The Study Of Mechanism Of Endogenous Toxic Bile Formation And Its Role In Bile Duct Injury After Liver Transplantation

BackgroundBiliary complications after orthotopic liver transplantation(OLT) have been a common problem since early beginning of this technique, which have been called"the Achilles'heel"of OLT by Sir Roy Calne. With the improvement of surgical techniques, the incidence rate of the biliary complications associated with bile duct anastomosis decreased remarkably, while the nonanastomotic stricture and dilatation involving only the biliary tree of the graft with a radiological appearance of biliary ischemia(Ischemic-type biliary lesions, ITBL) become the major type of biliary complications after OLT, which has be reported to occur at a relatively constant rate 15-26%. It is well known that the cold preservation-reperfusion injury(CPRI) plays an important role in the pathegenesis of ITBL.However, the details still remain unclear despite numerous studies. Recently, it is reported that hydrophobic bile salts play a role in the pathogenesis of bile duct injury. The hydrophobic bile salts are cytotoxic due to their potent detergent properities toward cellular membranes. Under normal circumstances, some protective mechanisms can prevent the cytotoxcity of bile salts. For instance, bile salts can be neutralized in the bile by complex formation with phospholipid and some hydrophilic bile salts can stabilize cell membranes. In addition, various selective transporter proteins in the sinusoidal and canalicular membrane of hepatocytes(hepatobiliary membrane transporters, HMTs) have been identified and were shown to play a role in the secretion of sepefic bile components. Impairment in the gene expression or function of HMTs may lead to intrahepatic cholestasis with or without bile duct injury. It has been reported that after OLT the composition of bile will change. Based on the above-mentioned results, we proposed the"toxic bile"hypothesis: After suffering CPRI, the protective mechanisms against bile salts cytotoxicity might be destroyed partly caused by the change of the gene expression and function of HMTs or other regulatory factors, which leads to the formation of"toxic bile"with excess hydrophobic bile salts. Therefore, a detailed systemic elucidation of the mechanism of the toxic bile formation is needed and will explore some new approaches for the prevention and treatment of biliary complications following OLT.