Protective role of tauroursodeoxycholate during harvesting and cold storage of human liver - A pilot study in transplant recipients

Background Ischemia-reperfusion injury is a major cause of early graft dysf unction after liver transplantation. Tauroursodeoxycholic acid (TUDCA), a n atural amidated hydrophilic bile salt, protects from cholestasis and hepato cellular damage in a variety of experimental models, as well as from ischem ia-reperfusion injury. We investigated in the human liver transplantation s etting the effect of the addition of TUDCA at time of liver harvesting and cold storage on the intra and postoperative enzyme release and liver histop athology at the end of cold storage, at reperfusion, and 7 days after trans plantation. Methods. Eighteen patients undergoing elective liver transplantation were s tudied, including 6 serving as controls. In six patients, TUDCA was added t o the University of Wisconsin solution used during hap vesting and cold sto rage, to reach final concentrations of 2 mM In three of these patients, TUD GA (3 g) was infused in the portal vein of the donor before organ explantat ion; in the other three cases, TUDCA was given through both routes. Results. The use of TUDCA did not cause adverse events. The release of aspa rtate aminotransferase in the inferior vena cava blood during liver flushin g was significantly lower (P=0.05) in TUDCA-treated than in control grafts, as were cytolytic enzyme levels in peripheral blood during the first posto perative week (P <0.02). At electron microscopy, an overt endothelial damag e (cytoplasmic vacuolization, cell leakage, and destruction with exposure o f hepatocytes to the sinusoidaa lumen) was invariably found in control graf ts, both at reperfusion and at day 7 after transplant. These features were significantly ameliorated by TUDCA (P <0.001), Several ultrastructural cyto plasmic abnormalities of hepatocytes were seen. Among these, damage to mito chondria matrix and crystae was significantly reduced in TUDCA-treated vers us control grafts (P <0.01). Mild to severe damage of bile canaliculi was a constant feature in control biopsies, with dilatation of canalicular lumen and loss of microvilli, Both these abnormalities were markedly ameliorated (P <0.001 by TUDCA). The best preservation was observed when HUDCA was giv en through both routes, Conclusions. The use of TUDCA during harvesting and cold storage of human L iver is associated with significant protection from ischemia-reperfusion in jury. The clinical significance of this findings must be studied.