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Biliary atresia (BA) is a condition in which the normal extra hepatic biliary system is disrupted. Biliary atresia affects approximately 1 in 10,000 – 15,000 births and occurs in 2 distinct clinical forms: fetal-embryonic (or syndromic) and perinatal (or acquired). The fetal embryonic form is characterized by early cholestasis, appears in the first 2 weeks of life, and accounts for 10-35% of all cases. In this form, the bile ducts are discontinuous at birth and 10-20% of affected neonates have associated congenital defects including situs inversus, polysplenia, malrotation, intestinal atresia and cardiac anomalies, among others. The perinatal form of biliary atresia accounts for the remaining 65-90% cases. This form is typically found in neonates and infants aged 2-8 weeks. Progressive inflammation and obliteration of the extra hepatic bile ducts occurs after birth. This form is not associated with congenital anomalies. Infection with cytomegalovirus (CMV), group C rotavirus and reovirus type 3 have been implicated in these patients.[1] Immune mediated ductal injury are important in the pathogenesis of BA, and CMV infection may trigger such inflammation.[2] CMV is the most common cause of congenital infection in humans.[3] CMV infection is ubiquitous in India with high seroendemicity and nearly 99% adults showing IgG antibodies.[4] Neonatal CMV infection may occur due to intrauterine or perinatal exposure to CMV infected cervicovaginal secretions and breast milk.[5] Transmission occurs predominantly via primary maternal infection but can also occur due to reactivation of a CMV infection during pregnancy.[4] Neonatal hepatitis and biliary atresia have been reported as isolated clinical manifestations of congenital CMV infection.[2,3,5,6-9] Patients with neonatal hepatitis and CMV have been treated with IV ganciclovir and its oral prodrug, demonstrating variable outcomes.[3,5,6,7,9] However, the effect of ganciclovir in patients with biliary atresia and associated CMV infection has rarely been reported.[10] Fischler et al in 2002 treated two patients with biliary atresia and ongoing CMV infection for 3-7 weeks, of which one patient responded and another did not.[10] We report for the first time, two patients with biliary atresia and CMV infection who had a variable response to ganciclovir.
Case reports
Case 1
A 2½-month-old girl born of non-consanguineous marriage presented with jaundice since four days along with high colored urine but no clay colored stools. She was born full term with a birth weight of 2.5 kg. She was fully immunized for date and was on breast feeds. The mother experienced no antenatal problems. On examination, the child’s weight was 4 kg, length 57 cm, and her vital parameters were normal. She had jaundice, rickets and hepatomegaly. Other systems were normal. Ultrasound abdomen showed hepatomegaly with nonvisualization of gall bladder. HIDA scan showed normal uptake of tracer but no excretion of dye in the intestines even after 24 hours. An intraoperative cholangiogam showed no passage of dye in the intestines and the patient underwent a Kasai’s surgery at 3 months of age. Operative liver biopsy showed an atretic gall bladder with multinucleate giant cells without inclusion bodies; and biliary atresia with bile channels measuring 150 microns at porta. Postoperatively the child continued to have jaundice. At six months of age, bilirubin was 11.3 mg/dl (direct bilirubin = 5.8 mg/dl) with elevated transaminases (SGOT = 266 IU/L, SGPT = 148 IU/L). A TORCH titre was done at that time which showed CMV IgM positive and CMV IgG level of 100 AU/ml. The child was started on oral ganciclovir (10 mg/kg/day) twice a day for 21 days and 5 mg/ kg/day for next 21 days but there was no response. At 10½ months of age, the child showed failure to thrive (weight = 6 kg) with hyperbilirubinemia (bilirubin = 19.7 mg/dl), bleeding per rectum, portal hypertension and liver cell failure. The parents were advised a liver transplant for the child but the parents refused.
Case 2
A 1½-month-old girl born of non-consanguineous marriage presented with jaundice and clay coloured stools since birth. On examination, her weight was 3.5 kg and length was 60 cm. Her vital parameters were normal. She had jaundice with hepatosplenomegaly. Other systems were normal. Ultrasound abdomen showed hepatosplenomegaly with presence of gall bladder. TORCH titres showed positive CMV IgG (7.7 IU/L). In view of clay coloured stools, an intraoperative cholangiogram was done that showed absence of dye in intestines and the patient underwent Kasai’s portoenterostomy at two months of age. Operative liver biopsy showed biliary atresia with periportal fibrosis and biliary channels sized 150 microns. Postoperatively, the child continued to have jaundice and clay coloured stools. At 4 months of age, the child was treated with intravenous antibiotics for sclerosing cholangitis and pneumonia. A repeat CMV IgG showed four fold elevation (30 IU/L). The child was then treated with oral ganciclovir for 6 weeks following which bilirubin decreased to 5.5 mg/dl and she started passing green coloured stools. At seven months of age, the child has chronic liver disease with portal hypertension and CMV IgG was 260 IU/ml.
Discussion
Treatment of CMV infection in children is controversial. However increasing number of studies indicate the necessity of treatment, especially in cases with symptoms of acute or chronic cholestatic hepatitis.[5-7,9,10] Ganciclovir has been used in only two patients with biliary atresia and CMV infection, of which one patient had a good outcome while the other did not.10 Both our patients underwent Kasai operation at three and two months of age, respectively. However both had bile duct size of 150 microns which suggested poor prognosis.[11] Both patients continued to pass clay-colored stools postoperatively. Infact the first child still had jaundice at six months of age (bilirubin = 11.3 mg/dl) suggestive of failed Kasai’s operation. Thus, a beneficial effect of ganciclovir was unexpected as was eventually noted. This child developed liver cell failure at 10½ months. In the second child, ganciclovir was started two months after Kasai surgery because of active CMV disease and four-fold rise in CMV IgG, besides presence of pneumonia and sclerosing cholangitis. On treatment with ganciclovir, clay-colored stools disappeared and jaundice also decreased. However, since there was already significant liver damage, the child subsequently developed chronic liver disease with portal hypertension. Though the treatment was started late, but it seemed be partially beneficial in this patient. In a study by Fischler et al, of 28 patients with biliary atresia who underwent Kasai procedure, 11 had CMV infection. The authors found that survival with native liver among CMV infected and non-infected was 50% and 36% at four and 10 years follow-up, respectively, with no significant difference in long term outcome with respect to early CMV infection.[8] However the role of ganciclovir in treatment of biliary atresia with CMV needs further investigation and may offer different outcome for these patients. Thus randomized controlled trials are needed in patients with biliary atresia and associated CMV to examine the effect of ganciclovir treatment.
References
- Schwarz SM. Pediatric biliary atresia. [cited 2014 Mar 18]. Available from: http://emedicine.medscape.com/article/927029-overview
- Fischler B, Woxenius 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.
- Meine Jansen CF, Toet MC, Rademaker CM, Ververs TF, Gerards LJ, van Loon AM. Treatment of symptomatic congenital cytomegalovirus infection with valganciclovir. J Perinat Med. 2005;33:364–6.
- Bhatia P, Narang A, Minz RW. Neonatal cytomegalovirus infection: diagnostic modalities available for early disease detection. Indian J Pediatr. 2010;77:77–9.
- Ozkan TB, Mistik R, Dikici B, Nazlioglu HO. Antiviral therapy in neonatal cholestatic cytomegalovirus hepatitis. BMC Gastroenterol. 2007;7:9.
- Muller 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.
- Vancikova Z, Kucerova T, Pelikan L, Zikmundova L, Priglova M. Perinatal cytomegalovirus hepatitis: to treat or not to treat with ganciclovir. J Paediatr Child Health. 2004;40:444–8.
- Fischler B, Svensson JF, Nemeth A. Early cytomegalovirus infection and the long-term outcome of biliary atresia. Acta Paediatr. 2009;98:1600–2.
- 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.
- 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.
- Sanghai SR, Shah I, Bhatnagar S, Murthy A. Incidence and prognostic factors associated with biliary atresia in western India. Ann Hepatol. 2009;8:120–2