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.


CONCLUSIONS
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.
Yska
Marit J
MJ
Section of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
Buis
Carlijn I
CI
Monbaliu
Diethard
D
Schuurs
Theo A
TA
Gouw
Annette S H
AS
Kahmann
Olivier N H
ON
Visser
Dorien S
DS
Pirenne
Jacques
J
Porte
Robert J
RJ
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000096:biosynthesis / Q000235:genetics; D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis / Q000235:genetics; D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism / Q000633:toxicity*; D001653:Bile Ducts, Intrahepatic / Q000293:injuries*; D001706:Biopsy; D002780:Cholestasis, Intrahepatic / Q000209:etiology* / Q000378:metabolism / Q000401:mortality; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression; D016031:Liver Transplantation / Q000009:adverse effects* / Q000401:mortality / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012307:Risk Factors; D012720:Severity of Illness Index; D015996:Survival Rate; D013552:Swine
D018435:ATP Binding Cassette Transporter, Subfamily B; D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters; C490549:Abcb11 protein, mouse; C490548:Abcb11 protein, rat; D001647:Bile Acids and Salts; D012333:RNA, Messenger; C095122:multidrug resistance protein 3