of neurological, 72% of hepatic and in 16% of asymptomatic WD.7
They are visible in some children as early as 5 years of age. This indicates the importance of KF
ring detection not only in neurological cases but also hepatic ones.
Histochemical staining for Cu is unreliable (< 10% of WD patients), due to the insensitivity
of staining techniques to pick up cytosolic Cu, and the heterogeneity of Cu deposition within
the liver.8 Hepatic copper is the single best predictive marker for WD and considered the gold
standard, with values usually above 250 µg/gm dry weight. Disorders like Indian childhood
cirrhosis, chronic cholestatic disorders also give rise to high hepatic coppers but can be clinically
differentiated from WD. There have been occasional reports of WD with normal hepatic copper,
but these are extremely uncommon and may reflect sampling errors.
ROLE OF GENETIC STUDIES

Mutational Analysis
Direct genetic diagnosis is difficult because of the occurrence of more than 200 mutations, each
of which is rare. Most patients are compound heterozygotes (carry two different mutations).
In Austria where a single mutation His1069Gln is present in 60% of WD patients, mutational
diagnosis would be helpful in screening family members of an index patient homozygous
for this mutation.9 However, in India, identification of common prevalent mutations is still
underway. Some mutations identified in some of our WD children are R778Q, 3146delC, C271X,
Gl101R and Il102T. His1070Gln was not found in any of the 47 WD children we have studied so
far (unpublished data).
Haplotype Analysis
There are a number of microsatellite markers around the WD gene which show linkage
disequilibrium. Some of these have been used for haplotype analyses. This is of use in
determining the disease status of asymptomatic sibs of index WD children. This can only
be carried if at least one parent (preferably both) and the index child is available.
What is the Diagnostic Approach?

In a neurological setting, diagnosis of WD is easier, as a KF ring would be positive in almost all
cases and along with either a low ceruloplasmin or high urinary copper, would be diagnostic. 261
In liver disease, diagnosis can be more complex. WD is strongly suggested by any two of the
following—low ceruloplasmin, high urinary copper, presence of KF rings, and confirmed by a
high hepatic Cu. If a liver biopsy is not possible due to coagulopathy, but other investigations
are suggestive of WD, chelation therapy can be started immediately. Liver biopsy must then be
done at the earliest opportunity, as hepatic Cu may remain elevated despite years of therapy and
clinical improvement.10
WD presenting as acute liver failure often presents a major diagnostic problem. A low Cp or
raised urinary Cu will not be discriminatory between WD and other causes of acute liver failure
and a liver biopsy may not be possible because of coagulopathy. In such situations, parameters
suggesting WD are (i) low Hb due to hemolysis, (ii) large increase in bilirubin (>6 times normal)
with small increase in transaminases (<4 times normal). AST raised significantly more than ALT,
(iii) low alkaline phosphatase, (iv) increased serum total and free Cu and (v) low Cp in siblings.11-13
THERAPEUTIC CHALLENGES
Diet
WD cannot be prevented or controlled by a low Cu diet alone. However, it is advisable to avoid
high Cu containing foods like organ meats (liver), chocolates, nuts, dry fruits and importantly, Cu
and brass vessels for water or cooking.
Drugs
Continuous lifelong drug therapy is essential in the management of WD. Treatment entails two
aspects: (i) Initial therapy: Aim of which is to reduce the Cu to sub-toxic threshold. This phase
usually takes 4 to 6 months (as indicated by urinary Cu < 500 µg/day, and non-Cp Cu < 25 µg/dl).
Various groups recommend D-Penicillamine (DP), Trientine or Zinc as initial therapy.14,15 Ammonium
Tetrathiomolybdate is also being used as initial therapy of choice in neurological WD,16 (ii) Maintenance
therapy: The objective of this phase of therapy is to maintain a slightly negative Cu balance so as
to prevent Cu accumulation and toxicity. DP and trientine have been traditionally used for this
phase for long periods. Zinc, in view of its low cost and low toxicity, is of promise for maintenance
therapy especially in asymptomatic sibs. At our center we use D-Penicillamine as initial therapy
and continue it lifelong unless the child develops side-effects, in which case we switch over to
Trientine, if financially affordable.
D-Penicillamine (DP)
This drug acts by reductive chelation (reduces protein bound Cu, binds and mobilises it and
excretes it in the urine). A large cupriuresis (2 to 5 mg) is seen in the initial months of therapy,
falling to 0.1–0.5 mg of Cu in maintenance period. Although a powerful chelator, and despite
having a vast experience in using DP, it has fallen into disrepute due to it’s many adverse effects,
common ones being depression of blood counts, neurological deterioration in 20% of cases17
(Table 20.2). Half of the patients who worsen never recover to their pre-penicillamine baseline,
probably because hepatic Cu mobilized by DP further elevates brain Cu. Smaller initiating doses
of DP to produce a cupriuresis of say 1–2 mg/day may prevent this neurological deterioration.
262
Table 20.2: Drug therapy of Wilson’s disease

Drug and cost per Dose Common toxicity Monitoring for side effects
month
1. D-Penicillamine Starting 10 mg/kg/day Fever, rash, proteinuria, Complete blood and
(` 1500) increase to 20–30 mg/ Thrombocytopenia, bone platelet counts, urine
kg/day in 2 to 3 divided marrow depression, analysis before therapy,
doses 1 hour before proteinuria, worsening of weekly during the first one
meals neurological symptoms, month, monthly in the first
autoimmune conditions, year and yearly thereafter
others
2. Trientine 25 mg/kg/day in 3 Gastritis, sideroblastic As above
(` 10,000) divided doses 1 hour anemia, aplastic anemia
before meals
3. Zinc (` 200) 25–50 mg of elemental Gastritis, biochemical
zinc. 3 times daily, 1 pancreatitis, possible
hour before meals immune dysfunction
4. Ammonium 120 mg/day in 6 Anemia, bone Complete blood counts
tetrathiomolybdate divided doses marrow depression, liver function tests, BUL,
(not available for hepatotoxicity creatinine, urine analysis
routine use) weekly
Trientine
This is an alternative chelating agent especially for children intolerant to DP. The mechanism
of action of trientine is similar to that of DP. Whether it is a weaker chelator than DP is
controversial.18-20 For some time now, Trientine has been used as an alternative drug in children
not tolerating DP. However, recently it is increasingly being used as a first line drug instead of DP,
with good avoid efficacy and fewer side effects.
Zinc (Zn)
Zinc has been used as acetate, sulphate or gluconate salts. Acetate salts are preferred due
to lesser incidence of gastric discomfort. Zn acts by inducing intestinal cell metallothionein,
which binds Cu, Zn and cadmium to form mercaptides. The metallothionein bound Cu is held
in the intestinal cells till it is sloughed out. Zinc also induces metallothionein in hepatocytes
and protects against Cu toxicity. Unlike DP and trientine, Zn acts by increasing the fecal
excretion of Cu. However, Zn is slow acting and takes much longer to achieve a negative
Cu balance, and hence is effectively used as maintenance therapy especially because of
its low cost and low toxicity.
Ammonium Tetrathiomolybdate (TM)

The anti-Cu action is two-fold (i) in the GI tract TM forms complexes with Cu and other proteins
which are not absorbed. But unlike zinc, TM acts immediately and acts throughout the GI
tract and (ii) TM forms complexes with Cu and albumin in blood rendering the complexed Cu 263
unavailable for cellular uptake and further toxicity. Preliminary results with TM suggest that it is
an extremely avoid efficacies drug in the initial therapy of neurological therapy with protection
of neurological function. It is also being studied in hepatic Wilson’s disease. However, it is not yet
available for routine clinical use.
Liver Transplant
Liver transplant is the treatment of choice in children with acute liver failure or decompensated
cirrhosis unresponsive to medical therapy. Liver transplants corrects the metabolic defect and
the transplanted children do not require any anti-Cu medications. One year survival ranges from
79 to 87%.21 In Wilsonion FHF, a prognostic index has been derived to select suitable patients for
liver transplantation.22
Management of Sibs of WD
All sibs carry a 25% chance of having WD. Hence, they should undergo a detailed clinical
examination, slit-lamp examination for KF ring, liver function tests, serum ceruloplasmin
and a 24 hour urinary Cu determination. If these are normal the child is unlikely to have WD
This screening should be done initially at 3 to 5 years and repeated again at 15 years. If any
abnormality is detected then a liver biopsy for hepatic Cu is necessary.23 As such, genetic linkage
studies (haplotype analysis) are of great promise because the disease/normal/carrier status of
sibs can be detected at birth or even earlier in antenatal period. The treatment of asymptomatic
sibs is identical to that recommended for children receiving maintenance therapy viz. zinc, DP
or trientine.
Outcome of Wilson’s Disease

Maintenance therapy is necessarily life long. Despite initiation and maintenance of adequate Cu
chelation therapy, the outcome is unpredictable. The types of outcome seen are:
i. Rapid and complete improvement especially of hepatic symptoms with reversal of
parenchymal lesions including early cirrhosis.
ii. Initial deterioration particularly of neurological symptoms with eventual improvement but
with residual handicap (speech, handwriting).
ii. Relentless deterioration and death inspite of therapy as in fulminant hepatic failure. Patients
with advanced cirrhosis and its complications may also succumb after prolonged survival.
iv. The best outcome is seen in asymptomatic siblings of index WD cases. If diagnosed early,
these children have the best chance of normal health and longevity provided they take
regular therapy.
Glycogen Storage Disease

Glycogen storage diseases (GSDs) are a heterogenous group of distinct entities classified on the
basis of specific enzyme defects in various
steps of glycogen synthesis or breakdown. Table 20.3: Classification of glycogen storage diseases
These result in the various clinical pheno- Primary organ involved Types
types. GSDs are broadly classified depending Liver I, IIIb, IV, VI, IX
264 on the main tissue involved (Table 20.3). All Muscle V, VII
GSDs except for some forms of type VI (X- Mixed II, IIIa
linked are autosomal recessive. Only the
hepatic forms of GSD will be considered here. Enzyme analyses is not available in most centers in
India and hence typing is done on clinical presentation and histological picture.
GSD Type I
Glucose 6 phosphatase deficiency is the most severe form of hepatic GSD and results in
defective gluconeogenesis. Patients usually present in infancy with doll-like facies, truncal
obesity, massive hepatomegaly (fat and glycogen deposition), nephromegaly, failure to
thrive, hypoglycemia (seizures) and lactic acidosis after short fasting intervals. Diagnosis
may be delayed in breastfed babies, since frequent feeding prevents hypoglycemia. Serum
triglycerides, cholesterol and uric acid are moderately elevated. 24 The kidneys are enlarged
on ultrasound due to increased glycogen content. Liver biopsy shows markedly increased
fat and glycogen without fibrosis. Hepatic enzyme activity assay from a fresh liver biopsy is
diagnostic but is available only in few centers. The gene has been localized to chromosome
17q21 and many mutations have been described. Strict dietary therapy leads to normal
growth and development, but these children are at risk of developing osteoporosis, renal
disease and hepatic adenomas after the second decade.25
GSD Type III

GSD III is due to abnormal activity of debrancher enzyme–amylo-1-6 glucosidase. Type IIIa is
usually associated with progressive (cardio) myopathy while IIIb has mainly liver disease. In
infancy presentation is similar to GSD I, but milder, with hepatomegaly and hypoglycemia.
With increasing age, hepatomegaly decreases and fasting hypoglycemia improves.26 However,
in some, hepatic fibrosis and cirrhosis may occur. Progressive muscle weakness and wasting
occurs in adulthood. Fasting hypoglycemia is milder, lactic acidosis is post-prandial and
hypertriglyceridemia is less marked. Transaminases are raised reflecting hepatocellular and
muscle damage. Liver histology demonstrates increased glycogen storage with fibrosis without
steatosis. Measurement of enzyme activity in leukocytes, fibroblasts or liver/muscle tissue yields
a definite diagnosis. The gene has been localized to chromosome 1p21. This appears to be the
commonest hepatic GSD in India.
GSD Type IV
This rare disorder occurs due to a defect in glycogen branching enzyme and results in the
formation of an abnormal glycogen which resembles amylopectin, a plant starch. The abnormally
structured glycogen probably acts as a foreign body in the hepatic architecture, to cause
progressive cirrhosis. Patients are normal at birth. Hepatomegaly and failure to thrive are seen
in infancy. Cirrhosis and splenomegaly soon become manifest and death from liver cell failure
usually occur before 3 years of age. Liver biopsy shows cirrhosis and abnormal glycogen which is
diastase resistant. Enzyme defect is demonstrated in muscle, leukocytes or cultured fibroblasts.
The gene is localized to chromosome 3p12.
GSD Types VI and IX 265

These GSDs are due to defect in the hepatic phosphorylase system. There is a marked
heterogeneity in their clinical presentation. They usually present in the pre-school age with
asymptomatic hepatomegaly. Symptomatic hypoglycemia is rare, but can occur after 10–12 hour
fast. Mild hyperlipidemia, ketosis and transaminitis may occur. The disorders are fairly benign
and long-term outlook for growth and liver function are good.
Management of GSD
Treatment of GSD I is primarily aimed at preventing hypoglycemia by frequent daytime feeding
with slowly resorbed carbohydrates (starch, glucose polymers) and continuous nocturnal feeding.
Lactose, fructose and sucrose is avoided or limited. In older children uncooked cornstarch every
4–6 hours may be adequate to maintain normoglycemia.27 GSD III, VI and IX requires similar but
less stringent dietary therapy. Liver transplant is the only available option for GSD IV but may not
prevent progression of extrahepatic disease.28
Galactosemia
Three inherited disorders of galactose metabolism resulting in galactosemia have been
identified–deficiency of enzymes galactokinase, galactose-1-phosphate uridyltransferase (GALT)
or uridinediphosphate galactose-4-epimerase. All these enzyme deficiencies are inherited in
autosomal recessive fashion. Classic galactosemia, caused by deficiency of GALT is by far the
commonest (1 in 50,000 live births, USA) and discussed in detail below.
GALT Deficiency
An infant with any of the following presentations should be investigated for galactosemia—
jaundice, hepatomegaly, hypoglycemia, cirrhosis, ascites, liver failure, coagulopathy, cataracts
E. coli sepsis. The commonest presenting feature is failure to thrive associated with vomiting or
diarrhea starting within a few days of milk ingestion. Most patients manifest jaundice during
the first week’s of life. This jaundice is quite often unconjugated to start with and becoming
conjugated later on. Ultimately, most children will exhibit evidence of liver disease—
hepatomegaly, abnormal liver function tests, coagulopathy, cirrhosis, ascites, etc. This may be
associated with severe hemolysis. Untreated the liver disease may progress to cirrhosis. Cataracts
have been observed within a few days after birth. Disease can be rapidly fatal if milk feeding’s
are continued. Later manifestations include mental retardation, hyperactivity, renal Fanconi’s
syndrome, hypergonadotropic hypogonadism in females, speech and language deficits.29
Pathogenesis
Cataracts occur as a result of the accumulation of galactitol in the lens. The other manifestations
appear to result from intracellular accumulation of gal-1-P.30 Whereas galactose can freely enter
cells, gal-1-P in cells exits only slowly. This is shown by the fact that when a galactose-free diet is
started in a galactosemia patient, RBC levels fall only slowly. Also, cord blood RBC gal-1-P levels
are high in the infant of a galactosemic mother. Even with strict dietary control, RBC gal-1-P
levels remain supranormal. This may be due to de novo galactose synthesis, from galactoside
breakdown, or from cryptic sources of galactose in the diet. It remains unclear whether
266 tissue damage results from gal-1-P itself, from a further metabolite such as galactosamine, or
from UDPgal depletion. The most severe hepatic disturbance in galactosemia occurs during
septicemia in infants. In animal models, both galactosamine and lipopolysaccharide are required
to produce acute liver failure, emphasising the importance of sepsis in galactosemic infants. The
gene is mapped to 9p13. There are many allelic mutations of which the commonest are Q188R
and S135L.31
Investigations
The laboratory findings besides those of deranged liver function include elevated blood
galactose and galactose-1-phosphate, hypoglycemia, hypergalactosuria, hyperchloremic
metabolic acidosis, albuminuria and hyperaminoaciduria. Urine reducing substances have
been the traditional screening test, but may produce both false negatives, if the baby is not
being fed, and false positives in babies with other liver disorders. The recommended diagnostic
method is RBC gal-1-PUT, for which the Buetler screening test is widely used. A kit method is also
available at relatively low cost. It is important to note that RBC gal-1-PUT will be falsely normal
if the baby has been transfused. In that case diagnosis may have to be presumptive until the
test is repeated after 6 weeks. Liver biopsy reveals fatty infiltration, pseudoacini formation and
eventual macronodular cirrhosis.
Treatment
Elimination of dietary galactose is the only available treatment. In neonates and small infants, the
preparations used are lactose free casein hydrolysates or soyabean milks. Casein hydrolysates may
contain small amounts of lactose, but this does not affect the therapeutic efficacy. As children
grow, it is important to be aware of sources of galactose in foods other than milk, e.g. fruits,
vegetables, etc. Complete elimination of galactose from diet is desired goal, but this may be
difficult to accomplish. Some have advocated that diets be restricted to less than 125 mg galactose
daily. Within 72 hours of elimination of galactose from diet, all acute symptoms show marked
improvement and hepatic dysfunction begins to normalize by end of one week. Cataracts also
regress substantially with elimination of galactose from diet. There is no evidence that the diet
can be relaxed in childhood or adolescents. Periodic measurement of galactose-1–phosphate in
red blood cells is useful in ensuring dietary compliance. Newly diagnosed patients have markedly
elevated values which may take upto several months of dietary therapy to decline to those of
patients with well treated disease. A level less than 4 mg% is considered acceptable for an infant
or child who is on diet treatment.
Long-term Management
The patients diagnosed to have galactosemia should be in constant touch with their primary
care physician throughout life and their management plan requires multidisciplinary approach
involving ophthalmologist, neurologist endocrinologist, dietician, speech and occupational
therapist.
Prenatal Diagnosis
Prenatal diagnosis is available by either measurement of enzyme activity or specific DNA testing 267
in fetal tissue obtained by amniocentesis or chorionic villous biopsy. Pregnant women at risk
for having a child with galactosemia are prescribed galactose restricted diet with vitamin C
supplementation.
Galactokinase Deficiency
This does not lead to mental retardation or liver disease but cataract formation is common.
Treatment involves lifelong galactose elimination.
Epimerase Deficiency
Two forms of epimerase deficiency has been described. One is benign, involves only red and
white blood cells without deranged metabolism in other tissues and is detected by screening
procedures that assay red cell galactose-1-phosphate. The other form having generalized
epimerase deficiency presents with clinical features resembling transferase deficiency and
responds to restriction of dietary galactose. In this condition, some dietary galactose is necessary,
since the exogenous sugar is required for the formation of uridine diphosphate galactose which
is essential in various metabolic processes.
REFERENCES
1. Pandit AN, Bavdekar AR, Bhave SA. Wilson’s disease. Indian J Pediatr. 2002;69:785–91.
2. Steindl P, Ferenci P, Dienes HP et al. Wilson’s disease in patients presenting with liver disease: A
diagnostic challenge. Gastroenterology. 1997;113:212–8.
3. Sternlieb I. Diagnosis of Wilson’s disease. Gastroenterology. 1978;74:787–9.
4. Sokol RJ, Narkewicz MR. Copper and iron storage disorders. In Suchy SJ, Sokol RJ, Balistreri WF, (Eds):
Liver disease in children, 2nd edn. Philadelphia: Lippincott Williams & Wilkins. 2001;595–640.
5. DaCosta CM, Baldwin D, Portman B, Lolin Y, Mowat AP, Mieli-Vergani G. Value of urinary copper excretion
after penicillamine challenge in the diagnosis of Wilson’s disease. Hepatology. 1992;15:609–15.
6. Gregorio GV, Mieli-Vergani G. Urinary copper excretion after penicillamine challenge in children with
prolonged hepatitis A infection. Hepatology. 1993;18:706–7.
7. Bavdekar AR. Wilson’s disease–A diagnostic dilemma. Indian J. Gastroenterol. 2003;22:2–3.
8. Pilloni L, Lecca S, Van Eyken P et al. Value of histochemical stains for copper in the diagnosis of Wilson’
disease. Histopathology. 1998;33:28–33.
9. Ferenci P. Wilson’s Disease. Indian J. Gastroenterol. 2001;20:S1;C71–C78.
10. Marecek Z, Feldman G. Effect of long-term treatment with penicillamine on the copper content of liver
in patients with Wilson’s disease. Acta Hepatol Gastroenterol. 1975;22:292–6.
11. McCullough AJ, Fleming CR, Thistle JL et al. Diagnosis of Wilson’s disease presenting as fulminant
hepatic failure. Gastroenterology. 1983;84:161–7.
12. Berman DH, Leventhal RI, Gavaler JS et al. Clinical differentiation of fulminant Wilsonian hepatitis from
other causes of hepatic failure. Gastroenterology 1991;100:1129–34.
13. Sallie R, Katsiyiannakis RI, Baldwin D et al. Failure of simple biochemical indices to reliably differentiate
fulminant Wilson’s Disease from other causes of fulminant hepatic failure. Hepatology. 1992;16:1206.
14. Roberts EA, Schilsky ML. A Practice Guideline on Wilson Disease. Hepatology. 2003;37:1475–92.
15. Hoogenraad TU, Van Hattum J, Van den Hamer CJ. Management of Wilson’s disease with zinc sulphate.
Experience in a series of 27 patients. J Neurol Sci. 1987;77:137–46.
16. Brewer GJ, Johnson V, Dick RD, Kluin KJ, Fink JK, Brunberg JA. Treatment of Wilson disease with
ammonium tetrathiomolybdate. Arch Neurol. 1996;53:1017–25.
17. Brewer GJ, Terry CA, Aisen AM, Hill GM. Worsening of neurological syndrome upon initial treatment of
268 Wilson’s Disease patients with penicillamine. Arch Neuro. 1987;44:490.
18. Walshe JM. Copper chelation in patients with Wilson’s disease. A comparison of penicillamine and
triethylenete tramine dihydrochloride. Quat J Med. 1973;42:441–52.
19. Sarkar B, Sass-Kortsak A, Clarke R, Laurie SH, Wei P. A comparative study of in vitro and in vivo interaction
of D-penicillamine and triethylene-tetramine with copper. Proc R Soc Med. 1977;70(Suppl 3):13–18.
20. Borthwick TR, Benson GD, Schugar HJ. Copper chelating agents. A comparison of cupruretic responses
to various tetramines and D-penicillamine. J Lab Clin Med. 1980;95:575–80.
21. Eghtesad B, Nezakatgoo N, Geraci LC et al. Liver transplantation for Wilson’s disease: a single-center
experience. Liver Transpl Surg. 1999;5:467–74.
22. Nazer H, Ede RJ, Mowat AP, Williams R. Wilson’s disease. Clinical presentation and use of prognostic
index. Gut. 1986;27:1377–81.
23. Walshe JM. Diagnosis and treatment of pre-symptomatic Wilson’s disease: Lancet. 1988;2:435–7.
24. Green HL, Swift LL, Knapp HR. Hyperlipidema and fatly and composition in patients treated for type Ia
GSD J Pediatr. 1991;119:398–403.
25. Smit GPA, Fernandes J, Leonard JV et al. The long-term outcome of patients with glycogen storage
diseases. J Inherit Metab Dis. 1990;13:411–8.
26. Fernandes J, Leonard JV, Moses SW Glycogen Storage disease: reccomendations for treatment. Eur J
Pediatr. 1988;147:226–8.
27. Chen YT, Cornblath M, Sidbury JB. Cornstarch therapy in Type I glycogen storage disease. N Engl J Med.
1984;310;170–5.
28. Dhawan A, Tan KC, Portman B, Mowat AP. Glycogenosis type IV: liver transplant at 12 years. Arch Dis
Child. 1994;71:450–1.
29. Ghishan FK, Ballew MP. Inborn errors of carbohydrate metabolism. In. Suchy SJ, Sokol RJ, Balistreri WF
(Eds): Liver disease in children, 2nd edn. Philadelphia: Lippincott Williams and Wilkins. 2001;565–72.
30. Holten JB. Galactosemia. Pathogenesis and treatment. J Inherit Metab Dis. 1996;19:3–7.
31. http://www.ich.bris.ac.uk/galtdb.
269
21
Ascites in Children
VS Sankaranarayanan
INTRODUCTION
Ascites is of Greek derivation (‘askos’), which means a ‘bag or sack’, and the word is a noun.
Ascites describes the abnormal and pathologic fluid accumulation within the peritoneal cavity.
The precise incidence of ascites in children is unknown but it is the most common clinical
manifestation of hepatic decompensation in patients with chronic liver disease especially,
cirrhosis.
ETIOLOGY
The etiologic spectrum of presentation of ascites comprises of fetal/neonatal ascites, ascites of
hepatic, renal, cardiac, malignant, biliary, pancreatic and miscellaneous causes.
FETAL ASCITES
The frequently encountered causes for fetal ascites are fetal malformations (especially
genitourinary tract abnormalities) (syndromic or non-syndromic), intrauterine infections,
intestinal perforation, genetic and chromosomal disorders (trisomy 21) or idiopathic. Active
syphilis, parvovirus infection, CMI virus in association with polyhydramnios are some of the
intrauterine infections. Zelop C et al1 observed no fetal hydrops in the above fetal ascites.1 Fetuses
that have isolated ascites are likely to have a good outcome with resolution of ascites antenatally.
The diagnostic protocol includes fetal blood sampling for karyotyping, serology and serial
prenatal ultrasound examinations to determine the etiology and pregnancy outcome assessment
by autopsy report or by a chart report.2
NEONATAL ASCITES
Ascites in neonates can present with or without hydrops as isolated or with peritonitis
1. With hydrops
a. Renal: Congenital nephrotic syndrome and posterior urethral valve
b. Cardiac: Congenital heart block, hypoplastic left heart syndrome, Ebstein’s anomaly
c. Genetic/Chromosomal: Down’s syndrome, Turner’s syndrome, Edward’s syndrome and
Patau’s syndrome
Ascites in Children
d. Hematologic: Homozygous α thalassemia and isoimmune hemolytic anemia

e. Infective: TORCH infections, Congenital active syphilis, HIV
f. Gastrointestinal and hepatic: Intestinal atresia, Congenital hemochromatosis
g. Malignant: Wilms’ tumor and Neuroblastoma
2. Without hydrops
a. Isolated (Chylous, Urinary, Biliary)
b. Peritonitis (Meconium, Bacterial).
Biliary Ascites
Biliary ascites3 in neonates is extremely rare and results from spontaneous perforation of the
bile duct, usually at the junction of the common bile duct and the cystic duct. Unexplained and
persistent jaundice with ascites will be the presentation in the newborn and USG abdomen and
hepatobiliary scintigraphy are diagnostic of neonatal ascites. Ascitic fluid will be bile stained and
treatment is surgical.
Chylous Ascites
Ascitic fluid is milky or creamy with a triglyceride content of more than 100 mg/dL.3 Chylous
ascites is rare but mostly seen in neonates without any known cause (idiopathic) though
a congenital lymphatic anomaly is thought to be the underlying cause.4 Lymphatic duct
obstruction or disruption of lymphatic ducts of its abdominal portion due to trauma resulting in
rupture of major lymph channel, tuberculosis, filariasis, nephrotic syndrome, cirrhosis or external
compression of the lymphatics due to malrotation, hernia, tumor (lymphoma), etc. can cause
chylous ascites.5
In pseudochylous ascites, the ascitic fluid color is similar to true chylous ascites (creamish)
resulting from the degeneration of inflammatory products (leukocytes/tumor cells) and may
lead to the confusion with chylous fluid; hence, the need for differentiating true chylous ascites
from pseudochylous ascites (Table 21.1).
Signs and symptoms of chylous ascites are non-specific. Ultrasonography or CT scanning
may demonstrate the fluid and rule out underlying causes (e.g. Tumor or cyst). Abdominal
paracentesis is the gold standard test for chylous ascites with an elevated content of triglyceride
(>100 mg/dL) and predominance of lymphocytes. In chylous ascites, the serum ascites albumin
gradient (SAAG) is <1.1 gm/dL, ascitic fluid total protein (AFTP) is >2.5 gm/dL and ascitic fluid
triglycerides > serum (often >200 mg/dL).
Table 21.1: Difference between true chylous and pseudochylous ascites

True chylous ascites Pseudo chylous ascites
Sudan stain Positive (stained fat globules) Negative (Not stained)
Ether test Positive (becomes clear) Unchanged and remains turbid
Alkali test Negative (no change in color) Positive (Becomes clear because of dissolu-
tion of cellular protein 271
Management
Diet with low fat (MCT) and high protein recommended. TPN and bowel rest for 2 to 4 weeks
tried by some when initial conservative line fails. If surgically correctable cause is identified,
exploratory laparotomy or laparoscopy is necessary. Peritoneovenous shunt is attempted when
direct repair fails. Idiopathic neonatal chylous ascites is associated with high mortality rate.
TUBERCULOUS ASCITES
Incidence varies from 2 to 11% of all TB cases and in India it accounts for 0.08% of all hospital
admissions.5 HIV seropositivity prevalence in patients of abdominal tuberculosis is significantly
higher (16.6%) compared to pulmonary tuberculosis (6.9%).6 In children ascetic (69%) form or
peritoneal tuberculosis is common among abdominal tuberculosis. History of contact with
tuberculosis among family members is often positive. The usual clinical presentation includes
abdominal distension, pain and ascites, fever, weight loss, anorexia , pallor or features of subacute
obstruction (intestinal form).7,8
Diagnosis of Tuberculous Ascites

Ascitic fluid for demonstration of AFB and culture of ascitic fluid for tuberculosis are the gold
standard tests, but microbiological proof may not be always possible because abdominal
tuberculosis is a paucibacillary disease.
Plain X-ray abdomen may show ground glass appearance with pooling of intestinal gas
shadows in the center of abdomen or subacute obstructive features and dilated jejunal or ileal
loops with multiple fluid levels and relative paucity of gas in colon and sometimes a mottled
calcification in the mesenteric lymph nodes in abdominal tuberculosis with tuberculous ascites.
Barium enema (80–85%) or barium meal shows radiological signs such as contracted or
pulled up and defective caecum with obtuse ileocaecal angle and gaping or stenotic ileocaecal
valve, strictures in small bowel, decreased transit time with malabsorption pattern of intestines
(Positive Moulage sign).9
Abdominal ultrasound will reveal thickened mesentery (15 mm or more) with increased
echogenicity (fat) and mesenteric lymph adenopathy (>15 mm), dilated small bowel loops and
ascites and regression of above findings on follow-up after ATT.10
CT scan abdomen findings include high density or loculated ascites, mesenteric adenopathy
and bowel, peritoneal and mesenteric thickening. The nodal masses are of low-density with
rim enhancement.11 Though CT scan findings of abdominal tuberculosis are non-specific, CT
abdomen can help in differentiating abdominal.
Cytology and biochemistry of ascitic fluid in abdominal tuberculosis will reveal a clear or
straw-colored exudates and at times an opalescent/turbid or haemorrhagic or even chylous fluid
with glucose concentration of less than 30 mg/dL, protein content >2.5 Gm/L and SAAG of <1.1
g/dL12 with the cell count mostly lymphocytes >100/mm.3 AFB smear and cultures are positive
in only 3–20% of cases with a better yield rate (83% positive rate) in one liter of ascitic fluid
concentrated by centrifugation.11
272 Ascitic fluid adenosine deaminase activity is an advance in the diagnosis of tuberculous
ascites. The sensitivity is 100% and specificity is around 95–97% at cut off value of more
than 33 u/v.13
Ascites in Children
Ileo-colonoscopy in abdominal tuberculosis presenting as ascites and abnormal barium

enema will reveal segmental narrowing, ulceration, nodularity and deformed ileocaecal valve
with shortening of ascending colon. Biopsy and histological examination, AFB stain, PCR and
culture of these lesions especially from ulcer edges helps definitive and rapid diagnosis in more
than 50% of cases.14
Laparoscopy with direct biopsy is the gold standard for diagnosing tuberculous peritonitis
in more than 85–95% of children and laparoscopic findings are presence of ascites which can
be used for cell counts, biochemical and microbiological tests. Naked eye findings include
military nodules, veil like adhesions and omental thickening, mesenteric adenitis, firm
hepatosplenomegaly and help peritoneal biopsy which is preferred over blind percutaneous
peritoneal biopsy.15 Laparoscopy in abdominal tuberculosis helps in ruling out other causes
of ascites like lymphoma16 and adhesiolysis. In the presence of equivocal diagnostic studies,
laparotomy to establish the diagnosis of abdominal tuberculosis or a therapeutic trial of
antituberculous drugs is recommended when patients are sick and from endemic areas on the
basis of strong clinical suspicion and supportive evidences like contact history of tuberculosis
and multi-system or disseminated tuberculosis because in peritoneal tuberculosis, effective
antituberculosis therapy is the mainstay of treatment.
Clinical Features of Ascites

Symptoms
Onset of ascites may be acute or insidious over the course of few months. Abdominal distension
is gradually increasing and the patient may experience dyspnea and increase in body weight. If
ascites is mild, child can also be asymptomatic.
Signs
General physical examination especially in advanced decompensated cirrhosis reveal a
‘Spiderman’ like appearance in view of generalized muscle wasting with thin limbs and
protuberant abdomen. Peripheral limb edema, scrotal edema, increase in body weight are
noticed as fluid accumulates.
Physical Examination Findings in Ascites

Earliest and the most sensitive sign of ascites is dullness on percussion in16 the flanks if approximately
1500 ml or more of fluid is present. In gross ascites umbilicus becomes everted and transverse
and the edges are edematous with a peu-de-orange appearance and pitting on pressure. Fluid
thrill or wave is felt when a large amount of ascites is present (more than 1000 ml) which is under
tension. Positive fluid thrill is a most specific but late sign of gross and tense ascites. Absence of
shifting dullness or of fluid thrill or both does not exclude a diagnosis of ascites as the above two
signs can be elicited in only about half the cases of ascites.17
Puddle or Lawson’s sign is invariably positive when there is a minimal amount 200 ml of
ascitic fluid; being the most dependent part of the abdomen to the flanks and to note a change
273
in the intensity and character of the percussion note (Positive Puddle sign).17
Secondary Effects
Pleural effusion if present, often right sided in some of the cirrhotic patients is due to defects in
the diaphragm as shown by introducing I131 albumin or air into the ascites and examining the
pleural space afterwards.18 Spontaneous bacterial empyema may be a complication.19 Edema is
often noticed in gross ascites due to gross hypoproteinemia (serum albumin is often less than 2.5
Gm/dL) or functional inferior vena caval block.
Diagnosis of Ascites
The gold standard test for presence of ascites is aspiration of ascitic fluid and the etiology is
possible by laboratory analysis after clinical diagnosis.20
Naked Eye Examination of the Ascitic Fluid

Color: Straw colored and transparent in cirrhotics. Milky in chylous ascites. Bloody in trauma,
malignancy, tuberculous peritonitis, pancreatitis, and perforated viscous and bleeding diathesis.
Cell count: Normal: less than 250 white cells per ml predominantly lymphocytes.
Fluid with ≥ 250 polymorphonuclear neutrophils/mm3 (and a predominance of PMNS) is
presumed infected and can lead to neutrocytic ascites.
For bloody ascites, one PMN is subtracted from the cell count for every 250 RBCs to correct
PMNS that enter fluid with the blood.
Cytology: Malignant cells are demonstrated in 50 to 80% of malignant ascites. Culture sample
should be sent before starting antibiotics when infective cause is suspected.
Total protein: Ascitic fluid total protein measurement assists in determining the cause of ascites
and the risk of ascitic fluid infection (values <1.0 gm/dL indicate a high risk).20 SAAG (Serum
Ascites Albumin Gradient) is approximately 97% accurate in differentiating portal hypertensive
ascites (SAAG >1.1 gm/dL) from other non-portal hypertensive causes (SAAG <1.1 gm/dL).21
Serum Ascites Albumin Gradient (SAAG)22

Both serum albumin and ascitic fluid albumin are required simultaneously on the same day.
SAAG = Serum albumin—ascitic fluid albumin.
The gradient is calculated by subtraction and it is not a ratio.
SAAG correlates directly with portal pressure and hence, the terms transudate and exudate,
are now replaced by high albumin gradient and low albumin gradient because of higher accuracy
rate of SAAG (97%) in detecting portal hypertension (Table 21.2).22
Radiology and Imaging Studies in Ascites

X-ray of the chest in ascites: Elevated diaphragm, pleural effusions (especially right sided in
cirrhosis liver). Cardiomegaly, tuberculous lesions in the chest, mediastinal adenitis, calcifications,
minor fissure opacifications, etc. should be noted.12
274
Ascites in Children
Table 21.2: Ascitic fluid total protein and SAAG value regarding the cause of ascites
High protein High SAAG Constrictive pericarditis, BCS, Ch.CCF
(AFTP > 2.5 gm/dL) (≥ 1.1 gm/dL)
High protein Low SAAG Tuberculous (WBC > 500/mm3 Lymphocyte)
Pancreatic (Ascitic fluid amylase > serum often >1000 u/L)
Chylous ascites (ascitic triglycerides > 200 mg/L)
Peritoneal carcinomatosis (cytology for malignant cells)
Low protein High SAAG Cirrhotic ascites
Low protein Low SAAG Nephrotic syndrome
Plain X-ray of the abdomen9

Non-specific findings:
Ground glass (Diffuse haziness of abdomen)
Pooling of bowel loops to the center and separation of air-filled bowel loops, bulging of the
flanks of abdomen, indistinct margins of psoas, liver and spleen.
Specific findings:
Lateral liver edge is medially displaced from the thoracoabdominal wall resulting in obliteration
of hepatic angle (Hellmer sign). Medial displacement of caecum and ascending colon and lateral
displacement of properitoneal fat line.
Symmetric densities on both sides of the bladder due to fluid accumulating in the rectovesical
pouch and paravesical fossa (Dog-ear or Micky mouse sign).
Abdominal Ultrasound in Ascites

Realtime ultrasonography is very sensitive and easiest in ascites and can be used to detect
minimal ascites (50–100 ml).
Confirms presence of portal hypertension when spleen is >12 cm maximum dimension
with tortuous splenic vein and patent or blocked portal vein or portal vein cavernoma. To
detect ovarian or mesenteric pathology including mesenteric cyst and lymphadenopathy. USG
abdomen may suggest that the ascites may be infected, loculated, hemorrhagic (coarse internal
echoes), multiple septa (tuberculous, pseudomyxoma peritonei).10
CT Scan of Abdomen11
Both ultrasound and CT scans show a space around the liver caused by even small amounts
of ascitic fluid as little as 100 ml. In addition, CT abdomen helps to detect irregular cirrhotic
small liver, splenomegaly, neoplasia, cystic or mass lesions arising from hepatic, adrenal, splenic,
lymph nodes and masses arising from the gut, ovary or pancreas (Likely to be malignant ascites).
MRI abdomen can also pick up ascites and vascular lesions by MR angiography and MRCP can
easily recognize choledochal cyst or even biliary atresia with ascitic fluid collection but not often
required in most of the patients. 275
Peritoneal biopsy in peritoneal disease is minimally invasive and is almost replaced by laparoscopy.
It helps in inspection of peritoneum, biopsy of the peritoneal lesions, aspiration and collection of
ascitic fluid even when there is minimal fluid for analysis, evaluation and biopsy of liver disease,
lymph nodes and pelvic organs. It is still a very useful diagnostic tool in widespread abdominal
tuberculosis in detecting peritoneal, liver, lymph nodal and pelvic lesions and helps adhesiolysis
and biopsy of the targeted lesions under direct vision.15
Management of Ascites
Appropriate management of ascites depends on the initial clinical assessment, diagnostic work
up including analysis of ascitic fluid and exact cause for the ascites in a given patient.
Management of High SAAG Ascites23,24

These patients have portal hypertension and often associated with decompensated liver
function due to underlying cirrhosis.
Principles of Treatment of Cirrhotic Ascites

Diet: The mainstay of successful treatment of cirrhotic ascites is Sodium restriction24
Daily intake of sodium can be half a teaspoon (2–3 gm/day) or 2–3 mEq/kg/day in older
children and adolescents but in smaller children and infants sodium intake should not be
>1 gm/day (quarter teaspoon daily). Salt containing snacks and common salt on the table is
to be avoided like pickles, chips, sauces, sea fish, etc. Addition of sweet to foodstuffs will help
children to overcome problems of salt restriction. One gram of table salt contains 43 mEq of
sodium and may result in retention of 200 ml of fluid and majority of cirrhotic patients excrete
less than 10 mEq of sodium in urine.
Low or no salt commercial preparations or white salt substitutes (containing sodium or
potassium) are discouraged.
Fluid restriction is needed when there is dilutional hyponatremia (Na < 120 mEq/L) due to
decreased renal free water clearance and retention of renal sodium where daily urinary sodium
excretion will be less than 78 mmol.
Indiscriminate fluid restriction in cirrhotics may result in hyponatremia. Sodium restriction
and not fluid restriction results in weight loss.25
Daily calories up to 150 comprising high carbohydrate 60%, protein (vegetable protein) 15%
and fat 30–35%.
Spicy fried basmati rice, chips, peppermints, partly cooked rice, drumstick or spicy food, etc.
can precipitate a variceal/gastropathy bleed and hence to be avoided.
Diuretic Therapy
Indications: Cirrhotic children with moderate to tense ascites.

No response to salt restricted diet as shown by increase in abdominal girth and fluid retention
276 and positive sodium balance.
Ascites in Children
Diuretics: Nearly 90% of patients respond to treatment while on salt restriction and diuretics
which are the mainstay of treatment for decompensated cirrhosis with ascites.
Spironolactone: Diuretic of choice for monotherapy of cirrhotic ascites (secondary
hyperaldosteronism).
Mode of action: Potassium sparing diuretic (retains potassium and hydrogen ions).
Aldosterone antagonist: Acts at Aldosterone-Sensitive-Sodium channels in the distal renal
tubules and collecting ducts and inhibits aldosterone secretion and is ideal for edema resulting
from excessive aldosterone excretion.26
Dose: 1–3 mg/kg/day in 3–4 divided doses.
Side effects: Hyperkalemia, hypochloremic acidosis, gynecomastia, impotence in men and
hypersensitivity reactions.
Disadvantages: Apart from the above-mentioned side effects, it is less potent natriuretic than
furosemide. It has prolonged half life (5 to 7 days) and delay in onset of action.
Maximum dose: 6 mg/kg/day after increasing the daily dose of spironolactone by 0.5 to 1 mg/kg.
Furosemide
Action: Loop diuretic. Acts at the ascending loop of Henle where maximum amount of sodium
filtered by the kidney is reabsorbed. Prevents reabsorption of sodium and water and deliver
them to the distal convoluted tubules by inhibiting the sodium-potassium-2 chloride binding
cotransport system and thereby increasing excretion of water.
Dose: 1–2 mg/kg/dose to a maximum dose of 6 mg/kg. Depending on the response step up
dose by 0.5 to 1 mg/kg/dose and is usually given in 2 doses in the morning and noon. Oral or
parenteral IM/IV dose should not exceed 1 mg/kg/6 hourly and to be given under supervision.
Side effects: Hyponatremia, hypokalemia, hyperuricemia, hyperglycemia, tinnitus, deafness, and
hypersensitivity reactions.
Disadvantages: Severe electrolyte depletion as mentioned earlier, hepatic encephalopathy and
hypovolemic shock, risk of anuria and aggravation of ascites in improperly selected patients.
Need for frequent monitoring of serum electrolytes, ABG, glucose, BUN, uric acid and calcium.
To note: In view of above-mentioned risks with furosemide therapy loop diuretics should be
ideally combined with spironolactone. Combination diuretic regimen is preferred in cirrhotic
ascites because of high efficacy, short hospitalization and maintenance of normokalemia.27
Evaluation of Diuretic Treatment Response and Complications
Serial monitoring is needed to determine the optimum diuretic doses and prevention of their
overt complications like azotemia, severe potassium and sodium abnormalities, intravascular 277
hypovolemia and hepatic encephalopathy which are limited to diuretic management of cirrhotic
ascites. Daily assessment of these patients by physical examination includes weight, abdominal
girth and ascitic fluid volume, peripheral edema, sensorium and consciousness of the patient
for encephalopathy, intake and output including 24-hour urine volume, 24-hour urine sodium
excretion value, and daily blood biochemistry value of sodium, potassium and creatinine.
Weight loss of 0.5 kg per day and a negative sodium balance is also an optimum criteria for
response to diuretic treatment. However, patients with peripheral edema can tolerate greater
rates of sodium excretion and more rapid weight loss.
Urinary sodium excretion of ≥ 78 mmol/day in any patient not responding (failing) to diuretic
treatment indicates dietary noncompliance as the cause.
Dose of diuretics increased once in 3 days of there has been no increase in urine sodium
excretion or decrease in body weight.
Ultimately the mainstay of treatment of cirrhotic ascites is based on sodium excretion and
diuretics and majority of patients respond to therapy.
Combination of spironolactone and furosemide along with satisfactory dietary compliance
of salt intake is most effective regimen for managing cirrhotic ascites, onset of encephalopathy,
anuria, clinical complications of diuretic therapy, serum sodium of <120 mmol/L despite fluid
restriction, serum creatinine > 2.0 mg/dL, azotemia and hypovolemia warrants discontinuation
of diuretics.
Refractory Ascites28
Definition: Ascites unresponsive to sodium restricted diet and high dose diuretic treatment is
considered as refractory.
Therapeutic Options for Patients with Refractory Ascites

1. Large volume paracentesis (LVP)
2. Transjugular intrahepatic portasystemic shunt (TIPS)
3. Peritoneovenous (Le Veen) shunt (PVS)
4. Liver transplantation.
Large Volume Paracentesis (LVP)

LVP is often used at least temporarily in patients with refractory ascites. It is safe and cost effective,
when combined with salt poor albumin at a dose of 6–8 gm/L of ascitic fluid removed.
Currently, a single large volume and total paracentesis (almost to tap the entire ascitic fluid
even up to 10 liters in adolescence and adults and > 5 L in children) over one hour period with
concomitant IV sodium—poor albumin 6 gm/L of fluid removed.29
Transjugular intrahepatic portosystemic shunt (TIPS) in post-cirrhotic refractory ascites.30 TIPS
reduces portocaval pressure gradient and significant improvement in ascites within 1–3 months
after TIPS. Second line choice in the treatment of refractory ascites and done in specialized
centers occasionally.
278 Peritoneovenous (Le Veen) Shunt (PVS)

PVS is a mechanical device aimed to allow the ascitic fluid to pass from the peritoneal cavity into
the general circulation via internal jugular vein and superior vena cava.
Ascites in Children
Liver Transplantation (LT) in Refractory Ascites31

LT is the only life saving modality of treatment for all end stage liver disease patients with
refractory ascites.
Prognosis
The prognosis is always grave after ascites develops in a patient with cirrhosis and in cases of
rapid accumulation of ascites following gastrointestinal hemorrhage. The prognosis of cirrhotics
with ascites depends on renal water excretion (diuresis after water load), mean arterial pressure,
Child-Pugh class and serum creatinine. and the underlying liver disorder. Proper monitoring and
follow-up of these patients, their cooperation and compliance, periodic counseling are necessary.
REFERENCES
1. Zelop C Benacerraf BR. The causes and natural history of fetal ascites. Prenat Diagn. 1994;10:941–6.
2. Schmider A, Henrich W, Reles A, Kjos s, Dudenhausen JW. Etiology and Prognosis of fetal ascites. Fetal
diagn ther. 2003;4:230–6.
3. Charles L Synder. Ascites. E medicine specialities. Continuing Education. 2004;2:3.
4. Aalami OO, Allen DB, Organ CH. Chylous ascites; a Collective review. Surgery. 2000;128:761.
5. Castro M, Balducci L, Cauffetti C, Lucidi V, Torre A, Bella S. Ascites as an unusual manifestation of chronic
granulomatous disease in childhood. Pediatr. Med Chir. 1992;3:317–9.
6. Rathi DM, Amarapurkar DN, Parikh S, et al. Impact of HIV infection on Abdominal tuberculosis in
western India J. Clin Gastroenteol. 1997;24:43.
7. Talwar BS, Talwar R, Chowdhary B, Prasa P. Abdominal tuberculosis in children: An Indian experience. J
Tropical Pediatr. 2000;46:368–70.
8. Thapa BR, Yacha SK, Mehta S. Abdominal tuberculosis, Indian Pediatr. 1991;28:1903–1100.
9. Kapoor VK, Chatterjee TK, Sharma LK. Radiology of abdominal tuberculosis. Aust Radiol. 1988;32:365–7.
10. Kedar RP Shah PP, Shinde TS, Malde HM. Sonographic findings in gastrointestinal and peritoneal
tuberculosis. Clin Radiol. 1994;49:24–7.
11. Sharma AK, Agarwal LD, Sharma CS, Sarin SK. Abdominal tuberculosis in children. Experience over a
decade. Indian Pediatr. 1993;30:1149–53.
12. Murshall JB, Vogele KA. Serum Ascites albumin difference in tuberculous peritonitis. AMJ Gastroenterol.
1988;83:59–61.
13. Dwivedi M, Mishra SP, Misra V, et al. Value of adenosine deaminase estimation in the diagnosis of
tuberculous ascites. AMJ Gastroenterol. 1990;85:13–5.
14. Bhargava DK, Kushwaha AK, Dasarathy S, Chopra P. Endoscopic diagnosis of segmental colonic
tuberculosis. Gastrointest Endosc. 1992,38:511–4.
15. Manohar A, Simjee AA, Petton gill KE. Symptoms and investigative findings in 145 patients with
tuberculous peritonitis diagnosed by peritoneoscopy and biopsy over a five-year period. GUT. 1990;31.
16. Bhargava DK, Shrinivas, Chopra P, et al. Peritoneal tuberculosis laparoscopic patterns and its diagnostic
accuracy. AMJ Gastroenterol. 1992;87:109–11.
17. Cattan EL, Benjamin SB, Kruff J E, et al. The accuracy of the physical exam in the diagnosis of suspected
ascites. JAMA 1982;247:1164.
18. Lazaridis KN, Frank JW, Krowka MJ, et al. Hepatic hydrothorax. Pathogenesis, diagnosis and
management. AM J Med. 1999;107:262.
19. Xiol X, Castellote J, Balellas C, et al. Spontaneous bacterial empyema in cirrhotic patients. Analysis of 11
cases, Hepatology. 1990;11:36.
20. Runyon BA. Paracentesis of ascitic fluid: A safe procedure. Arch Intern Med. 1986;146:2259.
21. Runyon BA. Low protein concentration ascitic fluid is predisposed to spontaneous bacterial peritonitis.
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Gastroenterology. 1986;91:1343.
22. Runyan BA, Montano AA, Akrividis EA, et al. The serum ascites albumin gradient is superior to the
exudate transudate concept in the differential diagnosis of ascites: ANN Intern Med. 1992;117:215–20.
23. Mathur P, Oberoi A, Arora NK. Management of ascites in children with chronic liver disease. Indian J
Practical Pediatrics. 2002:4(4): 339:7–15.
24. Ranyon BA, Care of patients with ascites. N Engl J Med. 1994;330(5):337–41.
25. A Drogue HJ,Madias NE. Hyponatremia.N Engl J Med. 2000;342:1581.
26. Surgaila J,Barrtie W, Walker S.Spironolactone pharmacokinetics and pharmacodynamics in cirrhosis
with ascites. Gastroenterology. 1992;102:168.
27. Runyon BA, Management of adult patients with ascites caused by cirrhosis. Hepatology. 1998;27:264–
72.
28. Arroyo V, Gines P, Gerbes AL,et al. Definition and diagnostic criteria of refractory ascites and hepatorenal
syndrome in cirrhosis. Hepatology. 1996;23:164.
29. Moore KP,Wong F,Gines P, et al.The management of ascites in cirrhosis:Report on the consensus
conference of the international ascites club. Hepatology. 2003;38: 258–66.
30. Rossle M, Ochs A, Gulberg V,et al. Acomparison of paracetesis and transjugular intrahepatic
portosystemic shunting in patients with ascites.N Engl J Med. 2000; 342:1701.
31. Baker A, Dhavan A, Heaton N. Who needs a liver transplant? (New disease specific indications) Arch.
Dischild. 1998;79(5): 460–4.
280
22
Liver Transplantation in
Children
Smita Malhotra, Akshay Kapoor, Subash Gupta, Anupam Sibal
INTRODUCTION
Pediatric liver transplant (LT) is now an established therapy. Refinement in surgical techniques,
improvements in anesthesia, perioperative care and access to newer immunosuppressant drugs,
have resulted in improved survival, with current 1 year and 5 years survival rates greater than
90% and 85% respectively.1 With increasing experience, LT is now offered to a growing number
of children less than 1 year of age and weighing less than 10 kg,2 which previously was associated
with increased risk of graft loss.3 Recently presented data on graft survival in 52 children who
survived more than 20 years after liver transplantation was 87%, 80%, 77%, 73%, and 59% at 1, 5,
10, 15, and 20 years, respectively.4
The first successful pediatric LT in India was performed at Indraprastha Apollo Hospital in
1998 in New Delhi.5 Liver transplantation programs in India have developed over the last decade
and with increasing expertise in pediatric transplant surgery, pediatric hepatology and intensive
care, outcomes have improved.
Indications
The commonest indication for pediatric LT in the world and in India is extrahepatic biliary atresia
(EHBA) followed by acute liver failure (ALF).6 The indications are summarized in Table 22.1.
Acute Liver Failure (ALF)

LT is the only definitive treatment for ALF. Several prognostic scoring systems have been devised
to predict mortality and to identify those requiring early LT. These include King’s College Hospital
(KCH) criteria,7 MELD score, APACHE II, and Clichy criteria. The KCH criteria (Table 22.2) appear
to have a higher specificity than sensitivity for acetaminophen-induced ALF, while its negative
predictive value for non-acetaminophen-induced ALF is low.8
An INR >4 or factor V concentration of <25% are the best available criteria for listing for ALF.9
Although INR and factor V concentration as prognostic markers are derived from small population
studies, to date they provide the best available indicators, predicting mortality without LT. A
study of ALF in the SPLIT database suggested that grade IV encephalopathy, age less than 1 year
and dialysis before transplantation were risk factors for poor outcomes.10
Table 22.1: Indications for pediatric liver transplantation

Indications Metabolic (primary hepatic) Hepatocellular
Cholestatic
Biliary atresia Alpha-1-antitrypsin deficiency* Acute and subacute hepatic failure
Biliary hypoplasia (Alagille) Tyrosinemia Autoimmune liver disease (Type I & II)
Nonsyndromic biliary paucity Wilson’s disease Chronic hepatitis B or C
Progressive familial Neonatal hemochromatosis Polycystic liver disease
intrahepatic cholestasis
Giant cell hepatitis/neonatal Glycogen storage disease type I, III, IV
hepatitis of unknown etiology Cystic fibrosis*
Metabolic (Primary nonhepatic)
Crigler-Najjar-syndrome Type I
Ornithine transcarbamylase (OTC)
deficiency
Maple syrup urine disease (MSUD)
Familial hypercholesterolemia
Methylmalonic acidemia
Propionic acidemia
Citrin deficiency
Hyperoxaluria (combined liver and
kidney transplant)
Atypical HUS (combined liver and
kidney transplant)
Non-resectable hepatic tumors
Hepatoblastoma
Hepatocellular carcinoma
*Uncommon in India
Table 22.2: King’s College criteria for LT in acute liver failure
Acetaminophen poisoning Other causes of FHF

Arterial pH <7.3 PT >100s/INR >6.5
or the following three factors: or three of the following:
Prothrombin time >100 s/ INR >6.5 Age <10 years or >40
S. creatinine >3.5 mg/dl Non-A, non-B hepatitis or drug induced disease
Encephalopathy grade III or IV Duration of jaundice >7 days before encephalopathy
INR > 3.5
S. bilirubin >17.6 mg/dl
End Stage Chronic Liver Failure

As the natural history of biliary atresia is well known, patients with a failed Kasai procedure
282 should be referred to a transplant center as soon as it is clear that the operation has failed. Failure
of jaundice to clear 3 months post-transplant is an indication for referral to a pediatric transplant
unit. In other forms of chronic liver failure, precise prediction of need for liver replacement is
Liver Transplantation in Children
difficult, as children with cirrhosis and portal hypertension can remain stable for months to
years. The best guide is a fall in albumin, prolongation of prothrombin time, and persistent rise
in bilirubin (Table 22.3).
The Pediatric End Stage Liver Disease (PELD) Scoring System

PELD score was developed to predict death in children while waiting for transplant or the need
for transfer to ICU, so as to prioritize donor liver allocation to children.11
It is calculated as 10*(0.480*In (bilirubin) + 1.857*In (INR) – 0.687*In (albumin) + 0.436 (if
patient <1 year) + 0.667 (if growth failure < 2 SD).
The PELD system confers special status and protection to pediatric organs and recipients but
does not accurately predict outcomes post-transplantation. PELD has limited relevance in the
Indian scenario as the vast majority of transplants are living related.
LT for Metabolic Disorders

LT in metabolic disorders is reported to have excellent outcomes. LT is indicated for chronic
Wilson’s disease (WD) for decompensated cirrhosis refractory to medical therapy and for patients
who present in ALF. A special prognostic score is available for children with WD and a score of 11 or
more indicates high mortality, with 93% sensitivity and 98% specificity.12 In MSUD the branched
chain amino acid levels normalize within hours of surgery.13 Neonatal hemochromatosis (NH) is
the most common cause of acute liver failure. Even though use of IVIG therapy in NH is evolving as
a definitive therapy, NH is the most common indication for LT in the neonatal period.14 Combined
liver and kidney transplant (CLKT) is now the procedure of choice for patients with primary
hyperoxaluria suffering from renal failure. CLKT has also offered new hope in patients with atypical
HUS. In tyrosinemia, LT is indicated only if there is failure of NTBC therapy, presentation as ALF,
hepatic dysplasia or hepatocellular carcinoma. In progressive familial intrahepatic cholestasis
(PFIC), decision to transplant is taken if there is established cirrhosis or intractable itching despite
maximal medical therapy or surgical diversion. In glycogen storage disorders type I, III and IV, LT
is indicated if there is poor metabolic control, cirrhosis decompensated or if multiple adenomas
develop. In cystic fibrosis LT, should be performed when the lung function is still preserved
(FEV1 > 50%). Expanding indications of LT have revolutionized the management of metabolic
disorders. In several metabolic conditions which do not result in liver failure, LT prevents the
extrahepatic complications such as kernicterus in Criggler Najjar syndrome, cardiac disease in
hypercholesterolemia and metabolic decompensation (urea cycle defects, organic acidemias).
Table 22.3: Indications for LT in end stage chronic liver failure

Clinical parameters Laboratory parameters
1. Recurrent variceal bleeding 1. Prothrombin ratio (INR) > 1. 4
2. Refractory ascites 2. Indirect bilirubin >6 mg/dl
3. Intractable pruritis 3. Albumin <3.5 mg/dl
4. Growth retardation 4. Cholesterol <100 mg/d 283
5. Unacceptable quality of life
There is a growing understanding on when not to transplant. Mitochondrial cytopathies,

Niemann-Pick types A and B, organic acidemias with severe mental handicap and Crigler-Najjar
disease with kernicterus are contraindications to transplantation (Table 22.4).
PRE-TRANSPLANT EVALUATION
Aims of assessment for LT are to confirm the diagnosis and severity of disease, to define the
patient’s general medical status, to determine eligibility and priority for transplant and to arrange
interim supportive care.
Pre-transplant Assessment Guidelines for Recipient

Nutritional status
Height, weight, triceps skinfold, mid-arm muscle area
Identification of hepatic complications
Ascites, varices
Cardiac assessment
ECG, echo (contrast ECHO for HPS), chest X-ray
Respiratory function
Oxygen saturation, ventilation perfusion scan, lung function tests (in cystic fibrosis)
Neurological and developmental assessment
EEG, Development Assessment Scale for Indian Infants (DASII), Development Profile (DP-2)
Renal function
Urea, creatinine, electrolytes
Urinary protein/creatinine ratio
Cr EDTA (if available)
Table 22.4: Contraindications to transplant
Absolute contraindications
Extrahepatic malignancy considered incurable by standard oncologic criteria
Sepsis
Uncontrolled systemic infection
Acquired immunodeficiency syndrome
Extrahepatic disease (incurable)
Irreversible massive brain injury
Uncorrectable congenital anomalies affecting major organs
Relative contraindications
Malignancy that is considered cured or curable by standard oncologic criteria
Sepsis
Treatable infection
Human immunodeficiency virus
284 Extrahepatic disease

Progressive extrahepatic disease
Substance abuse
Dental assessment
Radiology
Wrist X-ray for bone age and rickets
MRI/angiography (if portal vein anatomy equivocal)
Serology
Cytomegalovirus
Epstein-Barr virus
Varicella zoster
Herpes simplex
Hepatitis A, B, C
HIV
Measles
Hematology
Full blood count, platelets, blood group.
Pre-transplant Medical Management

Pre-transplant management includes nutritional rehabilitation, immunization and medical
management of end stage liver disease.
Nutritional Rehabilitation
Majority (70% at our center) of the children coming for LT are malnourished.15 Nutritional
rehabilitation is necessary as optimizing nutrition improves postsurgical outcomes. Lower
height z-score has been associated with longer post-transplant hospital stays and increased
hospitalization costs. Nutritional support also provides the opportunity to lessen the technical
difficulties seen in very small infants. Modular feeds allowing protein (3 gm/kg), carbohydrate
(using glucose polymers) and fat (50% medium and 50% long chain triglycerides) contents
to provide calories upto 150 kcal/kg along with fat soluble vitamins supplementation is
recommended.
Immunization
It is essential to make sure that routine immunizations are complete. Children undergoing LT
should be immunized against measles, mumps, rubella, varicella, diphtheria, tetanus, hemophilus
influenza type-B, pneumococcus, influenza, hepatitis A and B and polio. Vaccines should be
given at least one month before LT to ensure seroconversion. After LT, vaccination with killed
vaccines should be avoided in the first three months as these children are under high degree
of immunosuppression, which may result in inadequate seroconversion. Live vaccines should
be avoided. Parents and other siblings should be advised to have annual influenza vaccines and
pneumococcal vaccines should be repeated every five to six years.6
Management of Complications of ESLD

These include prevention and treatment of ascites, spontaneous bacterial peritonitis, hepatorenal 285
syndrome, esophageal varices, hepatic encephalopathy and pruritus. The use of extracorporeal
liver assist devices as a bridge to transplantation is not yet established.
Counseling
Counseling is a multi-disciplinary process involving the transplant surgeon, the hepatologist,
intensivist and a social worker. The family should be educated about the procedure, outcome
and complications of the surgery and long-term immunosuppression. Children over 18 months
may be prepared for the stressful procedure through innovative play therapy and books.
Transplant Surgery
The original surgery has undergone several modifications, but in general there are three phases:
1. Native liver dissection
2. Anhepatic phase: In this phase the placement of the graft begins but the patient is functionally
between livers. The vascular anastomoses are performed during this period
3. Revascularization of the graft
Reduction hepatectomy involves reducing the liver to transplantable portions comprising
of segments 5–8 (right lobe, predominantly used in adolescents and adults), 2, 3 (left lateral
segment) or 2, 3, 4 (left lobe) which by virtue of their independent vascular supply and venous
drainage can function as complete and independent hepatic units. The left lateral segment or
left lobe is most often used in pediatric LT.
TECHNICAL VARIANTS
Split-Liver Transplantation
Split-liver transplantation is an efficient transplant technique developed in response to donor
graft shortage involves dividing a deceased donor graft into a left lateral segment (segments
2, 3) and a right trisegment which can then be transplanted to a child and an adult.
Living Related Liver Transplantation

Living related liver transplantation (LRLT) has immensely benefited the pediatric population,
especially in our country, where there is limited availability of deceased donor grafts. This is a
procedure, in which a parent or a relative provides a part of their liver (commonly the left lateral
segment). The major advantages of LRLT over a cadaveric LT to the recipient are:
1. Elective procedure
2. Healthy donors
3. Short cold ischemia time which reduces graft non-function
4. Possible immunological advantage due to a related donor.
The donor must be a blood relative of the child and must be of a compatible blood group. All
donors undergo a comprehensive medical and psychological assessment. Optimum health of
the donor decreases post-transplant complications. A committee of several members appointed
by the government scrutinizes all living donors and recipients and gives the approval for surgery.
No organ transplant can be performed without prior approval of the authorization committee.
The objective of the committee is to ensure that living donor transplants are performed as per
286 Transplantation of Human Organs Act and Rules 1994 and subsequent amendments made there
under.
Monosegmental Liver Transplantation

In this technique the segment 2 alone is reduced from a lateral segment is possible for very small
infants.16
Auxiliary Partial Liver Transplantation

This is a novel type of liver transplantation (the graft is placed with the diseased native
liver in situ) that is performed where there is a possibility of native liver regeneration and
immunosuppression withdrawal as in acute liver failure. Careful, serial and meticulous follow
up with radiological screening and tapering of immunosuppression is required while the
transplanted liver shrinks and degenerates and the native liver regenerates.17
The Postoperative Course

Postoperative management is in the intensive care unit. The patient is monitored for early bile
production, acid-base balance and coagulation. If the new graft is functioning well the early
postoperative recovery may be straightforward, however, early-impaired graft function may
rapidly result in a hemodynamically unstable patient with severe metabolic disturbances and
multiorgan failure.
Retransplantation
Retransplantation in the pediatric liver population is not an uncommon event.18,19
Retransplantation can be classified as occurring early (<30 days) or late (>30 days) from the
original transplant. Early retransplantation is usually because of primary nonfunctioning (PNF)
of graft or hepatic artery thrombosis (HAT). Late retransplantation usually results from chronic
rejection or biliary complications. The list of complications is summarized in Table 22.5.
Immunosuppression
Apart from advances in surgical techniques, a huge contribution to successful LT is from the
ongoing development in immunosuppressive therapy. Optimal immunosuppression aims
prevention of rejection with least side effects and therefore demands a perfect balance of
Table 22.5: Complications of liver transplantation
Early complications Late complications
Primary graft non-function Infections
Acute rejection Varicella
Vascular thrombosis EBV
Sepsis HCV
Biliary leak, stricture Systemic fungal infections
GI complications: diarrhea, perforation Chronic rejection
Renal dysfunction
De novo hepatitis 287
Hypertension
treatment during the vulnerable state after transplantation. While the initial treatment regimen
of LT consisted of corticosteroids and azathioprine (AZT) with a graft survival of only 30%, the
introduction of calcineurin inhibitors in the 1980s and later tacrolimus (TAC), has revolutionized
transplant medicine with 1-year graft and patient survival rates as high as 90%.20 The drug
toxicities and doses are summarized in Tables 22.6 and 22.7 respectively.
The usual immunosuppressive regimen consists of TAC and prednisolone, with or without
AZT or mycophenolate mofetil (MMF). Although cyclosporin has been successfully used safely
and effectively in children, TAC based immunosuppression is preferred because it has been
associated with less acute rejection, less estimated corticosteroid-resistant acute rejection rates
and fewer cosmetic side effects such as hirsutism. It is also associated with better long-term
graft survival. There is no evidence for an increased risk of lymphoproliferative disease in children
treated with TAC.21 Long-term renal dysfunction may be reduced with the use of induction
immunosuppressants, such as daclizumab, a humanized antibody and basiliximab, a chimeric
antibody and with MMF or sirolimus in maintenance immunosuppression.22 The current protocol
at our center is TAC and MMF with prednisolone. Steroids are generally withdrawn 3 months
post-transplant.
Table 22.6: Immunosuppressant drug toxicities

Cyclosporin A Tacrolimus MMF Sirolimus
Nephrotoxicity Nephrotoxicity Cytopenias Hyperlipidemia
Neurotoxicity Neurotoxicity Gastrointestinal toxicity Gastrointestinal-toxicity
Hypertension Hypertension Cytopenias
Hyperlipidemia Hyperglycemia
Hirsutism Gastrointestinal toxicity
Table 22.7: Dosage and monitoring

Dosage* Monitoring
Cyclosporin A 5 mg/kg/dose twice daily Trough levels (C0)
2 hours post dose (C2)
Tacrolimus 0.15 mg/kg/dose (within first 12 Trough level
hours after abdominal closure), then
0.05 to 0.1 mg/kg/dose twice daily
per oral
Mycophenolate mofetil 15 mg/kg/dose twice daily or 600 Trough levels (C0)
mg/m2 twice daily 1 hour post dose (C1)
Sirolimus 15 mg/m2 once daily After 4 days of therapy, then C0 twice
weekly for 1st month, then weekly for
2nd month (target: 5–15 µg/L)
288
* recommended starting dose
NOVEL THERAPIES
Looking Beyond Immunosuppression: Tolerance
Tolerance (defined as the lack of an immune response to the foreign antigens expressed by an
organ allograft in the absence of ongoing immunosuppressive therapy) is being researched as
a means to eliminate the dependency on immunosuppressive agents and improve outcomes.
Experimental strategies like mixed allogenic chimerism, costimulation blockade and precondi-
tioning are presently being developed.23
Hepatocyte Transplantation
Hepatocyte transplantation is a potentially promising alternative to whole organ liver transplanta
tion, but use in humans is still limited due to the poor availability of cryopreserved cells, weak
initial cell engraftment, and lack of clinically safe procedures that can ensure a growth advantage
for the transplanted cells.24
Liver Assist Devices

Liver assist devices (LAD) are devices that remove the substances in failing liver till the recovery
of native liver and may serve as a bridge for LT. The available LADs can be grouped as biological
such as whole liver perfusion, liver cell transplantation, and bio-artificial liver support and non-
biological devices such as hemodialysis, charcoal hemoperfusion, selective plasma filtration,
plasma-exchange, hemodiadsorption, albumin dialysis and combination of both non-biological
and biological systems.25 Experience on the use of LAD in children is limited and restricted to
small series.
Life After Transplantation

Patients with growth failure secondary to liver disease resume growth with a general
improvement in lifestyle. They can attend school and participate in age related activities. The
majority of children resume normal growth within a year after liver transplant but in an analysis
of the SPLIT database more than 30% pediatric liver transplant recipients were less than the 10th
percentile for height at 24 months post-transplant.26 Renal dysfunction has been noted in 30%
long term survivors.27 Current immunosuppressant drugs are associated with an increased risk
for diabetes, dyslipidemia and obesity.28–30
Children who have received hepatic grafts enter puberty normally. Successful pregnancies
have been reported with both cyclosporin and tacrolimus immunosuppression. However,
pediatric liver transplant recipients from 1988–1992 who survived into adulthood were found
to have lower physical health related quality of life, measurable transplant related disability and
lower health utility two decades later and a significant percentage had psychological issues.31
Registries and Databases

Large, multi-institutional registry databases like the SPLIT registry are used to describe and
monitor trends in transplantation and planning clinical trials. In India published data is currently 289
available from individual centers conducting liver transplantation programs and there is an
urgent need to set up such a transplant registry.
Liver Transplantation in India

In the West, approximately 2–3 pediatric liver transplants per million population are performed
annually. At that rate, around 2-3000 children will need liver transplants in India every year. This
estimate is likely to be representative, since the incidence of EHBA (1/12,000 to 1/18,000), which
is the commonest indication for LT, is similar throughout the world.
Mehrotra et al32 report that 79% of babies with EHBA in their center from North India require
transplantation. Sixty one percent of older children with cirrhosis and 67% with FHF fulfill criteria
for liver transplantation. Biliary atresia was the most common indication, followed by metabolic
liver disease in a series of 28 children transplanted in South India.33
Selection of patients for transplantation requires consideration of not only medical criteria,
but also the socioeconomic and educational background of the family. This is of paramount
importance, because in addition to the initial expenditure, receiving a transplant also involves a
lifelong commitment on the part of the patient and family to spend on immunosuppression and
to adhere strictly to the postoperative care protocol including anti-infection precautions and
long-term medication. If a graft is lost due to poor patient compliance, it is a colossal waste of
efforts of the treating team, of the donor resources and the expenses incurred on the procedure.
The first successful pediatric liver transplant was carried out in November 1998 at our center.5
Fulminant hepatic failure is presently the most evolving indication even though biliary atresia
is still the commonest, followed by cryptogenic cirrhosis, PFIC and others. The first successful
transplant recipient from India is leading a normal life, attending regular school and has been
on follow up for 13 years. The first successful transplant for fulminant hepatic failure in India,
a transplant in the youngest child in India and the first successful transplant in a child with
Crigler-Najjar syndrome were reported from our center.34–36 With growing expertise, LT has also
been successful in small infants. Patient and graft survival of 100% at 11 months were reported
in our series of 5 children transplanted at weight below 7.5 kg.2 Successful transplants for MSUD,
hyperoxaluria. Factor VII have been reported by other centers. More than 200 pediatric liver
transplants have now been performed in India.
LT entails not only the initial expenditure of the procedure, but also a lifelong commitment of
a recurring expenditure of around ` 6000–8000 per month on immunosuppression. Although,
the cost of LT in India is less than one tenth of that in the West, this is at times prohibitive factor
for some families. Current concerns are now shifting from an initial aim of early post-transplant
survival to long term survival and quality of life. The other challenge is to improve the number
of cadaveric donations in our country. We will need to constantly work towards decreasing the
cost of transplantation which is currently ` 12–15 lakhs for children. With increasing acceptance
of LT amongst the medical community and the public at large there is now the potential for the
number of liver transplants to increase many fold so as to offer hope to the thousands of children
who suffer from liver failure.
SUMMARY
LT is now well established in India with the first recipient completing 13 years of normal life post-
290 transplantation. Graft and patient survival have continued to improve as a result of improvements
in medical, surgical, anesthetic management, organ availability and early identification and
treatment of postoperative complications. The utilization of living-related donors and split-liver

grafts has provided more organs for pediatric patients. Newer immunosuppression regimens,
including induction therapy, have had a significant impact on graft and patient survival. The
future entails identification of risk factors associated with long-term immunosuppression;
development of tolerance-inducing regimens and definition of biomarkers that reflect the
level of clinical immunosuppression. Other aspects of liver transplantation like development of
instruments for the measurement of health wellness; identification of risk factors that impede
growth and intellectual development before and after the surgery and transition of care for
adolescents will require attention in the future.
Key Messages
1. LT is now established therapy.
2. 1 year and 5 year post-transplant survival rates are above 90% and 85% respectively.
3. Success rate in children <1 year of age and those weighing <10 kg have improved.
4. EHBA and ALF are the most common indications for pediatric LT.
5. Expanding indications for LT include metabolic disorders and non-resectable tumors.
6. Auxiliary partial LT may be performed where there is possibility of native liver regeneration.
7. Hepatocyte transplant and liver assist devices are experimental.
8. Lifelong immunosuppression with regular monitoring of drug levels is required to prevent rejection
9. Majority of transplanted children are able to lead a normal life with resumption of growth and participation in age-
related activities.
10. LT is now well established in India.
11. The first successful liver recipient from India has now completed 13 years of a normal life.
REFERENCES
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2011;16(5):499–504.
2. Kaur S, Wadhwa N, Sibal A, Jerath N, Sasturkar S. Outcome of live donor liver transplantation in Indian
children with bodyweight <7.5 kg. Indian Pediatr. 2011;48(1):51–4.
3. Cacciarelli TV, Dvorchik I, Mazariegos GV, Gerber D, Jain AB, Fung JJ, et al. An analysis of pretransplantation
variables associated with long-term allograft outcome in pediatric liver transplant recipients receiving
primary tacrolimus (FK506) therapy. Transplantation. 1999;68(5):650–5.
4. Duffy JP, Kao K, Ko CY, Farmer DG, McDiarmid SV, Hong JC, et al. Long-term patient outcome and quality
of life after liver transplantation: analysis of 20-year survivors. Ann Surg. 2010;252(4):652–61.
5. Poonacha P, Sibal A, Soin AS, Rajashekar MR, Rajakumari DV. India’s first successful pediatric liver
transplant. Indian Pediatr. 2001;38(3):287–91.
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Index
Page numbers followed by f refer to figure and t refer to table
A B
Abdominal Bacterial overgrowth 63
computed tomography 153 Balantidium 116
examination in liver disease 172 Balloon tamponade 253
pain 163 Barium
tuberculosis 84 enema 90
ultrasound in ascites 275 meal series 103
Abetalipoproteinemia 67 Bile acids 185
Abnormal pancreaticobiliary junction 161f Biliary
Acquired immunodeficiency syndrome 65 ascites 271
Acute atresia 220
constipation in infants and children 131t Bilirubin 184
hepatitis 189 Bone disease 101
B infection 193f, 194t Bowel
liver failure 205t, 215t, 216t, 281 disimpaction 138
in children 202 training 129
pancreatitis 146, 149t, 151f, 153t Breastfeeding 97
simple constipation 135 Budd-Chiari syndrome 237
Alagelle syndrome 174f, 223
Albumin 183 C
Alkaline phosphatase 182 Carbamazepine 198
Aminotransferases 180 Categories of chronic pancreatitis 157
Ammonia 185 Causes of
Ammonium tetrathiomolybdate 263 acute pancreatitis 149t
Amylase chronic pancreatitis 159t
creatinine clearance ratio 152 isolated paroxysmal abdominal pain 26t
isoenzymes 151 pancreatitis in pediatric age group 148t
Antibiotics susceptibility testing 18 Celiac
Antimicrobial therapy in persistent diarrhea 51 disease 74, 75t
Antisecretory drugs in diarrhea 41 serology 77
Antituberculous drugs 198 Cerebral edema 210
Apley’s typical FRAP phenotype 22t Ceruloplasmin 186
Ascaris Characteristics of
detected on barium meal 113f helminths 111t
in common bile duct 113f intestinal parasites 111
Ascitic fluid total protein 275t Child with ICC 235f
Aspects of intestinal parasites 112t Childhood
Association of functional
chronic constipation 132 abdominal pain syndrome 24, 25
recurrent abdominal pain 15t defecation disorders 127t
Auscultation 177 pancreatitis 145
Auxiliary partial liver transplantation 287 Cholera diarrhea 38
Cholestasis in premature babies 228 E

Chronic
Empirical acid suppression 5
constipation 127t, 132t, 137
Encopresis 127
with impaction and encopresis 138
End stage chronic liver failure 282
constrictive pericarditis 238 Endocrine problems 171
diarrhea 54, 56, 56t, 60 Endoscopic
of neonatal onset 70 retrograde cholangiopancreatography 154
liver sclerotherapy 250
disease 233, 242, 244 ultrasonography 162f
disorders in children 231 criteria for chronic pancreatitis 163
failure 283t Endoscopy 4, 91
pancreatitis 157, 158 Endotherapy 250
Chylous ascites 271 Eosinophilic gastroenteropathy 18
Classification of Epimerase deficiency 268
abdominal TB 84 Esophageal
constipation 128t pH studies 4
glycogen storage diseases 264t TB 86
intestinal parasites 110, 110t Examination for endocrinologic abnormalities in
pH 240 liver disease 177
Clinical significance of liver span 177 Extraesophageal manifestations 8
Colonoscopic appearance of Extraintestinal manifestations 100
Crohn’s disease 102f
ulcerative colitis 102f F
Complications of Fecal
acute pancreatitis 150 incontinence 128
liver transplantation 287t soiling 128
Composition of reduced osmolarity ORS 37 Fetal ascites 270
Concept of chronic liver disease 231 Fluid and metabolic disturbances 209
Congenital immunodeficiency 64 Functional dyspepsia 24
Conn’s endoscopic classification of Furosemide 277
esophageal varices 245t
Constipation 126, 133, 136f G
in children 126 Galactokinase deficiency 268
Contrast enhanced computerized tomography 103 Galactosemia 222, 266
Conventional liver function tests 180t Gamma-glutamyl transpeptidase 183
Copper and Indian childhood cirrhosis 236 Gastric adenocarcinoma 17
Crohn’s disease 18, 89t, 98, 99, 104t Giant cell hepatitis 222
Cryptosporidium 115 Giardia 114
Cyclospora 117 Glycogen storage disease 264
Growth retardation 14
D Gynecomastia with visible veins in
Diagnosis of cirrhosis liver 176f
ascites 274
intestinal parasites 117 H
tuberculous ascites 272 Helicobacter pylori 11, 13t
Dietary management of persistent diarrhea 45 Hemodynamics of portal hypertension 247f
Diuretic therapy 276 Hepatic encephalopathy 204, 207t, 212
D-penicillamine 262 Hepatitis
Drug 262 A 190
induced hepatitis 195 B virus 192
294 therapy 33 E 194
Index
Hepatocyte transplantation 289 M

Hepatorenal syndrome 213t
Hereditary tyrosinemia 223 Magnetic resonance imaging scan 103
Hirschsprung’s disease 134f, 135t Malabsorption syndrome 54
Maldigestion 165
I Management of
acute
Idiopathic neonatal hepatitis 222
Ileocolonoscopy 101 hepatitis B 194
Immunization 285 variceal bleeding 247
Immunodeficiency 64 ascites 276
Immunological tests 92 cerebral edema in acute liver failure 211t
Immunosuppressant drug toxicities 288t chronic pancreatitis 166f
Immunosuppression 287 CLD 234
Indian childhood cirrhosis 235 coagulopathy 213t
Infection 97, 209, 240 fluid and metabolic complications
Inflammatory bowel disease in in acute liver failure 210t
children and adolescents 96 GSD 266
Inspection 172 hepatic encephalopathy 212t
Intestinal high SAAG ascites 276
lymphangiectasia 66 recurrent abdominal pain 32
parasites 121t sibs of WD 264
in children 109 variceal bleeding 247
Intrahepatic causes of pH 241, 242 Manifestations of chronic liver disease 232
Iron deficiency anemia 14 Metabolic liver diseases 259
Irregular Mild
PD 162f chronic constipation 138
ulcers 102f moderate disease 99
Irritable bowel syndrome 24 Moderate severe disease 99
Isospora 117 Modified Hosking’s classification
of gastric varices 245t
J Monosegmental liver transplantation 287
Jaundice 170
N
K Natural course of
King’s College criteria for LT HBV infection 192
in acute liver failure 282t hepatitis A infection in children 191f
Neonatal
L ascites 270
Lactate dehydrogenase 182 cholestasis 220t, 221f, 225t, 226t
Laparotomy 93 cholestatic jaundice 219
Large hemochromatosis 224
bowel diarrhea 57t liver failure 225t, 226t
volume paracentesis 278 Nervous system manifestations 170
Leuconychia in cirrhosis liver 174f Neurologic findings in liver disease 177
Liver Nitrovasodilators 248
assist devices 289 Nonalcoholic steatohepatitis 238
disease in childhood 169 Noncirrhotic portal fibrosis 242
function tests 179 Normal
transplantation 214, 279, 281, 290 bowel habits 128
Living related liver transplantation 286 intervening mucosa 102f
Loening-Baucke criteria of
pediatric constipation 127t
physiology of digestion 54 295
Novel therapies 289
Lymph nodal TB 86, 88 Nuclear scintigraphy 4
Nutritional Prothrombin time 183

rehabilitation 285 Protozoa 112
therapy 105 Pseudochylous ascites 271t
Psychological therapy 105
O Puborectalis muscle 130f
Oral
route 138 R
TB 86 Rectal and anal TB 87
ORS formulation 37 Recurrent abdominal pain 14
Refractory ascites 278
P Renal failure and hepatorenal syndrome 213
Palmar erythema 175f Retransplantation 287
Palpation 176 Ribonuclease 152
Pancreatic function tests 160, 160t
Pancreatitis 145 S
Paracetamol 196 Salvage therapy 18
Past illness in liver disease 171 Schemata for immediate intensive care 209
Pathogenesis of Sclerosant 251
acute pancreatitis 147f Segmental colonic TB 87
constipation 130 Sequential therapy 18
functional abdominal pain 27 Serology of acute hepatitis B infection 193
reflux disease 2 Serum
Pathophysiology of ascites albumin gradient 274
constipation 128 immunoreactive trypsin 152
IBD 98f Severe fulminant disease 100
reflux 2 Small bowel
Patterns of liver injury 179 barium meal 90
Paustian’s criteria 89 TB 87
Pediatric Somatostatin 249
end stage liver disease scoring system 283 Spectrum
liver transplantation 282t and prevalence of CLD in India 232
Peritoneal TB 86 of chronic liver disease 231t
Peritoneovenous shunt 278 Spider nevi 175f
Persistent diarrhea 43, 43t, 47t, 48t Split liver transplantation 286
Pharmacologic therapy for primary prophylaxis 253 Steps of management of acute bleeding 246
Phenobarbitone 198 Supportive management of neonatal cholestasis 228t
Phenytoin 197 Surgical management of acute pancreatitis 157
Physical signs in liver disease 172, 173t Symphysis pubis 130f
Physiology of defecation 129 Symptoms of liver disease 169
Plain
radiograph of abdomen 90 T
X-ray of abdomen 134f, 275 TB of vermiform appendix 87
Portal hypertension 240 Tests of
Positive physical examination signs in liver cell injury 180
children with liver disease 172 synthetic function 183
Prevention of Transmission of infection 12
hepatic encephalopathy 250 Transplant surgery 286
ICC 236 Treatment of
intestinal parasites 119 ICC 237
variceal bleeding 253 intestinal parasitic infections 119
Principles of treatment of cirrhotic ascites 276 persistent diarrhea 44f, 46f
296 Progressive familial intrahepatic Trichuris trichiura 110f
cholestasis 222, 223t Tropical sprue 62
Index
Tuberculous Veno-occlusive disease of liver 237

ascites 272 Venous outflow obstruction disorders 237
peritonitis 87 Viral hepatitis 189, 192
U W
Ulcerative colitis 99, 104t
Wilson’s disease 259, 260t, 263t, 264
Ultrasonography 90, 153
Ultrasound of abdomen 101
Z
Use of antibiotics 249
Zinc 263
V in diarrheal diseases 39
Valproic acid 197 supplementation in PD 49t
Vasopressin 248
297

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A Riyaz MD DCH DNB DM (Gastro) BR Thapa MD

Nitya Wadhwa Saravanapandian MD

Sutapa Ganguly VS Sankaranarayanan

17. Neonatal Cholestatic Jaundice 219

PREVALENCE AND NATURAL HISTORY

PATHOGENESIS OF REFLUX DISEASE

SYMPTOMS AND MANIFESTATIONS

Endoscopy and Biopsy

Empirical Acid Suppression as Diagnostic Test

Acid Lowering Agents

Table 2.1: Sero-epidemiology of H. pylori in India

Table 2.2: Virulence factors of Helicobacter pylori

Recurrent Abdominal Pain (RAP) and H. pylori

Table 2.3: Association of recurrent abdominal pain (RAP) and H. pylori

Whom to investigate for H. pylori and how?

H. pylori Infection in Children and Gastric Adenocarcinoma in Adults

Recommended Eradication Therapies for H. pylori Disease in Children

First Line Options

Second Line or Salvage Therapy (up to 14 days)

INCIDENCE AND PREVALENCE

Table 3.2: Prevalence of RAP according to various studies

Diagnostic Criteria as per Rome III

H2b. Diagnostic Criteria* for Irritable Bowel Syndrome

H2c. Diagnostic Criteria† for Abdominal Migraine10,11

H2d. Diagnostic Criteria* for Childhood Functional Abdominal Pain

H2d1. Diagnostic Criteria* for Childhood Functional Abdominal Pain Syndrome

H1c. Diagnostic Criteria* for Aerophagia

Approach to a Case of CAP

Functional abdominal pain 95% Organic abdominal pain <5%

Table 3.4: Other causes of isolated paroxysmal abdominal pain

CAP with dyspepsia

Functional abdominal pain 90% Organic abdominal pain 10%

Other Causes of RAP with Dyspepsia

Functional abdominal pain 75% Organic abdominal pain 25%

population is characterized by a heightened cortical sensitivity to afferent stimuli originating

Approach to Case of RAP

Level II: Investigations

Level III: Investigations

Management of Recurrent Abdominal Pain

NEW REDUCED OSMOLARITY ORS

COMPOSITION OF REDUCED OSMOLARITY ORS

Why was there a Need for a New ORS Formulation?

Efficacy of the New Reduced Osmolarity ORS in non Cholera Diarrhea

Efficacy of the New Reduced Osmolarity ORS in Cholera Diarrhea

Is Reduced Osmolarity ORS Safe?

Zinc in Diarrheal Diseases

Should Zinc be Mixed with ORS?

Lack of Evidence to use Probiotics and Antisecretory Drugs in

Antisecretory Drugs in Diarrhea

• Re-infection or protracted course of the initial infection

Fig. 5.1: Algorithm for the treatment of persistent diarrhea in outpatients

Recommendations for Dietary Management of Persistent Diarrhea (Fig. 5.3)

Successful treatment with either diet is characterized by:

Should Milk (Lactose) be Totally Eliminated or Only Restricted?

Basis for the Initial Reduced Lactose Diet

Basis for Diet B

The Third Diet C (Monosaccharide Based Diet)