Ileal bile acid transporter inhibition as an anticholestatic therapeutic target in biliary atresia and other cholestatic disorders

AbstractBiliary atresia is a rare cholestatic liver disease that presents in infants and rapidly advances to death in the absence of intervention. As a result of blockage or destruction of the biliary tract, bile acids accumulate and drive inflammation, fibrosis, and disease progression. The standard of care, Kasai portoenterostomy (KPE), is typically performed shortly after diagnosis (currently at  ~ 2 months of age) and aims to restore bile flow and relieve cholestasis. Nevertheless, most patients continue to experience liver injury from accumulation of bile acids after KPE, since there are no known effective therapeutics that may enhance survival after KPE. Improving cholestasis via in terruption of the enterohepatic circulation of bile acids may directly attenuate hepatic bile acid retention and reduce the risk of early organ failure. Directly addressing intrahepatic accretion of bile acids to avoid inherent bile acid toxicities provides an attractive and plausible therapeutic ta rget for biliary atresia. This review explores the novel therapeutic concept of inhibiting the sole ileal bile acid transporter (IBAT), also known as ASBT (apical sodium-bile acid transporter, encoded bySLC10A2), as a means to reduce hepatic bile acid concentration after KPE. By reducing return of bile acids to the cholestatic liver, IBAT inhibitors may potentially lessen or delay liver damage associated with the hepatotoxicity and cholangiopathy of bile acid accumulation. The clinical progr...

Source: Hepatology International - July 10, 2020 Category: Infectious Diseases Source Type: research