Pathogenesis of biliary atresia: defining biology to understand clinical phenotypes

Abstract

Biliary atresia is a severe cholangiopathy of early infancy that destroys extrahepatic bile ducts and disrupts bile flow. With a poorly defined disease pathogenesis, treatment consists of the surgical removal of duct remnants followed by hepatoportoenterostomy. Although this approach can improve the short-term outcome, the liver disease progresses to end-stage cirrhosis in most children. Further improvement in outcome will require a greater understanding of the mechanisms of biliary injury and fibrosis. Here, we review progress in the field, which has been fuelled by collaborative studies in larger patient cohorts and the development of cell culture and animal model systems to directly test hypotheses. Advances include the identification of phenotypic subgroups and stages of disease based on clinical, pathological and molecular features. Stronger evidence exists for viruses, toxins and gene sequence variations in the aetiology of biliary atresia, triggering a proinflammatory response that injures the duct epithelium and produces a rapidly progressive cholangiopathy. The immune response also activates the expression of type 2 cytokines that promote epithelial cell proliferation and extracellular matrix production by nonparenchymal cells. These advances provide insight into phenotype variability and might be relevant to the design of personalized trials to block progression of liver disease.

Biliary atresia: Where do we stand now?

“…To explain the pathogenesis of Biliary atresia, the concept of an initial viral infection damaging the biliary duct, followed by exaggerated autoimmune directed inflammation of biliary ducts and secondary biliary cirrhosis as a result of progressive ductal injury and obstruction has been mooted[17,18]. …”

Embryonic cholecystitis and defective gallbladder contraction in the Sox17-haploinsufficient mouse model of biliary atresia

“…Malformation of the gallbladder and bile ducts can cause disease, including cholesterol gallstones, chronic inflammation and biliary atresia (reviewed by Portincasa et al, 2004Portincasa et al, , 2008Asai et al, 2015). Congenital biliary atresia is a rare condition in newborn infants (Kohsaka et al, 2002;MieliVergani and Vergani, 2009) that causes inflammation in the bile ducts and liver due to the blockage of bile flow (cholestasis).…”

Using Zebrafish to Model Liver Diseases-Where Do We Stand?

“…BA accounts for nearly 40–50% of children who undergo liver transplantation. The etiology of BA is still unclear, but is likely caused by a combination of morphogenetic abnormalities, environmental factors, and inflammatory dysregulation [24]. The most well established animal model of BA is newborn Balb/C mouse infected with Rhesus rotavirus (RRV) [25–27].…”