Ped Gastro

Helicobacter Pylori in Children / 11
Ujjal Poddar
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Helicobacter Pylori
2 in Children
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
November 2005, there are 21,126 publications (1,915 of them are in 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). Helicobacter pylori infects at least 50% of the world’s human population10 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
12 / Pediatric Gastroenterology
EPIDEMIOLOGY
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Prevalence of H. pylori Infection in Indian Children
The prevalence of H. pylori mainly depends on socioeconomic status. In developing countries,
children are typically infected by 10 years of age. In India, like other developing countries,
due to poor socioeconomic status, 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
Table 2.1: Sero-epidemiology of H. pylori in India

Age group Graham et al13 Gill et al14 Age group
N = 238 celiac disease,
diarrhea, child,
serology
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
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” phenomena 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
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in 46% of 90 infants studied.19
H. pylori transmission is primarily “person-to-person” via fecal-oral, gastric-oral or oral-
oral routes. Children acquire infection mainly through feco-oral route as H. pylori has been
cultured from the stool 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).
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.
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 (Vac A)
4. Cytotoxin-associated antigen (Cag A)
Why only one in ten H. pylori infected persons develops peptic ulcer is not clear.21
However, in addition to host factor, the virulence of the organism plays an important
role. Lipopolysaccharides posses endotoxic 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 (Vac A) 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 the children with upper abdominal pain have more frequent association
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with H. pylori strains with s1m1 alleles compared to the 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
What are the 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.
Studies from Italy, Germany and USA have shown that H. pylori infection is associated
with growth delay especially in older children.26-28 However it is not yet clear whether this
differences in anthropometry between H. pylori infected and non-infected children are due
to socioeconomic and ethnic factors or due to H pylori infection. 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 al29 from Greece first time reported that
IDA in 3 children improved only after H. pylori eradication. Subsequently a report from
Korea30 on 937 children has shown that H. pylori infection was more common in IDA children
(35.5%) than in non-IDA children (19.4%). A recent report from Turkey31 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. 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 bacteria itself.
Recurrent Abdominal Pain 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. Table 2.3 has shown that
different studies from India and elsewhere have shown that there is no significant difference
of H. pylori prevalence between RAP and controls. Moreover a study on 945 children from
Germany32 and 695 children from Sweden33 have shown that there is no positive association
between H. pylori status and the occurrence of pain abdomen, in fact there was an inverse
IP Table 2.3: Association

: 112.133.195.17 of recurrent abdominal pain (RAP) and H. pylori
Positive association
Study Number of H. pylori +ve Response to
children treatment
Heldenberg et al (47) 50 54% 85%
Kumar et al (3) 33 43% 83%
Das et al (6) 65 77% 83%
Biswal et al (5) 76 65% Most
Negative association
Study Number of H. pylori H. pylori P
children positivity positivity in
in RAP Controls
O’Donhoe et al (48) 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 al (46) 47 30% 27% NS
NS= not significant
association of H. pylori positivity and pain abdomen.. However, a study on 240 children
from Lucknow4 has shown that the prevalence of H. pylori in upper abdominal pain (not
RAP) cases is significantly higher than controls (53% vs 28%, p < 0.001). Point to be remembered
here is that children with upper abdominal pain are different than children with RAP.
Secondly, if this association is true then after eradication of H. pylori symptoms should
disappear and with relapse, symptoms should reappear. Most of the studies from India
(Table 2.3) have shown that symptoms disappeared with eradication of H. pylori but none
of these studies have given a follow-up information. As we know a substantial proportion
(30% to 40%) of cases with functional disorders shows a placebo response with any form
of therapy. None of these studies have compared drugs with placebo. So we cannot say
for sure how much is true response and how much is placebo response. Oderda et al34 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 al35 have done a population based
cross-sectional study on 1221 children and showed that RAP was associated with single
parents, family history of nun-ulcer dyspepsia but not with H. pylori. Similarly Ashorn et
al36 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 meta-analysis37 of 45 series has shown that H. pylori is not associated
with RAP. Considering every thing, European Pediatric Task Force on H. pylori38,39 has
suggested that to date there is no evidence demonstrating a link between H. pylori associated
gastritis and abdominal pain except in those rare cases in which gastric or duodenal ulcer
disease is present. Therefore, screening for H. pylori infection should not be performed
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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) 90-95% 98%
Histology 98% 98%
Culture 90-95% 100%
PCR 95% 95%
routinely even in children with upper gastrointestinal symptoms, including abdominal pain.
The Canadian Helicobacter Study Group40 in their recent report on consensus conference on
H. pylori has further substantiated this view.
How to Diagnose H. pylori?

There are both invasive (requires endoscopy) and non-invasive tests for H. pylori (Table
2.4).41 For diagnosis invasive tests are used and to check eradication a non-invasive test
is used. Among the non-invasive tests, serology is unreliable in young children as antibody
production is low in them. Similarly,13C urea breath test is difficult to perform in < 5 yrs
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. To check eradication
(four weeks after 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.42,43
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)38,39 have recommended that only those children should be investigated whose
abdominal symptoms are severe enough to suspect organic causes. Primary goal of testing
is to diagnose the cause of clinical symptoms and not simply to detect the presence of
H. pylori infection. Therefore, endoscopy is the preferred method of investigation. There
is no role of non-invasive tests in the initial evaluation.
Table 2.5: Drugs

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treatment of H. pylori infection in children
Drugs Doses Maximum doses
Amoxycillin 50 mg/kg/day 1 g bid
Clarithromycin 15 mg/kg/day 500 mg bid
Omeprazole 1 mg/kg/day 20 mg bid
Metronidazole 20 mg/kg/day 500 mg bid
Bismuth subsalicylate 1 tablet (262 mg) qid
or 15 ml (17.6 mg/ml) qid
Tetracycline 50 mg/kg/day 1g bid
Ranitidine bismuth citrate 1 tablet qid
qid: four times daily. bid: twice daily
Whom to treat and with what drugs?

On endoscopy if there is duodenal ulcer or gastric ulcer, anti H. pylori treatment should
be given. However, if 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 option of refusing treatment.38,39
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.44 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.45
Recommended Eradication Therapies for H. pylori Disease in Children38-40

First line of treatment is twice daily triple drug regimen comprising one proton pump inhibitor
(PPI) and two antibiotics (Clarithromycin plus Amoxycillin or Metronidazole) for 10 to 14
days.
First Line Options

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1. Amoxycillin (50 mg/kg/day)+ Clarithromycin (15 mg/kg/day)+ Proton pump inhibitor
(Omeprazole)(1mg/kg/day)
2. Amoxycillin + Metronidazole (20 mg/kg/day) + PPI
3. Clarithromycin + Metronidazole + PPI (Omeprazole)
Second-Line Options
1. Bismuth subsalicylate (262 mg qid) + Metronidazole + PPI + Amoxycillin or Tetracycline
(50 mg/kg/day)
2. Ranitidine bismuth citrate (1 tab qid) + Clarithromycin + Metronidazole
Check for eradication: Check for eradication of the organism should be done 4 weeks after
completion of treatment. If the patient is asymptomatic then urea breath test and if the
patient is still symptomatic then repeat endoscopy should be done.
KEY MESSAGES
1. H. pylori infection is very common in Indian children but most infected children are
asymptomatic.
2. There is no association of H. pylori and RAP.
3. Endoscopy is the preferred method of investigation in children with upper digestive
symptoms suggestive of organic disease after exclusion of other causes with non-invasive
methods.
4. No role of non-invasive method of H. pylori detection in the initial evaluation.
5. Children with H. pylori related disease (ulcer, primary gastric B-cell lymphoma and atrophic
gastritis with intestinal metaplasia) should be treated with triple drugs comprising PPI
and two antibiotics.
6. In endoscopy negative H. pylori positive cases: treatment option should be kept open.
REFERENCES
1. Warren J, Marshall B. Unidentified curved bacillus on gastric epithelium in chronic active gastritis. Lancet
1983;I 1273-5.
2. Marshall BJ, Armstrong JA, McGechie DB, Glancy RJ. Attempt to fulfill Koch’s postulates for pyloric
campylobacter. Med J Aust 1985;142:436-9.
3. Kumar M, Yachha SK, Khanduri A, Prasad KN, Ayyagari A, Pandey R. Endoscopic, histologic and
microbiological evaluation of upper abdominal pain with special reference to Helicobacter pylori
infection. Indian Pediatr 1996;33:905-9.
4. Singh M, Prasad KN, Yachha SK, Saxena A, Krishnani N. Helicobacter pylori infection in children:
prevalence, diagnosis and treatment outcome. Trans R Soc Trop Med Hyg 2005;27.
5. Biswal N, Ananthakrishnan N, Kate V, Srinivisan S, Nalini P, Mathai B. Helicobacter pylori and recurrent
pain abdomen. Indian J Pediatr 2005;72:561-5.
6. Das BK, Kakkar S, Dixit VK, Kumar M, Nath G, Mishra OP. Helicobacter pylori infection and recurrent
abdominal pain in children. J Trop Pediatr 2003; 49:250-2.
7. Singh M, Prasad KN, Yachha SK, Krishnani N. Genotypes of Helicobacter pylori in children with upper
abdominalIP :pain.
112.133.195.17
J Gastroenterol Hepatol 2003;18:1018-23.
8. Bansal D, Patwari AK, Malhotra VL, Malhotra V, Anand VK. Helicobacter pylori infection in recurrent
abdominal pain. Indian Pediatr 1998;35:327-35.
9. Poddar U, Thapa BR. Helicobacter pylori in children. Indian Pediatr 2000;37:275-83.
10. Ernst PB, Gold BD. Helicobacter pylori in childhood: new insights into the immunopathogenesis of
gastric disease and implications for managing infection in children. J Pediatr Gastroenterol Nutr 1999;
28:462-73.
11. Fiedorek SC, Malaty HM, Evans DL et al. Factors influencing the epidemiology of Helicobacter pylori
in children. Pediatrics 1991;88:578-82.
12. Megraud F, Brassens-Rabbe MP, Denis F, Belbouri A, Hoa DQ. Seroepidemiology of Campylobacter
pylori infection in various populations. J Clin Microbiol 1989;27:1870-3.
13. Graham DY, Adam E, Reddy GT, et al. Seroepidemiology of Helicobacter pylori infection in India:
comparison of developing and developed countries. Dig Dis Sci 1991;38:1084-8.
14. Gill HH, Majumdar P, Shankaran K, Desai HG. Age-related prevalence of Helicobacter pylori antibodies
in Indian subjects. Indian J Gastroenterol 1994;13:92-4.
15. Dore SP, Krupadas S, Borgonha S, Kurpad AV. The 13C urea breath test to assess Helicobacter pylori
infection in school children. Natl Med J India 1997;10:57-60.
16. Katelaris PH, Tipett GHK, Norbu P, Lowe DG, Brennan R, Farthing MJG. Prevalence of Helicobacter
pylori and peptic ulcer and relation to symptoms in a Tibetan refugee population in Southern India.
Gut 1992;33:1462-6.
17. Misra V, Misra SP, Diwedi M, Singh PA. Point prevalence of peptic ulcer and gastric histology in healthy
Indians with Helicobacter pylori infection. Am J Gastroeterol 1997;92:1487-9.
18. Haruma K, Okamoto S, Kawaguchi H, et al. Reduced incidence of Helicobacter pylori infection in young
Japanese persons between the 1970s and the 1990s. J Clin Gastroenterol 1997;25:583-6.
19. Sarker Sa, Rahman MM, Mahalanabis D, et al. Prevalence of Helicobacter pylori infection in infants
and family contacts in a poor Bangladesh community. Dig Dis Sci 1995;40:2666-72.
20. Thomas JE, Gibson GR, Darboe MK, Dale A, Weaver LT. Isolation of Helicobacter pylori from human
faces. Lancet 1992;340:1194-5.
21. Sipponen P, Seppala K, Aarynen M, Helske T, Kettunen P. Chronic gastritis and gastroduodenal ulcer:
A case control study on risk of co-existing duodenal and gastric ulcer in patients with gastritis. Gut
1989;30:922-9.
22. Leunk RD, Johnson PT, David BC, et al. Cytotoxic activity in broth-culture filtrates of Campylobacter
pylori. J Med Micorobiol 1988;26:93-9.
23. Blaser MJ. Role of vac A and the cag A locus of Helicobacter. pylori in human disease. Aliment Pharmacol
Ther 1996;10:73-7.
24. Sarker SA, Nahar S, Rahaman M, et al. High prevalence of cagA and vacA seropositivity in asymptomatic
Bangladeshi children with Helicobacter pylori infection. Acta Pediatr 2004;93:1432-6.
25. Azuma T, Kato S, Zhou W, et al. Diversity of vacA and cagA genes of Helicobacter pylori in Japanese
children. Aliment Pharmacol Ther 2004;20 (Suppl 1):7-12.
26. Perri F, Pastore M, Leandro G, et al. Helicobacter pylori infection and growth delay in older children.
Arch Dis Child 1997;77:46-9.
27. Richter T, Richter T, List S, et al. Five to 7 year old children with Helicobacter pylori infection are
smaller than Helicobacter pylori–negative children: a cross-sectional population-based study of 3,315
children. J Pediatr Gastroenterol Nutr 2001;33:472-5.
28. Sood MR, Joshi S, Akobeng AK, Mitchell J, Thomas AG. Growth in children with Helicobacter pylori
infection and dyspepsia. Arch Dis Child 2005;90:1025-8.
29. Kostaki M, Fessatou S, Karpathios T. Refractory iron-deficiency anemia due to silent Helicobacter pylori
gastritis in chldren .Eur J Pediatr 2003;162:177-9.
30. Choe YH, Kim SK, Hong YC. The relationship between Helicobacter pylori infection and iron deficiency:
seroprevalence study in 937 pubescent children. Arch Dis Child 2003;88:178.
31. Kurekci AE, Atay AA, Sarici SU, et al. Is there a relationship between childhood Helicobacter pylori
IPand
infection : 112.133.195.17
iron deficiency anemia? J Trop Pediatr 2005;51:166-9.
32. Bode G, Rothenbacher D, Brenner H, Adler G. Helicobacter pylori and abdominal symptoms: A
population based study among preschool children in southern Germany. Pediatrics 1998;101:634-7.
33. Tindberg Y, Nyren O, Blennow M, Granstrom M. Helicobacter pylori infection and abdominal symptoms
among Swedish school children. J Pediatr Gastroenterol Nutr 2005;41:33-8.
34. Oderda G, Dell’Ollio D, Morra I, Ansaldi N. Campylobacter pylori gastritis: Long term results of
treatment with Amoxycillin. Arch Dis Child 1989;64:326-9.
35. Bode G, Brenner H, Adler G, Rothenbacher D. Recurrent abdominal pain in children: evidence from
a population based study that social and familial factors play a major role but not Helicobacter pylori
infection .J Psychosom Res 2003;54:417-21
36. Ashorn M, Rago T, Kokkonen J, Ruuska T, Rautelin H, Karikoski R. Symptomatic response to
Helicobacter pylori eradication in children with recurrent abdominal pain: double blind randomized
placebo control trial. J Clin Gastroenterol 2004;38:646-50.
37. Macarthur C, Saunders N, Feldman W. Helicobacter pylori, gastroduodenal disease and recurrent
abdominal pain in children. JAMA 1995;273:729-34.
38. Gold BD, Colletti RB, Abbott M, et al. Helicobacter pylori infection in children: Recommendations for
diagnosis and treatment. Medical postiton statement: The North American Society of Pediatric
Gastroenterology and Nutrition. J Pediatr Gastroenterol Nutr 2000;31:490-7.
39. Drumm B, Koletzko S, Oderda G. Helicobacter pylori infection in children: a consensus statement.
Medical position paper: Report of the European Pediatric task force on Helicobacter pylori on a
consensus conference, Budapest, Hungary, September 1998. J Pediatr Gastroenterol Nutr 2000;30:207-
13.
40. Bourke B, Ceponis P, Chiba N, et al.Canadian Helicobacter Study Group Consensus Conference: Update
on the approach to Helicobacter pylori infection in children and adolescents—an evidence-based
evaluation. Can J Gastroenterol 2005;19:399-408.
41. Marshall BJ. Helicobacter pylori. Am J Gastroenterol 1994;89:S 116-S 128.
42. Kato S, Nakayama K, Minooura T, et al. Comparison between the 13C urea breath test and stool
antigen test for the diagnosis of childhood Helicobacter pylori infection. J Gastroenterol 2004;39:1045-
50.
43. Hino B, Eliakin R, Levine A, et al. Comparison of invasive and non-invasive tests in diagnosis and
monitoring Helicobacter pylori of infection in children. J Pediatr Gastroenterol Nutr 2004;39:519-23.
44. Forman D, Webb P, Parsonnet J. H. pylori and gastric cancer. Lancet 1994;343:243-4.
45. Imrie C, Rowland M, Bourke B, Drumm B. Is Helicobacter pylori infection in childhood a risk factor
for gastric cancer? Pediatrics 2001;107:373-80.
46. Yoshida NR, Webber EM, Fraser RB, Ste-Marie MT, Giacomantonio JM. Helicobacter pylori is not
associated with nonspecific abdominal pain in children. J Pediatr Surgery 1996;31:747-9.
47. Heldenberg D, Wagner Y, Heldenberg E, et al. The role of Helicobacter pylori in children with recurrent
abdominal pain. Am J Gastroenterol 1995;90:906-9.
48. O’Donohoe JM, Sullivan PB, Scott R, Rogers T, Brueton MJ, Barltrop D. Recurrent abdominal pain and
Helicobacter pylori in a community-based sample of London children. Acta Pediatr 1996;85:961-4.
Recurrent (Chronic) Abdominal Pain in Children / 21
Bhaskar Raju B, Geetha M
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Recurrent (Chronic)
3 Abdominal Pain in Children
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 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 RAP, 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 RAP with no
organic cause that 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 definitive diagnosis. Presently, however
RAP wherein diligent investigations fail to pick up any recognizable etiology is referred
to as Functional (Recurrent) abdominal pain (FRAP). The phenotype description of a typical
FRAP patient is also no longer accepted.
Table 3.1: Apley’s typical FRAP phenotype

History : Recurrent disorders
Physique : Slightly underweight
Intelligence : Normal
Psyche : Emotional disturbances
Personality : Timid, anxious and over conscientious
In family : Recurrent pains, nervous disorders
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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
INCIDENCE AND PREVALENCE

Apley found an incidence of 10 to 15% among school going children and various studies
after that have also confirmed the high incidence of RAP in pediatric population.2 There
is evidence that almost as many do suffer RAP but do not complain or seek medical attention
making the problem of RAP even more common than what studies indicate. The marked
differences in data on RAP in different studies (0.3% to 20%) are due to choice of populations
studied-hospitalized patients, out patient clinics or school-based studies (Table 3.2).
CLASSIFICATION
70s Classification:
Organic (10%)
Psychogenic (90%)
80s Classification:
Organic (20%)
Dysfunctional Rap (75%)
RAP due to Psychiatric Pathology (5%)
The dysfunctional RAP of the 80s and 90s is presently referred to as functional RAP.
The seventies saw a dualistic approach which recognized RAP as either organic or, if
no organic cause is found, as psychiatric pathology. With time pediatricians saw that most
of the cases of RAP not only had no demonstrable organic cause for the pain, but no obvious
psychiatric problem as well to explain the pain. The term dysfunctional RAP was coined
to describe such cases wherein pain is significant, but no cause either organic or psychiatric
could be found. Today the term dysfunctional is replaced by the term functional RAP.
The Rome group has been studying the phenomenon of functional disorders of the GI
tract and have come up with codification of all functional disorders (esophageal to rectal)
as A to F. All pediatric disorders were classified under G. G1 referred to functional vomiting,
G2 to abdominal pain and associated disorders, G3 to functional diarrhoea and G4 to functional
constipation.9 The presently accepted classification was devised in 1999 and a new modification
of it is expected sometime this year (2006).
IP : 112.133.195.17Table 3.3: Abdominal pain

G2a Functional dyspepsia (ulcer, dys-motility, unspecified)
G2b IBS
G2c Functional abdominal pain
G2d Abdominal migraine
G2e Aerophagia.
Chronic Abdominal Pain G2

Defined as abdominal pain for at least 12 weeks, (which need not be consecutive), in the
preceding 12 months. Sub-classification is given in Table 3.3.
Definitions as per Rome II Criteria

Functional Dyspepsia
Defined as persistent or recurrent pain or discomfort in the upper abdomen for at least
12 wks (which need not be consecutive) in the preceding 12 months.
— No evidence of organic disease.
— Dyspepsia not related to defecation.
Classified as
Dyspepsia with:
— Ulcer like pain,
— Dysmotility
— Reflux like pain
Absence of significant vomiting, hemetemesis, nocturnal pain, and maintenance of normal
growth patterns are additional supportive evidence for the diagnosis of functional dyspepsia.
Abdominal Migraine
Defined as 3 or more paroxysmal episodes of intense acute midline pain, for at least 2 hours
or more in the past 12 months, with symptom free intervals of weeks or months in between.
Absence of any metabolic/biochemical disease and absence of structural defects of CNS/
GI tract is a must for confirmation of diagnosis of abdominal migraine. At least 2 of the
following features need to be present in addition.
Headache
Photophobia
Aura (Visual/sensory/motor)
Family history of unilateral headaches and/or migraine10,11
Aerophagia
Defined as two or more signs and symptoms of air swallowing, abdominal distension,
belching, increased flatus lasting at least 12 weeks (need not be consecutive) in the preceding
12 months.
Functional Abdominal Pain Syndrome

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Defined as 12 weeks of continuous or nearly continuous abdominal pain in a school-going
child or adolescent with no or occasional relationship with physiologic events like eating,
defecation, menstrual cycles. Some interference with daily functions may be seen. Malingering
should be clearly ruled out and the features seen should not fit into other known functional
disorders of GI tract.
Irritable Bowel Syndrome

Defined as, following symptoms for 12 weeks (not necessarily consecutive), in the previous
12-month period.
• Abdominal discomfort relieved by defecation and associated with change in stool frequency
and/or form. Passage of mucus and bloating also help in diagnosis.
• No structural or metabolic abnormalities of GI tract.
• Clinical presentation may be
— Diarrhea predominant
— Constipation predominant
— Variable stool pattern type
Nearly a quarter of patients with IBS may have developed it as a post-viral gastroenteritis
sequelae.12
Approach to a Case of RAP

Given the myriad causes of RAP, it helps to slot children presenting with RAP into one
the following, to narrow down diagnostic possibilities and investigations ordered.
• Isolated paroxysmal peri-umbilical abdominal pain
• Abdominal pain with dyspepsia
• Abdominal pain with altered bowel habits
Functional RAP can present with any of the above presentations and whatever the
presentation, it is still the commonest cause. Organic causes of RAP however will differ
with the type presentation and such classification will help narrow our 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.
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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
RAP with dyspepsia
Functional abdominal pain 90% Organic abdominal pain 10%

Important causes
– Gerd
– PUD
– H. pylori
– Giardiasis
– Pancreatitis
– Cholecystitis
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
• Ménétrier disease
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• 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
• Obstructive disorders from previous table
• Chronic pancreatitis
• Chronic hepatitis
• Chronic cholecystitis
• Ureteropelvic junction obstruction
• Abdominal migraine
• Psychiatric disorders13
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
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• Complications of constipation (megacolon, encopresis, intermittent sigmoid volvulus)
• Drug-induced diarrhea, constipation
• Gynecologic disorders
• Neoplasia (lymphoma, carcinoma)13
Pathogenesis of Functional Abdominal Pain

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 FRAP 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 FRAP children as dyspepsia
or pain. Quasi-pathological problems like lactose intolerance.15 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 FRAP is indicated
by the presence of headaches, vomiting, pallor, dizziness motion sickness and temperature
intolerance in almost a third of patients with FRAP. This further buttresses the concept
of disordered enteric nervous system playing a major role in perception of pain in FRAP.
Autonomic testing too is often abnormal in these patients.21
Along with augmented visceral perception, FRAP 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 FRAP. Sedentary lifestyle and irregular eating
and bowel habits, substance abuse and addictions predispose to FRAP.
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Fig. 3.1: Environmental factors and cortical stimulation of increased gut activity
• 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
FRAP to show a familial occurrence.
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 discomfort and induce painful contractions of the bowel.
Summarizing, the presently accepted concept of functional RAP suggests that
environmental and lifestyle factors cause abdominal pain in a susceptible population. The
susceptible population is characterized by a heightened 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
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— 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
• 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 peri-umbilical, 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
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• 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 RAP and many experienced pediatricians do not insist on any
investigations to confirm the it. However, much of treatment of functional RAP 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 uncommon (HSP/Porphyrias23)
causes of RAP to be missed on clinical exam. Hence, a structured investigatory approach
is needed in all cases wherein RAP is diagnosed and it is found disturbing enough to be
brought to the physician.
Level 1: Investigations
All cases of RAP 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 RAP since most will show no abnormality in the investigations
or be obvious clinically as FRAP. In selected cases one may need to resort to further
investigations.
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Indications
Presence of red flag signs/symptoms with strong clinical suspicion of organic cause for pain,
persistent and severe pain in clinically suspected FRAP 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 evaluation.
Diarrheas esp. with mucus and or blood, occult evidence of gastrointestinal bleeding,
involuntary weight loss or growth deceleration, iron deficiency anemia, elevated acute-
phase reactants (sedimentation rate, C-reactive protein), extraintestinal symptoms suggestive
of inflammatory bowel disease (fever, rash, joint pains, recurrent aphthous ulceration) would
need 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 3 investigations.
• EEG to R/O abdominal epilepsy/cyclical vomiting syndrome
• Porphyrias
• Collagen vascular disorders
• Lead poisoning
• Lactose intolerance
• Food allergy
• Motility disorders.
Generally, speaking such extensive work up should pick up most if not all causes of
RAP 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 FRAP even though
it has a 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
Management of Recurrent Abdominal Pain

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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
RAP to treat-functional RAP.
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 FRAP even though 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 RAP 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/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 contribution
by the pain itself is reduced.
Goals of Therapy
The major and 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 FRAP 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
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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 the pain and the capacity of the child to handle it.
Drug Therapy
True FRAP 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 RAP. Documented acid peptic disease will benefit from
anti-acid therapy27. H. pylori if identified will create a dilemma with reports suggesting good
response to therapy and with equal reports refuting its benefits28. 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 RAP a worthwhile idea.29-31
Other drugs/modalities that may have a role in FRAP include moderate fiber diet (Child’s
age + 5 gm per day) prokinetics, mineral oil/PEG/Lactulose/ esp. in constipation predominant
IBS with RAP. Antimotility agents are generally not advised unless there is disturbing diarrhea
with FRAP. Enteric-coated peppermint oil has found anecdotal benefit in some cases of
FRAP.32
Abdominal migraine, if suspected will benefit from Cyproheptadine and Propranalol.33,34
Drugs like 5HT receptor antagonists, which have been found useful in adults with, pain
predominant IBS have not been tried in FRAP 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 FRAP responds badly to psychiatric consults and children with FRAP 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
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• 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 FRAP since it is likely to reinforce
pain behavior.
Prognosis
A significant section of children with FRAP have complete relief of pain within 6 to 8 weeks
of diagnosis indicating the role of a positive diagnosis of FRAP. Many do get recurrences
of pain but handle it better without affecting their daily activities. In 30 to 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 FRAP as a diagnosis
is established.
• Strong family history of pains.
REFERENCES
1. Apley J, Naish N. Recurrent abdominal pains: a field survey of 1000 school children. Arch Dis Child
1958;50:429–36.
2. Faull C, Nicol AR. Abdominal pains in six-year olds: an epidemiological study in a new town. J Child
Psychol Psychiatry 1986;27:251–60.
3. Hyams JS, Burke G, Davis PM, et al. Abdominal pain and irritable bowel syndrome in adolescents:
a community-based study. J Pediatr 1996;129:220–6.
4. Apley J. The child with abdominal pains. London: Blackwell Scientific Publications, 1975.
5. Alfven G. The covariation of common psychosomatic symptoms among children from socio-
economically differing residential areas. An epidemiological study. Acta Paediatr 1993;82(5):484-7.
6. Groholt EK, Stigum H, Nordhagen R, Kohler L. Recurrent pain in children, socioeconomic factors and
IP : 112.133.195.17
accumulation in families. Eur J Epidemiol 2003;18(10):965-75.
7. Perquin CW, Hazebroek-Kampschreur AA, Hunfeld JA, van Suijlekom-Smit LW, Passchier J, van der
Wouden JC. Chronic pain among children and adolescents: physician consultation and medication use.
Clin J Pain 2000;16(3):229-35.
8. Bode G, Brenner H, Adler G, Rothenbacher D. Recurrent abdominal pain in children: evidence from
a population-based study that social and familial factors play a major role but not Helicobacter pylori
infection. J Psychosom Res 2003;54(5):417-21.
9. Rasquin-Weber A, Hyman PE, Cucchiara S, et al. Childhood functional gastrointestinal disorders. Gut
1999;45(Suppl:II)60–8.
10. Mortimer MJ, Kay J, Jarson A, Good PA. Does a history of maternal migraine or depression predispose
children to headache and stomach-ache? Headache 1992;32:353–5.
11. Abu-Arafeh I, Russell G. Prevalence and clinical features of abdominal migraine compared with those
of migraine headache. Arch Dis Child 1995;72:413–7.
12. P Gwee KA, et al. Role of psychological and biological factors in postinfectious gut dysfunction GUT
1999;44:400-06.
13. John TB. Abdominal pain. In: Walker WA, Goulet OJ, Kleinman RE, Sanderson IR, Sherman PM, Shneider
BL (Editors). Pediatric gastrointestinal disease: pathophysiology/diagnosis/management. Hamilton:
BC Decker Inc; 2004;225-43.
14. Zighelboim J, Talley NJ. What are functional disorders? Gastroenterology 1993;104:1196–201.
15. Barr RG, Levine MD, Watkins JB. Recurrent abdominal pain in children due to lactose intolerance.
A prospective study. N Engl J Med 1979;300:1449–52.
16. Dimson SB. Transit time related to clinical findings in children with recurrent abdominal pain. Pediatrics
1972;47:666–74.
17. Kopel FB, Kim IC, Barbero GJ. Comparison of rectosigmoid motility in normal children, children with
RAP, and children with ulcerative colitis. Pediatrics 1967;39:539–44.
18. Pineiro-Carrero VM, Andres JM, Davis RH, et al. Abnormal gastroduodenal motility in children and
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 pain. J Pediatr 2001;139:838–43.
20. van Ginkel R, Voskuijl WP, Benninga MA, et al. Alterations in rectal sensitivity and motility in childhood
irritable bowel syndrome. Gastroenterology 2001;120:31–8.
21. Chelimsky G, Boyle JT, Tusing L, Chelimsky TC. Autonomic abnormalities in children with functional
abdominal pain: coincidence or etiology? J Pediatr Gastroenterol Nutr 2001;33:47–53.
22. Levine MD, Rappaport LA. Pediatr Clin North Am 1984;31(5):969-91.
23. Stein JA, Tschudy DP. Acute intermittent porphyria: a clinical and biochemical study of 46 patients.
Medicine 1970;49:1–16.
24. Schisgall RM. Appendiceal colic in childhood. Ann Surg 1980;192:687–93.
25. Gorenstein A, Serour F, Katz R, Usviatsov I. Appendiceal colic in children: a true clinical entity? J Am
Coll Surg 1996;182:246–50.
26. Leahy AL, Fogarty EE, Fitzgerald RJ, Regan BF. Discitis as a cause of abdominal pain in children. Surgery
1984;95:412–4.
27. McQuaid KR. Dyspepsia. In: Feldman M, Friedman LS, Sleisenger MH (Editors). Gastrointestinal and
liver disease: pathophysiology/diagnosis/management. Philadelphia: WB Saunders; 2002;102–18.
28. Gold BD, Colletti RB, Abbott M, et al. Helicobacter pylori infection in children: recommendations for
diagnosis and treatment. J Pediatr Gastroenterol Nutr 2000;31:490–7.
29. Niyaz A. Buch, Sheikh Mushtaq Ahmad, S. Zubair Ahmad, Syed Wajid Ali, BA. Charoo and Masood-
ul-Hassan. Recurrent abdominal pain in children. IIndian Pediatrics 2002;39:830-4.
30. Dutta S, Mehta M, Verma IC. Recurrent abdominal pain in Indian children and its relation with school
and family environment. Indian Pediatr 1999;36(9):917-20.
31. Balani B, Patwari AK, Bajaj P, Diwan N, Anand VK. Recurrent abdominal pain—a reappraisal. Indian
Pediatr.IP : 112.133.195.17
2000;37(8):876-81.
32. Kline RM, Kline JJ, DiPalma J, Barbero GJ. Enteric-coated, pH dependent peppermint oil capsules for
the treatment of irritable bowel syndrome in children. J Pediatr 2001;138:125–8.
33. Russell G, Abu-Arafeh I, Simon DN. Abdominal migraine: evidence for existence and treatment options.
Paediatr Drugs 2002;4:1–8.
34. Worawattanakul M, Rhoads JM, Lichtman SN, Ulshen MH. Abdominal migraine: prophylactic treatment
and follow-up.J Pediatr Gastroenterol Nutr 1999;28:37–40.
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 Gastroenterol 2001;96:2662–70.
36. Prather CM, Camilleri M, Zinsmeister AR et al. Tegaserod accelerates orocecal transit in patients with
constipation predominant irritable bowel syndrome. Gastroenterology 2000;118:463–8.
37. Sanders MR, Rebgetz M, Morrison M, et al. Cognitive-behavioral treatment of recurrent nonspecific
abdominal pain in children: an analysis of generalization, maintenance, and side effects. J Consult Clin
Psychol 1989;57:294–300.
38. Sanders MR, Shepherd RW, Cleghorn G, Wolford H. The treatment of recurrent abdominal pain in
children: a controlled comparison of cognitive-behavioral family interventions and standard pediatric
care. J Consult Clin Psychol 1994;62:306–14.
39. Finney JW, Lemanek KL, Cataldo MF, et al. Pediatric psychology in primary health care: brief targeted
therapy for recurrent abdominal pain. Behav Ther 1989;20:283–91.
40. Walker LS, Garber J, van Slyke DA, Greene JW. Long-term health outcomes in patients with recurrent
abdominal pain. J Pediatr Psychol 1995;20:233–45.
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 they just grow out of it? Pedatrics 2001;108(1):E1.
43. Apley J, Hale B. Children with recurrent abdominal pain: how do they grow up? BMJ 1973;3:7–9.
Recent Trends in the Management of Acute Watery Diarrhea in Children / 37
Shinjini Bhatnagar, Nitya Wadhwa
IP : 112.133.195.17
Recent Trends in the
4 Management of Acute
Watery Diarrhea in Children
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 245mOsm/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
IP : 112.133.195.17
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 to 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 ORS4.
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
IP :data in patients with cholera, while limited, are reassuring. In the pooled
112.133.195.17
data of all studies with cholera diarrhea in children there was a small reduction (mean
4
difference 0.8 mEq/l, 95% CI: 0.6 to 1.0) in mean serum sodium at 24 hours in patients
receiving reduced osmolarity ORS (sodium 70-75 mEq/l, glucose 75-90 mmol/l, osmolarity
245-268mOsm/l) when compared with those given standard WHO ORS. This was similar
to results seen in adults 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 75mmol/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 intake5. 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 diarrhoea 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 years.10,11
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% to 22%) with a 34% reduction (95% CI 17% to 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% to 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 20mg daily dose of elemental zinc was
increased to 30-40mg daily10-13. Some studies also reported reduction in diarrhoea 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 programme in the community using a cluster randomized design was evaluated
in Bangladesh.14 There was a 24% shorter duration (95%CI 0.65 to 0.90) and 15% lower
incidence of diarrhea (95%CI 0.76 to 0.96) in the zinc cluster than those in the comparison
group. The zinc treated cluster had a 24% (95% CI 0.59 to 0.98) lesser rate of admission
to hospital of children with diarrhea and 51% (95% CI 0.25 to 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
IP : 112.133.195.17
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 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 programme. 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 diarrhoea.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 2 up to 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 diarrhoea is an important
step in public health. The administration of zinc with oral rehydration salts for diarrhoea
in the programme 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
IP : 112.133.195.17
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 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.
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 multicentre study evaluating efficacy and safety of the same drug.
REFERENCES
1. National Family Health Survey (NFHS-2) India, 1998-99.
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 diarrhoea 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 diarrhoeal 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
morbidityIP in
: 112.133.195.17
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 diarrhoea on morbidity and mortality in Bangladeshi children:
community randomized trial. BMJ 2002;325(7372):1059.
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-463S.
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;41:335-348
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 diarrhoea: 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;41:1203-04.
Shinjini Bhatnagar, Nitya Wadhwa
IP : 112.133.195.17
Recent Trends in the
4 Management of Acute
Watery Diarrhea in Children
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 245mOsm/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
IP : 112.133.195.17
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 to 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 ORS4.
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
IP :data in patients with cholera, while limited, are reassuring. In the pooled
112.133.195.17
data of all studies with cholera diarrhea in children there was a small reduction (mean
4
difference 0.8 mEq/l, 95% CI: 0.6 to 1.0) in mean serum sodium at 24 hours in patients
receiving reduced osmolarity ORS (sodium 70-75 mEq/l, glucose 75-90 mmol/l, osmolarity
245-268mOsm/l) when compared with those given standard WHO ORS. This was similar
to results seen in adults 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 75mmol/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 intake5. 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 diarrhoea 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 years.10,11
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% to 22%) with a 34% reduction (95% CI 17% to 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% to 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 20mg daily dose of elemental zinc was
increased to 30-40mg daily10-13. Some studies also reported reduction in diarrhoea 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 programme in the community using a cluster randomized design was evaluated
in Bangladesh.14 There was a 24% shorter duration (95%CI 0.65 to 0.90) and 15% lower
incidence of diarrhea (95%CI 0.76 to 0.96) in the zinc cluster than those in the comparison
group. The zinc treated cluster had a 24% (95% CI 0.59 to 0.98) lesser rate of admission
to hospital of children with diarrhea and 51% (95% CI 0.25 to 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
IP : 112.133.195.17
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 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 programme. 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 diarrhoea.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 2 up to 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 diarrhoea is an important
step in public health. The administration of zinc with oral rehydration salts for diarrhoea
in the programme 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
IP : 112.133.195.17
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 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.
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 multicentre study evaluating efficacy and safety of the same drug.
REFERENCES
1. National Family Health Survey (NFHS-2) India, 1998-99.
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 diarrhoea 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 diarrhoeal 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
morbidityIP in
: 112.133.195.17
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 diarrhoea on morbidity and mortality in Bangladeshi children:
community randomized trial. BMJ 2002;325(7372):1059.
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-463S.
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;41:335-348
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 diarrhoea: 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;41:1203-04.
Chronic Diarrhea and Malabsorption Syndrome / 57
Anshu Srivastava
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Chronic Diarrhea and

6 Malabsorption Syndrome
Diarrhea is defined as increased frequency, fluidity or volume of stools. According to WHO,

any diarrheal episode which begins acutely and lasts for more than 2 weeks is defined as
persistent diarrhea. On the other hand, chronic diarrhea is also of >2week duration but
it 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 any nutrient
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 solubilization, which is a
prerequisite for the absorption of nutrients like fat or calcium. Fat and fat-soluble vitamins
are solubilized through formation of micelles, and calcium through acidification. Digestion
of macromolecular compounds, like polysaccharides, triglycerides and proteins, to their
molecular components, like monosaccharides, 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 gastrointestinal
(GI) tract (Fig. 6.1) and specific vitamin and mineral deficiencies in any given subject can
often point to the involved anatomic site of the gut.
Etiology
The list of conditions which can lead to chronic diarrhea/malabsorption is extensive as shown
in Table 6.1. It can be broadly divided into impaired digestion and impaired absorption
although there is often an overlap. After exclusion of persistent diarrhea which is discussed
elsewhere, celiac disease, parasitic infestations, cow’s milk protein intolerance and chronic
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Fig. 6.1: Site of absorption of nutrients in gut
nonspecific diarrhea constitute the main causes in children as shown in the 4 studies of
chronic diarrhea in children in Table 6.2. In nearly 10%, a definite cause could not be found.
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. What is the duration of symptoms and whether the onset was acute or insidious?
3. Nature, frequency and consistency of stools along with diurnal variations. Ask for
presence of blood/mucus/visible oil in stools.
4. When did the symptoms start? Age of onset is important as various illnesses present
at different age groups.
5. Does the child have failure to thrive (FTT) and signs of nutrient deficiency like anemia,
rickets, vitamin B complex deficiency (glossitis/cheilitis) or is he thriving well?
6. Was there any relation with change in diet? Introduction of top feeds followed by
diarrhea suggests cow’s milk protein intolerance (CMPI) whereas onset after weaning
with wheat products suggests celiac disease. Symptoms worsen after a high fat diet
in patients with pancreatic insufficiency. Child passing stools only after eating is
suggestive of gastrocolic reflex. In this, the child does not get up during sleep to pass
stools and there is no growth failure.
7. Does the patient consume a diet high in poorly absorbable carbohydrates/sweeteners
(like sorbitol or fructose) or excess of fruit juices?
IP :Table 6.1: Causes of

112.133.195.17 chronic diarrhea and malabsorption in children
Diarrhea due to impaired intraluminal digestion
• Acid hypersecretion—Zollinger Ellison syndrome
• Exocrine pancreatic insufficiency-Cystic fibrosis, chronic pancreatitis, pancreatic hypoplasia with
lipomatosis (Schwachman syndrome), Metaphyseal chondrodysplasia (Johanson-Blizzard syndrome,
Pearson syndrome)
• Reduced bile acids and abnormal micellar solubilization—biliary obstruction, impaired bile acid
synthesis, blind loop syndrome, interrupted entero-hepatic circulation due to ileal resection , Crohn’s
disease, or congenital malabsorption of bile acids
• Isolated enzyme deficiencies—lipase, co-lipase, enterokinase deficiency
Enzyme deficiency-
Congenital sucrose isomaltase deficiency
Congenital lactase deficiency
Late onset lactase deficiency
Congenital glucose galactose malabsorption
Fructose intolerance
Diarrhea due to intestinal malabsorption
Mucosal disease-
Celiac disease
Sensitization to food proteins (CMPI, wheat)
Post enteritis syndrome
Bacterial overgrowth
Immunodeficiency syndrome
Parasitic infestation- Giardiasis
Inflammatory bowel disease
Autoimmune enteropathy
Radiation enteritis
Anatomical abnormalities
Short bowel syndrome
Lymphangiectasia
Metabolic abnormalities
A beta-lipoproteinemia
Acrodermatitis enteropathica
Hyperthyroidism
Hypoparathyroidism
Diabetes mellitus
Addison’s disease
Secretory disorders
VIPoma
Carcinoid
Systemic mastocytosis
Drugs
Antibiotics, laxatives, antacids
Others- Toddlers diarrhea, irritable bowel syndrome, microscopic and collagenous colitis
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Table 6.2: Published series on chronic diarrhea
1 2
Rastogi et al n-47 Yachha et al n-137 Lee et al3 n-27 Altuntas et al4 n-70
Tropical enteropathy Protracted diarrhea Post infectious
47% 33% 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%)- Lymphangiectasia 7%, Cystic fibrosis 10%
diarrhea 22% cystic fibrosis, glucose galactose
short gut, malabsorption 7.5%
acrodermatitis
enteropathica
Unknown- nil Unknown 13% Unknown 11% Unknown 10%
8. Does the patient have a history of abdominal pain? Is it suggestive of pancreatic origin
or obstructive in nature?
9. Has the patient undergone previous abdominal surgery? May point towards bacterial
overgrowth and short gut.
10. Are there features of an inflammatory syndrome like fever/joint pain/red eye/oral
ulcers suggestive of inflammatory bowel disease (IBD)?
11. Is there an increased likelihood of human immunodeficiency virus infection? (history
of blood transfusion, health of parents)
12. Is the patient on current therapy with a drug that may cause chronic diarrhea? (laxative/
magnesium in antacids)
13. Does the patient have a history of organ transplantation or abdominal radiation exposure?
14. Does the child have recurrent respiratory or skin infections? (suggestive of congenital
immunodeficiency)
15. Does the patient have other medical problems which predispose to diarrhea like liver
disease, congenital immunodeficiency, diabetes/hyperthyroidism, cystic fibrosis,
neurological disorders-abnormal motility, Down’s syndrome and other conditions
associated with celiac disease (CD)?
16. Is there a family history of food allergy, asthma or allergic rhinitis?
17. Is there a family history of celiac disease, Crohn’s disease or cystic fibrosis? Do other
family members have chronic diarrhea? First degree relatives of celiac disease have
a 5-15% risk of developing the disease.
Physical Examination
A complete general and systemic examination along with determination of growth is a must
in any child with chronic diarrhea. One should always look for drop in growth centiles.
Table 6.3:
IP :Common symptoms and signs of malabsorption and their pathophysiologic basis
112.133.195.17
Symptom/sign Pathophysiologic basis
Diarrhea Osmotic activity of carbohydrates or short chain fatty acids/
secretary activity of bile acids, fatty acids/decreased
absorptive surface
Abdominal distension Bacterial gas production from carbohydrates in the colon/
small bowel
Ascites/ edema Protein loss or malabsorption
Weight loss, FTT Nutrient malabsorption, poor intake
Muscle weakness, paresthesias Malabsorption of vitamin D, calcium, magnesium and
phosphate
Bone pain, osteomalacia, fractures Protein, calcium or vitamin D deficiency: secondary hyper-
parathyroidism
Easy bruisibility, ecchymoses Vitamin K and C deficiency
Glossitis, cheilosis, stomatitis Deficiency of vitamin B complex
Peripheral neuropathy Vitamin B12 or thiamin deficiency
Acrodermatitis, scaly dermatitis Zinc and essential fatty acid deficiency
Night blindness, Bitot’s spots Vitamin A deficiency
Koilonychia Iron deficiency
Anemia Iron, folate or vitamin B12 deficiency
Kidney stones Increased colonic oxalate absorption
Tiredness, fatigue, weakness Calorie depletion, anemia
The main features to be noted are:

1. Volume status and presence of dehydration.
2. Signs of vitamin and mineral deficiencies.
3. Edema-symmetric or nonsymmetric and pitting or non pitting.
4. Fever and other signs of toxicity.
5. Extra gastrointestinal manifestations in eye, skin, joints, oral cavity, thyroid.
6. Inspection of perianal area for fissures, anal tags and fistulae.
7. Oral thrush and scars of recurrent skin infections.
8. Abdominal examination, looking in particular for abdominal distention, localized or
generalized tenderness, masses, hepatosplenomegaly and ascites.
The common symptoms and signs of malabsorption and their patho-physiologic basis
are shown in Table 6.3. A practical and useful approach to a child with chronic diarrhea
is shown in Fig. 6.2 and it is very useful in investigating a given child.
After a detailed clinical evaluation, a differential diagnosis is made using the following
steps and then investigations are planned accordingly.
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Fig. 6.2: A practical approach to a child with chronic diarrhea
Step 1—Confirm that there is chronic diarrhea.

Step 2—Is it of small bowel or large bowel origin? A detailed history helps in differentiating
whether the diarrhea is of small bowel or colonic origin. Small bowel diarrhea is more often
large volume, watery or fatty and associated with nutrient deficiencies as small bowel is
the main site of nutrient absorption. In contrast large bowel diarrhea is usually smaller
volume, mixed with blood and mucus and associated with urgency and tenesmus. Pain is
periumbilical in small bowel as compared to hypogastric in large bowel diseases.
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Table 6.4: Difference between maldigestion and 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
Step 3—Is it mainly due to impaired digestion or due to impaired absorption?

Malabsorption syndromes due to mucosal diseases, such as celiac disease, typically produce
fatty diarrhea. Small bowel bacterial overgrowth causes steatorrhea by deconjugation of
bile acids. Maldigestion due to pancreatic exocrine insufficiency or inadequate duodenal
bile acid concentration produces steatorrhea. The following points help in differentiating
between maldigestion and malabsorption (Table 6.4).
Chronic watery diarrhea may be due to ingestion of osmotically active substances that
are poorly absorbed by the intestine (osmotic diarrhea- e.g. lactose intolerance), disordered
motility (thyrotoxicosis, short gut), ingestion of drugs or poisons and conditions causing
secretory diarrhea (tumors like gastrinoma and VIPoma’s). Measurement of stool sodium
(Na+) and potassium (K+) concentrations allows the physician to calculate an osmotic gap
in stool. The osmotic gap is calculated by subtracting twice the sum of the sodium and
potassium concentrations 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.
Investigations
The aim is to reach to a diagnosis with the simplest and least invasive tests. For every
patient a differential diagnosis should be made after history and examination and then
relevant investigations should be planned.
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 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
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fatty acid crystals; C difficile toxin assay (if suspected) and culture sensitivity.
4. Fat malabsorption—microscopic examination of random stool sample for fat globules
gives clue to the presence of steatorrhea. A sample of stool is placed on a glass slide,
Sudan III stain is added and examined under microscope. 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 to be the gold standard. Fecal
fat excretion is determined after supplementing the diet with 2 g/kg body weight of
fat (min 30 g for child <2y and 50 g for > 2 yr). Excretion of >4.5 g/day of fat in
stools is taken as abnormal. Accuracy depends on quantitative stool collections for
48 to 72 hours, adherence 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-g dose of d-xylose is swallowed 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 g of d-xylose in the urine collection or a serum xylose
concentration below 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. Hydrogen breath test: is a noninvasive test based on bacterial carbohydrate breakdown
and release of hydrogen, which is absorbed by the intestinal mucosa and excreted
in breath. The diagnosis of lactose malabsorption is established if there is an increase
in breath hydrogen concentration of more than 20 parts per million over baseline after
ingestion of 2 g/kg (max 50 g) of lactose. An increase within the first 30 minutes after
ingestion of lactose may be due to bacterial degradation of lactose in the oral cavity.
Breath hydrogen measurements obtained before and at 30, 60, 90, 180 and 240 minutes
after ingestion of 50 g of lactose provide the best diagnostic yield. Alternatively an
increase in glucose concentration of less than 20 mg/dL over baseline within 30 minutes
of ingestion of 50 g of lactose is also indicative of lactose malabsorption.
8. Fecal pH lower than 5.5 or presence of reducing substances >0.5% also suggests
carbohydrate malabsorption.
9. 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 labeled vitamin B12 and simultaneously a
large intramuscular “flushing dose” of non radio labeled 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.
10. Bacterial overgrowth—Quantitative culture of a small intestinal aspirate is the gold

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standard. Several breath tests, including the 14C-glycocholate breath test, the 14C-d-
xylose breath test, the lactulose-H2 breath test and the glucose-H2 breath test can be
used. The rationale for the breath tests is the production of volatile metabolites, that
is, 14CO2 or H2, from the administered substances by intraluminal bacteria, which is
measured in the exhaled air.
11. Endoscopy: Endoscopic inspection of the duodenal mucosa provides clues to some causes
of malabsorption like aphthae (Crohn’s disease), white punctate lesions
(lymphangiectasia) or scalloping of duodenal folds and reduction in number of duodenal
folds (celiac disease). Multiple biopsies should always be taken even with a normal
endoscopic appearance.
Fluid aspirated from the distal duodenum can be examined microscopically for parasites
or cultured to detect bacterial overgrowth. Small bowel histology may be diagnostic
or highly suggestive of a variety of small bowel disorders resulting in malabsorption
as shown in Table 6.5.
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.
12. Small bowel barium study—The main role of small bowel series is to identify abnormalities
that predispose to bacterial overgrowth, like diverticulum, intestinal hypo motility,
Table 6.5: Small bowel histology in various malabsorption states

Diagnosis Main histologic feature
Conditions with diagnostic
histologic abnormalities
Abetalipoproteinemia Lipid accumulation and vacuolization of enterocytes
Crohn’s disease Epetheloid granulomas (noncaseating)
Lymphangiectasia Dilated lacteals
Agammaglobulinemia Absence of plasma cells in lamina propria
Parasites (Giardia , strongyloidosis, Parasites may be seen on histology
coccidiosis, Mycobacterium avium complex) Acid-fast bacilli in MAC
Micro-villous atrophy Involutions of micro villi and secretory granules in
epithelial cells on electron microscopy
Tufting enteropathy Characteristic ‘tufts’ of extruding epithelium
Disorders with villous atrophy :not diagnostic
Celiac disease, tropical sprue, CMPI, post Varying degree of villous atrophy from partial to total
enteritis syndrome, bacterial overgrowth, and patchy to uniform changes
radiation enteritis and severe PEM
dilatation and intestinal fistulas. Ulcerations and strictures may be seen in Crohn’s
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disease, radiation enteritis, intestinal lymphoma and tuberculosis.
13. CT scan: CT is a good modality for pancreatic diseases. Calcification, dilatation of the
pancreatic duct and fatty pancreas can be easily picked up. It is a sensitive test to detect
enlarged abdominal lymph nodes, commonly present in tuberculosis, small bowel
lymphoma, or small intestinal Crohn’s disease.
14. 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.
15. Special tests—Antiendomysial and tissue transglutaminase antibodies are used for
screening of celiac disease. Antienterocyte 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 (NG) tube feeding may be required for severely
malnourished children. Diet modification is done according to the diagnosis (e.g. CMPI,
celiac disease etc.). TPN is required by a small subgroup especially those with neonatal
onset diarrhea and with short gut and even then small amount of enteral nutrition in
the form of ”trophic feeds” should be given to avoid TPN induced cholestasis.
4. Albumin infusion is needed only for severe symptomatic hypoalbuminemia.
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: is a common cause of diarrhea in thriving children, at about
6-20 months of age. The child has 3-6 loose stools, mostly during waking hours which often
contains undigested food. The diarrhea worsens with low residue, low fat or high
carbohydrate diet due to relative deficiency of pancreatic amylase in children and during
stress or infections. It resolves spontaneously by 3-4 years of age. These children have an
increased risk of developing irritable bowel syndrome (IBS) as adults and there is often
a family history of IBS. The postulated etiologies are abnormalities of bile acid absorption
in terminal ileum resulting in increased colonic secretions; incomplete carbohydrate absorption
or abnormal motor function.
The stool is negative for fat, red cells, white cells, parasites, and culture and sensitivity.
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Treatment is with a high (>40%) fat, low carbohydrate and high fibre diet and reduced
intake of juices. Maternal reassurance and explanation is very helpful. Medications are rarely
needed. Psyllium 1-2 tea spoon full twice a day or loperamide (0.1-0.2 mg/kg/day) in
2-3 divided doses may be tried for a short duration in exceptional circumstances.
Celiac disease: Celiac disease (CD) is an enteropathy caused by permanent sensitivity to
gluten in genetically susceptible subjects. The presenting features could be both gastrointestinal
(GI) and non GI and the disease may also remain asymptomatic for prolonged periods despite
the intestinal damage. The prevalence in children in the West is about 0.3-1.3%. CD is the
most common cause of chronic diarrhea in children over 2 years of age in North India2
but no prevalence data is available.
The common presenting symptoms are:
GI- diarrhea, FTT, abdominal distension, vomiting and mild abdominal pain.
Non GI–anemia, short stature, delayed puberty, osteopenia/osteoporosis, dental enamel
hypoplasia and dermatitis herpetiformis
Symptoms usually appear around 6-24 months of age, after weaning with wheat products.
Age of introduction and amount of wheat eaten and duration of breast feeding 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.5-7
The lag period between symptom onset and diagnosis runs into years in our country
and is mainly due to lack of awareness and often leads to severe growth failure and
malnutrition. Children with type I diabetes, autoimmune thyroiditis, Down’s syndrome,
Turner’s syndrome, William’s syndrome, selective IgA deficiency and first degree relatives
of celiac subjects are at an increased risk of developing CD and they should be screened.
Investigations: The following tests are done to make a diagnosis
• Serology: IgA antibody to tissue transglutaminase (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. IgA antiendomysial antibody (EMA) is an equally
accurate test (sensitivity 88-100%; specificity 91-100%) but as it is based on an
immunofluorescence technique, it is expensive, operator dependent and not universally
available. Both these tests are IgA dependent so if they are negative and still there is
a very high clinical suspicion of CD, one should get a total IgA estimation and in IgA
deficient individuals, IgG tTG estimation should be done. Antigliadin (IgA and IgG)
and antireticulin antibodies have high false positivity and thus are not recommended
as a test of choice now.
• Upper GI endoscopy may be normal or show absence of folds, scalloped folds, visible
submucosal vessels and mosaic pattern between folds. For a diagnosis of CD, intestinal
biopsy is a must and multiple endoscopic biopsies from second/third part of duodenum
are taken.
• Histology: The characteristic histological changes in CD are increased intraepithelial

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lymphocytes (>30/100 enterocytes), increased crypt length, partial to total villous atrophy,
decreased villous to crypt ratio and infiltration of plasma cells and lymphocytes in lamina
propria. The histological changes are graded according to Marsh criteria8 as follows:
- Grade 0—normal
- Grade 1—infiltrative (increased intraepithelial lymphocytes)
- Grade 2—hyperplastic (grade 1 + hyperplastic crypts)
- Grade 3—destructive (grade 2 + villous atrophy)
- Grade 4—hypoplastic (total villous atrophy + hypoplastic crypts)
Marsh 3/4 changes are characteristic of CD. Marsh 2 is compatible with CD but needs
serological positivity for definite diagnosis whereas grade 1 changes are not specific for
CD in children. The modified ESPGHAN criteria9 for diagnosis of CD are: suggestive clinical
picture, positive biopsy and unequivocal response to gluten free diet (GFD). Positive serology
(EMA/ tTG) gives more weight to the diagnosis, especially in our country where other
causes of villous atrophy like GI infections, malnutrition etc are more prevalent. Trial of
GFD without biopsy and serologic tests should not be used to make a diagnosis of CD
as this makes further confirmatory diagnosis more difficult and patients are unlikely to
comply with life long GFD without a confirmed diagnosis. HLA (DQ2/DQ8) positivity is
seen in majority (>99%) of subjects with CD and suggests the genetic association although
its determination has no role in routine clinical practice.
Treatment: It is indicated in symptomatic children with CD and asymptomatic children from
high risk groups with histological findings detected after screening.
The treatment is life long GFD, correction of iron and folate deficiency and avoidance
of lactose in the initial period for children with total villous atrophy. Repeated explanation
to parents by dieticians regarding both food items to be consumed and not to be eaten
is very helpful in sustaining compliance after the child is asymptomatic.
After initiation of GFD, there is prompt symptomatic response with rapid weight and
height gain in the first few months. Periodic visits for assessment of symptoms; growth
monitoring and dietary counseling are a must during this time. The celiac disease guideline
committee recommends tTG estimation after 6 months of GFD to show a decrease in titres
as an indicator of dietary compliance and also if there is recurrence of symptoms at any
time after GFD initiation.10
Repeat biopsy as a routine is not recommended by ESPGHAN in a subject who has shown
a prompt response to GFD. Adherence to GFD in various studies is found to vary between
45-81% and noncompliance is one of the causes of persisting histological abnormalities. Ideally
an annual assessment should be done as part of the long term follow up.
There is an increased risk of lymphoma, cancers, various autoimmune conditions and
osteoporosis in celiacs. Early treatment with GFD can avoid these complications. Repeat
biopsy with gluten challenge may be required in children who were diagnosed before two
years of age, had either atypical changes on first biopsy or no previous biopsy and adolescents
who are unlikely to continue with GFD.
Cow’s Milk Protein Intolerance (CMPI): is an allergic food intolerance to animal milk protein
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in which the infant develops symptoms after being fed animal milk. It is the most common
food allergy in small children who are top fed and can also occur occasionally in breast
fed children due to passage of cow’s milk antigen in breast milk.
Milk allergy can occur due to two mechanisms: one is IgE mediated which occurs within
minutes of milk intake and is characterized by vomiting, pallor, shock like state, urticaria
and swelling of lips. The other is the T-cell mediated which has an indolent course and
presents mainly with GI symptoms. The GI symptoms (seen in 50-80% patients) may be
reflux like i.e. vomiting, enteropathy like i.e. FTT, non bloody diarrhea, abdominal pain,
edema or proctocolitis like i.e. diarrhea, rectal bleeding. 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. Iron deficiency anemia,
hypoproteinemia and eosinophilia are commonly present. Chronic refractory constipation
and abdominal pain have been noticed to be related to milk allergy in older children in
recent years. Cow’s milk allergy (CMA) may develop after an episode of acute gastroenteritis
due to increased gut permeability and often leads to prolongation of diarrheal episode.
Onset of symptoms after introduction of cow’s milk along with a family/personal history
of atopy suggests CMA.
Investigations
• Skin prick test to cow’s milk antigen- reaction of > 3 mm is taken as positive
• Stool for blood, eosinophils and charcot layden crystals
• IgE antibodies against milk by ELISA or RAST
• Sigmoidoscopy in infants with colitic presentation shows edema, erythema, lymphonodular
hyperplasia, aphthous ulcers and histopathology shows eosinophilic infiltrates.
• Gastroscopy in children with chronic diarrhea and failure to thrive may show
lymphonodular hyperplasia in duodenum and biopsy reveals partial villous atrophy.
• The gold standard for diagnosis of any 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 fulfill
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 1year. 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 management of CMA includes removal of all cows milk/milk products from diet
IP : 112.133.195.17
and replacement with soy or hydrolyzed formula, both of which are equally effective in
terms of growth and nutrient intake. Soy is more palatable and cheap. 10-15% of CMA
subjects have soy allergy also and these children need special hydrolyzed formulae. A small
minority of children may not tolerate the hydrolyzed formulae and need elemental amino
acid formula. Parental education regarding diet and calcium supplementation is very
important. Introduction of solids like egg, wheat and fish is delayed as there is ~30% risk
of developing other food intolerance in these children. Most (90-95%) children outgrow
the intolerance by 3-4 years of age.
Tropical sprue: is a common cause of chronic diarrhea and malabsorption syndrome leading
to development of nutritional deficiency in adults from tropical countries but it is uncommon
in children. It is thought to occur due to persistent bacterial colonization of small bowel
by toxigenic strains of coliform bacteria. The onset is like acute diarrhea and then symptoms
become prolonged in form of diarrhea, abdominal cramping, anemia and weight loss. After
few months, fatigue and weakness develops secondary to anemia. On examination, pallor
glossitis, skin pigmentation and edema are present.
Investigations: macrocytic anemia (folate and vitamin B12 deficiency), abnormal D-xylose and
increased fecal fat is present. Hypocalcemia, hypoalbuminemia and deficiency of fat soluble
vitamins is common. Histopathology of small bowel reveals partial villous atrophy and a
completely flat mucosa in < 10% subjects. Small bowel barium study shows nonspecific changes
like thickened mucosal folds in jejunum and ileum along with luminal dilatation and flocculation
of barium.
Treatment: Administration of folate (5 mg/day) and vitamin B12 (100 μg intramuscularly once
a month) is done along with tetracycline which is usually given for 6 weeks but sometimes
it may be given for longer periods. Prognosis is good with rapid symptomatic response
and complete intestinal healing.
Bacterial overgrowth: The normal proximal small intestine is colonized by predominant
aerobic flora (<102-103 organisms/ml). Small bowel bacterial overgrowth is characterized
by malabsorption and overgrowth of bacteria (similar to normal colonic flora) in the small
intestine. Predisposing factors include anatomic abnormalities (diverticulum, duplication,
stricture and blind loop), motility problems (pseudo obstruction, diabetes mellitus and
scleroderma), abnormal host defense (malnutrition, immunodeficiency) and achlorhydria.
Bile salt deconjugation leads to inadequate fat absorption. 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. Anemia and growth
failure may also be present. As bacteria produce folate and vitamin K, their deficiency is
not present.
Investigations: Barium meal follow-through shows anatomic abnormalities. Duodenal fluid
aspiration reveals presence of deconjugated bile salts, short chain fatty acids (acetic, propionic
and butyric) and culture shows abnormal bacteria (> 105 CFU/ml is diagnostic). Lactulose
breath test reveals early H2 peak but may be falsely negative in patients with prior antibiotic
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use or colonization with non H2 producing bacteria.
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),
fat soluble vitamin and B12 is helpful. Repeated courses for 2-4 weeks of antibiotics like
metronidazole, tetracycline, co-trimoxazole, chloramphenicol and gentamycin are given and
improvement often lasts for months. Probiotics may have a role but more evidence is needed.
Short gut: Short gut syndrome is a collection of signs and symptoms occurring after intestinal
resection, characterized by weight loss and malabsorption of fluids, macro and micro nutrients.
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 by total parenteral nutrition (TPN) followed by gradual introduction of enteral
feeds as the next step. The dietary modification depends to a large extent on the presence
or absence of colon as it is efficient in sodium and water absorption and limiting calorie
loss by absorption of short chain fatty acids.
Immunodeficiency: Both congenital and acquired immunodeficiency can cause chronic
diarrhea.
Congenital immunodeficiency: The congenital immunodeficiency syndromes most commonly
associated with malabsorption are X-linked agammaglobulinemia, selective IgA deficiency, chronic
granulomatous disease and severe combined immunodeficiency.
X linked agammaglobulinemia: Gastrointestinal (GI) involvement can occur due to giardiasis,
cryptosporidium, bacterial overgrowth or chronic rota-virus 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.
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
IP : 112.133.195.17
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 γ interferon and antimicrobial administration.
Acquired immunodeficiency (AIDS): Chronic/recurrent diarrhea is present in 15-43% of
children with AIDS in India11, 12.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. AIDS enteropathy is characterized by chronic diarrhea and marked weight
loss in absence of enteric pathogens. Histopathology reveals partial villous atrophy, increased
intraepithelial lymphocytes and no hyperproliferative crypts. Perinatal infection generally
presents clinically in first two years of life. Associated intrauterine growth retardation is
common. Chronic diarrhea with oral thrush, lymphadenopathy, hepatosplenomegaly and
parotiditis (10-20% cases) is typical.
Investigations: Repeated stool examination is done for opportunistic infections by using special
stains and PCR. Colonic/terminal ileal biopsy and duodenal fluid samples can also pick up
these infections. Yield is higher if CD4 count is < 100 mm3 and the following organisms
may be isolated:
Viral: Cytomegalovirus, Herpes virus, Adenovirus, Coxsackie’s virus
Bacterial: Salmonella, Shigella, Mycobacterium avium complex (MAC), campylobacter
Fungal: Candida, Histoplasma
Parasites: Cryptococcus, Microsporidium, Isospora, Amoeba, Giardia and Strongyloidosis.
Treatment is with specific antimicrobials along with HAART (highly active anti retro
viral therapy).
Intestinal lymphangiectasia: Is characterized by ectasia of the bowel lymphatic system,
which on rupture leads to leakage of lymph in bowel. The disease is often associated with
abnormal lymphatics in extremities. It may be a primary intestinal abnormality or secondary
to conditions like congestive heart failure or constrictive pericarditis. 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
abdominal pain. Abdominal and/ or thoracic chylous effusions may be associated.
Investigations: Low albumin, low calcium, decreased immunoglobulin and lymphopenia is
characteristic. Fecal alpha1antitrypsin and fat is increased. Barium meal follow-through shows
thickening of jejunal folds with nodular lucencies in mucosa. Lymphangiography reveals
the abnormal lymphatics. On endoscopy scattered white plaques or chyle like substance
covering the mucosa may be seen and duodenal biopsy reveals dilated lacteals in villi and
lamina propria.
Treatment: Low fat, high protein diet with medium chain triglycerides (MCT), calcium and
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fat soluble vitamin supplementation helps in reducing diarrhea. Intravenous albumin is required
for symptomatic management and total parenteral nutrition (TPN) is reserved for management
of chylous effusions. Octreotide has some efficacy. If lesion is localized to a small part of
intestine, resection is curative.
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. 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 sensations and sensory ataxia with positive Romberg’s sign. Eye
involvement in form of retinitis pigmentosa and night blindness also appear after 5 years
of age.
Investigations: Chylomicron, very low density lipoprotein (VLDL) and low density lipoprotein
(LDL) are absent in plasma. Anemia, increase in reticulocyte count due to vitamin E deficiency
and hemolysis and 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 sino pulmonary infections are typical.
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.
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. If suspicion of PMC is present then a toxin assay in
stool and sigmoidoscopy is done for confirmation. 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.
Metaclopramide use for gastroesophageal reflux disease can cause significant diarrhea.
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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 vehicle can lead to osmotic diarrhea.
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 SBBO.
Loperamide may also be tried. There is an increased risk of celiac disease (5-7% incidence)
in patients with diabetes and diabetic diarrhea needs to be differentiated from celiac disease
in a diabetic.
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: 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 hydroxy tryptamine 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 secretion 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 tumor is curative and palliation
is done with proton pump inhibitors and octreotide.
VIPoma: VIP secreting tumor leads to increased intestinal secretion. High volume (>20ml/
kg/d) watery diarrhea with hypokalemia and achlorhydria is typical. Commonest VIPoma
in childrenIP
is :ganglioneuroma
112.133.195.17or 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 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 malabsorption typically leads to flatulence, borborygmus, abdominal
distention, pain and diarrhea. Stools are typically watery, explosive and with flatus.
Disaccharidase deficiency can either be congenital primary or secondary to mucosal
damage.
Primary disaccharidase deficiency
Sucrase isomaltase deficiency: The disease is heterogenous as all patients lack sucrase but
isomaltase deficiency is variable. It is a rare autosomal recessive condition and presents
with fermentive diarrhea on starch/sucrose ingestion and failure to thrive. Tolerance of
starch generally improves with age.
Diagnosis: sucrose is not a reducing sugar so reducing substances in stools will be negative
until the sucrose is hydrolyzed. Abnormal sucrose tolerance test and absence of enzyme
in small intestinal biopsy are diagnostic.
Treatment is by elimination of sucrose and starch from diet. Yeast sucrase preparation
is available which can be taken with meals.
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. It is the most common genetically determined disaccharidase
deficiency. Symptoms have a variable onset from 3 years to adolescence depending on
ethnicity. The effects of lactose ingestion are related to 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. Yogurt is well tolerated. Diagnosis is made by quick clinical response to
withdrawal and relapse on reintroduction of lactose, oral tolerance test with lactose, breath
hydrogen test and enzyme estimation in jejunal biopsy.
Management includes calcium supplementation, avoidance of excessive intake of milk,
and administration of lactase enzyme (tablets) with milk.
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.
Chronic Diarrhea of Neonatal Onset

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A large number of conditions lead to intractable watery diarrhea in infancy. 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
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 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 neonatal diarrhea. Simple dietary measures
are the mainstay of therapy in conditions like celiac disease and food allergy and utmost
importance should be given to adequate dietary councelling. Immune deficiencies, especially
HIV infection is likely to emerge as a problem in the coming years. A better understanding
of pathophysiology and therapy had lead to improved outcome 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
IP : 112.133.195.17
are the cornerstone of therapy in many conditions and detailed parental counseling 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 POINTS
1. Chronic diarrhea is an important cause of failure to thrive in infants and children.
2. Celiac disease, milk protein allergy, parasitic infestations and post enteritis syndrome
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.
6. Outcome is largely dependent on the primary diagnosis.
REFERENCES
1. Rastogi A, Malhotra V, Uppal B, et al. Etiology of chronic diarrhea in tropical children. Tropical
Gastroenterology 1998;19:45-49.
2. Yachha SK, Misra S, Malik AK, Nagi B, Mehta S. Spectrum of malabsorption syndrome in North Indian
children. Indian J Gastroenterology 1993;12:120-25.
3. Lee WS, Boey CCM. Chronic diarrhea in infants and young children: causes, clinical features and
outcome. J Pediatr Child Health 1999;35:260-63.
4. Altuntas B, Gul H, Yarali N, Ertan U. Etiology of chronic diarrhea Ind J Pediatr 1999;66:657-61.
5. 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;19:204-8.
6. Patwari AK, Anand VK, Kapur G, Narayan S. Clinical and nutritional profile of children with celiac
disease. Indian Pediatr 2003;40:337-42.
7. Poddar U. Celiac disease: clinical features and diagnostic criteria. Indian J Pediatr 1999;66(1 Suppl): S21-
5.
8. March MN. Gluten major histocompatibility complex and the small intestine. Gastroenterology 1992;102:
330-54.
9. 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 199065:909-11.
10. 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.
11. Merchant RH, Oswal JS, Bhagwat RV, Karkare J. Clinical profile of HIV infection. Indian Pediatr 2001;38:
239-46.
12. Doga SR, Verma B, Gasavi DV. HIV infection in children: Indian experience. Indian Pediatrics
1999;36:1250-53.
13. Smith ME, Morton DG. The digestive system: basic science and clinical conditions. Churchill Livingstone
2001. IP : 112.133.195.17
14. Walker Smith JA, Murch S. Diseases of the small intestine in childhood. ISIS Medical Media Fourth
Edition 1999.
15. Walker WA, Durie PR, Hamilton JR, Walker-Smith JA, Watkins JB. Pediatric Gastrointestinal disease
(3rd edn), 2000.
16. Baldassano RN, Liacouras CA. Chronic diarrhea: A practical approach for the pediatrician. PCNA 1991;
38:667-86.
17. Sampson HA, Anderson JA. Summary and Recommendations: Classification of Gastrointestinal
Manifestations due to immunologic reactions to foods in infants and young children. J Pediatr
Gastroenterol and Nutr 2000;30:S87-94.
18. Sicherer SH. Food Protein –induced enterocolitis syndrome: case presentation and management lessons.
J Allergy Clin Immunol 2005;115:149-56.
19. Guarino A, Bruzzese E, De Marco G, Buccigrossi V. Management of gastrointestinal disorders in children
with HIV infection. Paediatr Drugs 2004;6:347-62.
20. Scolopio JS. Short bowel syndrome. J Parenteral and Enteral Nutrition 2002;26:S11-16.
21. Sherman PM, Mitchell DJ, Cutz E. Neonatal enteropathies: defining the cause of protracted diarrhea
in infancy. J Pediatr Gastroenterol Nutr 2004;38:16-26.
22. Murch SH. Unusual enteropathies. Gastrointest Endosc Clin N Am 2001;11:741-66.
Abdominal Tuberculosis / 79
A Riyaz
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Abdominal
7 Tuberculosis
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 extrapulmonary 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. Genito-urinary 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, M. bovis was isolated in 80% of the 71 culture positive cases.4 Some
of the other species implicated are Mycobacterium avium and Mycobacterium intracellulare5,
especially in HIV infected children.
The routes of GI infection include the following:

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1. Hematogenous spread from the primary lung focus in childhood
2. Ingestion of infected sputum(as in sputum positive patients with cavitatory TB)
3. Direct spread from adjacent organs with primary tuberculous infection (as in renal TB
affecting the duodenum)
4. Lymphatic spread from tuberculous lymph nodes(as in spread to the esophagus from
mediastinal tuberculous nodes).
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 3 types:
1. 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 involvement of
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 present9. 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 normal.
The long axis of the ulcer lies transversely as it follows the lymphatics, unlike in Crohn’s
disease, in which the ulcers are 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.
2. Hypertrophic (10%)
IP : 112.133.195.17
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.
3. Ulcerohypertrophic (30%)
This is seen in the ileocecal region and colon. These patients have features of both the ulcerative
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/loculated
• 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. 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
IP : 112.133.195.17
This is the least common site of intestinal TB (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 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.
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, vomiting and fever.
There may be a doughy feel on abdominal palpation. A firm mass may be palpable in the
right iliac fossa. The most common complication is obstruction due to stricture. 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.
Ileocecal TB
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 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
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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 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 loops of intestine, especially
the ileum, to become matted together and distended. The distended bowel 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
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This may present as a firm lump in the abdomen due to enlarged lymph nodes. The lymph
nodes may obstruct bile duct, pancreatic duct, duodenum, inferior vena cava and ureter.23
The other causes of mass abdomen in abdominal TB could be loculated ascites, rolled up
omentum or thickened bowel loops.
DIAGNOSIS AND INVESTIGATIONS

Paustian’s Criteria24
At least one of the following criteria must be present to diagnose abdominal TB:
• Animal inoculation or culture of suspected enteric (exclusive of mucosal layer), mesenteric,
or regional lymph node tissue resulting in growth of the tubercle bacillus
• Histologic demonstration of typical acid–fast staining rods of M. tuberculosis in the lesion
• Histologic evidence of tubercles with caseation necrosis
• A typical gross description of operative findings with biopsy of mesenteric nodes showing
histologic evidence consistent with tuberculosis.
These criteria 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.25 Mantoux test is positive in about 50%.26
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
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.

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• Deep fissures, sinus tracts, enterocutaneous fistulae, and perforation can occur, although
less commonly, compared to Crohn’s disease
• Luminal stenosis with smooth but stiff contors (“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 contor 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
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.27
• 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
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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.
• Pseudo kidney sign - involvement of the ileocecal region which is pulled up to a sub
hepatic position.
CT Scan
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 hypodense centers and peripheral rim
enhancement. 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.28
Endoscopy
Endoscopy of the upper GI tract is useful in the diagnosis of lesions in the esophagus, stomach
and duodenum.
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.29
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
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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.30
Ascitic Fluid Examination

In tuberculous ascites, the fluid is typically straw colored. The protein content is more than
3g% 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.31 AFB staining is positive only in 3%. A positive culture
is obtained in about 20% of cases, but it takes 6 to 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. 32
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.
33
Laparoscopic Findings
The laparoscopic findings in peritoneal TB can be grouped into 3 categories 34
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.
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.35
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.36 The Revised National Tuberculosis Control
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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.37 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. 38
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 15mg/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 (Mention about use of SM/
quinolones)
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 grand parents, 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..39 For ileocecal lesions, previously a right hemicoelctomy 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.40
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 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, ascites, subacute obstruction, 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

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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 1 of RNTPC. 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 always
possible 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 re-emergent killer. Science 1992;257;1055.
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, Deshmukh MD, Pamra SP,
Sen PK, Bordia NL, et al. Textbook of tuberculosis, 2nd edn. 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. Mycobacterial infections. In Chamion RH, Burton JL, Burns DA, Breathnach SM Rook
textbook of dermatology 6th edn. Blackwell Science, London, 1998;2:1181-1214.
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.
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;72:712-2.
21. Arya TVS, Jain AK, Kumar M, Agarwal AK, Gupta JP. Colonic tuberculosis: a clinical and colonoscopic
profile. Indian J Gastroenterol 1994;13(Suppl):A116.
22. Widhwa N, Agarwal S, Mishra K. Reappraisal of abdominal tuberculosis. J Indian Med Asso 2004;102:
31-2. IP : 112.133.195.17
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. Paustian FF, Marshall JB. Intestinal tuberculosis. In Berk EJ (Ed). Bockus textbook of gastroenterology,
4th edn, Philadelphia, WB Saunders, 1985;3(4):2018-36.
25. Thapa BR, Yaccha SK, Mehta S. Abdominal tuberculosis. Indian Pediatr 1991,28: 1093-1100
26. 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.
27. Sharma AK, Aggarwal LD, Sharma CS, Sarin YK. Abdominal tuberculosis in children: experience over
a decade. Indian Pediatr 1993;30:1149-53.
28. Gulati MS, Sarma D, Paul SB. CT appearances in abdominal tuberculosis. A pictorial assay. Clin Imaging
1999;23:51-9.
29. Singh V, Kumar P, Kamal J, Prakash V, Vaiphei K, Singh K. Clinicocolonoscopic profile of colonic
tuberculosis. Am J Gastroenterol 1996;91.
30. 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
Gastroenterol 1992;87:105-8.
31. Murshall JB, Vogele KA. Serum-ascites albumin difference in tuberculous peritonitis. Am J Gastroenterol,
1988;83:59-61.
32. Dwivedi M, Misra SP, Misra V, Kumar R. Value of adenosine deaminase estimation in the diagnosis
of tuberculous ascites. Am J Gastroenterol 1990;85:1, 123-5, 565-8.
33. Delacourt C, Doveda JD. Use of polymerase chain reaction for improved diagnosis of tuberculosis
in children. J Pediatr 1995;126:703-9.
34. 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.
35. Riyaz A. Abdominal tuberculosis In: Riyaz A. Pediatric Gastroenterology and hepatology Paras
publishers, Hyderabad, 2003;108-12.
36. Bajpai M, Gupta DK. Abdominal tuberculosis: In Seth V, Kabra SK (Ed). Essentials of tuberculosis in
children, Jaypee Bros, New Delhi, 2001;108-17.
37. Management of pediatric tuberculosis under the revised National Tuberculosis Control Program. Ind
Pediatr, 2004;41:901-5.
38. Anand BS, Nanda R, Sachdev GK. Response of tuberculous stricture to antitubercular treatment. Gut
1988;29:62-9.
39. Pujari BD. Modified surgical procedures in intestinal tuberculosis. Br J Surg 1979;66:180-3.
40. Miller ALW, Cywes S. Abdominal tuberculosis in children –surgical management. A 10 year review
of 95 cases. Pediatr Surg Int 1990;5:392-6.
Inflammatory Bowel Disease in Children and Adolescents / 91
Malathi Sathiyasekaran, So Shivbalan
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Inflammatory Bowel Disease

8 in Children and Adolescents
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 non-specific and therefore this group is termed as
indeterminate colitis (IC)1. The worldwide distribution of IBD shows a higher prevalence
in the developed western countries compared to the developing countries of Asia and Africa.
In India both CD2 and UC3 have been reported in children and adolescents. IBD can occur
in any age group but is more common in older children and adolescents. Approximately
30% of all newly diagnosed cases of IBD occur in individuals less than 20 years of age.4
The clinical presentation of IBD is varied with relapses and remissions and it is necessary
for the pediatrician to recognize the problem and refer to the pediatric gastroenterologist
for appropriate investigation and management. This chapter describes the clinical presentation,
complications, prognosis and management of this disease.
Epidemiology
The incidence of IBD in children is much less than that seen in adults. It is more prevalent
in Scandinavian, Western European and North American countries compared to Asian, African
and South American countries. 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.5 The incidence of CD is on the rise in
children similar to the trend seen in adults. A comprehensive study from Scotland
demonstrated a 3-fold rise in CD from 1968 to 1988.6 Contrary to this finding the incidence
of UC shows a more stable pattern though in some countries there is a tendency for increase.
In India there are reports of both UC and CD in adults whereas data on pediatric IBD
is scarce except for a report on CD and another on UC.2,3
Age
The 2 main peaks in the age incidence of IBD occur in the early and later adult life. A much
smaller peak is seen 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.4 Pediatric
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IBD can manifest at any age but is rare in infancy. Only 1% of all childhood IBD are diagnosed
before the age of one year.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 have
registered children less than 2 years of age with IBD. Their data has depicted that the number
of children with IBD increase with age and the maximum is in the age group of 12 to 18
yrs.5 Early onset IBD (EOIBD) i.e. disease occurring before the age of 5 years is a unique
subset and accurate differentiation between UC and CD is difficult in this group.8
Sex
IBD is seen in both sexes. In US there seems to be a preponderance of CD in boys5 whereas
in the study reported from south India it was more prevalent in girls.2 UC affects both
sexes equally.
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 persons with hemophilia, von Willebrand’s disease and inherited disorders of coagulation
probably as these diseases might protect against microvascular thrombosis.9
Breast Feeding
Children who receive formula feeding during infancy do not appear to be at a greater risk
for developing UC than those who receive breast milk. The negative association between
breast-feeding and CD has not been validated and remains controversial.10
Smoking
Cigarette smoking apparently protects against the development of UC in adults but data
in childhood is less clear. Passive smoking during childhood protects against development
of UC in adulthood but similar protective effect has not been demonstrated in childhood.
Passive smoking however may increase the risk of developing CD in a child.10
Infections
Infection with various organisms such as measles virus, chlamydia, pseudomonas maltophilia,
mycobacterium (paratuberculosis and kansassi) have been related with 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. The recent surge in the incidence of CD in several countries including
India could be due to an “improved sanitation hygiene” hypothesis.11 Intestinal helminths
have disappeared in developed countries due to improved sanitation and this has coincided
with the appearance of IBD.11 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

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infarction, and eventually chronic sequelae such as ulcerations, fistulas, fibrosis, and strictures.
Genetics
A well-recognized risk factor for IBD is having a first degree relative with CD or UC. The
age-adjusted risk of developing CD during lifetime is about 4% for a first-degree relative
of a proband.12 The lifetime risk of developing IBD for daughters is 12.6% compared to
7.9% risk for sons.12 A high rate 44.4% of concordance is seen between monozygotic twins
compared to 3.8% among dizygotic twins, which also supports the genetic theory13. IBD
incidence is lower among relatives of probands with UC compared to CD. Familial IBD
is particularly common with EOIBD and the incidence of IBD among first degree relatives
may be as high as 56%.4 The alleles DRB1*01 and DRB1*07 are associated with increased
susceptibility to CD whereas DRB1*03 has a strong negative association with this disorder.
HLA-DR2 is present in 40% of patients with UC.
The CD susceptible gene or IBD 1 is linked to NOD2/CARD 15 (Cathapse Activation
Recruitment Domain) and identified on chromosome 16.The NOD2/CARD 15 encodes the
protein recognizing lipopolysaccharides of the bacterial cell wall membrane. Mutations of
this gene predispose to CD by the inappropriate response to bacterial components and
therefore alter the signaling pathways of the innate immune system. This in turn leads to
the development and persistence of intestinal inflammation. This genetic make up is associated
more with ileal disease, earlier onset and stricturing disease.14 The genomic region for UC
called as IBD2 is on chromosome 12q.
Immunologic Factors
The understanding that immunologic factors play a leading role in the pathogenesis of IBD
has changed the basis of management. IBD may represent an aberration in the normal balance
between physiologic inflammation and pro-inflammatory cytokines resulting in a conversion
of a physiological to 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.
Pathophysiology
The prevailing hypothesis regarding the pathogenesis of IBD seems to be an interplay of
three factors namely environment, altered immunologic response and a genetically predisposed
child leading to chronic inflammation of the gastrointestinal tract15 (Fig. 8.1).The active
mucosal inflammation of the small and large 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 In CD a dysregulated
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Fig. 8.1: Pathophysiology of IBD
TH1 response (T helper 1) seems to be crucial in the conversion of physiologic to pathologic

inflammation. The immunologic profile of patients with UC is characterized by a
predominantly humoral response, which is distinctly different from the predominantly cell-
mediated response, seen in CD. In UC, there is marked overproduction of immunoglobulin
G1 (IgG1) by both intestinal lymphocytes and those in the peripheral circulation.
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 is seen in 10-20 % and diffuse
small bowel disease involving the proximal ileum or jejunum is seen in 10-15 %.4 Younger
children (less than eight years of age) have more of colonic presentation. Isolated
gastroduodenal disease may be seen in less than 5% of children whereas endoscopic and
histologic gastroduodenal disease has been reported as high as 30-40% .17 In IBD the
involvement of the small intestine differentiates CD from UC. Perirectal disease is seen
in 20% of patients and is associated with recto sigmoid inflammation. Noncaseating
granuloma, the hallmark of CD, is found in about 30% of all cases. CD is subcategorized
as predominantly inflammatory, fistulizing or stricturing disease based on the clinical
phenotype.
Ulcerative Colitis
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Unlike CD where inflammation is transmural, 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). The distribution of UC in children depicts 5% with proctitis, 10% to
15% proctosigmoiditis, 30% to 40% disease left sided colitis, and 50% pancolitis.16 In the
evolution of the disease proximal extension of proctosigmoiditis is around 25% within 3
years of diagnosis and could increase to 70% over the course of 5 years.18 The histopathology
findings such as cryptitis, crypt abscess and depletion of goblet cells are features seen in
UC.
CLINICAL PRESENTATION
Gastrointestinal Manifestation
Ulcerative Colitis
Children with UC most commonly present with diarrhea, rectal bleeding, and abdominal
pain. Nausea and vomiting may be a presentation in some children. UC is classified as mild,
moderate and severe depending on the clinical presentation. The severity of symptoms is
variable 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 the most dangerous
complication of fulminant colitis is rare in the pediatric age group.
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. Nocturnal abdominal pain
is a common symptom and a dyspeptic-type of epigastric pain may occur in children with
gastroduodenal involvement. Diarrhea occurs in two thirds of affected children and may
be severe and nocturnal.16 In children with predominantly ileal involvement constipation
may be a rare presentation. Gross blood in the stools is unusual with isolated small bowel
disease but 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. The common clinical presentation of the children
with CD in south India was also abdominal pain and weight loss.2 Perirectal involvement
fistulae, fissure and skin tags are seen in 25-30% of children.10 CD can be classified as
mild,moderate and severe based on the clinical presentation and the working definitions
of Crohn’s disease activity help in choosing therapy.20
Mild-moderate Disease
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Mild-moderate Crohn’s disease applies to ambulatory patients 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, 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). Higher PCDAI scores correlates with disease severity
and is helpful in measuring response to therapy.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. Toxic
megacolon occurs in 5% of patients with UC but is rare in young patients. In toxic megacolon
the colon gets enormously dilated secondary to severe inflammation. This results in disturbed
intestinal motility and translocation of bacteria into the submucosal tissues resulting in necrosis
and peritonitis. There is also an outpouring of fluid into the lumen causing dyselectrolytemia.
Toxic megacolon presents with fever, abdominal distension and tenderness and is associated
with a high risk of colonic perforation, gram-negative sepsis and massive hemorrhaghe.4
Perforation is seen more in UC than in CD. In UC the perforation occurs secondary to toxic
megacolon or severe colitis whereas in CD the ulcers perforate into adjoining segments
of bowel especially between the ileum and sigmoid colon resulting in internal fistulae rarely
the ulcers can perforate into the retroperitoneum. Fistula and abscess formation is more
common in CD than UC, perirectal and perianal fistulae are common and perianal disease
can precede the intestinal manifestation by years. Carcinoma of the colon is a long-term
complication of IBD. The two well accepted risk factors are duration and severity of the
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disease. The absolute cumulative frequency of risk for development of colorectal cancer
in extensive Crohn’s colitis is 8% after two decades of disease and is 7% for subjects with
ulcerative colitis.23 The cumulative colorectal cancer incidence for children with UC is 5%
at 20 years and 40% at 35 years in those with onset of disease before the age of 15 years
whereas it is 5% and 30% for those whose colitis began between 15 and 39 years.4 Children
who develop UC before the age of 10 years should undergo surveillance and be prepared
psychologically for possible future colectomy.
Extraintestinal manifestations may be seen in 25-30% of patients with IBD and may have
some prognostic significance.4 They may occur before, concurrently with the disease or even
after the diseased colon is resected as in total colectomy. Some are directly related to intestinal
disease activity and respond to therapy directed against bowel disease, some unrelated
to bowel disease activity, others a direct result of the diseased bowel and a few may be
iatrogenic secondary to therapy. Skin manifestations of IBD include erythema nodosum
and pyoderma gangrenosum. Erythema nodosum appears as raised, tender nodules usually
on the anterior surface of the legs and is less frequent in pediatric IBD. Therapy of erythema
nodosum involves treating the underlying disease. Pyoderma gangrenosum is a chronic
indolent ulcer, which may occur even while the disease is in remission.4 Apthous ulceration
is the most common oral manifestation of IBD. The oral manifestations may occur along
with intestinal disease or may precede it. Oral manifestation of CD as the initial presentation
has also been reported in children from south India.2 Ocular manifestations such as episcleritis
and anterior uveitis are also less common in children than in adults and occur when the
disease is active. Arthritis is another common extraintestinal manifestation in children and
occurs in 7-25 % of pediatric IBD.24 In children the arthritis may occur years before the
intestinal symptoms occur. Hepatobiliary complications such as chronic hepatitis, sclerosing
cholangitis and cholelithiasis occur in children with IBD and may precede the active disease.
The renal manifestations of IBD include nephrolithiasis, hydronephrosis and enterovesical
fistula. Nephrolithiasis occurs in approximately 5 % of children with IBD. It is usually secondary
to fat malabsorption that occurs in small bowel CD. Various other extraintestinal
manifestations have been reported including thromboembolic manifestations, vasculitis
pancreatitis, interstitial pneumonitis and pericarditis.
Malnutrition
The nutritional status of the child with IBD is compromised more in CD than in UC and
failure to thrive is a common presentation of CD. Weight loss may occur in more than 50%
of children with CD at the time of presentation. The cause of malnutrition can include
suboptimal dietary intake, increased gastrointestinal losses, 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. Fecal calcium and magnesium losses may be increased. Deficiency states
for iron, folic acid, vitamin B12, nicotinic acid, vitamin D, vitamin K, calcium, magnesium,
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and zinc may occur.
Growth Failure
Decrease in growth velocity may precede gastrointestinal symptoms in more than 50% of
children with CD25 and permanent growth failure can also occur. In comparison to CD only
10% of children with UC demonstrate significantly impaired linear growth. The reason for
this difference could be due to the different cytokine profiles seen in the two diseases.
The probable reasons for growth failure include chronic undernutrition or administration
of corticosteroids.8 Serum levels of insulin-like growth factor (IGF 1) have been documented
to be low in growth retarded children with CD, however this has not been a consistent
finding. Growth hormone levels are normal or if depressed respond to stimulation testing.4
The delay in sexual maturation seen in some children with IBD may have significant effect
on self esteem and socialization. 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.5
Bone Disease
Bone disease is a common problem in children with IBD. In a normal child the acquisition
of bone mineral occurs throughout growth and development. The peak bone mass (PBM)
is the maximum amount of whole-body bone mineral content attained during the life cycle,
and is a major determinant for the risk of osteoporosis in later life. More than 90% of PBM
occurs during childhood and adolescence of which 25 % occurs during the peak height velocity.
Hence IBD, which occurs during this critical period, has the potential to cause life long
bone disease. The other reasons for bone disease in IBD include malnutrition, effect of
cytokines and glucocorticoid therapy.5 Despite the potential for children with IBD to develop
osteoporosis, the bone mineral density in adulthood can be normal if the disease is managed
properly.
DIAGNOSIS
Initial Evaluation
The initial evaluation of a child with suspected IBD includes a detailed clinical, family and
treatment history. Any child or adolescent presenting with recurrent abdominal pain associated
with or without fever, 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) in an Indian setting. 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 children with diarrhea due to IBD from
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those who have irritable bowel syndrome. Calprotectin constitutes ~60% of the soluble cytosol
proteins in neutrophil granulocytes and plays a central role in neutrophil defense.
Consequently, its concentration in stool correlates with the intensity of neutrophil infiltration
of the intestinal mucosa and with the severity of inflammation.26
An ultrasound (US) examination of the abdomen may detect thickened bowel loops,
pseudo kidney sign and enlarged lymhnodes in CD. The US findings of free fluid, lymph
nodes, thickened mesentry or omentum are more diagnostic of abdominal tuberculosis than
CD.The diagnosis of IBD in children is suggested by a combination of clinical observations
and confirmed by laboratory, radiologic, endoscopic, and histologic findings.
Endoscopic Evaluation
Colonoscopy has played a significant role in the diagnosis of IBD. In UC the distribution
of disease is categorized as distal disease , left sided colitis and pancolitis. 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 bleed and ulcerations (Fig. 8.2). 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. The ileocaecal valve may appear patulous. 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. 8.3).
The rectum is usually spared. Strictures may be present which may interfere with completion
of the procedure. If the terminal ileum is involved it is more a feature of CD than UC.
It is always necessary to attempt visualization and biopsy the ileal mucosa in children
suspected to have CD to exclude ileal involvement. The characteristic noncaseating granuloma
is diagnostic of CD. The transmural distribution of the inflammation and the fissuring ulcers
involving the muscularis propria are highly characteristic of CD. Gastric antral biopsy is
recommended in patients with CD and identification of focal active gastritis or microgranuloma
Fig. 8.2: Colonoscopic appearance of ulcerative colitis showing loss of vascular pattern, and ulcers
without normal intervening mucosa
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Fig. 8.3:Colonoscopic appearance of Crohn’s disease showing irregular ulcers with normal
intervening mucosa
also increases the diagnostic yield.27 Normal appearing colonic mucosa should also be biopsied
since microscopic inflammation is a feature of CD.
In India it is common to misdiagnose CD and treat it 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. Lymphnode involvement can occur without bowel involvement
in CD but not in TB.28
Barium Meal Series is useful especially in CD to detect small bowel involvement. Strictures,
fistulae, ulcerations may be identified. This contrast study has largely been replaced by
contrast enhanced computerized tomography of the abdomen.
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. Ultrasound abdomen is done as a primary modality of investigation and is useful
as a screening tool.
Serological markers are potentially important addition to the diagnostic panel of IBD.
Combination of perinuclear anti-neutrophil cytoplasmic antibody (pANCA) and anti
sacchromyces cerevisiae antibody (ASCA) in older children have shown 57 % sensitivity
with 92 % specificity in UC whereas in CD the specificity has been 95% with sensitivity
of 55%.29 At present they are not considered as a screening test for pediatric IBD. The usefulness
of these markers in children less than 5 years has also not been very rewarding.8 It is postulated
that several years of exposure to sacchromyces cerevesiae in an individual with increased
gut permeability may be necessary to produce detectable ASCA levels.29
Enteropscopy
Isolated small bowel CD poses a great problem in diagnosis. The double balloon enteroscopy
or an intraoperative endoscopy may be done to visualize and biopsy the small bowel
lesions.
Capsule Endoscopy
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The wireless capsule endoscopy has been used as a diagnostic tool in adults with isolated
small bowel CD. 30 The capsule is swallowed after an overnight fast and good bowel
preparation and the data recorded for 8 hrs on an external device. The captured images
are then analyzed by an experienced gastroenterologist. Great precaution should be taken
in those with suspected stricture as the capsule may result in bowel obstruction.
Gandolium enhanced Magnetic Resonance Imaging (MRI) Scan has been beneficial in
some cases of IBD to differentiate between CD and UC. Crohn’s disease is identified by
the transmural enhancement of the colon and bowel thickening of the terminal ileum or
small bowel. UC is diagnosed by the mucosal enhancement with submucosal sparing and
the changes extending from the rectum with variable involvement of the proximal colon.31
At present standard MRI with oral contrast enhancement is used in combination with CT
or small bowel contrast series for diagnosing CD related complications including pelvic
fistulae.
Difference between UC and CD

Though there are several distinctive features between CD and UC at times it may be difficult
to differentiate the two due to overlap of features. Some differentiating clinical, endoscopic
and histologic features are summarized in Table 8.1.
The differential diagnosis of IBD depends on the age and clinical presentation. In infants
Meckel’s diverticulum, allergic enterocolitis, Hirschsprung’s enterocoltis and even
Table 8.1: 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 Apthous ulcers, linear ulcers
Complications Toxic Megacolon Strictures, Fistula
Histopathology Cryptitis, crypt abscess Granuloma
intussusception constitute the differential diagnosis. In older children tuberculosis, lymphoma,

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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,
achievement of proper growth through adequate nutrition and ensuring good quality of
life while permitting the patient to function as normal as possible.4 The treatment regimen
should be directed towards relief of symptoms and improving quality of life and not
necessarily normalization of all laboratory studies. In adolescents the compliance should
be carefully monitored. Management includes pharmacological, nutritional, surgical and
psychosocial aspects.
Pharmacological therapy: The drugs used in children with IBD are 5-Aminosalicylates,
corticosteroids, antibiotics and immunomodulators.
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.
Mesalamine is coated with Eudragit, a pH sensitive acrylic resin or ethyl cellulose to release
the drug at the appropriate site. Uncoated mesalamine is also available as enema for use
in left sided colitis. The dose of mesalamine is 40-60mg/kg/day and 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.4
Steroids
Prednisolone is started at a dose of 1-2 mg/kg/day in moderate CD and also in moderate
or severe UC.. Once clinical remission is reached attempts are made to wean the medication
to alternate day therapy and then tapered before stopping within 6-8 weeks. Newer
corticosteroids such as oral budesonide at a dose of 6-9 mg/day may be prescribed to avoid
the systemic side effects of steroids.
Immunomodulators
The recognition of the central role of the immune system in the pathogenesis of IBD has
increased the use of immunomodulators in IBD.32 6-Mercaptopurine (1-1.5 mg/kg/day) and
azathioprine (2-2.5mg/kg/day) are effective in patients with active disease when added
to corticosteroid therapy. They facilitate the development of remission and promote tapering
of the corticosteroid dosage. Azathioprine and 6-MP are used as steroid sparing agents
and administered while the dose of steroids is being tapered. Either drug usually requires
3 to 6 months to show efficacy, and neither is effective as primary therapy. Cyclosporine

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has also been used to treat fulminant ulcerative colitis. Methotrexate has been in children
with 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.4
Probiotics have been also been used as a supplement in the management of IBD.
Biological therapy: Several novel therapies have been investigated in the treatment of IBD.
They may be biologic agents such as infliximab, natalizumab, interleukin10, IL11, parasites
and non-biologic agents such as thalidomide, granulocyte colony stimulating factor.33 The
use of infliximab an anti-tumour necrosis factor in adult CD has been well documented.
Infliximab has also been evaluated in pediatric CD and has proved effective as short-term
therapy in moderate to severe CD and in active draining external fistulae.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. It is evident that enteral nutrition with an oligopeptide formula
or amino acid based formula has fewer relapses. Patients who attain remission with exclusive
enteral nutrition could have prolonged remission and improved linear growth.35 Calcium
supplementation is an important adjuvant to prevent bone disease.
Psychological Therapy: Ulcerative colitis and CD are chronic conditions that may have a
profound influence on the lives of affected children and their family members. Adolescents
may have a difficult time in handling the disease. Every effort should be made to facilitate
normal age appropriate activities and early intervention by psychologists or psychiatrists
should be sought if problems develop.
Surgical Therapy: The indications for surgery in IBD include intractability, uncontrolled
hemorrhage, perforation, obstruction, severe fistula formation, growth retardation, and
carcinoma. About 10-25% of children and adolescents with ulcerative colitis will require
colectomy within 5 to10 years of diagnosis.4
Prognosis
The outcome of IBD is variable with disease activity remaining high in some individuals
in spite of aggressive treatment. Children with IC usually progress to CD than to UC. By
and large the prognosis of IBD depends greatly on the extent and severity of the disease.
Age of onset definitely has a role to play as the incidence of colorectal cancer increases
with the duration of the disease. In prepubertal children with CD one third have mild disease
not requiring steroids, one third have atleast one exacerbation requiring steroids, about
20% require either immunomodulatory or surgery to maintain remission and 10% are either
steroid dependent or steroid refractory.36 In CD one year after diagnosis 50% will be in
remission during any given year and less than 1 % will have a single episode of disease
activity.37 In UC the outcome depends on the extent and severity of involvement. Though
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the proximal extension of the disease in individuals is unpredictable it is reported to be
as high as 70 % within 5 years of diagnosis.18 Of those with severe UC about 20 % will
require surgery. The long term follow-up of children with UC showed that 10 % had a
single episode, 50% had chronic symptoms but were not incapacitated, 20% had intermittent
symptoms and 20% had incapacitating disease.37
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. The transition of the adolescent from the child centered health care systems
to the adult oriented health care system should be done with utmost care.
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. The two important entities ulcerative colitis and Crohn’s disease are seen
in all age groups. 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 multi disciplinary approach. Understanding the immunopathogenesis
of IBD has been the key factor in the introduction of novel forms of therapy.
MESSAGES
• Inflammatory Bowel Disease is a chronic inflammatory disease of the gastrointestinal
tract and is an important cause of morbidity in children and adolescents.
• An increasing incidence of IBD, especially CD has been reported in several pediatric centers.
• IBD occurs due to interplay of environmental factors and altered immune response in
a genetically predisposed individual.
• 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.
• The drugs used in the management of IBD include 5 amino salicylic acid, steroids and
immunomodulators.
• Novel biologic interventions help in the management of resistant disease and complications.
Surgery is recommended in certain specific situations.
• More research is necessary to identify the actual triggering factor and prevent the
occurrence of this morbid disease in childhood and adolescence.
REFERENCES
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1. Kirschner BS. Inflammatory Bowel Disease in Children. Pediatr. Clin. North Am. 1988;1:189-208.
2. Sathiyasekaran M, Raju BB, Shivbalan S, Rajarajan K. Pediatric Crohns disease in South India. Indian
Pediatr. 2005;42:459-63.
3. Mehta S. Inflammatory bowel disease in children: Indian perspective. Indian J Pediatr 1999;66:587-88.
4. Baldassano RN, Piccoli DA. Inflammatory bowel disease in Pediatric and Adolescent patients.
Gastroenterol clin North Am 1999;28:445-55.
5. Mamula P, Markowitz JE, Baldassano RN. Inflammatory bowel disease in early childhood and
adolescence: Special considerations. Gastroenterol Clin North Am. 2003;32:967-95.
6. 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.
7. Cosgrove M, Al-Atia RF; Jenkins HR. The epidemiology of pediatric inflammatory bowel disease. Arch
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 Sanders, 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. Peeters M, Nevens H, Baert F, Hiele M, de Meyer AM, Vlietinck R, Rutgeerts P. Familial aggregation
in Crohn’s disease: Increased age-adjusted risk and concordance in clinical characteristics.
Gastroenterology. 1996;111:597-603.
13. Tysk C, Lindberg E, Jarnerot G, Floderus-Myrhed B. Ulcerative colitis and Crohn’s disease in an
unselected population of monozygotic and dizygotic twins. A study of heritability and the influence
of smoking. Gut. 1988;29:990-6.
14. Bonen DK, Cho JK. The genetics of Inflammatory Bowel Disease. Gastroenterology 2003;124:521-30.
15. Papadakis KA, Targan SR. Current theories on the causes of inflammatory bowel disease. Gastroenterol
Clin North Am. 1999;28:283-96.
16. Hyams JS. Inflammatory bowel disease. In: Altschuler SM, Liacouras CA Eds. Clinical Pediatric
Gastroenterology. Philadelphia: Churchill Livingstone, 1998;213-21.
17. Lenaerts C, Roy CC, Vaillancourt M, Weber AM, Morin CL, Seidman E. 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 Sanders, 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
Gastroenterol Nutr. 1991;12:439-47.
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
diagnosisIPof :Crohn’s
112.133.195.17
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. Abdullah BA, Gupta SK, Croffie JM, Pfefferkorn MD, Molleston JP, Corkins MR, Fitzgerald JF. The
role of oesophagoduodenoscopy in the initial evaluation of childhood inflammatory bowel disease:
A 7-year study.J Pediatr Gastroenterol Nutr 2002;35:636-40.
28. Pulimood AB, Ramakrishna BS, Kurian G, Peter S, Patra S, Mathan VI. Endoscopic mucosal biopsies
are useful in distinguishing granulomatous colitis due to crohns disease from tuberculosis. Gut
1999;45:537-41.
29. Ruemmele FM, Targan SR, Levy G, Dubinsky M, Braun J, Seidman EG. Diagnostic accuracy of
Serological assays in pediatric Inflammatory bowel disease. Gastroenterology 1998;115:822-9.
30. Reddy DN, Kaffes AJ, Sriram PVJ, Venkat Rao G. Capsule endoscopic features of crohns disease.
Digestive endoscopy 2004;16:138.
31. Shoenut JP, Semelka RC, Magro CM, Silverman R, Yaffe CS, Micflikier AB. Comparison of magnetic
resonance imaging and endoscopy in distinguishing the type and severity of inflammatory bowel
disease. J Clin Gastroenterol. 1994;19:31-5.
32. Markowitz J, Grancher K, Kohn N, Daum F. Immunomodulatory therapy for pediatric inflammatory
bowel disease: Changing patterns of use, 1990-2000. Am J Gastroenterol. 2002;97:928-32.
33. Mamula P, Mascarenhas MR, Baldassano RN. Biological and novel therapies for inflammatory bowel
disease in children. Pediatr clin North Am 2002; 49:1-25.
34. Baldassano R, Braegger CP, Escher JC, DeWoody K, Hendricks DF, Keenan GF, Winter HS. Infliximab
(REMICADE) therapy in the treatment of pediatric Crohn’s disease. Am J Gastroenterol. 2003; 98:833-
8.
35. Griffiths AM, Ohlsson A, Sherman PN, Sutherland LR. Meta-analysis of enteral nutrition as primary
treatment of active Crohn’s disease. Gastroenterology 1995;108:1056-67.
36. Griffiths AM, Nguyen P, Smith C, Mac Millan JH, Sherman PM. Growth and clinical course of children
with Crohn’s disease. Gut 1993;34:939-43.
37. Hofley PM, Picollli DA. Inflammatory bowel disease in children. Med clin North Am 1994;78:1281-
302.
Intestinal Parasites in Children / 107
Pankaj Vohra
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Intestinal Parasites in
9 Children
“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 more so in developing
nations. In developing nations, it is the children of the urban poor and the rural population
who are most affected. In many cases, the parasite infestation is asymptomatic though multiple
organisms may be found. In some individuals who have a high worm burden or have some
other co-morbidity, parasitemia can result in a multitude of disorders including affecting
growth–physical and mental. However, in many individuals, no particular cause can be
attributed to development of symptoms. 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 in the
form of de-worming 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 round-
worm, 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
IP : parts of the developing world, incidence and consequences of intestinal
112.133.195.17
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 , 9 , 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. Hence, if there were multiple
adult worms found, it would imply that multiple larvae have been infected at one time
or multiple episodes of the infection have occurred over a period of time.
Classification of Intestinal Parasites

A simple classification of the various types of intestinal parasites found in children of India
is shown in Table 9.1.
Characteristics of Intestinal Parasites

Table 9.2 shows the medically important microbiological characteristics of some of the common
helminths affecting children while Table 9.3 shows their clinical aspects.
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
Table
IP : 112.133.195.17 9.1: Classification of intestinal
parasites
A. Helminths
Nematodes (Round worms)
1. Ascaris lumbricoides (Round worm)
2. Ancylostoma duodenale (Hook worm)
3. Necator americanus (Hook worm)
4. Enterobius vermicularis (Pin worm)
5. Strongyloides stercoralis (thread worm)
6. Trichuris trichiura (Whip worm) (Fig. 9.1)
Cestodes (Tape worms)
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
5. Isospora belli
6. Balantidium coli
* Cysticercosis - common
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 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
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 55oC. Asymptomatic or convalescent carriers
are the main source of infection as they pass cysts while patients with dysentery often pass
only trophozoites, which 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 commonly. Though steroids, cytotoxic drugs and malnutrition increase
susceptibility of disease, HIV infection does not seem to.
E. histolytica clinically also involves the recto-sigmoid 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.
Table 9.2: Characteristics of helminths

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Parasite and its Usual infective Usual form Comments
diagnosis form and route found in
of infection humans
Ascaris (Figs 9.2 Ingestion of eggs Adult worm in • Larvae penetrate intestinal epithelium,
and 9.3) Stool exami- containing larva jejunum; 15-40 reaches mesenteric lymphatics and portal
nation for typical (freshly passed cm circulation, reach pulmonary bed, molt in
eggs, rarely decorti- eggs are not alveolar space and travel up the respiratory
cate eggs or an infective) tract before being swallowed
ejected adult worm
itself (usually dead)
Ancylostoma/ Larvae penetrate Adult worms in • Larvae enter capillaries and reach
Necator skin usually small intestine; 1 lungs where they rupture into alveoli and
Stool examination for between toes cm long ascent the respiratory tract and are
typical eggs, rarely swallowed
skin lesions similar to
Stronglyloides may
be seen
Enterobius Ingestion of eggs Adult females • Ubiquitous and unrelated to sanitary
Adult worm often carried are 8-13 mm conditions
visualized at perianal under finger nails long • Re-infection due to hand-to-mouth
area at time of itching; (eggs are transmission and hence nail biters are
reversed cellophane infective at the difficult to treat
tape swab of time of laying) • Person to person spread easy as the
perianal area to eggs are infective at the time of laying
detect eggs; ova and common to find more than one family
rarely seen in stool member infected
Strongyloides Filariform larvae Duodenum; adult • Larvae enter capillaries and reach lungs
Larva in stool; penetrate skin female measures where they rupture into alveoli and ascend
duodenal aspirate, usually between 2-2.5 mm the respiratory tract and are swallowed
or jejunal biopsy. toes • Hatched eggs can develop into larva
Serodiagnosis for within the intestine and penetrate intestinal
screening available mucosa (internal auto-infection) or perianal
skin (external autoinfection), hence
starting another parasitic cycle
• Immunocompromised individuals are
most at risk to get heavy burden
Trichuris Ingestion of eggs Cecum; 3-5 cm • No visceral migration occurs

Characteristic eggs long; • Eosinophilia not common though part
in stool of the worm is embedded in the mucosa
• Adult worm sucks approximately 0.005
ml blood per day
Taenia Ingestion of Small intestine; • Cysticercosis more important disease
Eggs in stool; under-cooked 3-5 meters long than that caused by adult worms
perianal swabs pork or beef
useful; segments
required to identify
type of tapeworm
Hymenolepsis Ingestion of infective Jejunum;2.5-9 • Immunosuppressed hosts get heavy

Eggs in stool egg; external auto- cm infection load
infection may occur;
Table 9.3: Pathological

IP : 112.133.195.17 and clinical aspects of intestinal parasites
Parasite Development stages Adult stage

Ascaris Invasion of respiratory system may Usually asymptomatic; recurrent
result in pneumonia (Loffler’s abdominal pain, nausea, anorexia
pneumonia) leading to cough, and vomiting may occur; heavy
dyspnea, fever, urticaria, hemoptysis, infestation can result in obstruction;
creptitations, high eosinophilic counts, worms may migrate into CBD to cause
X-ray consolidation; larvae may reach biliary colic, acute pancreatitis, act as
other organs like eye, CNS and kidney a nidus for stone formation; adult worm
to produce lesions may migrate out via rectum or in
vomitus
Ancylostoma and Local skin lesion; cough, low grade Usually asymptomatic unless heavy
Necator fever, eosinophilia load leading 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 excoriations; rarely
worms may be seen peri-rectal; urinary
tract infection, vaginitis, ?acute
appendicitis
Strongyloides ‘Larva currens’–rapidly migrating Diarrhea, malabsorption, protein
urticaria on buttock, thigh and trunk as losing enteropathy, anorexia, pedal
a result of external autoinfection; edema, bloody diarrhea may occur if
wheezy cough, eosinophilia, Loefflers the worm load is high along with Gram
pneumonia negative sepsis, peritonitis;
Trichuris None Light infections are asymptomatic;
heavy infections can lead to diarrhea
with blood; anemia, clubbing, rectal
prolapse, ?acute appendicitis
Taenia None; Man may become intermediate Usually asymptomatic, abdominal

host to T. solium pain, bloating, nausea, passage of
proglottids is painful or itchy
Hymenolepsis None Usually asymptomatic; in heavy loads–
diarrhea with malabsorption
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
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Fig. 9.1: Trichura Trichuris (Whip worm) Fig. 9.2: Ascaris detected on barium meal
Fig. 9.3: Ascaris in Common bile duct (Arrow)

over both iliac fossa are common. Fulminant colitis with perforation is very rare. In children
IP : 112.133.195.17
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 (erythrocytophagous 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 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 9.8). The stool should be re-examined after a course of anti-amebic
therapy.
Giardia
Giardia lamblia though present worldwide is 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
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 as trophozoites multiply by binary fission
within the body. Infections are common in institutions, day-care centers and can occur from
contamination of water and food after it has been cooked. Outbreaks of Giardia have been
recorded.
The parasite inhabits the upper small intestine. It does not cause any local destruction
or invasion. Giardia infects several domestic animals but it is not clear whether the organism
is the same as the one that infects humans. There are several strains of Giardia.
Incubation period varies from 5-20 days. 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
IP : 112.133.195.17
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 9.8.
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 4oC. 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 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
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. IPThe incubation period is estimated as 5-7 days though it could range upto
: 112.133.195.17
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.
Treatment is with metronidazole, iodoquinol and in older children tetracycline. Prevention
is by avoiding contact with pig excreta.
Isospora
IP : 112.133.195.17
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 9.4.
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. 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
IP : 112.133.195.17
Table 9.4: 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
easier to collect stool 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.
The stool may be collected in formalin or poly-vinyl 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 poly-vinyl 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, Trichura 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
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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 test. Concentration of stool can be performed
by either the formol-ether sedimentation or zinc sulphate 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 Crytptosporidosis, 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 μm – Cryptosporidium
Oocyst size - 8-10 μm–Cyclospora
Oocyst size - ~25 μm - 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.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.
Table 9.5: Characteristics of commonly used anti-helminths

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Drug Dose Mechanism of action Common adverse affects and comments
Albendazole 400 mg single dose Inhibits polymerization • Rarely nausea, vomiting, abdominal pain,
(For Giardia infection of tubulin and uptake headache, elevated transaminases, rash and bone
400 mg daily for 5 of glucose marrow toxicity with prolonged administration
days) • 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 • Pruritus, fever, myalgia, headache, hypotension
dose; For dependent chloride
Strongyloides 2 days channels
therapy and in
hyperinfection 7-10
days
Mebendazole 100 mg twice daily Same as albendazole • Not recommended less than 2 years
for 3 days or 500 mg • Rarely nausea, vomiting, abdominal pain,
once. headache, elevated transaminases, rash and bone
For Enterobius marrow toxicity
100 mg/dose to be
repeated after 14
days
Niclosamide Taenia – 50 mg/kg Inhibits oxidative • Nausea, vomiting, dizziness, pruritus

single dose followed phosphorylation in • Purgative needed to prevent auto-infection that
by a saline purgative; parasite mitochondria can occur by liberation of eggs from the dead
Hymenolepis – Treat worm
for 1 week with
doses of 1 g for 5-15
kg, 1.5 g for more
than 15 kg weight
Nitazoxanide 1-3 y – 100 mg twice Blocks pyruvate: • Abdominal pain, diarrhea, vomiting
daily for 3 d ferredoxin • Avoid in children less than 1 year of age
4-11y – 200 mg twice oxidoreductase
daily for 3 d enzyme dependant
electron transfer
essential for
anaerobic metabolism
Piperazine 75 mg/kg dose for 2 Hyper-polarization of • Useful in heavy worm load of Ascaris as it kills
days neuro-muscular the worm and prevents migration
junction • Useful in intestinal or biliary obstruction
• Should not be used in conjunction with pyrantel
palmoate
Praziquantel For Taenia – 5-10 Alters intracellular • Malaise, abdominal discomfort, headache,
mg/kg single dose calcium levels dizziness, urticaria
For Hymenolepis 25
mg/kg single dose
Pyrantel palmoate 11 mg/kg single dose; Irreversible • To be used with caution in children with hepatic
to be repeated after depolarization of dysfunction
2 weeks in Enterobius neuromuscular junction • GI disturbances, headache, dizziness rare
and given for 3 days • Not recommended less than 12 months age
in hookworm
Thiabendazole 50 mg/kg/d in 2 Similar to albendazole • More adverse effects noted than with other
doses for 2 days benzimidazoles and hence not used commonly
• GI disturbances, headache, dizziness, drowsiness,
elevated transaminases, Steven-Johnson syndrome
Table 9.6: Characteristics

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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,
doses for 5-7 days irritability, 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,
40 mg/kg/day for 3 days for irritability, headache, vertigo, parasthesias but
Amebiasis less than 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,
50 mg/kg single dose for 3 days irritability, headache, vertigo, parasthesias but
for amebiasis less than metronidazole
Some of commonly used anti-helminths and anti-protozoals are shown in Table 9.5 and
9.6 respectively while the drug of choice and alternatives for treating various parasites is
given in Table 9.7.
Prevention of Intestinal Parasites

Short-term but effective strategy for controlling parasites in anti-parasitic therapy including
periodic anti-helminthic (6 monthly single dose) therapy in areas of high infestation or children
at high risk of developing disease is useful.42 ,43 This has been ratified by World Health
Organization.44 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
IPTable
: 112.133.195.17
9.7: Drug of choice and alternative for various intestinal parasites
Drug of choice Alternatives
Helminths
Ancylostoma/Necator Albendazole Mebendazole, Pyrantel palmoate$, provide iron therapy
as well
Ascaris Albendazole Mebendazole, Pyrantel palmoate, Ivermectin,
piperazine (if evidence of obstruction or migration)
Enterobius@ Pyrantel palmoate Albendazole, mebendazole, ivermectin
Hymenolepis Praziquantel Niclosamide
Strongyloides Albendazole# Ivermectin, Thiabendazole
Taenia Niclosamide Praziquantel
Trichura Mebendazole Albendazole, Ivermectin*
Protozoa
Cryptosporidium Nitazoxanide Paromomycin
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 diloxanide furoate alone; in active infection use diloxanide furoate
after or along with metronidazole
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 9.8.
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
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Table 9.8: 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
Round worm • 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
Tape worm • Proper cooking of pork or beef (above 56oC)
Whipworm • Elimination of use of human feces as fertilizer
• Sanitation
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
1. World Health Organisation, 2002, www.who.int/ctd/intpara/disease.php
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.
5. Glickman LT, Camara AO, Glickman NW, McCabe GP. Nematode intestinal parasites of children in
IP : 112.133.195.17
rural 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.
10. Sinha AK, Sahai BN. Prevalence of hookworm and other parasites in men of Patna; Bihar. Ind J Public
Health, 1977;21:29-33.
11. Fernandez MC, Verghese S, Bhuvaneswari R, Elizabeth SJ, Mathew T, Anitha A, Chitra AK. A
comparative study of the intestinal parasites prevalent among children living in rural and urban settings
in and around Chennai. J Commun Dis 2002;34:35-9.
12. Kaur R, Rawat D, Kakkar M, Uppal B, Sharma VK. Intestinal parasites in children as a cause of diarrhea
in Delhi, India. Southeast Asian J Trop Public Health 2002;33:725-9.
13. Mirdha BR, Samantray JC. Hymenolepis nana: a common cause of pediatric diarrhea in urban slum
dwellers in India. J Trop Pediatr 2002;48:331-34.
14. Bansal D, Sehgal R, Bhatti HS, et al. Intestinal parasites and intra-familial incidence in a low socio-
economic area of Chandigarh (North India). Nepal Med Coll J 2004;6:28-31.
15. Stauffer W, Ravdin JI. Entamoeba histolytica: an update. Curr Opin Infect Dis 2003;16:479-85.
16. Parija SC, Khairnar K. Entamoeba moshkovskii and Entamoeba dispar-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
TechLab Entamoeba histolytica II antigen detection and antibody tests. J Clin Microbiol 2000;38:3235-
9.
23. Krupp IM. Antibody response in intestinal and extraintestinal amebiasis. 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. Semin Pediatr Infect Die 2004;15:229-36.
30. Smith HV, Corcoran GD. New drugs and treatment for cryptosporidiosis. Curr Opin Infect Dis 2004;
17:557-64.
31. Cohen SA. Use of nitazoxanide as a new therapeutic option for persistent diarrhea: a pediatric
IP : 112.133.195.17
perspective. Curr Med Res Opin 2005;21:999-1004.
32. Bidinger PD, Crompton DW, Arnold S. Aspects of intestinal parasitism in villagers from rural peninsular
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. Senay H, MacPherson D. Parasitology: diagnostic yield of stool examination. CMAJ 1989;140:1329-31.
35. Fritsche TR, Smith JW. Medical Parasitology. In Henry JB (Ed). Clinical Diagnosis and Management
by Laboratory Methods. 20th Edition, Sauders Elseiver.
36. Moon TD, Oberhelman RA. Antiparasite therapy in Children. Pediatr Clin 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 Giardia duodenalis in children in
Bangladesh. Trans R Soc Trop Med Hyg 1993;87:84-6.
39. White Jr AC. Nitazoxanide: an important advance in anti-parasitic therapy. Am Trop Med Hyg 2003;
68:382-3.
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.
Constipation in Children / 125
BR Thapa
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Constipation in
10 Children
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 10.1) 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
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Table 10.1: 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 10.2: 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
functional gastrointestinal disorders in children called Rome II criteria in Table 10.2.6 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 10.3.7
Table 10.3: 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
EncopresisIP : 112.133.195.17
Encopresis is the in-voluntary 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
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 10.4. 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 duration of constipation is more than 8 weeks
Table 10.4: Classification of constipation

I. Depending upon the age of onset
a. Congenital constipation (Since birth)
b. Acquired constipation
II. Depending upon the duration
a. Acute or simple constipation (2 weeks to 3 months)
b. Chronic constipation (> 2 months)
• Mild
- No megarectum/megacolon or impaction
- No encopresis
• Severe (complicated)
- Associated with megarectum and megacolon or impaction
- Associated with encopresis
and is labeled chronic constipation. This may or may not be associated with megarectum
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and megacolon or impaction and encopresis. Chronic constipation is mild when there is
no encopresis or megarectum and megacolon or impaction whereas when it is complicated
by presence of encopresis, megarectum and megacolon or impaction is termed as severe
constipation.9,10
Pathophysiology of Constipation
Normal Bowel Habits
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 breast-feeding 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 levator ani
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 110o) 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 10.1A 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
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Fig. 10.1: Shows anorectal anatomy in the cross section of pelvis in Figures A and B. (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
in the toilet. The recto-sphincteric 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 required. Mother should ensure child sits comfortably on the lavatory seat without
fear.
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
IP : 112.133.195.17
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 janam gutti and opiate like drugs given by parents may be
responsible for constipation in infants.16,17
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 given in Figure 10.2. 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 soiling in the underwear subsequently.
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
Fig. 10.2: Pain a common factor in constipation in toddlers

Table 10.5: Etiology

IP : 112.133.195.17 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, Janam gutti etc. Drugs
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 10.5 and 10.6 respectively.18-20
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,
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
Clinical Presentation
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
Table 10.6:IP
Etiology of chronic constipation with or without megarectum, megacolon or encopresis
: 112.133.195.17
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
• Colonic neuropathies • Hypotonia
Hirschsprung’s disease • Mental retardation
Intestinal neuronal dysplasia • Tumor of spinal cord
• Colonic defects • Tethered cord
Colonic atresia • Metabolic
Short colon • Hypokalemia
• 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
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

IP : 112.133.195.17
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 fiber diet 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 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 10.3A and B).
Barium enema is mandatory when the constipation is since birth. To rule out the diagnosis
of Hirschsprung’s disease as shown in Figures 10.4A and B. Investigations like anorectal
Figs 10.3A 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
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Figs 10.4A 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
manometry, 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
The points to differentiate acquired constipation and Hirschsprung’s disease are given
in Table 10.7. The childhood constipation differs from that of adolescent/adulthood
constipation and the differences are given in Table 10.8. A meticulous practical approach
in management of chronic constipation is shown in Figure 10.5. 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 10.6.
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 time the toilet training should also be imparted. This is very common in children.
Table 10.7:
IP :Difference between acquired constipation and Hirschsprung’s disease in children
112.133.195.17
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 Hugely dilated colon
rectum and colon with fecal matter.
Barium enema No narrow segment, Narrow segment with
rather dilated rectum and proximal dilatation
colon
Rectal biopsy Normal ganglion Absent ganglion cells &
cells and ACHE* increased ACHE*
Rectal manometry Normal Abnormal contraction
*ACHE: Acetylcholinestrase
Table 10.8: 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 squating position and strain
stool in standing posture lot
Encopresis Common Rare
Use of medications or Rare Common
due 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 May be helpful in slow transit
anomalies but not in functional constipation
constipation
*HD: Hirschsprung’s disease
IP : 112.133.195.17
Fig. 10.5: Practical approach to constipation
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 given below.
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
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Fig. 10.6: Management of constipation summarized
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
IP : 112.133.195.17
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 g/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
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
avacuate 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

IP : 112.133.195.17
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 g/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 10.9.
Dietary Modification
Encourage breast feeding 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 g 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 (eg for
5 years + 5 = 10 g)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 which dietary unabsorbed carbohydrates known as
prebiotics increase the stool bulk is given in Figure 10.7.
Retraining/Toilet Training
There should be positive reinforcement for toilet sitting and defecation. Toilet timing should
be 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 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
IP : Table
112.133.195.17
10.9: 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
secondary hypocalcemia
Magnesium hydroxide Maintenance
1-3 ml/kg/ day in 2 doses
Polyeythylene glycol Disimpaction: 1.5 g/kg 1 day in Nausea, vomiting, cramps and
(PEG) 3350 240 ml water x 3-4 days diarrhea
Disimpaction:14-50 ml/kg/h till
Polyethylene glycol clearance
Electrolyte solution Maintenance: 5-10 ml/kg/day
Lubricant
Mineral oil (liquid paraffin) Disimpaction: 15-30 ml/ Aspiration risk
year of age Lipoid pneumonia, nausea
Maintenance: 1-3 ml/kg/ day
in 2 doses
Sodium docusate Oral 100 mg twice a day,
can be used as enema.
Stimulants (given for
short course)
Sodium pecosulphate 5-10 mg daily Cramps, diarrhea
Bisacodyl oral & enema 5-10 mg daily oral Cramps, pain abdomen and
5 mg per rectally irritation anal irritation
Glycerine suppository Pediatric suppository up to Anal irritation
6 years, adult suppository
>6 years.
Disimpaction: 6 ml/kg/
12 hourly 3 times
Sodium biphosphate enema 2.5-7.5 ml/day (2-6 years)
Senna 5-15ml/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= g/ day
Titrate up to 20 g/day
Prokinetic drugs
Cisapride 0.5 to 1 mg/kg body weight in Diarrhea
diabetes, chronic intestinal
pseudo-obstruction
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Fig. 10.7: Mechanism of action of fiber and CHO
Biofeedback
Biofeedback is required when other measures are not working and there is anorectal
dyssynergia. This helps in relaxation of EAS and levator ani muscles. This is only possible
above 5 years of age because co-operation 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. 10.5). Appropriate psychiatric consultation
should be taken when required. If there is atypical presentation or poor response. Pathological
cause 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, teen age occurrence, mental retardation, severe
IP : 112.133.195.17
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.
REFERENCES
1. Seth R, Heyman MH. Management of constipation and incopresis in infants and children. Gastroenterol
Clin Nor Am 1994; 23:621-36.
2. Nurko S. Advances in the management of paediatric constipation. Curr Gastroenterol Rep 2000;2:234-40.
3. Loening Baucke V. Encopresis and soiling. Pediatr Clin Nor Am 1996;43:279-98.
4. Lennard Jones JE. Constipation form Sleisenger and Fordtran’s Gastrointestinal and liver disease edited
by Feldman M, Scharschmidt BF and Sleisenger MH. WB Saunders Company: Philadelphia 7th edition
volume I, 2002; p181-210.
5. Loening-Baucke V. Chronic constipation in children. Gastroenterology 1993;105:1557-64.
6. Voskuijl WP, Heijmans J, Heijmans HAS, et al. Use of Rome II criteria in childhood defecation disorders:
applicability in clinical and research practice. J Pediatr 2004;145:213-7.
7. Finkel Y, Rosenthal P (Eds). The Paris consensus on childhood constipation terminology (PCCT) group.
IPGastroenterol
J Pediatr : 112.133.195.17
Nutr 2005;41:273-5.
8. Loening –Baucke V. Functional fecal retention with encopresis in childhood. J Pediatr Gastroenterol
Nutr 2004;38:79-84.
9. Yousef NN, Di Lorenzo C. Childhood constipation evaluation and treatment. J Clin Gastroenterol 2001;
33: 199-205.
10. Rasquin Weber A, Hyman PE, Cucchiara S, et al. Childhood functional gastrointestinal disorders. Gut
1999; 45 (Suppl 2): 60-8.
11. Benninga MA, Voskuil WP, Taminiau JAJM. Childhood constipation: Is there new light in the tunnel?
J Pediatr. Gastroenterol Nutr. 2004;39:448-64.
12. Talley NJ, Jones M, Nuyts G, et al. Risk factors for chronic constipation based on a general practice
sample. Am J Gastroenterol 2003;98:1107-11.
13. Weaver LT. Bowel habit from birth to old age. J Pediatr Gastroenterol Nutr 1988;7:637-40.
14. Fontana M, Bianchi C, Cataldo F, et al. Bowel frequency in healthy children. Acta Paediatr Scand
1989;78:682-4.
15. Weaver LT, Steiner II. The bowel habit of young children. Arch Dis Child 1984;59:649-52.
16. Loening Baueke V. Constipation in early childhood: patient characteristics, treatment, and long-term
follow up. Gut 1993;34:1400-4.
17. Partin JC, Hamill SK, Fischel JE, et al. Painful defecation and fecal soiling in children. Pediatrics
1992;89:1007-9.
18. Aranjo Sant’Anna AM. Calcado AC. Constipation in school-aged children at public schools in Rio de
janciro. Brazil. J Pediatr Gastroenterol Nutr 1999;29:190-3.
19. Borowitz SM, Cox DJ, Tam A, et al. Precipitants of constipation during early childhood. J Am Board
Fam Pract 2003;16:213-8.
20. Borowitz SM, Brooks R, Kovatchev B, et al. Constipation in early childhood: precipitating factors and
treatment outcome. Pediatrics Res 1999;45.
21. Hatch TE. Encopresis and constipation in children. Pediatr Clin North Am 1988;35:257-80.
22. Youssef NN, Langseder AL, Verga BJ, Mones RL, Rash JR. Chronic childhood constipation is assiciated
with impaired quality of life: A case controlled study. J Pediatr Gastroenterol Nutr 2005;41:56-60.
23. Van Kuyk EM, Brugman–Boezeman ATM, Wissin K, et al. Defecation problems in children with
Hirschsprung’s disease: a prospective controlled study of a multidisciplinary behavioral therapy. Acta
Pediatr 2001;90:1153-9.
24. Afzal N, Murch S, Thirrupathy K, et al. Constipation with acquired megarectum in children with autism.
Pediatrics 2003; 112:939-42.
25. Vander Plas RN, Benninga MA. Staalman CR, et al. Megarectum in constipation. Arch Dis Child
2000;83:52-8.
26. Blethyn AJ, Verrier JK, Newcombe R, et al. Radiological assessment of constipation. Arch Dis Cluld
1995;73:532-3.
27. Leech SC, Mellugh K, Sullivan PB. Evaluation of a method of assessing feccal loading on plain abdominal
radiographs in children. Pediatr Radiol 1999;29:225-8.
28. Tolia V, Lin CH, Elitsur Y. A prospective randomized study with mineral oil and oral lavage solution
for treatment of faecal impaction in children. Aliment Pharmacol Ther 1993:7:523-9.
29. Youssef NN, Peters JM, Henderson W, et al. Dose response of PEG 3350 for the treatment of childhood
fecal impaction. J Pediatr 2002;141:410-4.
30. Pashankar DS, Uc A, Bishop WP. Polyethylene glycol 3350 without electrolytes: a new safe, effective,
and palatable bowel preparation for colonoscopy in children. J Pediatr 2004:144:358-62
31. Loening Bacueke V, Polyethylene glycol without electrolytes for children with constipation and
encopresis. J. Pediatr Gastroenterol Nutr 2002:34:372-7.
32. Andorsky RI, Goldner E. Colonic lavage solution (polyethylene glycol electrolyte lavage solution) as
a treatment for chronic constipation: a double blind. Placebo-controlled study. Am J Gastroenterol
1990:85:261:5
33. Sondheimer JM. Sokol RJ, Taylor SF, et al. Safety efficacy and tolerance of intestinal lavage in pediatric
patientsIP : 112.133.195.17
undergoing diagnostic colonoscopy. J Pediatr 1991:119:148-52.
34. Bell EA, Wall GC. Pediatric constipation therapy using guidelines and polyethylene glycol 3350. Ann
Pharmacother 2004;38:686-93.
35. Voskuijl W, de Lorijn F, Verwijs W, et al. PEG 3350 Versus Lactulose in the treatment of childhood
functional constipation: a double blind randomised controlled multicentre trial. Gut 2004;53:1590-4.
36. Pfeifer J, Agachan F, Wexner SD. Surgery for constipation a review. Dis Colon Rectum 1996;39:440-
60.
37. Keuzenkamp Jansen CW, Fijuvandraat CL, Kneepkens CM, et al. Diagnostic dilemmas and results
of treatment for chronic constipation Arch Dis Child 1996;75:36-41.
38. Kot TV. Lactulose in the management of constipation: a current view. The annals of pharmacotherapy
1992:26:1277-82.
39. Pashankar DS, Loening Baueke V, Hishop WP. Safety of polyethylene glycol 3350 for the treatment
of chronic constipation in children. Arch Pediatr Adolese Med 2003:157:661-4.
40. Gremse DA, Hixon J. Crutecfield A. Comparison of polyethlene glycol 3350 and lactulose for treatment
of chronic constipation in children. Clin Pediatr (Phila) 2002;41:225-9.
41. Sharif F, Crushell E, O’ Driscoll K, et al. Liquid paraffin: a rappraisal of its role in the treatment of
constipation. Arch Dis child 2001:85:124-4.
42. Nurko S, Garcia-Aranda JA, Worona LB, et al. Cisapride for the treatment of constipation in children:
A double-blind study. J Pediatr 2000:136:35-40.
43. Taylot R. Management of constipation. I. High libre diets work. BMJ 1990:300:1063-4.
44. Williams CL, Bollella M, Wynder EL. A new recommendation for dietary fibre in childhood. Pediatrics
1995;96: 985-8.
45. Morais MB, Vitolo MR, Aguirre AN, et al. Measurement of low dietary fiber intake as a risk factor
for chronic constipation in children. J Pediatr Gastroenterol Nutr 1999:29:132-5.
46. Loening-Baucke V. Modulation of abnormal dynamics by biofeedback treatment in chronically
constipated children with encopresis. J Pediatr 1990;116:214-22.
47. Van der Plas RN, Benninga MA, Buller HA, et al Biofeedback training in treatment of childhood
constipation: a randomised controlled study. Lancet 1996:348:776-80.
48. Van der Plas RN, Benninga MA, Redehop WK, et al. Randomised trial of biofeedback training for
encopresis Arch Dis Child 1996;75:367-74.
49. Benninga MA, Biiller HA, Taminiau JA. Biofeedback training in chronic constipation. Arch Dis Child
1993;68:126-9.
50. Van Ginkel, Reitsma JB, Buller HA, et al. Childhood constipation longitudinal followup beyond puberty.
Gastroenterology 2003; 125: 357-363.
Acute Hepatitis / 145
John Matthai, Sarah Paul
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11 Acute Hepatitis
INTRODUCTION
The term acute hepatitis refers to any inflammatory process of the liver that lasts for less
than 6 months. The most common etiology of acute hepatitis in children is infection due
to hepatitis viruses, followed by drug induced liver disease.
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 as well as the epidemiology and molecular biology
of hepatitis viruses has advanced very rapidly, but there has been little advance in treatment.
The mainstay of therapy is still supportive care, because the inflammation is self-limited
in most cases.
PATHOGENESIS
The acute response of the liver to infection with any of the 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 can be 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. There is no fatty change. In fulminant hepatitis,
there is total destruction of the lobules, leaving only connective tissue septae. In children
who recover the liver histology returns to normal by 3 months.
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, since the
latter can be elevated after injury to skeletal muscle, myocardium and erythrocytes. 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. Bilirubin
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levels are elevated in patients who advance to the icteric phase of acute hepatitis. A normal
bilirubin does not rule out the presence of acute viral hepatitis, since many children have
anicteric disease. Elevations of serum alkaline phosphatase (ALP), and gamma glutamyl
transpeptidase (GGT) reflects injury to the biliary system. Abnormal synthesis of coagulation
factors is reflected by a prolonged prothrombin time (PT). Since the half life of these proteins
is very short, it is a sensitive indicator of acute severe liver injury. Serum albumin has a
long half life and therefore not useful in monitoring the extent of 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 85oC for
a minute for disinfection. Sodium hydrochloride in tap water 1:100 dilution can be used
for surface disinfection .The only natural hosts for HAV are humans and primates. As there
is no known carrier state, HAV infection is maintained in nature by transmission from an
infected person to a susceptible individual.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. The ingested virus multiplies in the small bowel and migrates via
the portal vein to reach the liver. Majority of infections are mild and sub-clinical and occur
in children below 5 years of age. Parenteral and vertical transmission are rare. Parenteral
transmission is possible from a blood donor who is in the incubation period or prodromal
phase of infection. 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 acute liver failure
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% (check) 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
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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. 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 within a week after
the icterus disappears.
Some children with hepatitis A may develop atypical manifestations like ascites, pleural
effusion, apastic anemia, skin rashes and firm hepatomegaly(check). Liver biopsy shows
no features of chronic hepatitis. The course of the disease is prolonged but recovery is
complete. ALF is a dreaded complication of HAV infection.8 Progressive rise in bilirubin
with falling ALT and AST and uncorrected prolonged prothrombin time is characteristic.
Diagnosis
A specific diagnosis is based on the detection of the specific antibody response to HAV.
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 titers by 1 to 2 months and persists for years. Thus the presence of
Anti–HAV IgM in serum suggests a recent HAV infection and the presence of Anti-HAV
IgG in serum indicates previous infection and immunity. In patients with biphasic or relapsing
Hepatitis A, anti HAV IgM persists at low titers for 12–24 months.9 HAV RNA is present
in the stool from 2 weeks before to 1 week after the onset of symptoms. It can be detected
by nucleic acid amplification but the test is performed only in research setting and not readily
available (Fig. 11.1).
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%.
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Fig. 11.1: Natural course of hepatitis A infection in children
It is effective immediately and the dose is 0.02 ml/kg. It is indicated in (1). Newborns
of HAV infected mothers (2).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. Considering the high cost, it is currently
an optional vaccine in India. All children with chronic liver disease should receive the
vaccine. The immune response in immunocompromised children may be sub-optimal.
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 of Hepatitis B infection may be much higher, since up to 30% of individuals
have been reported to have positive HBsAbs in some parts of the country.11
Hepatitis B Virus
This is a 3.2 Kb, circular, partially double-stranded DNA virus belonging to the family
hepadnaviridae. The intact virion, is spherical (Dane particle) and approximately 42 nm in
diameter andIP :is112.133.195.17

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. Hepatitis B virus replicates predominantly in the liver, but also occurs in
the lymphocytes, spleen and kidney.
Epidemiology
HBV infection is a worldwide health problem. Recent epidemiological studies suggest that
the true prevalence of HBV infection in India may be 1-2%. In the absence of multi-centric
community based studies, the true prevalence among children in India is not known. Various
studies have reported it to be 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 to children. The risk is much higher in mothers who are also HBeAg positive.
In areas of low endemicity, horizontal transmission is important. The two routes of horizontal
transmission which are important in children are close contact with infectious family
members and use of unsterile syringes.13 After the advent of strict blood bank screening
practices, blood transfusion is no more considered an important route of transmission.
However a large number of children who develop Hepatitis B have no known risk factor
for the disease.
Natural Course of HBV Infection

Hepatitis B virus does not directly kill hepatocytes. Liver injury occur 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 weak and ineffective and lasts many
years or even 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. Active viral replication continues in this
phase with little or no hepatocyte damage. In perinatal infection, this phase lasts for
many years.
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. The infection has cleared for all practical purposes,
even though the HBsAg remains positive.
4. Integrative phase with viral clearance: In this phase there is complete cessation of viral
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replication and even the HBsAg becomes negative. The person is completely cured of
the disease. Patients with acute Hepatitis B will achieve this phase, but those with chronic
infection may not always reach this phase.
Clinical Features
The incubation period is 50 to 180 days and depends on the size of the inoculum, route
of infection and the kinetics of virus–host interaction. The typical clinical course of acute
icteric hepatitis B shows three phases:- a) the prodromal phase. b) the symptomatic phase.
c) the convalescent phase. The prodromal phase lasts for 2 to 3 weeks and precedes the
development of jaundice. It may be associated with non-hepatic manifestations. These are
immunologically mediated and include membranous nephropathy and vasculitis syndrome.
The acute symptomatic episode is similar to that of hepatitis A. The symptomatic phase
is heralded by acute symptoms such as fever, fatigue, myalgia, anorexia, nausea, vomiting
and abdominal pain. In the early stages, jaundice may be associated with extra-hepatic
manifestations like arthralgia, or skin lesions ,which may be urticarial, purpuric, macular
or maculopapular. Papular acrodermatitis of childhood (Gianotti Crosti syndrome) occurs
during the phase of HBsAg antigenemia. This is characterized by non-pruritic, symmetrical,
monomorphous papules on the face, buttocks and limbs with or without lymphadenopathy
and lasts for about 2-3 weeks. The extra-hepatic manifestations are related to circulating
immune complexes composed of HBsAg and Anti HBsAbs. Jaundice lasts longer than in
hepatitis A and the usual duration is about 4 weeks. In the usual course of resolving
hepatitis B, the symptoms last for about 6-8 weeks. Physical examination findings are similar
to that of any acute hepatitis. Splenomegaly and lymphadenopathy are more common with
hepatitis B.
Unlike hepatitis A, the percentage of children who develop icteric disease is much higher
in Hepatitis B. 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 Acute liver failure has a mortality rate of 55 to 70% without liver transplant
and 30 to 50% with transplant. Recovery is complete, without sequelae if the HBV is rapidly
cleared from the host after an acute or acute liver failure B. There is no evidence that Pre
core mutants are associated with increased risk of acute liver failure in children.16
Serology of Acute Hepatitis B Infection (Fig. 11.2)

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
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Fig. 11.2: Natural history of acute hepatitis B infection
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 11.1).
Most patients with acute infection clear the HBsAg by 6 to 8 months An individual who
is unable to clear the virus from the body within 6 months is deemed to have chronic infection.
Subsequently, the spontaneous clearance is approximately 1–2% every year. Anti HBcAbs
of the IgM class may be the only marker of HBV infection soon after clearance of the HBsAg.
Anti HBsAbs are neutralizing antibodies and can be detected in the serum for many years
after infection. Immunization does not lead to positive HBsAg in blood. Successful active
or passive immunization against Hepatitis B is associated with high serum titers of Anti
HBsAbs.
Table 11.1: 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 B e antibodies, HBcAbs: Hepatitis B core
antibodies).
The outcome of HBV infection depends on the age at infection, the immune status of
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the host and virologic factors.17 95 % of infected neonates may develop chronic infection,
compared to only 20% in older children. This is due to the high immune tolerance to the
core antigen and e antigen in newborns. Mutant forms of hepatitis B is associated with
low spontaneous clearance and poor long-term outcome.
Treatment of Acute Hepatitis B

Currently there is no evidence to suggest that treatment improves recovery from acute
hepatitis B infection. Alpha interferon has been used in the treatment of adult patients with
acute as well as fulminant hepatitis B, with no significant improvement in outcome. 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
in acute hepatitis B.
Immunoprophylaxis
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 titers. 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. It should
be administered intramuscularly and never given intravenously. In children, 32–48 iu/Kg
body weight and in neonates 100–200 iu is recommended. HBIG does not interfere with
antibody response to hepatitis vaccine.
Babies born to mothers who are HBsAg positive should receive the first dose of vaccine
within 12 hours of birth and the HBIG should be 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 alone offers 90-95% protective efficacy in preventing vertical transmission. Risk factors
for failure of immunization in newborns includes high level of maternal HBV DNA and
low levels of maternal anti HBcAbs.19 Early administration of the vaccine is a cost effective
means of prevention of disease in newborns .Simultaneous administration of HBIG increases
the success to over 98%.
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. Hepatitis E is
predominantly a fecal or water-borne infection. Contamination of water sources may result
in massive epidemics of hepatitis E. The rate of person to person transmission however
is relatively lower compared to HAV. It is endemic to south east Asia and India. The first
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large epidemic documented retrospectively was in Delhi in 1955.
Clinical Features
The mean incubation period is about 6 weeks. The mean duration of symptoms is about
1-2 weeks. The pathology and clinical features of HEV infection are similar to those of HAV
infection. In children, it is usually an icteric self limited disease. The virus is excreted in
the stool for about 2 weeks after the onset of symptoms. Mortality due to acute liver failure
is low, except in pregnant women, in whom it may reach 20%. Among children
with acute liver failure, however hepatitis E is an important etiology, constituting up to
45%.20
Intrauterine infection has been observed with HEV. Unlike HAV, sub-clinical infection
is less common. The prevalence of anti HEV immunoglobulin among children in endemic
areas is around 25 % compared to 90 % for HAV. It is believed that antibody levels decline
with time–over a period of 2-6 years.21 Data on co–infection of HEV and HAV is scant.
Acute HEV infection does not result in chronic liver disease. HEV super infection worsens
liver injury in chronic HBV infection.
Diagnosis
Anti HEV Immunoglobulin can be detected in the serum by enzyme immunoassay about
1 week after the onset of illness. It remains positive for 2–3 months hepatitis E Virus RNA
can be detected in the stool by PCR, but this is done only in research laboratories. Abnormalities
in transaminases and alkaline phosphatase normalize within 6 weeks.
Management
There is no specific treatment available. Improved sanitation and water supply may prevent
epidemics. Efforts are being made to develop an effective HEV vaccine. A candidate vaccine
has been evaluated in clinical trials.
OTHER VIRUSES
About 10% of acute viral hepatitis in immunocompetent individuals may be due to viruses
other than hepatitis viruses. These include Cytomegalovirus (CMV), epstein barr virus (EBV),
herpes virus, adenovirus and parvovirus.
Primary CMV infection in immunocompetent host is usually asymptomatic.22 It may
sometimes cause a systemic disease, and the liver may also be involved. In immunocom-
promised individuals, the disease tends to be more severe. The incubation period ranges
from 3-12 weeks. In general, CMV infection leads to a life-long latent phase in the host,
that can reactivate later, when the person becomes immunocompromised. CMV may infect
and replicate in both hepatocytes and cholangiocytes.
The diagnosis of CMV infection can be suspected by detecting anti CMV IgM antibodies
in the serum .Viral particles can be detected by PCR in the serum or the organism can be
cultured from urine. In severe cases, therapy with ganciclovir may be effective. A recombinant
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CMV vaccine has recently 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, in about 1 in 3,000 cases it may take
a more fulminant course with severe hepatitis, bone marrow failure and acute respiratory
distress syndrome that is fatal.
DRUG INDUCED HEPATITIS

The liver plays a very important role in the metabolism of most drugs. Transformation
of most drugs to their active form, and their excretion from the body are facilitated by
the liver. The liver in children is in the process of metabolic maturation and the manifestations
of drug induced liver disease may therefore be varied. Hepatitis due to drugs is under
reported in children. This could be due to under diagnosis, because there is wide spread
notion that drug induced liver disease is rare in children. It could also be because children
take far fewer drugs compared to adults. Anti TB drugs, anti convulsants, and paracetamol
are most commonly involved.
Biotransformation
The liver has two important functions in drug metabolism namely, activation (Phase I) and
detoxification (Phase II). This balance is affected by age, maturation of the liver, state of
nutrition and the effect of other drugs. Enzyme inducers enhance the enzyme cytochrome
P-450, and can lead to increased production of toxic metabolites. Barbiturates, alcohol,
anesthetics, hypoglycemic and anticonvulsant drugs, rifampicin, omeprazole are all enzyme
inducers and lead to increased production of toxic metabolites. Phase II reactions inactivate
such chemicals up to a certain extent. Any positive imbalance between toxic metabolites
produced in phase I and the phase II capacity of the liver results in hepatotoxicity.
Hepatotoxicity may have a number of clinical presentations.23 The pattern of injury depends
on the type of drug involved. In children it is mostly 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 and prominent
elevation of ALP. There may be a 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. This may lead to fatty
liver similar to that in Reyes syndrome.
Acute liver injury occurs over a period of days to a week or two. Acute hepatotoxic
injury is usually associated with complete recovery on prompt withdrawal of the drug. Sub-
acute hepatotoxicity refers to changes that have occurred over a period of weeks to a few
months and take longer to resolve. Hepatotoxic drugs have been classified as intrinsic and
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idiosyncratic hepatotoxins. Intrinsic hepatotoxins have dose related toxicity. Idiosyncratic
reactions are unpredictable and are not dose related. It is thought to have a biochemical
basis. Underlying liver disease, concomitant therapy with multiple hepatotoxic drugs and
malnutrition increase the risk of drug induced hepatitis.
Diagnosis
Children must be carefully monitored while on long-term hepatotoxic drugs. A good history
and evaluation for underlying liver disease in important before starting a child on a potentially
hepatotoxic drug. 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 may be seen in hypersensitivity type reaction. Alkaline phosphatase,
transaminases and prothrombin time may be used to monitor the extent of liver injury.
A liver biopsy may be helpful in select cases. It helps to asses the severity of damage and
also exclude other causes of liver disease.
Specific Drug Hepatotoxicity

1. 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
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 to the production of a toxic metabolite N acetyl benzo quinon 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
more resistant to paracetamol hepatotoxicity than adolescents and adults. Rectal
administration of acetaminophen may also cause hepatotoxicity. Absorption from the
suppository is often unpredictable because of variable bioavailability.
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. It may lead to acute liver failure. 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
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be diluted to a 5% concentration and given through a nasogastric tube. Continuous intravenous
infusion is not superior to the oral regimen.27 Early haemodialysis 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.
2. Valproic Acid
Valproate hepatotoxicity is unique in that it is much more common in young children than
in adults.(28 Some children may develop mild hepatomegaly with elevated transaminases.
It can occur 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
most 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. (4 en VPA). This
affects the mitochondria of the hepatocytes. Conjugation with carnitine is an efficient excretory
pathway of valproate, and therefore decreased carnitine levels are associated with
hepatotoxicity. Though earlier reviews did not show any positive response, a recent study
showed that carnitine supplementation when started very early had a beneficial role.30
3. 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.
Histopathology of the liver shows spotty necrosis of hepatocytes with features of
mononucleosis. It can also result in hepatic necrosis and severe liver failure. Hypersensitivity
reactions are thought to occur due to an 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 gamma globulin has shown some benefit in patients with severe Stevens-Johnson
syndrome.32
4. 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.
5. Phenobarbitone
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Phenobarbitone is very widely used but very rarely results in hepatitis. When it occurs,
it is usually part of a multisystem drug hypersensitivity reaction. The liver disease is never
severe and 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
6. 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.
7. 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 the newer low dose regimens
may eliminate this. 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.
8. Antibiotics
All forms of erythromycin are potentially hepatotoxic. Toxicity is uncommon in children
below 10 years of age. The clinical presentation includes anorexia, nausea, upper abdominal
pain and jaundice. Pruritus is seen only in adults. Hepatosplenomegaly is frequent in children.
Investigations show eosinophilia in the peripheral blood with elevated SGPT and bilirubin,
but ALP and GGT may be normal.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 any of the sulfonamide antibiotics. Hepatotoxicity has
been reported with sulfanilamide, trimethoprim –sulfamethoxazole and pyrimethamine–
sulfadoxine. Sulfasalazine has been associated with severe liver disease in adolescents. The
Liver injury may present as an asymptomatic enzyme elevation, granulomatous hepatitis
or acute fulminant hepatic failure. Sulfonamide hepatotoxicity represents metabolic

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idiosyncrasy. It is due to the production of an electrophilic toxic metabolite in the liver.
The nitrosoderivative of the hydroxylanine metabolite of the particular sulfonamide is
responsible for the hepatotoxicity. Slow acetylators are unable to detoxify this, and are more
at risk for liver damage.
Management
Early recognition of drug induced hepatitis is very important. The offending drug must
be stopped immediately. Acute hepatitis and cholestasis resolve in a few weeks. Treatment
of hepatitis 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 one of the hepatitis viruses and drugs are the commonest 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.
KEY MESSAGES
• Common causes of acute hepatitis in children include infection with hepatitis A, E or
B virus and hepatotoxic drugs. In most children, it is mild and anicteric. Clinical features
are similar in all types of acute hepatitis.
• Hepatitis A is usually a sub-clinical infection with few complications. Acute liver failure
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may occur only in older children and in those with underlying chronic liver disease.
The two dose schedule of Hepatitis A vaccine given to children above 2 years of age,
results in seroconversion rate close to 100%.
• In acute hepatitis B, HBsAg, HBeAg and HBV DNA are positive. During recovery, HBcAbs
appear first, followed by HBeAbs and finally HBsAbs.
• Currently available anti-viral viral drugs do not improve recovery from acute hepatitis
B.
• Perinatal transmission is an important route of acquiring hepatitis B , and 95% of them
develop chronic infection. Babies born to mothers who are HBsAg positive, should receive
the vaccine, and if possible, the HBIG (given at a separate site) at the earliest.
• Hepatitis E is water borne infection which can result in massive epidemics. In children,
it is usually an icteric self-limited disease.
• Drug induced hepatitis is under diagnosed in children. It is predominantly a cytotoxic
liver disease and drug withdrawal results in prompt recovery.
• 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.
REFERENCES
1. Fishman LN, Jonas MM, Lavine JE .Update on viral hepatitis in children. Pediatr Clin North Am
1996;43:57–74.
2. Snyder JD, Pickering LK. Viral hepatitis In Behrman RE, Kliegman RM, Jenson HB (Ed). Nelson Text
book of pediatrics 17th Edn. Elsevier, New Delhi 2004:1324-32.
3. Koff RS. Hepatitis A. Lancet 1998;351:1643–9.
4. Alter MJ, Mast EE. The epidemiology of viral hepatitis in the United States. Gastroenterol Clin North
Am 1994;23:437–55.
5. Arslan S, Caksen H, Oner AF, Odabas D, Rastgeldi L. Relapsing Hepatitis A in children: Report of
two cases. Acta Paediatr Taiwan 2002;43(6):358-60.
6. Malathi S, Mohanavalli B, Menon T, et al. Clinical and viral marker pattern of acute sporadic hepatitis
in Chennai, South India. J Tropical Pediatr 1998;44:275–8.
7. Panda SK, Datta R, Gupta A, et al. Etiologic spectrum of acute sporadic viral hepatitis in children in
India . Tropical Gastroenterology 1989:106–10.
8. Debray D, Cuulufi P, Devictor D, et al. Liver failure in children with hepatitis A. Hepatology 1997;
26:1018–22.
9. Yazigi NA, Balistreri WF. Acute and chronic viral hepatitis In Suchy FJ, Sokol RJ, Balistreri WF (Eds).
Liver disease in children 2nd Edn. Lippincott Williams &Wilkins, Philadelphia, 2001;365–427.
10. American Academy of Pediatrics. Hepatitis A. In Pickering LK (Ed). Red Book: Report of the Committee
on Infectious Diseases 25th Ed. Elk Grove Village, IL: American Academy of Pediatrics; 2000;280–9.
11. Thyagarajan SP, Jayaram S, Mohanavalli B. Prevalence of HBV in general population in India. In Sarin
SK, Singhal AK eds Hepatitis B in India: Problems and Prevention. New Delhi; CBS Publications; 1996;
5–16.
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.

15. DurandIP : 112.133.195.17
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
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.
Acute Liver Failure in Children / 161
Narendra Kr Arora, Prashant Mathur
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Acute Liver Failure

12 in Children
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.
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
factor alpha,IPan endogenous mediator of septic shock, are increased in many but not all
: 112.133.195.17
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 sub-acute 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 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
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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
is between 7 days to 28 days. There is high incidence of cerebral edema but their
prognosis is poor without a liver transplantation.
• Sub-acute liver failure: Also known as late onset hepatic failure (LOHF), sub-fulminant
hepatic failure (SFHF), protracted viral hepatitis with impaired regeneration, sub-
chronic atrophy of the liver and sub-acute 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, its detection in young children is difficult.7
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;
sedative 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.
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Table 12.1: 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 1
• Mitochondrial disorders
• Hereditary fructose intolerance
• Alpha–1 antitrypsin deficiency
• Niemann-Pick disease
• Indian childhood cirrhosis
• Glycogen storage disease Type IV
Hypo perfusion
• 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
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. Table 12.1 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 (15%), acute hepatitis B (10%), drug induced (5%), those with underlying chronic
liver disease (5%) and non A to E infections (15%).
Risk Factors
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Acute liver failure is an uncommon complication of acute viral hepatitis, occurring in about
0.2- 4% of cases depending on the underlying etiology.9 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 live size, rising bilirubin levels in face of falling aminotransfersases, 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 cases10 and has a case fatality rate of 0.14% for hospitalized
patients.11 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,10 and hepatitis A infection
superimposed on underlying liver disease.12 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.13,14
Hepatitis B is the most common identifiable viral agent responsible for acute liver failure
worldwide10 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.15 Super-infection with HDV may carry greater
risk of fulminant hepatitis than simultaneous infection.16 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.17 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%. 18,19
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
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The possible precipitating factors of acute liver failure include infections, sepsis, persistent
fever, persistent vomiting, hypovolemia, gastrointestinal bleeding, constipation, use of
hepatotoxic 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 (Staphyloccocal 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 12.2 gives the early indicators of hepatic encephalopathy.
Every clinician should carefully ask and/or look for these early manifestations of hepatic
encephalopathy in all children with acute hepatitis.
Table 12.2: Early clinical

IP : 112.133.195.17 indicators of hepatic encephalopathy
• Confusion/euphoria
• Combative behavior/restlessness/irritability
• Short attention span
• Disordered sleep or sleep inversion
• Changes in handwriting
• Tremors
• In-coordination or dropping objects
• Headache/dizziness/nightmares
Cerebral edema is a major cause of mortality in patients with acute liver failure. A sustained
rise of ICP to 30 mmHg or more is taken as an indication of raised ICP. Fifty to eighty
percent of patients with acute liver failure have cerebral edema;20 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.21 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 hypoxymia 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 multi-organ failure
3. to provide hepatic support
4. to assess prognosis and evaluate for liver transplantation, where available
Immediate Intensive Care

IP : 112.133.195.17
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 intra-venous 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 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 12.3.
Table 12.3: 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 12.4)

Appropriate management of fluid and metabolic abnormalities can go a long way in the
ultimate outcome in patients with acute liver failure.
IPTable 12.4: Management

: 112.133.195.17 of fluid and metabolic complications in acute
liver failure
Total fluid intake: normal maintenance requirement (10 % Dextrose in N/5
saline)
Hypot]ension
• 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 mm Hg -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 (@ 1ml/Kg).
• Maintain blood sugar between 100–200 mg/dl.
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 hours and routine culture of removed catheter tips is essential.
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
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Table 12.5: 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 30o-45o
• Place head in neutral position
• Minimum handling of the patient
• Elective ventilation (aim is to maintain pCO2 between 22-26 mm Hg)
• 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 mm Hg and CPP > 50 mm Hg
Factors that Increase ICP

• Body movement and handling
• Frequent suctioning/noxious stimuli
• Horizontal decubitus
• Severe hypoxemia/hypercapnia
• Coughing/sneezing/vomiting
• Seizures
is no improvement within 72 hr, it is prudent to step up antibiotics to cover Pseudomonas

aeruginosa, fungal sepsis and anaerobic organisms depending upon individual patient
requirements.
Cerebral Edema (Table 12.5)

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 20 degrees with the head in the neutral position.22 Nursing of the patient should be carried
out in an ICU setting, with a quiet comfortable atmosphere and minimum handling of the
patient. 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.23 It has
been seen that short term hyperventilation with the aim to maintain pCO 2 between
22-26 mm Hg may be helpful in reducing ICP.20
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 mm Hg.23 Serum osmolality should be monitored in patients
being given mannitol. The drug is contraindicated if serum osmolality exceeds 320 mOsm/Kg.
IP : 112.133.195.17
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 found to be of any use, unlike its beneficial effects on patients with brain tumors.23,24
Monitoring the ICP using intracranial electrodes may improve selection of patients for
liver transplantation, but does not affect survival.25
Hepatic Encephalopathy (Table 12.6)

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 ammonia26 and decreases the bacterial
counts.27 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 naso-gastric tube in doses of 0.5 ml/kg/dose (max. 30ml/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 Grade 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
Table 12.6: Management of hepatic encephalopathy

Bowel washes
• With acidic fluid (1 teaspoon vinegar in 1/2 litre plain water), 6-8 hrly
Lactulose
• Oral/NG tube - 0.5 ml/kg/dose (max. 30ml/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)

• Dilantin/phenobarbitone: 2-3 mg/kg/day
• No sedatives
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Table 12.7: 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
anticonvulsant. No sedatives should be given as they interfere with the assessment of the
status of consciousness of the child.
Coagulopathy (Table 12.7)

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 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 12.8)

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 conventional hemodialysis may be preferable.28 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.
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Table 12.8: 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
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:25
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. Hypoglycaemia <4 mmol/l with increasing dextrose requirements
7. Hepatic encephalopathy grade 2 or 3.
Certain etiologies like paracetamol poisioning and hepatitis A have the best prognosis
for spontaneous recovery.
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 (MARS) or plasmapheresis.29
Hepatocyte transplantation involves attempts to inject hepatocytes which will home in the
liver and would rapidly replicate. The extracorporeal liver assist device (ELAD) consists
Table 12.9: Intensive

IP : 112.133.195.17 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 12.10: 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.
• Urinary electrolytes, creatinine and osmolality.
• Other investigations as required
of a hemodialysis cartridge with the extracapillary spaces occupied by cultured cells that
are derived 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 12.9 to 12.11)

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
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Table 12.11: 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. Vit. 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
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.
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

IP : 112.133.195.17
tests are proposed. Reduced levels of group-specific component (Gc)-globulin (a molecule
that binds actin) are reported in FHF, and a 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.30 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 available in India, it would be an attractive option.
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.
5. LC EE, RW Shepherd, GJ Cleghorn, PJ Lewindon, J Fawcett, RW Strong, SV Lynch. Acute liver failure
in 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. O’Grady J. Acute liver failure. In: O’Grady J, Lake J, Howdle P, (Eds): Comprehensive clinical hepatology,
1st ed. IP : 112.133.195.17
London: Mosby 2000;30:1-20.
10. Fagan EA, Williams R. Fulminant viral hepatitis. (Review) Br Med Bull 1990;46:462-80.
11. 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.
12. Akriviadis EA, Redeker AG. Fulminant hepatitis A in intravenous drug users with chronic liver disease.
Ann Intern Med 1989;110:838-9.
13. 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.
14. O’Grady JG, Alexander GJM, Hayllar KM et al. Early indicators of prognosis in fulminant hepatic failure.
Gastroenterol 1989;97:439-45.
15. 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.
16. 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.
17. Acharya SK, Dasarathy S, Kumer TL, et al. Fulminant hepatitis in tropical population: Clinical course,
cause, and early predictors of outcome. Hepatology 1996;23(6):1448-55.
18. Krawcznski K. Hepatitis E. Hepatology 1993;17:932-41.
19. Herrera JL. Hepatitis E as the cause of acute non-A non- B hepatitis. Arch Intern Med 1993;153:773-
5.
20. Ede RJ, Gimson AES, Bihari D, et al. Controlled hyperventilation in the prevention of cerebral edema
in fulminant hepatic failure. J Hepatol 1986;2:43-51.
21. Caranci P, Van Thiel DH. Acute liver failure. Lancet 1995;345:163-9.
22. 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.
23. Hanid MA, Davies M, Mellon PJ, et al. Clinical monitoring of intracranial pressure in fulminant hepatic
failure. Gut 1980:820-5.
24. 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.
25. Kelly DA. Managing acute liver failure. Postgrad Med J 2002;78:660-7.
26. 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.
27. 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.
28. Golper TA. Continuous arteriovenous hemofiltration in acute renal failure. Am J Kidney Dis 1985;
6:373-86.
29. O’Grady JG. Acute liver failure. Postgrad Med J 2005;81:148-54.
30. Bernuau J. Acute liver failure: avoidance of deleterious cofactors and early specific medical therapy
for the liver are better than late intensive care for the brain (Editorial). J Hepatol 2004;41:152-5.
Surender Kumar Yachha
IP : 112.133.195.17
13 Neonatal Cholestasis
In this book chapter emphasis is laid upon etiology of neonatal cholestasis (NC), practical
approach and management pertinent to Indian setting. 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 west 1, 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 < 5mg/dL or > 20% of the total bilirubin if
> 5mg/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 13.1. 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.
Surgical procedures of portoenterostomy were done in 86% (n = 242) and hepatico-
jejunostomy in 3.2% (n = 9) cases. Perioperative mortality of average 6.7% (range 0-10%)
was observed.3
Neonatal Cholestasis / 179
Table 13.1: IP
Etiology of 1008 cases of neonatal cholestasis(Combined data of 8 medical centers in India)
: 112.133.195.17
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)*1 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*2 4%
C. Ductal Paucity 3% (n = 29) Syndromic variety 17%, Non-syndromic varietyî 83%
D. Uknown 6% (n = 63)
*1
Recent studies using confirmatory test of isoelectic focussing reported 57/58 children of liver disease
having normal PIMM phenotype24; *2 mostly now considered secondary to other causes and not as a
primary defect.
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. Two forms of BA exist:
a) peri- or post natal is the most common, b) fetal or embryonic associated with situs inversus
and polysplenia syndrome (also includes cardiovascular malformations, poly or asplenia
and anomalies of the portal vein and hepatic artery. 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 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 13.1 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 (Fig. 13.1). 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
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Fig. 13.1: Approach to a case of neonatal cholestasis
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 (90% at our institute). Histopathological features are those of bile ductular
proliferation, fibrosis and widening of portal tracts. 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 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. 6 The survival rate with native liver is 32 - 60% after 5 years and between
22 and 53% after 10 years. 7-10 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
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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.10
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.11 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 2004.12
GALACTOSEMIA
Classical galactosemia is an autosomal recessive disorder of galactose metabolism, caused
by a deficiency of the enzyme galactose-1-phosphate uridyltransferase (GALT; EC 2.7.712).13
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 life long 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. PFIC2 is due to mutations of the SPGP
(sister of P-glycoprotein) gene encoding the ATP-dependent canalicular bile acid transporter
Table 13.2:
IP :Clinical features, investigations, treatment and outcome of babies with progressive
112.133.195.17
familial intrahepatic cholestasis12, 14
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*2, Cirrhosis in
pancreas and diarrhea PILBD, granular bile*1 first decade of life, LT in
second decade
Type 2 Liver-specific involvement, GGT not increased; Supportive*2, worse
overlap with type I liver biopsy-giant cells prognosis, LT in first
hepatitis, canalicular and decade.
hepatocellular cholestasis,
amorphous bile*1
Type 3 Delayed until early adulthood Markedly elevated GGT; Supportive, UDCA,
H/o cholestasis of pregnancy Liver biopsy may mimic non-response to UDCA
in the mother biliary atresia need LT
GGT- gamma glutamyl transpeptidase, PILBD- paucity of interlobular bile ducts, LT- liver transplantation,
UDCA-ursodeoxycholic acid, *1 on electron microscopy, *2 surgical biliary diversion may reduce pruritus
(also called BSEP, bile salt export pump) located on chromosome 2q 24. PFIC3 is due to
mutations of the MDR3 (multi drug resistance-3) gene encoding the biliary phospholipid
transporter and is located on chromosome 7q 21.12 Clinical features, investigations, treatment
and outcome of each subtype are shown in Table 13.2.
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) occular 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 during early period of life and also liver biopsy may show bile ductular pro-
liferation. 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. Hepatocellular carcinoma is reported to develop in patients with Alagille
syndrome.
HEREDITARY
IP : TYROSINEMIA
112.133.195.17
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 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 metabolic 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.15 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 percent. Historical data for children treated with dietary restrictions
alone indicates a survival rate of 29 percent 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.16
NEONATAL
IPHEMOCHROMATOSIS
: 112.133.195.17
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.17 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 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 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. 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- weighted MRI (pancreas, heart) characteristic of iron. Serum ferritin
level may be elevated.
Treatment has to be instituted fast for this condition. A medical regimen consists of
N-acetyl cysteine, selenium, desferroxamine, 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,18 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.19
MANAGEMENT
What steps should be adopted in evaluation are shown in Figure 13.1. 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. 13.1). 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
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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 Disorers 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. 13.1)
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 breastfd 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, 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 13.3 shows supportive drug therapy and treatment
required to manage pruritus in NC. Pruritus can be reduced by giving one or more than
one drug in combination (Table 13.3). Naloxone and terfemadine (1-3 mg/kg/day) can also
be tried to control pruritus.
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 > 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
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.Table 13.3: Supportive management of neonatal cholestasis
Drug Dose Side effects
Vitamin K (Phytonadione) 2.5-5 mg on alternate day None
Vitamin D
Cholecalciferol 2500-5000 IU/d Hypercalcemia
25-OH cholecalciferol 3-5 mcg/Kg/d Nephrocalcinosis
Vitamin A Aquasol A: 2500-5000 IU/d Hepatotoxicity, Hypercalcemia,
or Pseudotumor cerebri*
Injectable: 30,000 IU IM at Avoid hyper-vitaminosis as it
diagnosis and then 10,000 IU can enhance fibrosis.
monthly till 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,
hyperchloremic metabolic acidosis
*Observed at our center with a higher than 30,000 IU/ dose by injectable route,
TPGS: d-α-tocopheryl polyethylene glycol 1000 succinate. Vitamins to be administered in all cases of
NC irrespective of etiology
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.20,21
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) 22 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
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from 121 days (period A) to 107 days (period B) and then to 78 days (period C). 23 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 under
IAP will certainly help salvage a number of infants and thus contribute in reducing infant
mortality rates.
REFERENCES
1. Suchy FJ. Approach to the infant with cholestasis, in Suchy FJ, Sokol RJ, Balistreri WF (Eds): Liver
Disease in Children (ed 2). Philadelphia, PA, Lippincott Williams and Wilkins, 2001;187-194.
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 Perinatolo 2002; 29:180-
2002.
6. Shneider BL, Brown MB, Haber B, Whitington PF, Schwarz K, Squires R, Bezerra J,Shepherd R, Rosenthal
P, Hoofnagle JH, Sokol RJ; Biliary Atresia Research Consortium. J Pediatr. 2006;148:467-74.
7. Ohi R. biliary atresia. A surgical perspective. Clin Liver Dis 2000;4(4):779-804.
8. Davenport M. biliary atresia. Semin Pediatr Surg 2005;14(1):42-8
9. Peterson C. Surgery in biliary atresia–futile or futuristic? Eur J Pediatr Surgery 2004;14(4): 226-9.
10. Peterson C. Pathogenesis and treatment opportunities for biliary atresia. Clin Liver Dis 2006;10:73-
88.
11. Venigalla S and Gourley G R. Neonatal cholestasis. Semin in Perinatology 2004;29:348-55.
12. Balistreri WF and Bezerra JA. Whatever happened to “Neonatal hepatitis”. Clin Liver Dis 2006;10:27-
53.
13. Bosch AM. Classical galactosaemia revisited. J Inherit Metab Dis. 2006;29:516-25.
14. 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.
15. Nitisinone: new drug. Type 1 tyrosinemia: an effective drug. Prescrire Int. 2007;16:56-8
16. McKiernan PJ. Nitisinone in the treatment of hereditary tyrosinemia type 1. Drugs 2006;66:743-50.
17. Kelly AL, Lunt PW, Rodrigues F, Berry PJ, Flynn DM, McKiernan PJ, Kelly DA, Mieli-Vergani G, Cox
TM. 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.
18. Gissen P, Kelly D. New hope for treatment of neonatal haemochromatosis. Lancet. 2004;364:1644-5.
19. Grabhorn E, Richter A, Burdelski M, Rogiers X, Ganschow R. Neonatal hemochromatosis: long-term
experience with favorable outcome. Pediatrics. 2006;118:2060-5.
20. Yachha SK, Sharma A. Neonatal cholestasis in India. Indian Pediatr. 2005;43:491-2.
21. Yachha SK. Cholestatic jaundice during infancy. Indian J Gastroenterol. 2005;24(2):47-8.
22. 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
23. Sharma A, Poddar U and Yachha SK. Positive impact of awareness campaign on referral of neonatal
cholestasis syndrome in India. J Gastroenterol Hepatol. 2004;19 (Suppl.):A800.
24. Khanna R, Alam S, Sherwani R, Arora S, Arora Nk, Malik A. Alpha-1 antitrypsin deficiency among
Indian children with liver disorders. Indian J Gastroenterol 2006;25:191-3.
Sheila Bhave
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Chronic Liver Disorders

14 in Children
CONCEPT OF CHRONIC LIVER DISEASE (CLD)1-3

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
14.1). 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
Table 14.1: 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 disorders
• Ductal paucity (Watson Alagelle syndrome) • Hemochromatosis
• Choledochal cyst (CC) 5. Venous congestion/vascular problems
• Progressive familial intrahepatic cholestasis • Budd-Chiari syndrome, venocaval webs
(PFIC), etc. • Venoocclusive disease (VOD)
2. Chronic hepatitis • Congestive heart failure, constrictive
• Chronic viral hepatitis–B/C/D/others pericarditis
• Autoimmune hepatitis • Non-cirrhotic portal fibrosis
• Chronic drug induced hepatitis (e.g. 6. Miscellaneous
paracetamol, isoniazide) • Cystic fibrosis (CF)
• Sclerosing cholangitis • Fibropolycystic disorders (polycystic disease
3. Genetic/metabolic liver disease of liver, kidney)
• Alpha 1 antitrypsin deficiency • Histiocytosis X
• Galactosemia, fructosemia • Fatty liver, “NASH”
• Tyrosinemia, inherited urea cycle defects • Chronic liver abscess
• Mucopolysaccharoidosis–Hurler’s • Idiopathic cirrhosis, nutritional cirrhosis
• Glycogen storage disease–type III, type IV
• Gaucher’s, Niemann-Pick disease, Wolman’s
disease
• Peroxisomal (Zellweger) mitochondrial
disorders
Chronic Liver Disorders in Children / 189
than 3 to 6 months) leading to various manifestations and complications of liver cell failure.
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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 on acute liver disease and eventually may obscure the nature of the original
insult.
SPECTRUM AND PREVALENCE OF CLD IN INDIA3,4

Chronic liver disease accounts for atleast 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 25 years is
depicted in Table 14.2.
Table 14.2: Changing patterns of chronic liver disorders in India, KEM Hospital, Pune 1980-2005
Liver disease Average annual incidence (case/year)
1980-84 85-89 90-94 95-99 2000-04 05 +
Indian childhood cirrhosis 37 22 4 2 1 1
Neonatal cholestasis 9 10 28 34 44 40
Metabolic liver disease 2 5 6 10 14 22
Chronic hepatitis 9 6 6 7 8 6
Wilson’s disease 2 4 5 7 14 16
Miscellaneous 18 9 13 23 32 28
TOTAL 77 56 62 83 113 113
Acute hepatitis 52 48 56 68 84 82
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
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• Ascites
• Bleeding manifestations: Nose bleeds, hematemesis, mealena - (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
• Growth failure, muscle wasting
• Endocrine abnormalities (such as menstrual irregularities, gynecomastia)
• Encephalopathy
• Renal dysfunction–hepatorenal syndrome (azotemia, oliguria in patients with cirrhosis).
Presentation
i. CLD usually presents with vague ill health, irregular fever, anorexia, vomiting, abdominal
pain and abdominal distension with prolonged jaundice.
ii. Child may present with a respiratory or a gastrointestinal infection with findings typical
of CLD.
iii. 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 thrombin time (inspite 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: Alternate/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 scaring 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
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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 Disease5,7,8

All cases
LFTs–S.bilirubin, Transaminases, Full blood count
Alkaline Phosphatase S.urea and electrolytes
S.proteins, S.immunoglobulins Chest X-ray
Lipids, cholesterol USG abdomen
Prothrombin time Liver biopsy
Endoscopy
Etiological Investigations in Selected Patients

• HBsAg, and other viral markers for Hepatitis A, B, C, E
• Serum tissue autoantibodies ANA, SMA, LKM
• Ceruloplasmin, 24 hours urinary 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
• Intravenous pylography, inferior venocacogram
• Cardiac Doppler
• Radio isotopic imaging.
Management of CLD and its Complications6,9

The principles of management are:
1. Assessment: Is it CLD? What stage? Any features requiring critical care?
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.
2. Look for treatable causes of CLD and aim for specific therapy,
e.g. copper chelating drugs in Wilson’s Disease
Kasai surgery in biliary atresia
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

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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
Medical/Surgical
9. Management of anemia and renal failure
10. Liver transplantation in appropriate cases.
Indian Childhood Cirrhosis (ICC)4,6,11

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. 14.1)

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.
Histopathology (Fig. 14.2)

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 limiting plate are also seen. Parenchymal fat is usually absent and
cholestasis a late feature.
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Fig. 14.1: Child with ICC
Figs 14.2A 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 mg/g, the values in ICC are usually over 1000 mg/g. 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
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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 sibs 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 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, reduc-
tion 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 clinically 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

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These disorders are not uncommon in children in India.
1. Venoocclusive 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
pyrrolizolidines 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
veins upto the entry of inferior 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
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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 pericardectomy 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.
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 and venous outflow obstruction disorders. Details of other CLDs such
biliary atresia and chronic hepatitis will be found in related chapters.
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. Suzanne D. Chronic hepatitis. In Kelly DA (Ed): Diseases of the liver and biliary system in children.
Blackwell Science Ltd., Oxford, UK 1999;97-115.
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 1999;3-11.
6. Mowat AP. Chronic hepatitis in liver disorders in children (3rd edn). Butterworths & Co., Publishers.,
London. Oxford 1999;317-29.
7. Malathi Satyasekharan. Approach to a child with CLD. IJPP Hepatology 2002;4:363.
8. Nelson Textbook of Pediatrics. Liver 2004;1303-23.
9. Ross S. Complications and management of chronic liver disease. In Kelly DA (Eds): Diseases of the
liver and biliary system in children. Blackwell Science Ltd., Oxford, UK1999;3-11.
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.
Portal Hypertension / 197
Sutapa Ganguly
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15 Portal Hypertension
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, pyelephlebitis and inflammatory masses around the portal vein leading to
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development of portal vein thrombosis.12 Dehydration and increased coagulability of blood
associated with disseminated intravascular 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 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,
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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, α1
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
nonthrombotic 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 3 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 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 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
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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. Polycythemia rubra vera, 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.
At the time, when occlusion of portal vein by a thrombus develops, patient may remain
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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 15.1). 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 esophageal varices causing massive GI bleed.64,65 Esophageal varices are considered
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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 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 15.2). 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. Non-invasive techniques are ultrasound with duplex Doppler, CT scan and MIRI.
Invasive techniques include splenoportovenography (SPV), arterioportography, percutaneous
transhepatic portography and inferior venocavography.67-69
IMAGING
Non-invasive 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, 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.
MRI shows an area of abnormal signal within the lumen of the portal vein which appears
iso-intense on T1-weighted image with a more intense signal on T2-weighted image.
Though the last two investigations are highly sensitive and specific but they are not
cost effective in our set up.
Invasive Imaging (Portography)

Defined as roentengenographic visualization of portal venous system achieved by introduction
of contrast into the system. It is not generally not required as cross-sectional imaging scan
show as many collaterals. It is indicated in following situations.
1. Equivocal cases where adequate information is not available by color Doppler study.
2. To identify the site of bleeding varices that are not seen on endoscopy.
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3. Prior to TIPS.
Splenoportovenography: It was used previously due to ease in technique. Risk of bleed is 2-
4%. It shows false positive portal vein thrombosis if contrast flows through splenic collaterals.
Splenic pulp pressure can be measured. It may be useful in persistant undiagnosed
splenomegaly where splenoportovenography and diagnostic splenic pulp aspiration for
abnormal cells and organisms may be done simultaneously.58
Arterioportography (contrast injected into celiac and superior mesenteric artery and venous phase angio
is seen): Once considered gold standard is largely replaced by Doppler sonography. Previously
it was also used for transcatheter homeostasis of esophageal varices but now with widespread
use of endoscopic sclerotherapy his has fallen out of favor. In certain situations, e.g. GI
bleed and endoscopy showing no varices, AV fistula, etc. it can be useful. It shows excellent
visualization of portal system. Hepatic arterial hemodynamics are well studied. It is safer
than splenoportovenography and can be sued in situations of splenectomy, splenic infarction
and non-palpable spleen. In this retroperitoneal shunts may not seen as dense as in
splenoportography, when available it replaces other angiographies.57,58
Percutaneous transhepatic portovenography: It is highly invasive and technically complex and
is seldom performed even though it is one of the most accurate procedure for investigation
of PH and gives best anatomically delineation. Fine catheter is passed percutaneously to
peripheral portal vein branch and advanced into splenic and superior mesenteric veins.
Table 15.1: Conn’s endoscopic classification of esophageal varices82

Grade–I On inspiration only Can be effaced Straight Red
Grade–II Both on inspiration Can be effaced Straight Red
and expiration
Grade–III Projecting into lumen Cannot be effaced Straight Blue
less than 50% ,Wavy ±
Grade–IV Projecting into lumen Tense Tortuous Blue
more than 50% and coiled ±
Table 15.2: 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
Medical and Endoscopic Management of PH in Children

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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%.
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
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• Transjugular intrahepatic portosystemic shunting (TIPS)
• Surgery.
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
Fig. 15.1: Hemodynamics of portal hypertension
Drugs used in PHT exert their effect by reducing portal inflow or reducing intrahepatic
or collateral resistance (Fig. 15.1). 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
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
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• Vasopressin/terlipressin
• Somatostatin/Octreotide
• β adrenergic antagonist.
Vasodilators
• Nitroglycerine
• Isosorbide mononitrate
• Isosorbide dinitrate.
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 percent 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 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
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

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in terms of both control of bleeding and mortality.
It case 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 glucagons
an 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.
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 Prophylaxis

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 β1 blockade they reduce
the cardiac output and thereby lower the portal pressure and by β2 blocking action they
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produce splanchnic vasoconstriction due to unopposed a 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 sue 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.
Secondary Prophylaxis or Prevention of Recurrent Hemorrhage

To prevent recurrent hemorrhage, trials have been given with β blockers, long acting nitrates
and confirmed drug therapy. Concerns have been raised regarding difficulty in
hemodynamically resuscitating patients on β blocker therapy, but in practice this problem
is uncommon and has not been identified as a cause of morbidity and mortality. In adult
cirrhotic patients β blockers have shown additional benefit of reducing the risk of bleeding
from portal hypertensive gastropathy.
Twelve randomized, controlled trials have compared non-selective β blockers with no
active treatment in the prevention of recurrent variceal hemorrhage.77,78 Propranolol was
used in 10 studies nadolol in one study and both propranolol, atenolol in addition to placebo
in one study. There was a lower rate of variceal rebleeding with β blocker therapy in each
trial.
There is only one trial comparing the efficacy of combination therapy with isosorbide
mononitrate and β blocker with a therapy of β blocker alone. Although a lower rate of
rebleeding was associated in the former group the difference was not statistically significant.
β blockers has also been compared directly with EST on 10 RCT, EST was associated
with a lower rate of rebleeding but no survival advantage. A 1993 trial where two modalities
were compared highlighted some of the issues which are critical. In this study the initial
treatment of active bleeding was conservative, thereby avoiding the impact of acute EST
on long-term rebleeding risk. The acturial probability of rebleeding at 1 year was 33% in
the EST group and 53% in the propranolol group, and almost all the difference between
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these two groups occurred in the first two months. The benefits of EST in preventing
rebleeding may be balanced by an increased rate of complication.
Balloon tamponade: 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.
Endotherapy
Immediately after resuscitation diagnostic endoscopy is essential to detect:
• Presence or absence of esophageal varices
• Gastric varices
• Portal hypertensive gastropathy
• Gradation of varices
• Site of active bleeding if any.
ENDOSCOPIC SCLEROTHERAPY (EST)

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 years,2,81
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 becomes
more.
At our center, for small children and infants intramuscular ketamine is used is dosage
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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 confidence about the procedure, yields better results than any sedative.
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 prodecure 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
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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 considered an accompaniment of EVS as they are of little clinical consequenses.
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 al 90 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
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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 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 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
Surgical Management of EHPVO

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.
The absolute indication for surgery is inability to control an episode of variceal bleeding
by sclerotherapy and other medical means, and splenic vein thrombosis with gastric variceal
bleeding in absence of esophageal varices; other relative indications include rare blood group,
living in places far away from centers with facility for endotherapy and symptomatic
hypersplenism. In absence of these indications for surgery, the first preference should EVL
and/or EST.
REFERENCES
1. Alvarez F, Bernard O, Brunella F, et al. Portal obstruction is children. Clinical investigation and
hemorrhage risk. J Pediatr 1980;103:696-702.
2. Howad ER, Stamatakis JD, Mowat AP. Management of oesophageal varices in children with
sclerotherapy. J Pediatr Surg 9184;19:20-5.
3. Henderson JM. Endoscopic variceal sclerosis compared with distal splenorenal shunt to prevent recurrent
variceal bleeding in cirrhosis. A prospective randomized trial. Ann Intern Med 1990;112:262-9.
4. Basu SK, Iyengar P, Mitra SK. Juvenile Portal Hypertension. J Indian Med Assoc 1971;56:39-41.
5. Sarin SK.IPSclerotherapy
: 112.133.195.17
for variceal, bleeding in children. Indian Pediatr 1988;25:231-5.
6. Bhalerao RA. In: Nandy S, Tandon BN (Eds): Portal hypertension in India. New Delhi: Rajagharia
Clinical Research Unit, 1978: 11.
7. Dilwari JB, Kaur U, Narayanan VT, et al. Pattern of upper gastrointestinal haemorrhage in Northern
India–an endoscopic study of 316 patients. J Gastroenteral Hapatol 1978;2:443-9.
8. Khanduri A, Yachha SK, Kumar M. Etiologic spectrum of gastrointestinal bleeding in children–experience
at a tertiary center. Indian J Gastroenterol 1994;13(suppl 1):A3.
9. Bernard O, Alvarez F, Brinelle F, et al. Portal hypertension. Clin Gastroenterol 1985;14:35-55.
10. Altman RB, Krug JK, Portal hypertension, American Academy of Pediatrics Surgical Section Survey,
J Pediatr Surg 1982;17:567-70.
11. Mowat AP. Liver disorders in childhood. London. Butterworth and Co. 1987;298-323.
12. Webb LJ, Sherlock S. The etiology, presentation and natural history of extrahepatic portal venous
obstruction. Q J Med 1979;192:627-39.
13. Valla P, Casadevalli N, Huisse MG, et al. Etiology of portal venous thrombosis in adults: A prospective
evaluation of primary myeloproliferative disorders. Gastroenterol 1988;94:1063-9.
14. Diwari JB, Chawla YK. Extrahepatic portal venous obstruction. Gut 1988;29:554-5.
15. Boles ET Jr, Wise WE Jr, Birken G. Extrahepatic portal hypertension in children: Long-term evaluation.
Am J Surg 1986;151:734-9.
16. Thompson EN, Sherlock S. The etiology of portal vein thrombosis with particular reference to role
of infection and exchange transfusion. Q J Med 1964;132:464-79.
17. Do umbilical vein catheterization and sepsis lead to portal vein thrombosis? H prospective, clinical
and sonographic evaluation. J of Pediatr. Gastroenterol and Nutrition 1993;7(4):392-6.
18. Prosad AS, Gupta S, Kohli V, Pande CK, et al. Proximal splenorenal shunts for extrahepatic portal
venous obstruction in children. Ann Surg 1964;219:193-6.
19. Mitra SK, Kumar V, Datta DV, et al. Extrahepatic portal hypertension: A review of 70 cases. J Pediatr
Surg 1978;13:51-54.
20. Diab S, Nema TA, Zindan FA, Portal hypertension complicating abdominal tuberculosis. Acta Clin
Scand 1990;156:495-7.
21. Valla D, Denninger WH, Delvigne JM, et al. Portal vein thrombosis with ruptured esophageal varices
as presenting manifestation of hereditary protein C deficiency. Gut 1988;29:856-9.
22. Thaler E, Lechner K. Antithrombian III deficiency and thromboembolism. Bailliers Clin Haematol
1981;10:369-90.
23. Morteau P, Cadranel JF, Messing B, et al. Association of Hepatic vein obstrunction and celiac disease
in North African subjects. J Hepatol 1994;20:650-3.
24. Ghosal UC, Saraswat VA, Yachha SK. Association of splenic vein obstruction and coeliac disease in
our Indian patient. J Hepatol 1995;22.
25. More SS, Taylor KJW, Straiss EB, et al. Congenital absence of the portal vein in oculoauriculo–vertebral
dysplasia (Goldenhar syndrome), Pediatr. Radiol 1986;16:437.
26. Odjenvre M, Pige G, Alagille D, Congenital abnormalities associated with extrahepatic portal
hypertension. Arch Dis Child 1977;52:383-5.
27. Devarbhavi H, Sanwat P, Nanivadekar SA, et al. Congenital anomalies in a case with extrahepatic
portal venous obstruction, Indian J Gastroenterol 1995;14:33.
28. Bernades P, Baetz A, Livy P, et al. Splenic and portal venous obstruction in chronic panareatitis. A
prospective longitudinal study of a medical–surgical series of 266 patients. Dig Dis Sci 1992;37:340.
29. O Kudh K, Okmishi K, Kimura, et al. Incidence of portal venous thrombosis in liver cirrhosis; an
angiographic study in 708 patients. Gastroenterology 1985;89:279-86.
30. Belli-L, Sansalone CV, Aseni P, et al. Portal thrombosis in cirrhosis; a retrospective analysis. Ann Surg
1986;203:286-91.
31. Nonami T. Incidence of portal vein thrombosis at liver transplantation. Hepatol 1992;16:1195-8.
32. Bayer JL, Sengupta KP, Biswas SK, et al. Idiopathic portal hypertension: Comparison with the portal
IP : 112.133.195.17
hypertension of cirrhosis and extrahepatic portal vein obstruction. Ann Intern Med 1967;66:41-67.
33. Maksoud JG, Miles S, Gayottoo LC. Hepatoportal sclerosis in childhood. Am J Surg 1986;151:484-8.
34. Yachha SK, Sharma BC, Kumar M, et al. Endscopic sclerotherapy for esophageal varices in children
with extrahepatic portal obstruction: A follow-up study. J Pediatr Gastroenterol Nutr 1997;4:49-52.
35. Diswari JB, Ganguly S, Chawla Y. Non-cirrhotic portal pitrosis. Indian J Gastroenteral 1982;11:31-6.
36. Okuda K. Idiopathic portal hypertension In: Recent advances in Hepatology. Thomas HC, Jones EA,
(Eds). Edinburgh: Churchill Livingstone 1986;93-108.
37. Sarin SK, Non-cirrhotic portal fibrosis. Gut 1989;30:406-15.
38. Amrapukar DN, Dhawan PS, Chopra K, et al. Stomach in portal hypertension 1993;41(10):638-40.
39. Thapa BR, Mehta S, et al; Endoscopic sclerotherapy of esophageal varices in infants and children. J
Pediatr Gastroenterol Nutr 1990;10(4):430-4.
40. Poddar U, Thapp BR, Puri P, et al. Non-cirrhotic portal fibrosis in children. Indian J of Gastroenterol
2000;19(1):12-3.
41. Ganguly S, Dasgupta J, Das AS, et al. Study of portal hypertension in children with special reference
to sclerotherapy. Tropical Gastroenterology 1997;18(3):119-21.
42. Ganguly S, Ganguly SB, Chronic hepatobiliary disease in children: An aetiological study. Trop
Gastroentero 1999;0:82-84.
43. Dangwal TR, Agarwal V, Malhotra V, et al. Clinical spectrum of chronic liver disease in North Indian
children. Trop Gastroentrol 1997;18:174-6.
44. Stuart KL, Bras G. Veno-occlusive disease of the liver. Am J Med 1957;26:291-319.
45. Shulman HM, Fisher LB, Schoch HG, et al. Veno-occlusive of the liver after marrow transplantation:
histological correlation of clinical signs and symptoms, Hepatology 1994;19:1171-80.
46. Wimot FC, Robertson GW. Senecio disease or cirrhosis of the liver due to senecio poisosning. Lancet
1920;ii:848-9.
47. Krishnamachari KAVR, Bhat RV, Krishnamurthi D, et al. Aetiopathogenesis of endemic ascites in
Surguja District of Madhya Pradesh. India J Med Res 1977;65:672-8.
48. Budd G. On diseases of the liver. London: Churchill 1845:147.
49. Chiari H, U Ber die sela standige Philibitles obliterau der venae hepatical als Toderlursache. Beite Pathol
Anat Allg Pathol 1899;26:1-18.
50. Madangopalan N, Soloman V, Jayanthi V, et al. Clinical spectrum of Chronic Budd-Chiari and surgical
relief for codraction of the inferior venacave. J Gastroentrol Hepatal 1986;1:359-69.
51. Datta DV, Saha Samanta S, Singh A, et al. Clinical spectrum of Budd-Chiari Syndrome in Chandigarh
with particular reference to obstruction of intrahepatic portion of inferior vena cava. Ind J Med Res
1972;60:385-402.
52. Mahmoud AEA, Wilde JT, Elease. Budd-Chiari syndrome and factor V Leiden mutation. Lancet 1995,
345-526.
53. FouKuloned EW. Surgical management of portal hypertension in childhood. Long-term results. Ann
Surg 1980;115:1042-45.
54. Martel C, Bologuesi M, Bellen S, et al. Long-term follow-up study of adult patients with non-cirrhotic
obstruction of portal system; comparison with cirrhosis patients. J Hepatol 1992;15:299-303.
55. Koshy A, Bhasin DK, Kapur KK. Bleeding in extrahepatic portal vein obstruction. Indian J Gastroenterol
1984;3:13-4.
56. Frankalsrud EW, Myers NA, Robinson MJ. Management of extrahepatic portal hypertension in Children
Ann Surg 1974;180:487-91.
57. Raffensperger JH, Shkolint AA, Bogga JD, et al. Portal hypertension in children. Arch Surg 1972;105:
249-54.
58. Hassalle E, Berquist WE, Amout ME, et al. Sclerotherapy for portal hypertension in children. J Pediatr
1989;115:69-74.
59. Alvarez F, Bernard O, Brunelle F, et al. Portal hypertension in children. 1. Clinical investigation and
hemorrhage risk. J Pediatr 1983;103:696-702.
60. Witte CL, Brewer ML, Witte WH, et al. Protean manifestation of pyelothrombosis. A review of thirty
IP : 112.133.195.17
four patients. Ann Surg 1985;202:191-202.
61. Calis P, Zabotto B, Meskens C, et al. Gastroesophageal endoscopic features in cirrhosis. Observer
variability, inner associations and relationship to hepatic dysfunction. Gastroenterology 1990;98:156.
62. Labreo D, de Flury P, Rueff B. Portal hypertension, size of esophageal varices and risk of gastrointestinal
bleeding in alcoholic cirrhosis. Gastroenterology 1980;79:1139.
63. Planas R, Quer JC, Boix J, et al. A prospective randomized trial comparing somatostatin and
sclerotherapy in the treatment of acute variceal bleeding. Hepatology 1994;20:370.
64. Bhagwat SS, Borwarankar SS, Ramadwar RH. Isolated jejunal varices. J Postgrad Med 1995;41:43-4.
65. Heisonmez A, Karagiizel G, Tanyel FC. Duodenal varices causing intractable bleeding in 12 year old
child. Eur J Pediatr Surg 1994;176-7.
66. Spence RAJ. Variceal bleeding. In Gastroenterologic endoscopy. Sivak MV (Eds): WB Saunders Co
2000;356-70.
67. Davenport M, Howard ER. Surgical disorders of liver and bile ducts. In Diseases of the liver and biliary
system in children. Kelly DA (Eds): Blackwell Science Ltd. 1999;253-78.
68. Bayer TD, Henderson JM. Portal Hypertension in Hepatology. A Textbook of Liver Diseases. Zakim
D, Bayer TD (Eds): WB Saunders Co. 1996;720-83.
69. Baron RL, Gore RM. Diffuse liver diseases. In Textbook of Gastrointestinal Radiology. Gore RM, Levine
MS (Eds): WB Saunders Co. 2000;1590-1639.
70. Yau Gansbeke D, Avni EF, Delcour C, et al. Sonographic features of portal vein thrombosis. Am J
Roentgenol 1985;1985;144:749-52.
71. Schewerk WB. Portal vein thrombosis; real time sonographic demonstration and follow-up. Gastrointest
Radiol 1986;11:312-8.
72. Walker DW, Tonsin AK, Joly D. Portal vein thrombosis shown by ultrasonography. South Med J 1983;
76:925-6.
73. Jahansen K, Paum M. Duplex ultrasonographic of the portal vein. Surg Clin North Am 1990;70:181-
90.
74. Sharma MP, Dasavathy S, Mitra SC, et al. Sonographyc signs in portal hypertension: A multiple variate
analysis. Trop Gastroenterol 1996;17:23-9.
75. Garcia–Pagani JC, Escorsell A, Moutinho E, et al. Influence of pharmacologic agents on portal
hemodynamics: Bug’s for its use in the treatment of portal hypertension. Seminar Liver Dis 1999;19:427.
76. Merkel C, Bolognesi M, Sacerdoti P, et al. The hemodynamic response to medical treatment of portal
hypertension as a predictor of clinical effectiveness in the primary prophylaxis of variceal bleeding
in cirrhosis. Hepatology 2000;32:320.
77. D’Amico G, Pagliaro L, Bosch J. Pharmacological treatment of Portal Hypertension. An evidence-based
approach. Semin Liver Dis 1999;19:475.
78. Jenkens ST, Shields R, Danis M, et al. A multicentric randomized trial comparing octreotide and injection
Sclerotherapy in the management and outcome of acute variceal hemorrhage. Gut 1997;41:526.
79. Hwange SJ, Linc HC, Chang CF, et al. A randomized controlled trial comparing octreotide and
vasopressin in the control of acute esophageal variceal bleeding. J Hepatol 1992;16:320-5.
80. Teran JC, Imperiale TF, Mullen KD, et al. Primary prophylaxis of variceal bleeding in cirrhosis: A cost-
effectiveness analysis. Gastroenterology 1997;112:473.
81. Mowat AP. Prevention of variceal bleeding. J Pediatr Gastroenterol Nutr 1986;5: 679-97.
82. Conn H O. Ammonia tolerence in the diagnosis of esophageal varices. A comparison of endoscopic,
radiologic and biochemical techniques. J Lab Clin Med 1967;70:442-51.
83. Terblanche J, Bornman PC. Endoscopic sclerotherapy. Surg Clin North America 1990; 70:341-59.
84. Westby D, Melia WM, Macdougall BR, et al. Injection sclerotherapy for esophageal varices: A prospective
randomized trial of different treatment schedules. Gut 1984;25:129-32.
85. Sarin SK, Sachdev G, Nanda R, et al. Endoscopic sclerotherapy using absolute alcohol. Gut 1985;26:120-
24.
86. Mathur SK, Shah SR. Current status of endoscopic variceal sclerotherapy in the management of variceal
IPSurgery
bleeding. : 112.133.195.17
1995;1:2-39.
87. Thapa BR, Mehta S. Investigative approach and management of portal hypertension Indian Pediatr
1992; 29:945-54.
88. Kochhar R, Mishra V K, Tambi SS, et al. Upper G1 endoscopy in infants and children Indian pediatr
1989;26: 129-33.
89. Hosking SW, Johnson AG. Gastric varices: A proposed classification leading to management. Br J Surg
1988;75:195-6.
90. Stiegmann GV, Goff JS. Endoscopic esophageal variceal ligation, (EVL) preliminary clinical experience.
Gastrointest Endosc 1988; 34:113-7.
91. Stiegmann GV, Goff JS, Michaletz-onody PA, et al. Endoscopic sclerotherapy as compared with
endoscopic ligation for bleedng esophageal varices. N Engl J Med 1992;326:1527-32.
92. Hou MC, Lin HC, Kno BI, et al. Comparison of endoscopic variceal injection sclerotherapy and ligation
for the treatment of esophageal variceal hemorrhage: A prospective randomized trial. Hepatology
1995;21:1517-22.
93. Saeed ZA. The Saeed six-shooter: A prospective study of a new endoscopic multiple rubber-band ligator
for the treatment of varices. Endoscopy 1996;28:559-64.
94. Hall RJ, Lilly JR, Steigmann GV. Endoscopic esophageal varix ligation: Technique and preliminary results
in children. J Pediatr Surg 1988; 23:1222-3.
95. Price MR, Sartorelli KH, Karrer FM, et al. Management of esophageal varices in children by endoscopic
variceal ligation. J Pediatr Surg 1996; 31: 1056-59.
96. McKiernan PJ, Beath SV, Davison SM. A prospective study of endoscopic oesophageal variceal ligation
using multiband ligator. J Pediatr Gastro enterol Nutr 2002; 34: 207-11.
97. Hill ID, Bowie MD. Endoscopic sclerotherapy for control of bleeding varices in children. Am J
Gastroenterol 1991; 86: 472-6.
98. Stringer MD, Howard ER. Long-term outcome after injection sclerotherapy for esophageal varices
in children with extrahepatic portal hypertension. Gut 1994; 35: 257-9.
99. Yachha SK, Sharma BC, Kumar M, et al. Endoscopic sclerotherapy for esophageal varices in children
with extrahepatic portal venous obstruction: A follow–up study. J Pediatr Gastroenterol Nutr 1997;
24: 49- 52.
100. Dilawari JB, Chawla YK, Ramesh GN, et al. Endoscopic sclerotherapy in children. J Gastroenterol Hepatol
1989; 4: 1551-60.
101. Thapa BR, Mehta S. Endoscopic sclerotheapy of esophageal varices in infants and children. J Pediatr
Gastroenterol Nutr 1990; 10: 430-4.
102. Howard ER, Stringer MD, Mowat AP. Assessment of injection sclerotherapy in management of 152
children with esophageal varices. Br J Surg 1988; 75: 404-8.
103. Lo G, Lai K, Cheng J, et al. Prevalence of paraesophageal varices and gastric varices in patients achieving
variceal obliteration by banding ligation and by injection sclerotherapy. Gastrointest Endosc 1999; 49:
428-36.
104. Sarin SK, Gupta RG. Endoscopic ligation plus sclerothrapy: Two plus two makes only three. Gastrointest
Endosc 1999; 50:129-133.
Metabolic Liver Diseases / 217
Ashish Bavdekar
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16 Metabolic Liver Diseases
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 childern. They now account for upto 40% of all chronic liver admissions to large medical
centres 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 centres 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 centres.
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 in
Indian children.1 During the last 20 years, over 1,000 children with chronic liver disease
have been assessed at the Liver Unit, KEM Hospital, Pune. The copper associated disorder,
Indian Childhood Cirrhosis was the commonest chronic liver disease in the 1980’s, but is
now a rarity. WD is now commonly seen at our center and till date 124 children with WD
IPClinical
Table 16.1: : 112.133.195.17
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 10 10.8 (3.4) 14.0 (19.57) 9 (90)
(Rickets, hemolysis)
Asymptomatic sibs 19 7.3 (4.1) — 15 (79)
* Values expressed as sean (SD)
have been diagnosed. Selected clinical information of these children with regard to type
of presentation, age and outcome is presented in Table 16.1. Younger the age at presentation,
more acute were the manifestations and higher the mortality, except in asymptomatic sibs.
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
IP : 112.133.195.17
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 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.
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/g 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
IP : 112.133.195.17
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. 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 < 25ug/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 asympto-
matic sibs. At our center we use D-Penicillamine as initial therapy and continue it lifelong
Table 16.2:
IP : 112.133.195.17 Drug therapy of Wilson’s disease
Drug and cost per Dose Common toxicity Monitoring for side
month effects
1. D-Penicillamine Starting 10 mg/kg/day Fever, rash, proteinuria, Complete blood

(Rs 1500) increase to 20-30 mg/ Thrombocytopenia, and platelet
kg/day in 2 to 3 bone marrow counts, urine
divided doses 1 hour depression, proteinuria, analysis before
before meals worsening of therapy, weekly
neurological symptoms, during the first one
autoimmune conditions, month, monthly in
others the first year and
yearly thereafter
2. Trientine (Rs 25 mg/kg/day in 3 Gastritis, sideroblastic As above

10,000) divided doses 1 hour anemia, aplastic anemia
before meals
3. Zinc (Rs 200) 25-50 mg of Gastritis, biochemical

elemental zinc. 3 pancreatitis, possible
times daily, 1 hour immune dysfunction
before meals
4. Ammonium 120 mg/day in six Anemia, bone marrow Complete blood
tetrathiomolybdate divided doses depression, counts liver
(not available for hepatotoxicity function tests, BUL,
routine use) creatinine, urine
analysis weekly
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 16.2). 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.
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 efficacy and fewer side effects.
Zinc (Zn): Zinc has been used as acetate, sulphate or gluconate salts. Acetate salts are preferred
IP : 112.133.195.17
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 unavailable for cellular uptake and
further toxicity. Preliminary results with TM suggest that it is an extremely efficacious 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 IP survival. (iv) The best outcome is seen in asymptomatic siblings of index WD
: 112.133.195.17
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 (GSD) are a heterogenous group of distinct entities classified
on the basis of specific enzyme defects in various steps of glycogen synthesis or breakdown.
These result in the various clinical phenotypes. GSDs are broadly classified depending on
the main tissue involved (Table 16.3). All GSDs except for some forms of type VI (X-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 hypoglycemea 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
Table 16.3: Classification of glycogen storage

diseases
Primary organ involved Types
Liver I, IIIb, IV, VI, IX
Muscle V, VII
Mixed II, IIIa
with fibrosis without steatosis. Measurement of enzyme activity in leukocytes, fibroblasts

IP : 112.133.195.17
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: These GSD’s 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 uridyl transferase
(GALT) or uridine diphosphate 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
IP : 112.133.195.17
if milk feedings are continued. Later manifestations include mental retardation, hyperactivity,
renal Fanconis 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 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
IP : 112.133.195.17
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 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
generalised 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;74:787-89.
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.

IPLecca
8. Pilloni L, : 112.133.195.17
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;22:292-96.
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 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
triethylene tetramine 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-
572.
30. Holten JB. Galactosemia. Pathogenesis and treatment. J Inherit Metab Dis 1996;19:3-7.
31. http://www.ich.bris.ac.uk/galtdb.
Ashish Bavdekar
IP : 112.133.195.17
16 Metabolic Liver Diseases
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 childern. They now account for upto 40% of all chronic liver admissions to large medical
centres 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 centres 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 centres.
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 in
Indian children.1 During the last 20 years, over 1,000 children with chronic liver disease
have been assessed at the Liver Unit, KEM Hospital, Pune. The copper associated disorder,
Indian Childhood Cirrhosis was the commonest chronic liver disease in the 1980’s, but is
now a rarity. WD is now commonly seen at our center and till date 124 children with WD
IPClinical
Table 16.1: : 112.133.195.17
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 10 10.8 (3.4) 14.0 (19.57) 9 (90)
(Rickets, hemolysis)
Asymptomatic sibs 19 7.3 (4.1) — 15 (79)
* Values expressed as sean (SD)
have been diagnosed. Selected clinical information of these children with regard to type
of presentation, age and outcome is presented in Table 16.1. Younger the age at presentation,
more acute were the manifestations and higher the mortality, except in asymptomatic sibs.
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
IP : 112.133.195.17
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 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.
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/g 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
IP : 112.133.195.17
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. 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 < 25ug/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 asympto-
matic sibs. At our center we use D-Penicillamine as initial therapy and continue it lifelong
Table 16.2:
IP : 112.133.195.17 Drug therapy of Wilson’s disease
Drug and cost per Dose Common toxicity Monitoring for side
month effects
1. D-Penicillamine Starting 10 mg/kg/day Fever, rash, proteinuria, Complete blood

(Rs 1500) increase to 20-30 mg/ Thrombocytopenia, and platelet
kg/day in 2 to 3 bone marrow counts, urine
divided doses 1 hour depression, proteinuria, analysis before
before meals worsening of therapy, weekly
neurological symptoms, during the first one
autoimmune conditions, month, monthly in
others the first year and
yearly thereafter
2. Trientine (Rs 25 mg/kg/day in 3 Gastritis, sideroblastic As above

10,000) divided doses 1 hour anemia, aplastic anemia
before meals
3. Zinc (Rs 200) 25-50 mg of Gastritis, biochemical

elemental zinc. 3 pancreatitis, possible
times daily, 1 hour immune dysfunction
before meals
4. Ammonium 120 mg/day in six Anemia, bone marrow Complete blood
tetrathiomolybdate divided doses depression, counts liver
(not available for hepatotoxicity function tests, BUL,
routine use) creatinine, urine
analysis weekly
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 16.2). 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.
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 efficacy and fewer side effects.
Zinc (Zn): Zinc has been used as acetate, sulphate or gluconate salts. Acetate salts are preferred
IP : 112.133.195.17
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 unavailable for cellular uptake and
further toxicity. Preliminary results with TM suggest that it is an extremely efficacious 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 IP survival. (iv) The best outcome is seen in asymptomatic siblings of index WD
: 112.133.195.17
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 (GSD) are a heterogenous group of distinct entities classified
on the basis of specific enzyme defects in various steps of glycogen synthesis or breakdown.
These result in the various clinical phenotypes. GSDs are broadly classified depending on
the main tissue involved (Table 16.3). All GSDs except for some forms of type VI (X-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 hypoglycemea 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
Table 16.3: Classification of glycogen storage

diseases
Primary organ involved Types
Liver I, IIIb, IV, VI, IX
Muscle V, VII
Mixed II, IIIa
with fibrosis without steatosis. Measurement of enzyme activity in leukocytes, fibroblasts

IP : 112.133.195.17
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: These GSD’s 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 uridyl transferase
(GALT) or uridine diphosphate 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
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if milk feedings are continued. Later manifestations include mental retardation, hyperactivity,
renal Fanconis 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 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
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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 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
generalised 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;74:787-89.
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.

IPLecca
8. Pilloni L, : 112.133.195.17
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;22:292-96.
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 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
triethylene tetramine 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-
572.
30. Holten JB. Galactosemia. Pathogenesis and treatment. J Inherit Metab Dis 1996;19:3-7.
31. http://www.ich.bris.ac.uk/galtdb.
Anupam
252 / Pediatric Gastroenterology Sibal, Mritunjay Pao, Sheena Sharma
Vijaya Rajakumari, Rajasekar MR
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Liver Transplantation
18 in Children
INTRODUCTION
The diagnosis of liver disease today can be specified more precisely, thanks to better
understanding and advanced diagnostic methods. The confirmation of the etiology and
comprehension of its pathogenesis have led to improved management and prognosis of
previously unexplained liver conditions.
However, in spite of newer therapeutic agents and fine-tuning of nutritional support,
in cases of end-stage liver disease (ESLD), liver transplantation is the only treatment option.
The management of ESLD has evolved tremendously since the milestone was laid in 1963
with Starzl performing the first human liver transplantation (LT) on a 3-year old boy. Since
then a tremendous revolution has taken place in the complicated process of LT, which in
1983 in a consensus by the National Institutes of Health, was confirmed to be a valid procedure
in cases of ESLD. Especially in the last two decades, refinement in surgical techniques,
improvement in anesthesia, perioperative care and access to newer immunosuppressant drugs,
have resulted in improved survival, with 1 year survival rates of 90% and 5-8 year survival
rates of 75 - 80%.1 With increased experience, this modality has further been able to be
offered to a growing number of children less than 1 year of age and weighing less than
10 kg, which previously was associated with increased risk of graft loss.2 Children operated
at an older age have no less survival rates to that of adult patients3 and with this trend,
an increasing number of general pediatricians are confronted with the long-term care of
LT patients.
Given that liver transplantation is performed in two to three children per million in the
West, between two to three thousand children would require liver transplantation in India
every year, as the indications are similar. While the All India Institute of Medical Sciences
(AIIMS) attempted the first adult LT in 1994, the first successful pediatric and adult LT
in India were performed at Indraprastha Apollo Hospital in 1998 in New Delhi.4 Liver
transplantation programs in India have developed over the last decade and with increasing
expertise in pediatric transplant surgery, pediatric hepatology and intensive care has resulted
in improved outcomes.
Liver Transplantation in Children / 253
Indications and Contraindications

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The commonest indication for pediatric LT in the world and in India is extrahepatic biliary
atresia followed by acute liver failure.5 Other indications include chronic liver failure due
to intrahepatic cholestasis, inborn errors of metabolism, like alpha-1-antitrypsin deficiency,
fulminant hepatic failure (FHF) and non-resectable hepatic tumors. Inherited metabolic
disorders wherein liver replacement prevents or minimizes extraheptic manifestation are
growing indications, as e.g. in primary oxalosis, and propionic aciduria4,6 (Table 18.1).
The Pediatric End Stage Liver (PELD) Disease Scoring System

In the United States in view of the increasing number of deaths while on the waiting list,
inability to accurately categorize liver patients according to severity of liver disease using
the partially subjective Child-Turcotte-Pugh classification and evidence that waiting time
correlated poorly with death while on waiting list led to the creation of a revised allocation
system the PELD scoring system in 2002 (essential elements include total bilirubin, INR,
albumin, age< 1 year and evidence of failure to thrive) 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 children7 . Shneider et al8 reported that the current PELD score
was not adequate. Severe coagulopathy, admission in an intensive care unit and the need
for dialysis or hemofiltration are significant predictors of death and needs to be included
Table 18.1: Indications for pediatric liver transplantation

Indications
Cholestatic Metabolic Hepatocellular
Biliary atresia Alpha-1-antitrypsin deficiency Acute and subacute hepatic failure
Biliary hypoplasia (Alagille) Tyrosinemia Autoimmune liver disease (Typ 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
hepatitis of unknown etiology
k
Cystic fibrosis
Inborn errors of metabolism
(not resulting in liver failure)
Crigler-Najjar-syndrome Type I,
ornithine transcarbamylase
(OTC) deficiency, maple syrup
liver disease (MSUD), familial
hypercholesterolemia
Non-resectable hepatic tumors
Hepatoblastoma
Hepatocellular carcinoma
in the PELD score in order to more accurately prioritize organ donation to children awaiting
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LT for acute liver failure.9
End Stage Chronic Liver Failure

As the natural history of biliary atresia is well known, patients with failed Kasai procedures
should be referred to a transplant center as soon as it is clear that the operation has failed.
Such children account for up to 76% of children transplanted under the age of 2 years in
Europe and America. In other forms of chronic liver failure, including progressive biliary
cirrhosis (familial cholestatic syndromes, sclerosing cholangitis), chronic active hepatitis
(hepatitis B and C, autoimmune, idiopathic), alpha-1-antitrypsin deficiency and Wilson’s
disease, precise prediction of need for liver replacement is 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 18.2).
Children should be referred to a transplant center before significant hepatic complications
(such as variceal bleeding and encephalopathy) and impairment of growth and development
set in.
Table 18.2: Indications for LT in end stage chronic liver failure

A) Clinical parameters B) 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
5. Unacceptable quality of life
Fulminant Hepatic Failure

Fulminant Hepatic Failure (FHF) resulting from massive liver necrosis can be defined as
presence of coagulopathy (prothrombin time >24 seconds or INR > 2.0) with or without
hepatic encephalopathy within 8 weeks of the onset of symptoms of liver failure.10 In the
western countries metabolic diseases, hemophagocytic lymphohistiocytosis and cryptogenic
hepatitis account for majority of the causes. In developing countries including India, hepatitis
A singly or in combination with other infectious agents is the most important etiological
agent.11 ,12
The decision to perform an LT in FHF should take into account three questions13 : 1.
Is spontaneous recovery possible? 2. If not, is transplant feasible? 3. Have irretrievable
complications occurred?
The indications for LT in FHF are progressive coagulopathy or progressive hepatic
encephalopathy despite supportive management. Age and sex at diagnosis are not significant
indicators for survival with supportive management. Prognosis is better in patients with
autoimmune hepatitis, hepatitis A and acetaminophen toxicity. Amongst variables useful
in predicting the outcome of FHF, the combination of rising bilirubin and falling transaminases
are poor prognostic indicators. The time of onset of hepatic encephalopathy more than 7
days after onset of clinical symptoms of FHF, prothrombin time > 55 seconds and alanine
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aminotransferase ≤ 2384 IU/L are significant prognostic indicators for eventual death or
the likelihood of requiring an LT in patients with FHF.10
Generally, criteria of King’s College14 , London, are used to predict the outcome of acute
liver failure as well as the need for LT (Table 18.3).
Table 18.3: King’s College criteria for LT in fulminant hepatic failure

Acetaminophen poisoning Other causes of FHF
Arterial pH < 7. 3, PT > 6.5 (INR), or the following three factors
Prothrombin time > 6.5 INR Age < 10 years
S. creatinine > 3.4 mg/dl Cause: non-A, non-B hepatitis or drug induced disease
Duration of jaundice > 7 days before encephalopathy
INR > 3.5
S. bilirubin > 17.6 mg/dl
Inborn Errors of Metabolism

LT is now a therapeutic option for metabolic disorders due to a deficiency of a hepatic
enzyme, which leads to15 acute or chronic liver failure and/or hepatic cancer or extra hepatic
disease. Successful auxillary partial orthotopic living donor liver transplantation with 5 year
survival rate of 83.3% has been reported in children with non cirrhotic metabolic liver diseases
such as urea cycle defects, tyrosinemia, citrullinemia, ornithine transcarbamylase deficiency,
glycogen storage disease, Crigler-Najjar syndrome type-I, methylmalionic acidemia and
propionic acidemia.16
The indications for LT in metabolic disorders depend on the prognosis of the metabolic
disease and the quality of life associated with the treatment for the metabolic disease and
its associated complications, such as restricted diet or frequent episodes of metabolic acidosis
and the presence of irreversible disease in the affected organs, such as end-stage renal failure
or coronary artery thrombosis (familial hypercholesterolemia).
LT reverses the hepatic and extrahepatic manifestations of tyrosinemia type-I despite
the production of toxic metabolites by the kidneys. The availability of 2-(2 nitro-4-
trifluoromethylbenzoyl)-1, 3 cyclohexenedione (NTBC), which prevents the formation of
toxic metabolites and thereby reverses the manifestations of this disorder, has altered the
indications for transplantation. LT is offered to children not responding to NTBC. In children
with Wilson’s disease, LT is indicated in those, who present with acute liver failure and
those in whom penicillamine therapy is ineffective. Maple syrup urine disease (MSUD) is
a potentially volatile metabolic disorder that requires strict dietary control, LT is indicated
for MSUD to obviate the need for dietary protein restriction and relieve the potential for
unpredictable metabolic decompensation during illness. Mazariegos et al17 reported successful
LT in eight children with MSUD, their patients were alive and well at follow-up, ranging
from 3 months to 7.5 years.
Hepatic Tumors
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Children with benign tumors such as adenomas or focal nodular hyperplasia are considered
for LT if there is severe hepatic dysfunction or if they have replaced the whole liver and
hepatic resection is impractical. Malignant tumors like hepatoblastoma, or hepatocellular,
which are unresectable or refractory to chemotherapy, are taken up for LT.18
Contraindications
Contraindications to LT are active, uncontrollable and untreatable sepsis or multi-organ
failure, mitochondrial cytopathy, irreversible cardiopulmonary disease, extra hepatic
malignancy and active HIV infection unresponsive to highly active antiretroviral therapy,
as well as severe cardiopulmonary or central nervous system disease, which is not reversible
by transplantation (Table 18.4). There are no internationally agreed absolute contraindications
to liver transplantation.
Although previous abdominal surgery, portal vein thrombosis or vascular anomalies
increase the operative risk, these are no longer considered contraindications. LT can now
be offered to children with hepatitis B and C, as the chances of recurrence have been decreased
by improvements in pharmacotherapy of these conditions. LT should not be considered
if quality of life is expected to be sub optimal post-transplantation. It has been reported
that liver transplantation is contraindicated in fulminant hepatic failure if the cerebral perfusion
pressure is less than 50 mm Hg for more than two hours as these children develop irreversible
neurological injury.19
Table 18.4: Contraindications for pediatric liver transplantation

Contraindications
Active uncontrollable and untreatable sepsis
Severe cardiopulmonary disease
Multi-organ failure
Extra-hepatic malignancy
Mitochondrial disease
Active substance abuse
Advanced Grade-IV encephalopathy with severe neurological impairment
Active HIV infection
PRE-TRANSPLANT EVALUATION
Assessment of the Recipient
Selection of patient, preparation and proper timing of transplantation are as important as
the surgery. The 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. Hepatic function is assessed by
measurement of albumin and prothrombin time (synthetic function) and bilirubin,
transaminases, alkaline phosphatase and gamma glutamyl transpeptidase. The vascular
anatomy of the liver is delineated by doppler ultrasonography and in special situations by
magnetic resonance or conventional angiography. Nutritional status is assessed by

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anthropometry including mid arm circumference and skin fold measurements. A
developmental, cardiac and dental assessment is performed in all children. Immunity to
viral pathogens (measles, chicken pox, herpes simplex, Cytomegaloviruses (CMV) and Epstein
Barr virus (EBV) is documented by examining the sera. Screening for active hepatitis B
(HBsAg, HBcAg, HBeAg) and hepatitis C (anti hepatitis C serology), HIV I & II (ELISA),
CMV and EBV infection are done.
Assessment of the Donor (for live related LT)

The donor must be a blood relative of the child and must be of the same blood group.
The donor under goes extensive medical and psychological assessment and preparation.
Optimum health of the donor decreases posttransplant complications. Donors are screened
for HIV, CMV, EBV infection, viral hepatitis B and C. Donors with diabetes mellitus or
malignancy are excluded. The left lobe of the liver is assessed for adequacy of size.20
Nutritional Rehabilitation
Recent data suggest that pre-operative malnutrition is an important risk factor. Majority
(70% at our center 21 ) of the children coming for LT are malnourished. Both morbidity and
mortality are increased in malnourished children with chronic liver disease. Modular feeds
allowing protein, carbohydrate and fat contents to be individually prescribed for each child
are recommended. It is usual to provide a high protein (3 g/kg) and high carbohydrate
intake using glucose polymers. The fat content of the feed should be balanced to provide
50% medium chain triglyceride and 50% long chain triglyceride to reduce steatorrhea and
to prevent essential fatty acid deficiency. Many children require a high-energy intake (150%
of recommended daily allowance) to maintain growth. It is unusual for such sick babies
to tolerate intensive feeding orally and most need nocturnal enteral feeding. A small minority
may need supplemental parenteral nutrition if oral feeds are not tolerated. Supplements
of fat-soluble vitamins are required to prevent deficiency of vitamins A, D, E and K.
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 B and A and polio. Vaccines
should be given at least one month before LT to ensure seroconversion. After LT, vaccination
should be avoided in the first three months as these children are under high degree of
immunosuppression, which may allow development of disease. Parents and other siblings
should be advised to have annual influenza vaccines and pneumococcal vaccines should be
repeated every five to six years.20
Pre-transplant medical management
Pre-transplant management aims at preventing and treating complications associated with
end stage liver disease. These may include ascites, spontaneous bacterial peritonitis,
hepatorenal syndrome, esophageal varices, hepatic encephalopathy and intense pruritus.

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Ascites and fluid retention is managed by restricted sodium and fluid intake and the use
of diuretic therapy (spironolactone, furosemide and hydrochlorothiazide). Fluid restriction
should be avoided unless patients have gross anasarca or severe hyponatremia.
Bleeding esophageal varices is a major cause of morbidity and mortality in patients with
ESLD. Initial management includes hemodynamic stabilization with aggressive fluid
management and blood products. Subsequent treatment options include intravenous
somatostatin/ octreotide or endoscopic variceal band ligation. It is preferable to employ
band ligation instead of sclerotherapy because of the potential risk of portal vein thrombosis
arid ulceration. Successful placement of transjugular intrahepatic portal shunts (TIPS), resulting
in stabilization until transplantation, has been reported in children.22
Hepatic encephalopathy may range from subtle neurological dysfunction to frank coma.
Potential precipitating factors such as GI bleed, infection, constipation or electrolyte imbalance
should be identified and treated. Treatment includes low-protein diet and oral lactulose.
The role of branched chain amino acids and flumazenil remains controversial. The use of
extracorporeal liver assist devices as a bridge to transplantation is not yet established, but
the benefit from extracorporeal hemoperfusion, while awaiting transplantation has been
described in a child.
Pruritus may be very severe in some patients with cholestatic liver disease. A majority
of patients will respond to oral antihistamines, ursodeoxycholic acid and cholestyramine.
Intractable pruritus sometimes responds to rifampicin. Opiate antagonists like naloxone,
nalmefine and naltrexone have been used in refractory pruritus.
Counseling
One cannot underestimate the need to educate and counsel the family and child. The counseling
process is multi disciplinary 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.
The Surgical Procedure

The donor is selected by blood group and size. An ABO compatible blood group may be
used for urgent cases. The liver can be procured from a cadaver or a living donor. Suitable
liver donors are brain dead, usually younger than 65 years, have no underlying malignancy
and test negative for HIV or hepatitis B surface antigen (HBsAg). While whole organ grafts
normally come from pediatric cadaver donors, partial grafts are acceptable from living or
brain dead donors up to 50 years age. Organ size is important as a large graft may lead
to vessel size mismatch, compression ischemia of the graft, low blood flow state in the graft
and increased likelihood of vascular thrombosis, impaired breathing and may prevent closure
of the abdomen. Therefore, a whole graft from a donor within 15 to 20% of the recipient’s
size is ideal. Even in the West, this situation is possible only in 30-50% transplants in children
(especially in those less than 6 years of age) due to shortage of pediatric donors. This problem
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is even more acute in India as there is as yet no record of any pediatric liver donor.
The original surgery has undergone several modifications, but in general there are three
phases: native liver dissection, anhepatic phase, and revascularization of the graft.
In the, last decade, reduction hepatectomy has been used increasingly to circumvent the
shortage of donors and decrease waiting list mortality. It is possible to reduce the liver
to transplantable portions comprising of segments 5-8 (right lobe), 2,3 (left lateral segment)
and 2,3,4 (left lobe) based on Couinaud’s segmental anatomy (Fig. 18.1) such that each has
its own biliovascular supply as well as venous drainage and the ability to function as a
complete and independent hepatic unit. Due to enormous hepatic reserve, this portion can
actually suffice even if it is less than ideal liver weight for the recipient as long as it is
at least 1% of recipient weight. Furthermore, it has the capacity to regenerate to the right
size in 3-4 months time.
Fig. 18.1: Segmental anatomy of the liver
The following techniques based on the above principles are now standard in liver
transplantation
Split-Liver Transplantation
This procedure was developed in response to the shortage of donor organs. In the split-
liver technique, one liver is split in half and is used for two recipients.23 ,24 The split-liver
transplantation is more challenging because there is a need for extensive reconstruction of
segmental vessels and biliary system. Complications of the split-liver method include portal
vein thrombosis (4%), hepatic artery thrombosis (12%), biliary complications (19%), and
relatively high retransplantation rates (19%). It is now accepted that split liver transplantation
is an efficient transplant technique with graft and patient survival rates comparable to
conventional transplants.
Living Related Liver Transplantation

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Living related liver transplantation (LRLT) was developed to overcome the shortage of
cadaveric livers. 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.) the procedure is elective and can be done before severe hepatic
decompensation has occurred, 2.) a healthy donor is assured, 3.) a very short cold ischemia
time facilitates better graft quality and may reduce primary non-function of grafts and 4.)
there may be an immunological advantage to the recipient if an organ is received from
a parent or a sibling. LRLT has resulted in improved intra-operative stability, improved
survival rates, shorter recuperation times, reduced time for hospitalization and markedly
reduced overall cost of care. The donor mortality has been estimated at 0.5%, which is
low enough to allow a parent or a close relative the option to donate a segment of their
liver.
Bourdeaux et al25 in a study comparing results of pediatric LT in 235 children receiving
either living-related donors (LRD, n =100) or post mortem donor (PMD, n = 135), concluded
that overall posttransplant outcome at 5 years was better after primary LT with LRD. In
addition, a higher rate of hepatic artery thrombosis and, notably, a lower rate of rejection
were observed in the PMD group, which the investigators hypothesized suggested a reduced
impact of HLA matching in this setting. The biliary complication rate was higher in the
LRD group, but this did not reach statistical significance.
In India, as very few cadaveric organ donations take place and the adult waiting lists
are long, it is unrealistic for a cadaveric organ to be offered to a pediatric recipient. In
this situation, the only option is living related liver transplantation. Efforts are being made
to encourage organ donation, but till then live related transplantation will have to be used
more frequently. To ensure ethical practice in LRLT, the Indian government has laid down
strict guidelines.
Monosegmental Liver Transplantation

In this technique the segment 2 alone is reduced from a lateral segment is possible for very
small infants.26
Auxiliary Partial Liver Transplantation

In this operation, the left lobe of the patient’s liver is replaced with a similar portion from
a donor liver. This procedure has a role in the treatment of acute liver failure where sufficient
liver mass is transplanted to support the patient while the native liver regenerates and in
patients with non cirrhotic liver based inborn errors of metabolism, who have morphologically
normal livers (Crigler-Najjar syndrome type-I, urea cycle defects, propionic acidemia and
disorders of fatty acid metabolism). This procedure is more suited to children because they
have a better capacity to regenerate their native livers then adults. For some non cirrhotic
inborn errors of metabolism where the liver is the site of production of abnormal proteins
or enzyme such as in familial amyloid polyneuropathy and primary oxaluria the whole liver
has to be replaced to correct the underlying cause.27 The main advantage of this procedure
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is that the patient recovers more rapidly than orthotopic liver transplant patients
because the native liver keeps them metabolically stable throughout the postoperative
period and should the graft fail the patient does not go into liver failure and can be
retransplanted electively at a suitable time. These patients can also hope for gene therapy
in the future.12
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 multi-organ failure.
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 (Table 18.5) and therefore demands a perfect
balance of treatment during the vulnerable state after transplantation (Table 18.6). While
the initial treatment regimen of LT consisted of corticosteroids and azathioprine (AZT) with
a graft survival of only 30%, the introduction of calcineurine inhibitors in the 1980s and
later tacrolimus (Tac), has revolutionized transplant medicine with 1-year graft and patient
survival rates as high as 90%.28
The usual immunosuppressive regimen consists of: cyclosporin (CsA) or Tac and
prednisolone, with or without AZT or mycophenolate mofetil (MMF). Although CsA and
Tac have 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 also is associated with better long-term graft survival. There is no
evidence for an increased risk of lymphoproliferative disease in children treated with Tac.29
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
MMF30 or sirolimus in maintenance immunosuppression. The current protocol at our center
is Tac with prednisolone. Recently use of a low-level monotherapy immunosuppression without
the use of maintenance corticosteroids using either tacrolimus (TAC) or sirolimus (SRL)
in combination with rabbit-derived antithymocyte globulin (rATG) induction therapy in
pediatric liver transplantation was reported.31
COMPLICATIONS
Liver transplantation remains a high-risk procedure with a mortality of 10-20% with high
perioperative morbidity. The commonest complications are rejection (60-70%), sepsis (70%),
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Table 18.5. Immunosuppressant drug toxicities (simplified)
Cyclosporin A Tacrolimus MMF Sirolimus
Nephrotoxicity Nephrotoxicity Cytopenias Hyperlipidemia
Neurotoxicity Neurotoxicity Gastrointestinal-toxicity Gastrointestinal-toxicity
Hypertension Hypertension Cytopenias
Hyperlipidemia Hyperglycemia
Hirsutism Gastrointestinal-toxicity
Table 18.6: Dosage and monitoring

Dosage* Monitoring
Cyclosporin A 5 mg/kg/dose twice daily 2 hours post dose (C2)
Tacrolimus 0.15 mg/kg/dose (within first
12 hours after abdominal closure),
then 0.05 to 0.1 mg/kg/dose twice
daily per oral Trough level
MMF 15 mg/kg/dose twice daily** Studies awaited
2
Sirolimus 15 mg/m once daily** After 4 days of therapy, then C0 twice weekly
for 1st month, then weekly for 2nd month
(target:5-15 µg/L)
* recommended starting dose
**limited pediatric data
arterial and venous thrombosis (20%) and biliary complications (20%) with biliary leaks
and/or strictures and primary graft failure (2.5%).
Early Complications
Primary Graft Non-function
Early graft failure is relatively infrequent (2.5-5%) and re-transplantation is the only life
saving therapy. Underlying causes may be due to the mode of death of the donor, problems
with retrieval, preservation or implantation. Signs of poor graft function are hemodynamic
instability requiring continuing inotrope support, persistent or increasing acidosis and bleeding
due to persistent coagulopathy. International normalized ratio (INR) greater than 4 and
first day AST levels of greater than 2000 IU/L reflects major cell damage, but even levels
of more than 5000 IU/L may settle with good long-term graft function.
Acute Rejection
Acute hepatic allograft rejection among first pediatric liver transplant recipients according
to an analysis from the Studies in Pediatric Liver Transplantation registry (SPLIT)7 usually
occurs in the first 3 months after transplant. It occurs most commonly in the second week
after transplant. It remains a common cause of graft loss, occurring in 20% in infants to
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70% in older children.32 Rejection is diagnosed by clinical criteria and always confirmed
by histological examination. It is clinically manifested by malaise, fever, abdominal pain
or tenderness, jaundice, dark urine or clay colored stool, graft enlargement and diminished
graft function. There is a rise in bilirubin and transaminase levels. Occasionally the patient
may be asymptomatic and the only indicator may be a deranged liver function test. Its
pathophysiology is not properly understood. Severe acute rejection, re-perfusion injury,
inadequate immunosuppression and CMV infection may contribute. Early detection may
allow acute rejection to be treated successfully. Treatment with pulse steroids, OKT 3 or
mycophenolate or a change over to tacrolimus if patient is on cyclosporin will reverse the
changes, some will require retransplantation as a last resort if therapy fails.
Vascular Thrombosis
Hepatic artery thrombosis leading to primary graft failure is more common in children (10%)
than in adults (5-8%). Early recognition and immediate surgical revascularization may salvage
the graft. It is now becoming less common because of the larger donor blood vessels in
reduction hepatectomies. The use of antiplatelet drugs may also reduce the incidence of
thrombosis. Portal vein occlusion is relatively more common (30%), which can be detected
early only on ultrasound. Late manifestations include splenomegaly, hypersplenism and
variceal bleed. These conditions are managed by thrombectomy or surgical revision.33
Sepsis
In the immediate postoperative state, bacterial infections-Streptococcus faecalis, Pseudomonas
and Staphylococcus aureus, are common and related to central line infections and bacterial
translocation of the intestine. Gram-positive line infections occur from day 5 onward and the
access therefore must be changed regularly. Gram-negative sepsis is often associated with
biliary leak, bowel perforation or graft ischemia.
Biliary Complications
Biliary leak and stricture are the commonest technical complications occurring in 5-30% of
children post transplant.33 It is manifested as jaundice, steatorrhea, pruritus and increased
alkaline phosphatase and gamma-glutamyl transferase (most sensitive indicator). Management
options include dilatation and stenting, endoscopic cholangio pancreatography or surgical
resection.
Gastrointestinal Complications
The exact incidence of diarrhea in the liver transplant recipient is not known, possibly ranges
from 10-43%. Infectious etiologies including cytomegalovirus (CMV), Clostridium difficile and
occasionally atypical intestinal infections are the most common causes. Diarrhea is also a
common side effect of immunosuppressive agents and to a variable extent MMF, CSA,
tacrolimus and sirolimus are all known to be associated with diarrhea. Rarely graft versus
host disease, lymphoproliferative disorder, de novo inflammatory bowel disease or colon

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cancer may present as diarrhea.34
Other gastrointestinal complications may occur within the first two weeks and include
intestinal perforation, which is more common in children with previous abdominal surgery,
and hematemesis from varices or gastritis.
Renal Dysfunction
Oliguria or renal failure may develop in, association with poor graft function, hypovolemia
or with calcineurine inhibitor therapy-strict fluid balance is necessary. Less than 5 percent
of children will need dialysis for renal failure unless this was a preoperative requirement.
Others
Hypertension due to cyclosporin and prednisolone is common and responds to fluid restriction
and treatment with nifedipine and atenolol.
Late Complications
Infections
Herpes viruses are the most important viral pathogens post-transplant. Up to 60 per cent
of pediatric patients undergoing liver transplantation are negative to cytomegalovirus (CMV)
and Epstein Barr Virus (EBV). In a study of 146 survivors of children transplanted between
1981 and 1986, now ≥20 years post transplantation, the most common infections include
varicella (66.7%), CMV (22%), EBV (14.8%), and hepatitis C virus (14.8%).35 CMV infections
occur two-six weeks post-transplant, particularly in children who have received CMV -positive
livers and should be treated by a reduction of immunosuppression and ganciclovir. High-
risk cases, for example CMV positive donor and negative recipient should be considered
for prophylactic acyclovir or ganciclovir. CMV hepatitis presents with flu-like symptoms,
high fever and relative neutropenia with a mild rise in serum transaminases. Serology is
of limited value and has been replaced by new diagnostic tests, which monitor levels of
antigenemia or CMV DNA. Herpes simplex and varicella zoster infections occur within one
and three months respectively post-transplant and both respond to early treatment with
acyclovir.
EBV infection may occur as a primary infection from a positive donor or reactivation
of a previous infection. It presents with a spectrum ranging from a mononucleosis-like illness
to a malignant lymphoma. Previously EBV negative children appear to be particularly at
risk of developing EBV related post-transplant lymphoproliferative disease (PTLD). The
overall incidence of PTLD after transplantation is 2%, but may be as high as 5-10% in children
less than one year. Two-third of children receiving LT are usually EBV negative, out of
which 75% will get primary infection and some will develop PTLD. Posttransplant
lymphoproliferative disorder (PTLD) is more common in EBV-negative (4.8%) than EBV-
positive (2.4%) recipients. Advised treatment is reduction of immunosuppression and
thereafter some tumors will regress. Rituximab and HLA-matched T-cell therapy directed
against the EBV virus are under investigation. Chemotherapy should be given to all children
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with tumors showing signs of progression.36
Systemic fungal infections are fatal and are particularly common in children who have
been transplanted for acute liver failure. The use of prophylactic oral antifungals is mandatory
posttransplant, and children awaiting LT for acute liver failure should also have prophylactic
antifungal treatment. Pneumocystis carinii is rare in this group of children and is easily
prevented with low-dose cotrimoxazole.
Chronic Rejection
Chronic rejection occurs in approximately 10% of children33 usually six weeks to six months
post-transplant. It can be defined as an indolent but progressive form of primary immunologic
injury to the allograft, which comprises organ function more slowly than acute rejection.37
The characteristic hallmark of chronic rejection is progressive bile duct disappearance and
obliterative arteriopathy known as ductopenia and vanishing bile duct syndrome. The duct
is damaged by direct immunological injury and ischemia from the obliterative arteriopathy,
which is caused by antibody-mediated intimal damage of hepatic arterioles. It is manifested
as progressive jaundice and allograft dysfunction. Diffuse hepatic fibrosis occurs in late phase
of chronic rejection ultimately resulting in loss of synthetic function and portal hypertension.
Increase in immunosuppression with tacrolimus, mycophenolate or sirolimus may rescue
some grafts in the early phases but ultimately advanced chronic rejection will require re-
transplantation.
Causes of Late Graft Loss and Death

Of 1611 children reviewed (SPLIT registry database), 872 were alive at 1 year after LT.38
The main cause of graft loss after the first year post-LT was chronic rejection. The main
causes of late deaths reported were recurrent tumor, either hepatoblastoma or hepatocellular
carcinoma, or acute liver failure. The most common cause of late graft loss is non-compliance.39
Re-transplantation
Re-transplantation is performed in 5% of children, usually for hepatic artery thrombosis
or chronic rejection. If performed electively, patient survival is 80% versus 50% when
performed as an emergency.
NOVEL THERAPIES
Looking Beyond Immunosuppression: Tolerance

Despite development of new immunosuppressive agents for solid organ transplantation
during the past 15 years, allograft half-lives have not increased substantially.40 Long-term
graft survival rates and the need for maintaining a continual state of immunosuppression
with its associated complications, have prompted investigators to develop methods to induce
tolerance (defined as the lack of an immune response to the foreign antigens expressed
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by an organ allograft in the absence of ongoing immunosuppressive therapy) as a means
to eliminate the dependency on immunosuppressive agents and improve outcomes. 41
Experimental strategies that can be utilized clinically to induce tolerance, like mixed allogenic
chimerism, costimulation blockade and preconditioning are presently being developed.42
Further assays to detect tolerance and to identify recipient rejection need to be developed.
Important questions that need to be resolved, include defining which agents will facilitate
the development of tolerance and which will block it, whether tolerance will prevent the
development of chronic rejection, and what happens when tolerance is lost.
Hepatocyte Transplantation
Hepatocyte transplantation is a potentially promising alternative to whole organ liver
transplantation, 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. Recently successful transplantation of fetal
liver slices has been reported in the rat model, which could serve as a model for genetic
metabolic liver diseases. 43 The major concerns about xenotransplantation or
crosstransplantation are the potential spread of infection from animal to the human recipient
and hyperacute and vascular rejection. In the future genetic engineering of a chimeric
transgenic animal may make long-term xenograft function a reality.
Outcome of Liver Transplantation in Children

Although LT is being done since the past four decades, a dramatic increase in the survival
rate has been mainly witnessed in the second half. The SPLIT registry was initiated in 1996
and has accumulated data on 1968 liver transplants performed at 44 centers in 2400 patients.11,44
Of all patients listed, 87.7% underwent transplantation, with a waiting list mortality of 0.9
to 6.6%, depending upon recipient age.45 Current 4-year patient and graft survival rates
are 83 and 74%, respectively. Older age and greater recipient height are associated with
better outcomes, while fulminant hepatic failure and ABO incompatibility are associated
with poorer outcomes. Better experience has led to transplantation of children less than
1 year of age and weighing less than 10 kg. Contrary to earlier data showing that this group
of patients is associated with higher risk of graft loss, now survival rates over 90% have
been reported.
Life after the Transplant

Patients with growth failure secondary to liver disease resume growing and there appears
to be a general improvement in lifestyle. The majority of children’s resume normal growth
within a year after liver transplant, and there appears to be a dramatic increase in general
energy and activity. In a review or psychological adjustment and quality of life over a 5-
year period, all children achieved normal growth velocity and 80% had normal height and
weight measurement.46 If children undergo transplant early, before significant, growth or
developmental retardation, normal psychosocial development may be expected. Liver

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recipients participate in most age-related activities and attend school regularly including
physical education classes. Increased numbers or severity of infectious illness does not appear
to reduce school attendance. Children who have received hepatic grafts enter puberty
normally. Successful pregnancies have been reported with both CsA and tacrolimus
immunosuppression.
There has been a dramatic increase in survival as a result of greater experience. Survival
as high as 90% in babies less than 10 kg has been achieved. Children who survive the initial
three months after transplantation should achieve a normal lifestyle. The long-term prognosis
of children after liver transplantation is unknown, although survival up to 25 years has
been recorded.
Registries and Databases

The volume, accuracy, and reliability of the data available on solid organ transplantation
continue to be unprecedented in medicine. Large, multi-institutional registry databases like
the SPLIT registry are used to describe and monitor trends in transplantation and have
become important tools for assessing transplantation use and outcome, determining the
impact of allocation policies and patient waiting, identifying prognostic factors for transplant
outcomes, evaluating new transplant therapies, comparing transplant and non-transplant
therapies, evaluating late transplant complications, and planning clinical trials. In India
published data is currently 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.
The achievement of pediatric LT in developed countries has increased the awareness and
need for such procedures in the developing world and has resulted in the establishment
of transplant facilities with successful pediatric LT now being offered in India.47 ,48
Mehrotra et al49 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. Overall, 30% of children with liver diseases
constituted by cirrhosis (45%), biliary atresia (38%) and FHF (11%) were found to have
an indication for liver transplantation. As more Indian children receive transplants, the
indications and need of facilities will increase, as more children will be referred for
consideration. At our center there were 1667 hepatological referrals out of which 172 had
an indication for LT as per international criteria. The commonest indications were biliary
atresia, followed by fulminant hepatic failure, cryptogenic cirrhosis, progressive familial
intrahepatic cholestasis and others.
Selection of patients for transplantation requires consideration of not only medical criteria,
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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.
Liver transplantation entails not only the initial expenditure of the procedure, which
presently amounts to Rs.12-15 lakhs, but also the lifelong commitment of a recurring
expenditure of around Rs.8000-l0000 per month on immunosuppression. Although, the cost
of liver transplantation in India is less than one fifth of that in the West, this is definitely
a prohibitive factor for most families. Also, since awareness of medical health insurance
is still in its infancy and therefore mostly all expenses must be carried out single-handedly.
As the procedure becomes better established, it is hoped that a number of children from
poor socioeconomic backgrounds will also be transplanted as charities and funds to support
such children are set up. Furthermore, cultural barriers with a bias towards the girl child
and clear male predominance in patients requiring the procedure are problems that still
exist. Almost three fourths of the children where families refused transplantation were girls.
Another big challenge is the scarcity of cadaveric donors in India and therefore, living
related liver transplantation is currently the only realistic option. Misconceptions that LT
is “too complex” for India, LT is “experimental” and “all infections after LT will be lethal”
need to be removed. Early referral is of utmost importance so that there is enough time
to prepare the child and the family for LT. Twenty two transplants have been performed
at the largest center, of which 15 have been successful.21 Another 16 transplants have been
performed at 6 other centers. The longest follow up is 7 years and the first successful recipient
is leading a normal life and attending regular school.
Efforts to educate both public and physicians about the availability of this modality in
India, development of a cadaver program, indigenous production of consumables and
immunosuppressive agents which will reduce costs, which hopefully, in the near future will
help in firmly establishing liver transplantation in India.
REFERENCES
1. Eckhoff DE, D’ Alessandro AM, Knechtle SJ, et al. 100 consecutive liver transplants in infants and
children: An 8-year experience. J Pediatr Surg 1994;29:1135-9
2. Cacciarelli TV, Dvorchik I, Mazariegos G, et al. An analysis of pretransplantation variables associated
with long-term allograft outcome in pediatric liver transplant recipients primary tacrolimus (FK506)
therapy. Transplantation 1999;68(5):650-5
3. Mazariegos GV. American Transplant Congress. Pediatric Kidney and Liver Transplantation: Cause
for Optimism, 2005
4. Poonacha V, Sibal A, Rajakumari DV, Soin AS, Rajasekar MR. India’s first successful pediatric liver
transplantation. Indian Pediatr 2001;38:287-91.
5. Taylor R M, Franck L S, Gibson F, Dhawan A. Liver transplantation in children: part 1–perioperative
issues. Jr Child health. 2005;9:256-73.
6. Vilca-Melendez H, Heaton ND. Paediatric liver transplantation: the surgical view. Postgrad Med Jr
IP : 112.133.195.17
2004;80:571-6.
7. Studies in pediatric liver transplantation bibliography. Available at: http://spitfire.emmes.com/study/
lvr/about/Bibliography_072505.pdf.
8. Shneider B L, Neimark E, Tamara F, et al. Critical analysis of the Pediatric end-stage liver disease scoring
system: a single center experience. Liver Transpl. 2005;11(7):788-95.
9. McDiarmid SV, Arnand R, SPLIT Research Group. Death on the waiting list for children with fulminant
liver failure registered in the studies of pediatric liver transplant (split) database. Liver Transpl. 2005;11:C-
21.
10. Lee SA, McKiernan, Kelly DA. Childhood fulminant hepaic failure. J Pediatr Nutr. 2005;40(5):575-81.
11. Bendre SV, Bavdekar AR, Bhave SA, et al. Fulminant hepatic failure: etiology, viral markers and
outcome. Indian Pediatr 1999;36:1107-2.
12. Arora NK, Nanda SK. Acute viral hepatitis types E, A and B singly and in combination in acute liver
failure in children in North India. J Med Vir 1996;48:215-21.
13. Hoofnagle JH, Carithers RL, Shapiro C, et al. Summary of a Workshop. Hepatology 1995;21(1):240-
52.
14. O’Grady JG, Alexander GSM, Hallyner KM, Williams R. Early prognostic indicators in fulminant hepatic
failure. Gastroenterology 1989;97:439-45.
15. Kelly DA. Organ transplantation for inherited metabolic disease. Arch Dis Child 1994;71:181-83.
16. Kasahara, et al. Auxillary partial orthotpic living donor liver transplantation: Kyoto University
experience. Am J Transplant. 2005;5:558-66.
17. Mazariegos G, Morton H, Strauss K, et al. Liver transplantation for maple syrup urine disease (MSUD).
Program and abstracts of the American Transplant Congress 2005: 6th Annual Joint Meeting of the
American Society of Transplant Surgeons and the American Society of Transplantation; 2005; Seattle,
Washington. Abstract 1392. Accessed from www.medscape.com
18. Whitington PF, Alonso EM, Piper JB. Pediatric liver transplantation. Seminars in Liver Disease 1994;
14(3): 303-17.
19. Goss Ja, Shackleton CR, Maggard M, et al. Liver transplantation for fulminant hepatic failure in the
pediatric patient. Arch Surg. 1998;133:839-46.
issues. Jr Child Health. 2005;9:256-73.
21. Sibal A, Pao M, Sharma S, Rajakumari DV, Rajasekar MR. Liver Transplantation. Apollo Medicine
2005;2(4):324-7.
22. Cao S, Monge H, 5emba C, Cox KL, et al. Emergency transjugularintrahepatic portosystemic shunt
(TIPS) in an infant: A case,report. J Pediatri Surg 1997;32(1):125–7.
23. Busuttil R, Goss J. Split liver transplantation. Ann Surg 1999;229:313-21.
24. Ville de Goyet J. Split liver transplantation in Europe: 1988-1993. Transplantation 1995;59:1371-6.
25. Bourdeaux C, Gras J, Jamart J, et al. Technical and immunological complications in pediatric liver
transplantation: a multivariate analysis in 100 living-related and 135 post-mortem donor grafts. Program
and abstracts of the American Transplant Congress 2005: 6th Annual Joint Meeting of the American
Society of Transplant Surgeons and the American Society of Transplantation; May 21-25, 2005; Seattle,
Washington. Abstract 1391. Accessed from www.medscape.com
26. Mentha G, Belli D, Berner M, Rouge JC, Bugmann P, Morel P, Le Coultre C. Monosegmental liver
transplantation from an adult to an infant. Transplantation. 1996;62:1176-8.
27. Rela M, Dhawan A. Liver transplantation in children. Indian J Pediatr. 2002;69:175-83.
28. Al-Hussaini AR, Tredger M, Dhawan A. Immunosuppression in Pediatric Liver and Intestinal
Transplantation: A closer look at the arsenal. J Pediatr Gastroenterol Nutr 2005;41:152-65.
29. Kelly DA, et al. Tacrolimus and steroids versus ciclosporin microemulsion, steroids, and azathioprine
in children undergoing liver transplantation: randomised European multicentre trial. Lancet 2004;364:
1054-61.
30. Nobili V, Comparcola D, Sartorelli MR, Diciommo V, Marcellini M. Mycophenolate mofetil in pediatric
IP : 112.133.195.17
liver transplant patients with renal dysfunction: preliminary data. Pediatr Transplant. 2003;7(6):454-
7.
31. Mazariegos GV, Sindhi R, Smith A, McGhee W, Fung JJ, Reyes J. Rabbit anti-thymocyte globulin (rATG)
induction therapy for pediatric steroid free liver transplantation. Program and abstracts of American
Transplant Congress 2003: The Fourth Joint American Transplant Meeting; May 30-June 4, 2003;
Washington, DC. Abstract 1174. www.medscape.com
32. Belle SH, Beringer KC, Detre KM. An update on liver transplantation in the United States: recipient
characteristics and outcome. Clin Transpt 1995;19-33.
issues. Jr Child health. 2005;9:256-73.
34. Ginsburg PM, Paul J T. Diarrhea in liver transplant recipients: etiology and management Liver Transpl.
2005;11(8):881-90.
35. Kosmach-Park B, Rosenbleet J, Zitelli B, Mazariegos G. Pediatric liver transplant recipients at >20 years:
perceptions of cognitive and physical functioning in the long-term survivor. Program and abstracts
of the American Transplant Congress 2005: 6th Annual Joint Meeting of the American Society of
Transplant Surgeons and the American Society of Transplantation; May 21-25, 2005; Seattle, Washington.
Abstract 1390. Accessed from www.medscape.com
36. Kelly DA, Sibal A. Current Status of Liver Transplantation. Indian J Pediatr 2003; 70(9):731-6.
37. Demetris AJ, Duquesnoy RJ, Fung JJ, et al. Pathophysiology of chronic allograft rejection. Medscape
Transplantation, 2000.
Available at: http://transplantation.medscape.com/Medscape/transplantation/ ClinicalMgmt/CM.v02/
public/index.CM.v02.html
38. Soltys K, Mazariegos G, Anand R, Smith A. The SPLIT Research Group. Late graft loss or death in
pediatric liver transplantation: analysis of the SPLIT database. Liver Transpl. 2005;11:C-21.
39. Sudan DL, Shaw BW Jr, Langnas AN. Causes of late mortality in pediatric liver transplant recipients.
Ann Surg. 1998;227:289-95.
40. Sayegh MH. State of the art presentation I. Transplantation tolerance: reality or elusive dream? Program
and abstracts of the International Pediatric Transplant Association 3rd Congress; August 6-9, 2005;
Innsbruck, Austria.
41. Matthews J. New renal transplant registry targets immune tolerance. Available at: http://www.
medscape.com/view article/483993.
42. Lechler RI, Sykes M, Thomson AW, Turka LA. Organ transplantation — how much of the promise
has been realized? Nat Med. 2005;11:605-13.
43. Oren R, Breitman Y, Gur E, Traister A, et al. Whole fetal liver transplantation - A new approach to
cell therapy. Liver Transpl. 2005;11:929-33.
44. Shapiro R. Highlights of the International Pediatric transplant Association 3rd congress August 6-9.
Medscape Transplantation. Accessed from www.medscape.com.
45. McDiarmid SV. Registry reports. SPLIT. Program and abstracts of the International Pediatric Transplant
Association 3rd Congress; August 6-9, 2005; Innsbruck, Austria. Pediatric Heart Transplant Study.
Available at: http://www.uab.edu/ctsresearch/phts/
46. Stone RD, Beasley PI, Treacy SJ, et al. Children and families can achieve normal psychological adjustment
and a good quality of life following pediatric liver transplantation: A long term study. Transpl Proc
1997;29:1571-2.
47. Sibal A, Rajasekar MR, Soin AS. Liver transplantation in the developing world. Indian J Pediatr 1999;66(1
Suppl): S120-3.
48. Kelly DA, Sibal A. Liver Transplantation in children. Indian Pediatr 1999;36:353-5.
49. Mehrotra P, Yachha SK. Living related liver transplantation in Indian Children. Indian Pediatr.
1999;36:357-62.
Childhood Pancreatitis / 271
Neelam Mohan, Anupam Sehgal
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19 Childhood Pancreatitis
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 including the (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:

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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. 19.1)

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The primary initiating event, whether traumatic, infections 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 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. 19.1: 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 hydrolase’s 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.
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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, ascaris lumbricoides
(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 19.1 and 19.2.
Table 19.1: Causes of pancreatitis in pediatric age group

Trauma Systemic Drugs Toxin
Abdominal Disease Chlorthalidone Ethyl alcohol
trauma Infections L- Asparaginase Methyl alcohol Metabolic
Child abuse Sepsis Azathioprine Heroin Disorders
Burns Shock 6-Mercaptopurine Amphetamines Diabetes mellitus
Surgical trauma Collagen Sulfonamides Organophosphate Hyperlipidemia
vascular disease Sulfasalazine insecticides (Type I, IV, and V)
Henoch Nitrofurantoin Acetaminophen Hyper
Schonlein Furosemide Yellow Scorpion parathyroidism
purpura Metronidazole bite Wilson’s disease
DVS Estrogens Renal failure
Kawasaki Tetracycline Hypercalcemia
disease Valproic acid Hyperlipidemia
Inflammatory Corticosteroids Uremia
Bowel Disease NSAIDS Alpha 1-antitrypsin
Reye’s Methyldopa deficiency
syndrome Procainamide
Iatrogenic
hypercalcemia
Pancreatic Gastrointestine Transplantation Miscellaneous
Disorders disorders Renal Hereditary
Cystic fibrosis Duodenal ulcer, transplantation Idiopathic
Diarrhea penetrating Graft-versus-host Postoperative
Pancreatic Duplications disease
divisum
Duplication
Abnormalities of
duct
Table 19.2: Causes

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Cause Incidence (%)
Idiopathic causes 22
Trauma 20
Infections 15
Biliary tract disease 14
Drugs 13
Miscellaneous 11
Congenital anomalies 5
Clinical Spectrum
Acute pancreatitis can present with a wide spectrum of symptoms and complications (Table
19.3);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.
Table 19.3: The important clinical features of Acute pancreatitis

Symptoms Signs
• Abdominal Pain • Localized epigastric tenderness
• Abdominal wall rigidity
• Anorexia • Rebound tenderness
• Nausea • Abdominal distention
• Vomiting • Diminished or absent bowel sounds
• Coma (rare) • Hypotension or shock
• Dyspnea (rare) • Low-grade fever
• Pleural effusion
• Ascites
• Oliguria/anuria
• Respiratory distress
• Grey—Turner sign (Bluish discoloration of periumblical area)
• Cullen’s sign (Bluish discoloration of flanks)
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 in severity and reaches maximal intensity after a few hours. It is located most
commonly in the epigastrium, other sites include right upper quadrant, periumblical 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
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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 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
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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 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 19.4.
Table 19.4: 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
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 pancreatitits 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 pancreatitits, but at the expense
of sensitivity. There are several GI condition where serum amylase may be elevate such
as appendicitis, biliary tract disease, choledocholithiasis, endoscopic retrograde

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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
Amylase Creatinine Clearance Ratio

The higher ratio in pancreatitits 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.21, 20
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 by 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
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The most useful and frequently used imaging procedures in evaluating acute pancreatitits
are abdominal ultrasonography and CT scan.
Conventional Radiology
It’s of limited value in evaluating acute pancreatititis. 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 in Table 19.5.
Table 19.5: 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 califications
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 predicitive 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, contor
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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 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 pancreatis 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 report 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
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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.
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-pancreatitits
complications, detection of anatomic abnormalities associated with acute pancreatitits, and
study of the pancreatic ducts in chronic relapsing pancreatitits or hereditary pancreatitis.28,29
In the largest series done, mild pancreatitits 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 pancreatitits). 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 pseudaneurysm 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
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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, α1 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 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
o Sterile
o Infected
• Hemorrhage
• Pancreatic abscess
• Duct rupture
• Duct stricture
• Pseudocyst
Systemic Complication
• Shock
• Pleural effusion
• ARDs
• DIC
• Acute renal failure
• Distal fat necrosis
• Multi organ system failure
• Septicemia
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• 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 in 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 19.6)
Various nonspecific and specific clinical measures have been proposed to achieve this objective,
but the therapeutic benefit of most of the strategies has not been validated in clinical trials.
Table 19.6: Proposed methods of interrupting auto digestion

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
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 disease.18 Supportive measures, such
as total parenteral nutrition or fresh frozen plasma, also have not proved to be effective.
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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 needs to be managed in a 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 long standing 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 3 categories:
1. Chronic calcifying pancreatitis,
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

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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 lead to chronic pancreatitis. The causes of chronic calcific and
non-calcific chronic pancreatitis are given in Table 19.7.
Table 19.7: Causes of chronic pancreatitis

Calcific Non-calcific
• Juvenile tropical pancreatitis • Traumatic stricture
• Pancreatic divisum,
• Hereditary pancreatitis • Sphincter of Oddi dysfunction (SOD)
• Hypercalcemia • Gall stone pancreatitis
• Hyperparathyroidism • Fibrosing pancreatitis
• Hyperlipidemia • Sclerosing cholangitits
• Cystic fibrosis • Autoimmune pancreatitis
• Hemachromatosis • Misc
• Idiopathic o Inflammatory Bowel Disease, Coeliac disease
o Alpha 1 trypsin deficiency
o Radiation
o Henoch Schonlein Purpura (HSP)
o Systemic Lupus Erythematosis Sjogiren’s
Diagnosis
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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
like cystic fibrosis, Shwachman–Diamond syndrome. Morphologic 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 19.8.
Table 19.8: Commonly used PFTs

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
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(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: fecal elastase 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 (ERCP)

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 of pancreatic duct (Fig. 19.2). In more moderate
disease, these changes are found in main pancreatic duct as well (Fig. 19.3).
Fig. 19.2: ERCP—Grossly dilated PD with multiple calculi

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Fig. 19.3: APBJ—Abnormal pancreatobiliary Fig. 19.4: Irregular PD

junction
Tortuosity, stricture, calcification and cysts may also be seen as disease becomes more
severe (Fig. 19.4). 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 cholangiopancreatography (MRCP) is gaining
popularity particularly in children. It does not routinely require sedation, is noninvasive
and avoids ionizing radiation and contrast administration. It has a resolution that approaches
1mm 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. 19.5)

EUS is likely to play an important role in diagnosis and management of patients with chronic
pancreatitis. High resolution (<1mm) 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.
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Fig. 19.5: EUS
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 contor
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 experienceIP debilitating pain for decades.46 The AGA technical review states “a strategy
: 112.133.195.17
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 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
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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, 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. 19.7).
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 mucosal disease
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Fig. 19.6: A general approach to treatment of maldigestion in CP is shown
Fig. 19.7: Approach to Management of Chronic Pancreatitis

• Loss of enzyme potency

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• 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. 19.6).
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 cyst-gastrostomy
and cyst-jejunostomy.
Biliary and gastric outlet obstructions are best managed through surgical decompression
Complications of pancreatic duct disruption or fistulae (pancreatic ascites or pleural
effusions) are managed by prolonged pancreatic rest (parenteral nutrition) and endoscopic
placement of pancreatic duct stents.
REFERENCES
1. Tietz NW. Support of the diagnosis of pancreatitis by enzyme tests-old problems, new techniques.
Clin Chim Acta 1997; 257:85-98.
2. Weizman Z. Acute pancreatitis. In Wyllie R, Hyams JS (Eds): Pediatric Gastrointestinal Disease.
Philadelphia, Pa: WB Saunders Co; 1993;873-79.
3. Knaus WA, Draper EA, Wagner DP, Zimmerman JE. APACHE II: A severity of disease classification
system. Crit Care Med 1985;13(10):818-29.
4. Ranson JHS, Pasternak BS. Statistical methods for quantifying the severity of acute pancreatitis. J Surg
Res 1977;22(2):79-91.
5. Bradley EL: A clinically based classification system for acute pancreatitis. Arch Surg1993;128(5):586-
90.
6. Steer ML, Meldolesi J, Figarella C. Pancreatitis. The role of lysosomes. Dig Dis Sci 1984;29:934-38.
7. Schoenberg MH, Buchler M, Gaspar M, Stinner A, Younes M, Melzner I, Bultmann B, Beger HG. Oxygen
free radicals in acute pancreatitis of the rat. Gut 1990;31:1138-43.
8. Nonaka A, Manabe T, Kyogoku T, et al. Changes in lipid peroxide and oxygen radical scavengers
in cerulein-induced acute pancreatitis. Imbalance between the offense and defense systems. Digestion
1990; 47:130-7.
9. Gobo JC, Abraham E, Bland RD, et al. Sequential hemodynamic and oxygen transport abnormalities
in patients with acute pancreatitis. Surgery 1984; 95:324-30.
10. Kusterer K, Enghofer M, Zendler S, Bloechle C, Usadel KH. Microcirculatory changes in sodium
taurocholate-induced pancreatitis in rats. Am J Physiol 260. Gastrointest Liver Physiol 1991;(23):G346-
G351.
11. Kaplan MH. Pathogenesis of pancreatitis. A Unified concept. Int J Pancreatol 1986;1: 5-8.
12. Jordan SC, Ament ME. Pancreatitis in children and adolescents J Pediatr 1977;91(2):211-6.
13. Buntain WL. Wood JB, Wooley MM. Pancreatitis childhood. J Pediatr Surg 1978; 13:143-49.
14. Weizman Z, Durie PR. Acute pancreatitis in childern. J Pediatr 1988;113: 24-29.
15. Warshaw AL. Dominant dorsal duct syndrome–pancreas divisum redefined. J Pediatr Gastroenterol
Nutr 1990;10: 281-89.
16. Weizman Z, Durie PR. Acute pancreatitis in childhood. J Pediatr 1988;113: 24-28.
17. Nguyen T and others. Clinicopathologic studies in childhood pancreatitis. Hum Pathol 1998;19:343-
349. IP : 112.133.195.17
18. Arvanitakis C, cooke AR, Greenberger NJ. Laboratory aid in the diagnosis of pancreatitis, Med Clin
North Am 1978;62:107-120.
19. Steinberg WM, Goldstein SS, Davis ND, et al. Diagnostic assays in acute pancreatitis: A study of
sensitivity and specificity. Ann Intern Med 1985;102:576-80.
20. Steinberg WM, Tenner S. Acute pancreatitis. N Engl J Med 1984;330:1198-1210.
21. Cox KL, Ament ME, Sample WF, et al. The ultrasonic and biochemical diagnosis of acute pancreatitis.
J Pediatr 1980;96:407-411.
22. Durie PR, Gaskin KJ, Ogilvie JE, et al. Serial alternations in the forms of immunoreactive pancreatic
cationic trypsin in plasma from patients with acute pancreatitis. J Pediatr Gastroenterol Nutr 1985;4:199-
207.
23. Warshaw AL, Lee KH. Serum ribonuclease elevations and pancreatic necrosis in acute pancreatitis.
Surgery 1979;86:277-234.
24. Fleischer AC, Parker P, Kirschner SG, et al. Sonographic findings of pancreatitis in children. Radiology
1983;146:151-155.
25. Balthazar EJ. CT diagnosis and staging of acute pancreatitis. Radiol Clin North Am 1989;27:19-37.
26. Block S, Maier W, Bittner R, et al. Identification of pancreas necrosis in severe acute pancreatitis: Imaging
procedures versus clinical staging. Gut 1986;27:1035-42.
27. London NJM, Leese, T, Lavell JM, et al. Rapid- bolus contrast-enhanced dynamic computed tomography
in acute pancreatitis: A prospective study. Br J Surg 1991;78:1452-56.
28. Allendorph M, Werlin SL, Geenen JE, et al. Endoscopic retrograde cholangiopancreatography in children.
J Pediatr 1987;110:206-11.
29. Ricchieri JP, Chapoy P, Bertolino JG, et al. Endoscopic retrograde cholangiopancreatography in
adolescents. Gastroenterol Clin Biol 1994;18:21-25.
30. Soergel KH. Acute pancreatitis. In Sleisenger MH, Fordtran JS (Eds): Gastrointestinal disease (4th edn),
Philadelphia: WB Saunder 1989;1814-42.
31. Durr HK. Acute pancreatitis. In Howat HT, Sarles H (Eds): The exocrine pancreas, London, WB Saunders,
1969;352-401.
32. Leach SD, Gorelick FS, Modlin IM. New perspectives on acute pancreatitis. Scand J Gastroenterol 1992;27
(suppl 192):29-38.
33. Marshall JB: Acute pancreatitis. Arch Intern Med 1993;153:1185-98.
34. Wilson C, Imrie CW. Current concepts in the management of pancreatitis, Drugs 1991;41:358-56.
35. R.Pezzilli, et al. Pancreatology 2001;1: 129-199, P3 80 abstracts
36. Dominguez-Monoz JE. Monitoring of serum proteinase-antiproteinase balance and systemic
inflammatory response in prognostic evaluation of acute pancreatitis. Dig Dis Sci 1993;38:507-513, (133,
1462)
37. Pederzoli P, Bassi C, Vesentini S, et al. A randomized multicenter clinical trail of antibiotic prophylaxis
of septic complications in acute necrotizing pancreatitis with imipenem. Surg Gynecol Obstet
1993;176:480-80.
38. Etemad B, Whitcomb DC. Chronic pancreatitis: diagnosis, classification, and new enetic developments.
Gastroenterology 2001;120:682-707.
39. Buscail L, Escourrou J, Moreau J, Delvaux M, Louvel D, Lapeyre F, Tregant P, frexinos J. Endoscopic
ultrasonography in chronic pancreatitis: A comparative prospective study with conventional
ultrasonography, computed tomography and ERCP. Pancreas 1995;10: 251-57.
40. Malfertheiner P, Buchler M, Stanescu A, Ditschuneit H. Exocrine pancreatic function in correlation to
ductal and parenchymal morphology in chornic pancreatitis. Hepatogastroenterology 1986;33: 110-
14.
41. Kusano S, Kaji T, Sugiura Y, Tamai S. CT demonstration of fibrous stroma in chronic pancreatitis:
pathologic correlation. J comput Assist Tomogr 1999;23:297-300.
42. Caletti G, Brocchi E, agostini d, Balduzzi A, Bolondi L, Labo G. Sensitivity of endoscopic retrograde
IP : 112.133.195.17
pancreatography in chronic pancreatitis. Br J Surg 1982;69: 507-509.
43. Poddar U, Yaccha SK, et al. Pancreatic diseases in children. Indian Pediatrics 2005;(42):848–49.
44. Mohan N, Bansal S, Arora A, Sud R, et al. Role of Endoscopic retrograde cholangiopancreatography
in the management of pancreatitis in children Journal of Pediatric Gastroenterology and Nutrition
2004;39(Suppl 1)(S44).
45. Warshaw AL, Banks PA, Fernandez-Del Castillo C. AGA technical review: treatment of pain in chronic
pancreatitis. Gastroenterology 1998;115:765-76.
46. Layer P, Yamamoto H, Kalthoff L, Clain JE, Bakken LJ, DiMagno EP. The different courses of early-
and late-onset idiopathic and alcoholic chronic pancreatitis. Gastroenterology 1994;107:1481-87.
47. Brown A, Hughes M, Tenner S, Banks PA. Does pancreatic enzyme supplementation reduce pain in
patients with chronic pancreatitis: a meta-analysis. Am J Gastroenterol 1997;92:2032-35.
48. Conwell DL, Vargo JJ, Zuccaro G, et al. Role of differential neuroaxial blockade in the evaluation and
management of pain in chronic pancreatitis. Am J Gastroenterol 2001;96:431-36.
49. Gress F, Schmitt C, Sherman S, Ikenberry S, Lehman G. A prospective randomized comparison of
endoscopic ultrasound- and computed tomography-guided celiac plexus block for managing chronic
pancreatitis pain. Am J Gastroenterol 1999;94:900-05.
Gastroesophageal Reflux / 1
John Matthai, Sarah Paul
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1 Gastroesophageal Reflux
INTRODUCTION
Mother’s frequently complain about babies “bringing up” or “regurgitating” during the first
a few months of life. Gastroesophageal reflux (GER) is the most common esophageal disorder
in children. The incidence of GER has been increasing in western countries and is now being
more widely recognized in India. Formula feeding and restraining of infants in car seats are
probable reasons of increased incidence of reflux in western countries. Gastroesophageal reflux
is physiological in most infants and needs no investigations or treatment. A few have symptoms
that can be termed pathological and is referred to as gastroesophageal reflux disease (GERD).
DEFINITION
GER is defined as the involuntary passage of gastric contents into the esophagus. The
regurgitated gastric content may be saliva, ingested food, gastric secretions, pancreatic or
biliary secretions.
NATURAL HISTORY
The incidence of GERD in the general population in infants and children has been estimated
to range from 1 to 8%.1 In most symptomatic infants, regurgitation decreases appreciably
by 12 to 24 months of age.2 Neurologically normal children over 1 year of age with significant
regurgitation most commonly have “Endoscopy negative GERD” and the inflammation on
microscopy usually resolves with time. Older children with persisting regurgitation are
unlikely to improve with age and may continue to remain symptomatic. Chronic untreated
esophagitis can result in strictures, Barretts esophagus and adenocarcinoma in adults.
PATHOPHYSIOLOGY
The esophagus is not under voluntary control. Distal to the mid-esophagus the muscular
layer is composed of smooth muscle fibres. Peristaltic waves involving the external circular
muscular layer propels the ingested food through the esophagus into the stomach. The lower
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esophageal sphincter is an area of thickened circular muscle that is tonically contracted at
rest. A well co-coordinated relaxation of the lower esophageal sphincter is essential for
the transport of food into the stomach. Tonic LES pressure is maintained above 4 mm Hg
to prevent reflux. The notion that infants with GER have abnormally low basal tone at the
LES has been disproved by pressure studies in animal models and humans.
It is now believed reflux occurs due to transient LES relaxations (TLESR) unassociated
with esophageal peristalsis and mediated primarily through vagal pathways via the brain
stem.3 The pressure changes at the gastroesophageal junction are dependent on motor
mechanisms like the volume-pressure relationship in the stomach as well as the proximal
esophageal clearance of the refluxed material. Sensory phenomena are also important not
only in causation of the pain symptoms but also as the gastric afferent limb to the TLESR.
The TLESR can be thought of as either a “belch equivalent” releasing gastric pressure with
the afferents being in the stomach or as an “aborted swallow” with the 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 be mediated by inhibitory neurotransmitters released from
the enteric neurons.5 Vasoactive intestinal peptide is known to play an important role in
mediation. Abnormal functioning of the CNS or a developmentally exaggerated enteric reflex
could result in abnormal gastric motor activity, retrograde peristalsis and relaxation of the
LES. The crural diaphragm that surrounds the LES increases its tone especially when straining.
Complex neural connections ensure that TLESR’s are physiologically accompanied by
co-ordinated crural relaxation. This explains why hiatus hernia is often associated with GERD.6
A recent study reported hiatus hernia in 6% of children with GERD.7 One-fourth of children
with hiatus hernia were neurologically impaired and had severe GER requiring surgery.
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 13q 14.8
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
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. Supine and
seated position (as in car seats) is provocative in infants. In normal children, 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 active during sleep.
The pathogenesis of reflux in premature infants is not well understood.11 They have limited
gastric capacity but need good calorie intake. 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
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pressure is excessive, it relaxes and allows the refluxate to escape. Gravitational force may
however sometimes lead to aspiration into the lung. Since laryngeal stimulation can cause
apnea in premature babies, upper airway obstruction can be a hazardous complication in
them. The refluxate is usually not acidic in premature babies because frequent feedings buffer
the gastric acid. Naso-gastric tubes impair clearance of the refluxed material if they are
of large size.12
CLINICAL PRESENTATION
Some degree of reflux is normal in the first year of life. GER is physiological and age related
while GERD is pathological and should not be missed. Healthy, thriving infants with reflux
need no evaluation at all. 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.
Children with gastroesophageal reflux disease present with failure to thrive due to loss
of calories, symptoms of esophagitis or respiratory tract related problems like apnea, acute
life threatening episode (ALTE), recurrent pneumonia, or asthma.13
“Regurgitating” or “bringing out” is a feature of GER. Significant GER can however exist
even in the absence of this symptom. Reflux esophagitis may present as irritability (colic),
epigastric or retrosternal pain, failure to thrive, malena or hematemesis, dysphagia or belching
and postprandial fullness. 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. Severity of lesions on endoscopy or biopsy
does not correlate well with the extent of symptoms and proven severe esophagitis may
have only minimal symptoms and vice versa.
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, convincing proof is lacking.16 It is possible that asthma and GER
coexist without any etiological association. The GER may be secondary to the increased
respiratory effect or coughing. If there are strong reasons to suggest an etiological association,
the infant may be managed as GERD.
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 predisposes them to severe
disease.17
EVALUATION IP : 112.133.195.17
Detailed evaluation is necessary only in children with pathological GER. Investigations in
GER have different goals and 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,
with the sole purpose of making therapeutic decisions in a patient. Standardized questionnaires
are useful to diagnose or quantify the extent of reflux. It is a good objective assessment
and may help avoid costly and invasive diagnostic procedures.18 It may be repeated after
a period of time to quantify improvement, stability or worsening of disease.
Contrast Studies
Barium studies have been used for many decades. It has a low sensitivity and specificity
in diagnosis of GERD, but can rule out structural abnormalities like a large hiatus hernia,
esophageal stricture, duodenal web or atypical pyloric stenosis.19 The mere demonstration
of GER on a barium study in of little significance, since it may be normal in infants. Barium
esophagography may be useful in identifying abnormalities of pharyngeal, laryngeal or upper
esophageal function.
Esophageal pH Probe 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
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. An acidic
feed like apple juice, can be given to partially overcome this handicap.
Nuclear Scintigraphy
This is also called “Milk Scan” wherein radionucleotides like 99mTC can be added to the
infants 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.
Endoscopy and Biopsy

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
IP : 112.133.195.17
loss of the normal vascular pattern. The severity of the endoscopic esophagitis in children
in graded according to the classification of Savary and Miller. A large majority of reflux
esophagitis in children are restricted to grades 1 and 2. Esophageal mucosa for study can
be obtained either by endoscopic punch biopsy or suction biopsy. A good visual inspection
must be done before taking a biopsy. Histological diagnosis is better with a suction biopsy
specimen and multiple biopsies improve the yield. 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 a reliable criteria for histological diagnosis.
Longstanding untreated reflux esophagitis results in barretts esophagus with aberrant
columnar epithelium lining the distal esophagus. Diagnosis requires multiple biopsies to
show the transition from squamous to columnar epithelium. This condition is potentially
malignant and aggressive medical or surgical therapy may revert the mucosa to normal.
Miscellaneous Techniques
Esophageal manometry is used to assess pressure profile and dynamic changes. This is mostly
used for research and is not very useful in the practical management of GER. It can be
used to demonstrate volumetric reflux. Impedance is another method of demonstrating bolus
reflex, irrespective of the acidity of the reflux. It complements an esophageal pH study,
but is difficult to perform and analyse.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 noninvasive 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 wide and requires a careful history
and evaluation. Gastrointestinal obstruction [Malrotation/volvulus, pyloric stenosis, duodenal
stenosis, strictures] need consideration. Achalasia, food intolerance, food allergy, dysphagia
and esophagitis due to other causes must be carefully differentiated. Systemic infections
may sometimes present with regurgitation and should be considered in young infants with
acute onset of symptoms. GERD can sometimes have some unusual presentations such as
apnea, recurrent otitis and sinusitis, stridor and hoarseness of voice, wheezing or chronic
IP : 112.133.195.17
cough, recurrent pneumonia and sometimes severe dental erosions.
MANAGEMENT
Regurgitation being physiological in infancy, only those with pathological GER need to be
treated. The risks and benefit of therapy need to be carefully evaluated in terms of age
of the patient, with consideration for cost effectiveness. 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
Life Style Measures

Positioning has an important role. The “head elevated prone position” is clearly effective
in reducing the reflux when compared to the supine or seated positions. It’s use has been
limited only because of the worry of sudden infant death syndrome.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 The time
spent crying and the time spent awake are reduced. Thickened formula may however increase
coughing during feeds. Thickening of feeds is usually achieved by adding rice cereal. Formulae
that contain carob flour or locust bean gum as thickening agents are available in Europe
and one with added rice starch is available in the US.
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 related to the acid that is refluxed,
like esophagitis, or heartburn. Most infants therefore do not require powerful acid
suppression. In increasing order of 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 PPI’s the most effective acid
suppressants, covalently bond and deactivate the H+K+ ATPase pumps.30 They require acid
for activation and are most effective when the parietal cell is stimulated by a meal. For
optimal action, it should be administered 1 hour before breakfast. There is limited data
on the pharmacology of PPI’s in children and there is no accepted dosage. Omeprazole at

IP : 112.133.195.17
0.5 to 0.7 mg/kg/day is commonly used.31 One study reported that doses as high as 3.3
mg/kg/day may be required to normalize the esophageal pH in some cases. For children
unable to swallow the capsules, granules can be administered orally in weakly acidic foods
such as apple juice or yogurt. Other PPI’s like lansoprazole (1.4 mg/kg/day), Pantoprazole
and Rabeprazole which have been introduced recently have proven efficacy in adults, but
data in children is limited. PPI’s are superior to H2 blockers in relieving symptoms and
healing esophagitis. In patients with nocturnal acid breakthrough, a morning dose of PPI’s
and night dose of H2 blockers has been used.
Barrier Agents
Sucralfate complexes with the base of ulcers and erosions and is effective in settings where
the esophageal epithelium has been severely damaged. The action in comparable to H2 receptor
antagonists in adults but its safety and usefulness in children is unproven. Gaviscon acts
by forming a floating barrier on top of the gastric contents and thus reducing reflux.
Prokinetic Agents
Prokinetic agents have been used in GERD, since it has many features in common with
motility disorders. 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 Q8h) 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. It has been shown
to increase tolerance of oral feeding in premature newborns also. Cardiotoxicity is the major
side effect. However, among currently available prokinetics, cisapride has the best risk benefit
ratio. Concomitant use of medications such as erythromycin, clarithromycin and miconazole
must be avoided in patients on cisapride. As per 1999 ESPGHAN consensus statement and
1999 NASPGAN consensus statements “cisapride has a place in pediatric therapeutics when
used in conditions in which a prokinetic drug is indicated”. Needless to state that it must
be used only under supervision.32,33
Mosapride has fewer side effects, but its use and efficacy in young children has not been
documented.
Surgical Treatment
Surgery is indicated only in children with GERD which is refractory to adequate medical
treatment. 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
IP : 112.133.195.17
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. Complications after a fundoplication may require reevaluation with
barium fluoroscopy, endoscopy or pH probe studies. Laparascopic fundoplication can be
as effective as open fundoplication in children but requires expertise.35 Endoscopic therapies
are being tried in adults and may prove useful enough to be applied to children.
Extraesophageal Manifestations
In these situations, therapy must be aggressive and for longer duration.36 Twice daily PPI’s
maintained for at least 3 months is recommended.37 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. Neurologically abnormal
children have more severe and complicated GERD than normal children.
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 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. Among
the H2 blockers ranitidine is better tolerated. PPI’s are most effective, but data on safety
in children is still inadequate. Prokinetics do have a role in spite of side effects, and should
be used only under supervision. Among currently available prokinetics, Cisapride has the
IP : 112.133.195.17
best risk benefit ratio. Fundoplication is not always successful and should be done only
in exceptional cases.
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. PPI’s are
the most potent, but more studies are needed in children.
7. Prokinetics may be used under supervision in selected cases. Cisapride is the best available.
8. GERD with extraesophageal manifestations need aggressive management for longer
duration.
ACKNOWLEDGEMENT
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
8. Orenstein SR, Shalaby TM, Barmada MM, et al. Genetics of gastroesophageal reflux disease: a review. J Pediatr
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 nasogasric 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,
IP : 112.133.195.17
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; 11 Suppl 8A:60S–3S.
16. Tolia V. Gastroesophageal reflux and supraesophageal complications: really true or ballyhoo [editorial]?
J Pediatr Gastroenterol Nutr 2002;34:269–73.
17. Orenstein S R, Khan S, Gastroesophageal Reflux in Walker AW, goulet O, et al (Eds). Pediatric Gastroenterol
disease. New York. B C 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
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. Current Pediatric Indication for Cisapride. J Ped Gastro Nutr. 2000;31:480-489.
33. Shulman RJ, Boyle JT, Colletti RB et al. for NASPGHN. The use of Cisapride in Children. J.Pediatr Gastroenterol
Nutr 1999;28:529 -33.
34. Di Lorenzo C, Orenstein SR. Fundoplication: friend or foe? J Pediatr Gastroenterol Nutr 2002;34:117–24
35. Meehan JJ, Georgeson KE. The learning curve associated with laparoscopic antireflux surgery in infants
and children. J Pediatr Surg 1997;32:426–9.
36. De Vault KR. Overview of therapy for the extraesophageal manifestations of gastroesophageal reflux disease.
Am J Gastroenterol 2000;95(8 Suppl):S39–44.
37. Klaus A, Swain JM, Hinder RA. Laparocopic antireflux surgery for supraesophageal complications of
gastroesophageal reflux disease. Am J Med 2001;11(8A):202S–6S.

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Helicobacter Pylori in Children / 11

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

Table 2.2: Virulence factors of Helicobacter pylori

What are the diseases caused by H. pylori?

Recurrent Abdominal Pain and H. pylori

IP Table 2.3: Association

NS= not significant

How to Diagnose H. pylori?

Whom to investigate for H. pylori and how?

Table 2.5: Drugs

Whom to treat and with what drugs?

H. pylori Infection in Children and Gastric Adenocarcinoma in Adults

Recommended Eradication Therapies for H. pylori Disease in Children38-40

First Line Options

Table 3.1: Apley’s typical FRAP phenotype

INCIDENCE AND PREVALENCE

IP : 112.133.195.17Table 3.3: Abdominal pain

Chronic Abdominal Pain G2

Definitions as per Rome II Criteria

Functional Abdominal Pain Syndrome

Irritable Bowel Syndrome

Approach to a Case of RAP

Functional abdominal pain 95% Organic abdominal pain <5%

RAP with dyspepsia

Functional abdominal pain 90% Organic abdominal pain 10%

Causes of RAP with dyspepsia

RAP with altered bowel habits

Functional abdominal pain 75% Organic abdominal pain 25%

Pathogenesis of Functional Abdominal Pain

Approach to Case of RAP

Complete and Diligent Physical Examination

Management of Recurrent Abdominal Pain

Avoid as much as possible

Make a positive diagnosis

Identify and Assuage Stress and Trigger Factors

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 treatment of diarrhea

Antisecretory Drugs in Diarrhea

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 treatment of diarrhea

Antisecretory Drugs in Diarrhea

Chronic Diarrhea and

Diarrhea is defined as increased frequency, fluidity or volume of stools. According to WHO,

NORMAL PHYSIOLOGY OF DIGESTION

Fig. 6.1: Site of absorption of nutrients in gut

APPROACH TO A PATIENT WITH CHRONIC DIARRHEA

IP :Table 6.1: Causes of

The main features to be noted are:

Fig. 6.2: A practical approach to a child with chronic diarrhea

Step 1—Confirm that there is chronic diarrhea.