The pathogenesis of biliary atresia is
poorly understood. Association with congenital anomalies in some
infants suggests genetic factors. Infection with cytomegalovirus
(CMV), group C rotavirus and reovirus type 3 has been associated
in certain cases and Fischler, et al. found ongoing CMV
infection in 39% of patients with biliary atresia [1-3]. CMV
positive patients may present with a later onset; however, long
term outcome is similar to non-CMV patients [2]. Outcome may
also depend on other factors such as age of surgery, bile duct
size and presence of liver damage [4]. Though CMV is known to
cause neonatal cholestasis, use of antiviral drugs such as
ganciclovir and its oral prodrug valganciclovir in patients with
neonatal hepatitis and CMV has been tried in few patients, with
generally good outcome [5-7]. We report a child with biliary
atresia who underwent portoduodenostomy at 2˝ months of age but
continued to have jaundice which improved after treatment.
Case Report
A 2 months old girl born of
non-consanguineous marriage at full term with birth weight of
2.6 kg presented with jaundice with clay colored stools since
birth, increasing pallor and left focal convulsion. There was no
fever, altered sensorium or abdominal distension. She was on
exclusive breast feeds. On examination, weight was 3.75 kg,
length was 54 cms, she had pallor, icterus, tense bulging
anterior fontanelle and hepatosplenomegaly. There was no focal
neurological deficit. Investigations showed hemoglobin of 6.8 g/dL,
white cell count of 9,500/cumm (50% polymorphs, 50%
lymphocytes), platelets of 4,25,000/cumm. Her bilirubin was 9.6
mg/dL (direct = 5.1 mg/dL), SGOT was 166 IU/L, SGPT = 106 IU/L,
total proteins = 5.3 g/dL, albumin=2.7 g/dL. Prothrombin time
and partial thromboplastin time were more than 2 minutes. Serum
ammonia was 190 µg/dL and blood sugar was 68 mg/dL. Serum
electrolytes, blood gases and creatinine were normal. CT brain
showed right frontal lobe hemorrhage with perifocal edema with
mild shift of midline to left side. USG abdomen showed
hepatomegaly with non-visualization of gall bladder. She was
treated with fresh frozen plasma, blood transfusion and
anticonvulsants. Her TORCH titres (sent before blood transfusion
was given) showed positive CMV IgM. HIDA scan after a 5 days
priming with phenobarbitone and urseodeoxycholic acid showed
poor tracer uptake and no excretion even after 24 hours in the
intestine. After stabilization of condition, she underwent an
intraoperative cholangiogram that confirmed the diagnosis of
biliary atresia and a portoduodenostomy was done at 2˝ months of
age. Liver biopsy at that time showed early cirrhosis with bile
ductular proliferation, and biliary channels more than 150
microns. Post- operatively, even at 3˝ months of age, she
continued to have jaundice (bilirubin = 23.6 mg/dL). Her CMV
viral load at that time was 100 copies/mL and ophthalmological
examination and hearing test were normal. She was given
valganciclovir (250 mg/m2/day)
for 3 weeks following which CMV viral load became undetectable,
bilirubin decreased to 5.9 mg/dL and liver transaminases
decreased. Valganciclovir was then tapered to 125 mg/m2/day
and given for another 3 weeks. Currently the child is 2 years,
has normal milestones, is seizure-free and off anticonvulsant,
has normal liver function tests, no hearing or visual deficit
but has umbilical varices. Endoscopy showed no esophageal
varices.
Discussion
An association between cytomegalovirus
infection and intrahepatic and extrahepatic forms of neonatal
cholestasis has been reported in literature [6]. Whether CMV
triggers mechanisms that lead to pathogenesis of biliary atresia
remains unproven [8]. CMV replicates in both hepatocytes and
cholangiocytes during infection and liver damage may be related
to direct cytopathic effect or the immune response of the host
[9].
Chang, et al. have reported that CMV
DNA was detected in 46% of babies with neonatal hepatitis and
suggested that CMV could play a major role in pathogenesis of
neonatal hepatitis [10]. Fischler, et al. [8] found that
in patients with biliary atresia and CMV, IgM deposits were
significantly higher on liver biopsies than in biliary atresia
patients without CMV, suggesting that CMV may be triggering
immunologic processes causing biliary atresia.
However, treatment of CMV in patients with
biliary atresia has not been studied much and its effect on
outcome is not known. Increasing number of studies indicate the
necessity of treatment, especially in cases with symptoms of
acute or chronic cholestatic hepatitis or proven
histopathological findings [5-7,9]. Currently, there are four
antivirals available for treatment of CMV: ganciclovir,
valganciclovir, foscarnet and cidofovir, of which ganciclovir
and its oral prodrug valganciclovir have been studied in
neonates. Ganciclovir has been used in 2 patients with biliary
atresia and CMV, of which one responded [2]. Similarly in our
patient, since the child was still passing clay stools even
after 1 month of portoduodenostomy and jaundice was still high,
a trial of valganciclovir was given in view of detectable CMV
viral load. However, whether ganciclovir or valganciclovir will
be useful in all patients with biliary atresia and CMV needs to
be evaluated in larger studies.
Funding: None. Competing interests:
None stated.
References
1. Zukotynski K, Babyn PS. Biliary Atresia.
Available from: http://www.emedicine.com. Accessed on 5
February, 2010.
2. Fischler B, Svensson JF, Nemeth A. Early
cytomegalovirus infection and the long-term outcome of biliary
atresia. Acta Paediatr. 2009;98:1600-2.
3. Rauschenfels S, Krassmann M, Al-Masri AN,
Verhagen W, Leonhardt J, Kuebler JF, et al. Incidence of
hepatotropic viruses in biliary atresia. Eur J Pediatr.
2009;168:469-76.
4. Sanghai S, Shah I, Bhatnagar S, Murthy A.
incidence and prognostic factors associated with biliary atresia
in western India. Annals Hepatol. 2009;8:120-2.
5. Miiler A, Eis-Hubinger AM, Brandhorst G,
Heep A, Bartmann P, Franz AR. Oral valganciclovir for
symptomatic congenital cytomegalovirus infection in an extremely
low birth weight infant. J Perinatol. 2008; 28:74-6.
6. Fischler B, Casswall TH, Malmborg P,
Nemeth A. Ganciclovir treatment in infants with cytomegalovirus
infection and cholestasis. J Pediatr Gastroenterol Nutr.
2002;34:154-7.
7. Tezer H, Secmeer G, Kara A, Ceyhan M,
Cengiz AB, Devrim I, et al. Cytomegalovirus hepatitis and
ganciclovir treatment in immunocompetent children. Turk J
Pediatr. 2008;50:228-34.
8. Fischler B, Wozenius S, Nemeth A,
Papadogiannakis N. Immunoglobulin deposits in liver tissue from
infants with biliary atresia and the correlation to
cytomegalovirus infection. J Pediatr Surg. 2005;40:541-6.
9. Ozkan TB, Mistik R, Dikici B, Nazlioglu
HD. Antiviral therapy in neonatal cholestatic cytomegalovirus
hepatitis. BMC Gastroenterol. 2007;7:9.
10. Chang MH, Huang HH, Huang ES, Kao CL, Hsu
HY, Lee CY. Polymerase chain reaction to detect human
cytomegalovirus in livers of infants with neonatal hepatitis.
Gastroenterology. 1992;103: 1022-5.
|