title: Protective role of tauroursodeoxycholate during harvesting and cold storage of human liver: a pilot study in transplant recipients.
abstract: BACKGROUND
  Ischemia-reperfusion injury is a major cause of early graft dysfunction after liver transplantation. Tauroursodeoxycholic acid (TUDCA), a natural amidated hydrophilic bile salt, protects from cholestasis and hepatocellular damage in a variety of experimental models, as well as from ischemia-reperfusion injury. We investigated in the human liver transplantation setting the effect of the addition of TUDCA at time of liver harvesting and cold storage on the intra- and postoperative enzyme release and liver histopathology at the end of cold storage, at reperfusion, and 7 days after transplantation.
  
  
  METHODS
  Eighteen patients undergoing elective liver transplantation were studied, including 6 serving as controls. In six patients, TUDCA was added to the University of Wisconsin solution used during harvesting and cold storage, to reach final concentrations of 2 mM. In three of these patients, TUDCA (3 g) was infused in the portal vein of the donor before organ explantation; in the other three cases, TUDCA was given through both routes.
  
  
  RESULTS
  The use of TUDCA did not cause adverse events. The release of aspartate aminotransferase in the inferior vena cava blood during liver flushing was significantly lower (P=0.05) in TUDCA-treated than in control grafts, as were cytolytic enzyme levels in peripheral blood during the first postoperative week (P<0.02). At electron microscopy, an overt endothelial damage (cytoplasmic vacuolization, cell leakage, and destruction with exposure of hepatocytes to the sinusoidal lumen) was invariably found in control grafts, both at reperfusion and at day 7 after transplant. These features were significantly ameliorated by TUDCA (P<0.001). Several ultrastructural cytoplasmic abnormalities of hepatocytes were seen. Among these, damage to mitochondria matrix and crystae was significantly reduced in TUDCA-treated versus 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 TUDCA was given through both routes.
  
  
  CONCLUSIONS
  The use of TUDCA during harvesting and cold storage of human liver is associated with significant protection from ischemia-reperfusion injury. The clinical significance of this findings must be studied.
authors.affiliation: Department of Surgery, University of Rome Tor Vergata, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Falasca
authors.forename: G
authors.initials: G
authors.lastname: Tisone
authors.forename: G
authors.initials: G
authors.lastname: Palmieri
authors.forename: A
authors.initials: A
authors.lastname: Anselmo
authors.forename: D
authors.initials: D
authors.lastname: Di Paolo
authors.forename: L
authors.initials: L
authors.lastname: Baiocchi
authors.forename: E
authors.initials: E
authors.lastname: Torri
authors.forename: G
authors.initials: G
authors.lastname: Orlando
authors.forename: C U
authors.initials: CU
authors.lastname: Casciani
authors.forename: M
authors.initials: M
authors.lastname: Angelico
mesh_terms: D000241:Adenosine; D000328:Adult; D000493:Allopurinol; D001706:Biopsy; D003080:Cold Temperature; D005260:Female; D005978:Glutathione / Q000187:drug effects; D022781:Hepatocytes / Q000648:ultrastructure; D006801:Humans; D007328:Insulin; D008099:Liver / Q000473:pathology; D016031:Liver Transplantation / Q000502:physiology; D008297:Male; D008854:Microscopy, Electron; D008875:Middle Aged; D009926:Organ Preservation / Q000379:methods; D019188:Organ Preservation Solutions; D010865:Pilot Projects; D011182:Postoperative Care; D020011:Protective Agents / Q000494:pharmacology*; D011887:Raffinose; D015424:Reperfusion; D013655:Taurochenodeoxycholic Acid / Q000494:pharmacology / Q000502:physiology*; D009927:Tissue and Organ Procurement
chemical_list: D007328:Insulin; D019188:Organ Preservation Solutions; D020011:Protective Agents; C055206:University of Wisconsin-lactobionate solution; D013655:Taurochenodeoxycholic Acid; C031655:ursodoxicoltaurine; D000493:Allopurinol; D005978:Glutathione; D000241:Adenosine; D011887:Raffinose