Cytomegalovirus in biliary atresia : coincidental or causal ?

Introduction Neonatal cholestasis (NC) has been documented in 19–33% of neonates with chronic liver disease attending tertiary care hospitals in India. Of these, almost one third have been attributed to biliary atresia. Cytomegalovirus (CMV) is known to cause intrahepatic bile duct paucity and destruction and has been suggested to cause extra hepatic biliary atresia (EHBA) in a few case series. We present a series of 4 cases admitted to our hospital over the last 18 months having EHBA with CMV infection.


Introduction
Neonatal cholestasis (NC) has been documented in 19-33% of neonates with chronic liver disease attending tertiary care hospitals in India [1][2][3] .Of these, almost one third have been attributed to biliary atresia 3 .Cytomegalovirus (CMV) is known to cause intrahepatic bile duct paucity and destruction and has been suggested to cause extra hepatic biliary atresia (EHBA) in a few case series 4 .We present a series of 4 cases admitted to our hospital over the last 18 months having EHBA with CMV infection.Case 1: A 3 month old female baby was admitted with yellowish discolouration of eyes and urine since 3 weeks of age.She was having pale stools since 1 month of age.Investigations were suggestive of NC (table 1).As she had CMV immunoglobulin M (IgM) and immunoglobulin G (IgG) reactive (table 1), a CMV deoxyribonucleic acid (DNA) polymerase chain reaction (PCR) was sent to assess the viral load.Liver biopsy was suggestive of EHBA.Gancyclovir was started because of the high viral load and child being symptomatic.As even after 3 weeks the jaundice was persisting, Kasai portoenterostomy was done.The child continues to have conjugated hyperbilirubinemia with progressive enlargement of liver and spleen at 21 months of age.occasional whitish stools since 3 weeks.On examination, he had hepatosplenomegaly.CMV DNA PCR was suggestive of infection and liver biopsy of EHBA (Table 1

Discussion
Viral infection has been proposed as a cause of EHBA.In a study from Pakistan, patients with EHBA were searched for evidence of infection with CMV, Epstein Barr virus, toxoplasma, herpes, hepatitis B and C. It was concluded that CMV may play a role in pathogenesis of EHBA 5 .In a study from Brazil on 76 patients with NC, CMV IgM was positive in 28.5% patients with extra hepatic cholestasis and 29.4% with intra hepatic cholestasis 6 .All our 4 patients had CMV IgM positive along with significantly detectable copies of CMV DNA PCR.The liver enzymes, HIDA and liver biopsy were suggestive of EHBA.
Cases 1 and 2 underwent Kasai portoenterostomy without any improvement in follow up.Case 1 underwent the operation after 3 months and case 2 underwent it early.A study from London found CMV IgM positive cases with biliary atresia as a distinct entity with late presentation and a poor to Kasai operation.Except case 2 who presented early, all other patients presented late.Two patients underwent operation with poor response in follow up.Cases 1, 3 and 4 also had significant inflammation and fibrotic changes on liver biopsy as has been documented in this study 7 .A study from China reports a strong association between CMV and lower rate of jaundice disappearance following operation.They also found increased fibrosis as we found in our patients 8 .However a study from Canada, with CMV DNA analysis on bile duct biopsy specimens showed negative results ruling out any association of CMV involved in the pathogenesis of EHBA 9 .
There is still no consensus on whether the association between CMV and EHBA is causal or coincidental.A study by Tarr et al has stated that infants with cholestasis with CMV infection should also be investigated for EHBA and monitored accordingly 10 .Till further data are available, CMV should be considered as a potential aetiological agent for EHBA with poor prognosis even after operative intervention.

Case 2 :
A 6 week old male infant was admitted with yellowish discolouration of eyes and urine and ________________________________________ 1 Department of Pediatric Medicine, Institute of Child Health, Kolkata, West Bengal, India *Correspondence: devdeep_dm@rediffmail.com(Received on 13 December 2015: Accepted after revision on 21 January 2016) The authors declare that there are no conflicts of interest Personal funding was used for the project.Open Access Article published under the Creative Commons Attribution CC-BY License.

Table 1 : Investigations in the 4 cases
CMV: cytomegalovirus, IgM: immunoglobulin M, IgG: immunoglobulin G, DNA: deoxyribonucleic acid, PCR: polymerase chain reaction ). Gancyclovir was administered for 2 weeks.Her jaundice persisted and she was lost to follow up.