The Role of Bile Salt Toxicity in the Pathogenesis of Bile Duct Injury After Non-Heart-Beating Porcine Liver Transplantation

Background. Intrahepatic bile duct strictures are a serious complication after non-heart-beating (NHB) liver transplantation. Bile salt toxicity has been identified as an important factor in the pathogenesis of bile duct injury and cholangiopathies. The role of bile salt toxicity in the development of biliary strictures after NHB liver transplantation is unclear. Methods. In a porcine model of NHB liver transplantation, we studied the effect of different periods of warm ischemia in the donor on bile composition and subsequent bile duct injury after transplantation. After induction of cardiac arrest in the donor, liver procurement was delayed for 0 min (group A), 15 min (group B), or more or equal to 30 min (group C). Livers were subsequently transplanted after 4 hr of cold preservation. In the recipients, bile flow was measured, and bile samples were collected daily to determine the bile salt-to-phospholipid ratio. Severity of bile duct injury was semiquantified by using a histologic grading scale. Results. Posttransplantation survival was directly related to the duration of warm ischemia in the donor. The bile salt-to-phospholipid ratio in bile produced early after transplantation was significantly higher in group C, compared with group A and B. Histopathologic condition showed the highest degree of bile duct injury in group C. Conclusion. Prolonged warm ischemia in NHB donors is associated with the formation of toxic bile after transplantation, with a high biliary bile salt-to-phospholipid ratio. These data suggest that bile salt toxicity contributes to the pathogenesis of bile duct injury after NHB liver transplantation.

[1]  J. Boyer,et al.  Molecular pathogenesis of cholestasis. , 2012, The New England journal of medicine.

[2]  J. Pincemail,et al.  Primary graft nonfunction and Kupffer cell activation after liver transplantation from non‐heart‐beating donors in pigs , 2007, Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society.

[3]  M. Trauner,et al.  MDR3 (ABCB4) defects: a paradigm for the genetics of adult cholestatic syndromes. , 2007, Seminars in liver disease.

[4]  F. Suchy,et al.  Bile salt excretory pump: biology and pathobiology. , 2006, Journal of pediatric gastroenterology and nutrition.

[5]  B. Stieger,et al.  Bile salt toxicity aggravates cold ischemic injury of bile ducts after liver transplantation in Mdr2+/− mice , 2006, Hepatology.

[6]  R. Porte,et al.  Biliary complications after liver transplantation: A review , 2006, Scandinavian journal of gastroenterology. Supplement.

[7]  R. Busuttil,et al.  Ischemic cholangiopathy after liver transplantation. , 2005, Hepatobiliary & pancreatic diseases international : HBPD INT.

[8]  T. Roskams,et al.  Livers from non-heart-beating donors tolerate short periods of warm ischemia. , 2005, Transplantation.

[9]  C. Spirlí,et al.  Pathophysiology of cholangiopathies. , 2005, Journal of clinical gastroenterology.

[10]  P. Jansen,et al.  Rapid increase of bile salt secretion is associated with bile duct injury after human liver transplantation. , 2004, Journal of hepatology.

[11]  N. LaRusso,et al.  The cholangiopathies: disorders of biliary epithelia. , 2004, Gastroenterology.

[12]  P. Friend,et al.  Liver transplantation from non–heart‐beating donors: Current status and future prospects , 2004, Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society.

[13]  K. Olthoff,et al.  Survival Following Liver Transplantation From Non-Heart-Beating Donors , 2004, Annals of surgery.

[14]  M. Trauner,et al.  Molecular aspects of bile formation and cholestasis. , 2003, Trends in molecular medicine.

[15]  M. Devita,et al.  Non-Heartbeating Organ Donation: A Review , 2003, Journal of intensive care medicine.

[16]  J. Boyer,et al.  Bile salt transporters: molecular characterization, function, and regulation. , 2003, Physiological reviews.

[17]  F. Lammert,et al.  Effects of ursodeoxycholic and cholic acid feeding on hepatocellular transporter expression in mouse liver. , 2001, Gastroenterology.

[18]  P. Bosma,et al.  The wide spectrum of multidrug resistance 3 deficiency: from neonatal cholestasis to cirrhosis of adulthood. , 2001, Gastroenterology.

[19]  C. Ihling,et al.  First results 24 hours after orthotopic heart transplantation from non-heart-beating donors in pigs. , 2001, The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation.

[20]  P. Gianello,et al.  Simplified technique of orthotopic liver transplantation in pigs. , 2001, Transplantation.

[21]  J. Visa,et al.  Evaluation of Ischemic Injury during Liver Procurement from Non-Heart-Beating Donors , 1999, European Surgical Research.

[22]  G. Hooiveld,et al.  3-Hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) induce hepatic expression of the phospholipid translocase mdr2 in rats. , 1999, Gastroenterology.

[23]  P. Bosma,et al.  Mutations in the MDR3 gene cause progressive familial intrahepatic cholestasis. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[24]  V. Vollrath,et al.  Overexpression of mdr2 gene by peroxisome proliferators in the mouse liver. , 1997, Journal of hepatology.

[25]  Randall G. Lee,et al.  Banff schema for grading liver allograft rejection: An international consensus document , 1997, Hepatology.

[26]  M. Hadchouel,et al.  Defect of multidrug‐resistance 3 gene expression in a subtype of progressive familial intrahepatic cholestasis , 1996, Hepatology.

[27]  A. Rigotti,et al.  Fibrates induce mdr2 gene expression and biliary phospholipid secretion in the mouse. , 1996, The Biochemical journal.

[28]  T. Howard,et al.  Evidence of preservation injury to bile ducts by bile salts in the pig and its prevention by infusions of hydrophilic bile salts , 1995, Hepatology.

[29]  Jenkins Rl,et al.  Biliary strictures after liver transplantation. , 1994 .

[30]  G. Gores,et al.  THE GREATER VULNERABILITY OF BILE DUCT CELLS TO REOXYGENATION INJURY THAN TO ANOXIA , 1993, Transplantation.

[31]  K. Kitani,et al.  Hepatic injury induced by bile salts: Correlation between biochemical and morphological events , 1990, Hepatology.

[32]  P. Neuhaus,et al.  Developments in liver transplantation , 1985, The Japanese journal of surgery.

[33]  J. Dietschy,et al.  Re-evaluation of the 3 alpha-hydroxysteroid dehydrogenase assay for total bile acids in bile. , 1978, Journal of lipid research.

[34]  C. Buis.  Molecular and biochemical mechanisms of bile duct injury after liver transplantation , 2008 .

[35]  K. Olthoff,et al.  Liver transplantation from controlled non-heart-beating donors: an increased incidence of biliary complications. , 2003, Transplantation.

[36]  Recommendations for nonheartbeating organ donation. A position paper by the Ethics Committee, American College of Critical Care Medicine, Society of Critical Care Medicine. , 2001, Critical care medicine.