Does ursodeoxycholic acid exert a protective effect on liver grafts in orthotopic liver transplantation?

UDCA renders bile acid composition more hydrophilic, shifts the bile-acid/phospholipid ratio towards less toxic effects and, thus, might protect against hepatobiliary injury by hydrophobic bile acids. UDCA is a constituent of human bile in a low concentration of 3% of total bile acids. It is the major bile acid of the bile of black bears and has been used for centuries in traditional Chinese medicine as a remedy for liver disease [5] . First reports of beneficial effects on serum liver tests in cholestatic disorders appeared in the 1980s in the Western literature, but similar observations were also made in Japan. In the meantime the potential molecular mechanisms of the cytoprotective effects of UDCA have become apparent. Obviously, UDCA does not only antagonize toxic bile acids at a biophysical level. A series of observations revealed that UDCA blocks cell death by interfering with apoptotic pathways and stimulating survival signals which, in turn, stimulate the activation of the intracellular MAPK pathway through the activation of the epidermal growth factor receptor [6] . Moreover, UDCAs have been shown to modulate intracellular calcium levels and cellular trafficking [7] . These effects of UDCA have been recognized to be therapeutically useful and exploited for the treatment of a variety of chronic cholestatic liver diseases. It is the only drug approved by the United Stated Food and Drug Administration for the treatment of primary biliary cirrhoBiliary lesions remain a frequent problem after liver transplantation. In addition to ischemic and immunologic factors, toxic bile acids may cause severe bile tract injury [1] . A high bile-acid/phospholipid ratio and intrahepatic bile retention has been suggested to contribute to hepatobiliary injury early after orthotopic liver transplantation (OLT) [2] . Indeed, during the past 40 years, hepatic retention of bile acids has been postulated to significantly contribute to progressive liver damage in cholestatic liver disease. In 1962, Blomquist and Holsti [3] were able to show that hydrophobic lithocholic acid and taurolithocholic acid induce cholestasis and subsequently cirrhosis. Hydrophobic, endogenous bile acids are potent hepatobiliary cytotoxicins with detrimental effects ranging from the disruption of cellular membrane integrity to the induction of apoptosis. Hepatocellular cell death is induced mainly via ligand-independent death receptor pathways as the Fas receptor [4] . Indeed, bile acids trigger death receptor aggregation and activation, recruitment of adaptor proteins and consecutively the activation of caspases and cleavage of downstream apoptosis molecules, which induce mitochondrial dysfunction and, thus, cellular damage, resulting in cell death and cast formation. The cytotoxicity of hydrophobic bile acids is naturally inhibited by formation of micelles with phospholipids and can be influenced by biliary enrichment with hydrophilic bile acids like ursodeoxycholic acid (UDCA). Published online: August 29, 2012