BILE ACID ABNORMALITIES IN CHOLESTATIC LIVER DISEASES

Cholestasis is caused by the blockage of the hepatic bile acid flux and results in elevated serum bile acid concentrations. This condition may result from abnormal hepatic bile acid transport or obstruction of the common bile duct. Whatever the reason, the onset of cholestasis results in decreased synthesis of bile acids and their reduced biliary secretion and increased renal excretion. Intestinal bile acid excretion is also diminished, with the result that secondary bile acids in plasma and bile are reduced even though total bile acid concentrations are high. The retained bile acids undergo further metabolism (1β-hydroxylation and 6α-hydroxylation, sulfation, glucuronidation) to make them more water soluble, which facilitates renal clearance. The increased amount and decreased clearance of bile acids in the hepatocyte, however, cause further damage leading to cell death. Cholestatic liver diseases are a group of diseases characterized by progressive intrahepatic retention of bile acids resulting in liver injury, cirrhosis, and frequently death. So far, medical therapies to prevent the development of cirrhosis or symptoms of cholestasis have not been successful. Increased attention has focused on the role of bile acids as either cause or treatment of a number of important gastrointestinal or hepatic disorders. In particular, primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), and a number of pediatric cholestatic disorders that previously were untreatable now seem to respond to bile acid therapy. The therapy has so far been limited to postponement of end-stage disease, and hepatic transplantation still remains the definitive treatment. This article reviews these disorders, with emphasis on the metabolic effects of ursodeoxycholic acid (3α,7β-dihydroxy-5β-cholan-24-oic acid, UDCA) in protecting and normalizing bile acid metabolism. This more hydrophilic bile acid, which is currently used in the treatment of gallstones, offers great promise in improving liver function.