M1008 The PeLTQL: A Newly Developed Disease-Specific Health-Related Quality of Life Questionnaire for Pediatric Patients Post-Liver Transplant

Abstract

Background: The murine model of biliary atresia is based on a rotavirus induced CD4+ Th1 cell mediated inflammation of bile ducts followed by progressive biliary obstruction with extrahepatic cholestasis and liver injury. Little is known about the role of intrahepatic cholestasis and the regulation of hepatobiliary transporters in this model. Aim: To determine changes in hepatobiliary transporters in relation to inflammation and/or extrahepatic cholestasis during development of biliary atresia. Methods: In murine biliary atresia, mRNA expression of hepatobiliary transporters, nuclear receptors and inflammatory cytokines were determined by QPCR at 7-days, 14-days and 18-days after inoculation and compared to healthy controls. Total liver bile salts and serum bilirubin were assessed. Liver inflammation and damage were investigated histologically. Independent-sample t test was used to compare between groups. Results: Seven days after inoculation, cholestasis occurred. Despite high bile acids concentration, both canalicular and basolateral hepatobiliary transporters were down-regulated, with a decline of nuclear receptors. This was paralleled by an increase in expression of inflammatory cytokines. At 14 days, hepatobiliary transporters and nuclear receptors remained downregulated. The percentage of conjugated bilirubin started to increase remarkably, as extrahepatic biliary obstruction occurred. At 18 days, hepatobiliary transporters expression remained low, nuclear receptors tended to return to normal, while inflammatory cytokines decreased. Moreover, histology demonstrated progressive inflammation, bile duct damage and ductular proliferation. Conclusion: Intrahepatic cholestasis due to inflammation-induced down-regulation of basolateral and canalicular hepatobiliary transporters is an early event in the development of biliary atresia. Intrahepatic cholestasis contributes to the development of jaundice and occurs before extrahepatic biliary obstruction.