Cholestatic liver disease in children

Abstract

Inherited syndromes of intrahepatic cholestasis and biliary atresia are the most common causes of chronic liver disease and the prime indication for liver transplantation in children. Our understanding of the pathogenesis of these diseases has increased substantially by the discovery of genetic mutations in children with intrahepatic cholestasis and the findings that inflammatory circuits are operative at the time of diagnosis of biliary atresia. Building on this solid foundation, recent studies provide new insight into genotype-phenotype relationships and how mutations produce altered bile composition and cholestasis. New evidence exists that although liver transplantation is curative for patients with end-stage liver disease owing to cholestasis, some patients may develop recurrence of cholestasis because of the emergence of autoantibodies that disrupt canalicular function in the new graft. Progress is also evident in biliary atresia, with recent studies identifying candidate modifier genes and directly implicating lymphocytes and inflammatory signals in the pathogenesis of bile duct injury and obstruction.

Fig. 1

Clinical phenotypes induced by deficiency of individual canalicular transporters. The phenotypes are grouped based on a perceived level of severity (from less to more severe). BRIC—benign recurrent intrahepatic cholestasis; BSEP—bile salt export pump; FIC—familial intrahepatic cholestasis; ICP—intrahepatic cholestasis of pregnancy; LPAC—low phospholipid–associated cholestasis; MDR—multidrug resistance protein; NASH—nonalcoholic steatohepatitis; PFIC—progressive familial intrahepatic cholestasis

Fig. 2

Diagram depicting an invasion of the duct epithelium by inflammatory cells and progression to biliary atresia. New evidence links natural killer (NK) cells to the injury of cholangiocytes in an experimental model of rotavirus-induced biliary atresia [48••]. Following the disruption of epithelial integrity by NK cells, CD4⁺ T cells populate the bile duct along with CD8⁺ T cells, which lead to obstruction of the lumen and progression to atresia