The next challenge in pediatric cholestasis: Deciphering the pathogenesis of biliary atresia

Cholestasis is a common presenting symptom of liver disease in infants. Chief among diseases presenting as neonatal cholestasis is biliary atresia, the most common cause of chronic liver disease in children, but little is known about the pathogenesis of this disease. In search for the molecular basis of biliary atresia, we began two areas of investigation. In the first, we interrogated the hepatic transcriptome of children with biliary atresia and found an interferon-gamma (IFN gamma)-rich proinflammatory footprint at the time of diagnosis. To directly explore if IFN gamma plays an important role in biliary injury and obstruction, we used a mouse model of experimental biliary atresia and found that inactivation of the murine Ifn gamma gene decreases the tropism of lymphocytes to neonatal bile ducts and prevents the inflammatory obstruction of the duct lumen. Further analysis of the extrahepatic biliary tract also outlined a broader network of proinflammatory genes at the onset and during progression to duct obstruction, with the time-specific activation of IFN gamma-, apoptosis-, and complement-driven networks. In the second approach, we searched for molecular profiles that differentiate clinical forms of biliary atresia by analyzing the hepatic transcriptome of age-matched subjects at the time of diagnosis. We found a preliminary profile that differentiates the embryonic from the perinatal forms of biliary atresia. The profile contained the differential activation of genes involved in epigenetic mechanisms of disease. Collectively, these studies provide new insight into pathogenesis of biliary atresia and identify potential therapeutic targets to foster long-term outcome with the native liver.