Bile salt toxicity aggravates cold ischemic injury of bile ducts after liver transplantation in Mdr2 +/− mice

Abstract

Intrahepatic bile duct strictures are a serious complication after orthotopic liver transplantation (OLT). We examined the role of endogenous bile salt toxicity in the pathogenesis of bile duct injury after OLT. Livers from wild-type mice and mice heterozygous for disruption of the multidrug resistance 2 Mdr2 gene (Mdr2؉/؊) were transplanted into wild-type recipient mice. Mdr2؉/؊ mice secrete only 50% of the normal amount of phospholipids into their bile, leading to an abnormally high bile salt/phospholipid ratio. In contrast to homozygous Mdr2 ؊/؊ mice, the Mdr2؉/؊ mice have normal liver histology and function under normal conditions. Two weeks after OLT, bile duct injury and cholestasis were assessed by light and electron microscopy, as well as through molecular and biochemical markers. There were no signs of bile duct injury or intrahepatic cholestasis in liver grafts from wild-type donors. Liver grafts from Mdr2؉/؊ donors, however, had enlarged portal tracts with cellular damage, ductular proliferation, biliostasis, and a dense inflammatory infiltrate after OLT. Parallel to this observation, recipients of Mdr2؉/؊ livers had significantly higher serum transaminases, alkaline phosphatase, total bilirubin, and bile salt levels, as compared with recipients of wild-type livers. In addition, hepatic bile transporter expression was compatible with the biochemical and histological cholestatic profile found in Mdr2؉/؊ grafts after OLT. In conclusion, toxic bile composition, due to a high biliary bile salt/phospholipid ratio, acted synergistically with cold ischemia in the pathogenesis of bile duct injury after transplantation. (HEPATOLOGY 2006;43:1022-1031

Optimized endoscopic treatment of ischemic-type biliary lesions after liver transplantation

“…29 Factors that lead to such damage may include prolonged warm and cold ischemia times 30 ; older age of the donor 31 ; preservation injury 31,32 ; immunological factors such as ABO incompatibility, chronic rejection, and chemokine 5⌬32 polymorphism 33 ; and bile salt toxicity. 34 The frequency of ITBLs in liver transplantation is reported to be in the range of 5% to 10%, 30,35 and therefore the incidence of 7.8% in our study is in accord with the literature. In our study, ITBLs were diagnosed a median of 8 months after liver transplantation, which is slightly later than the 6 months reported in other series.…”

A Biliary HCO3 − Umbrella Constitutes A Protective Mechanism Against Bile Acid–Induced Injury in Human Cholangiocytes

“…21 Alteration of the transmembrane Cl À gradient, driving HCO À 3 secretion, or altered flux of HCO À 3 via a dysfunctional cystic fibrosis transmembrane conductance regulator, CFTR, might be the basis for the development of cystic-fibrosis-associated liver disease, which may resemble sclerosing cholangitis. 23 Ischemia-type biliary lesions and nonanastomotic bile duct strictures after liver transplantation with denervation in man 42 may be a consequence of disrupted vagal acetylcholine signaling, a physiologic driving force of biliary HCO À Our data may have particular impact on the understanding of the pathogenesis and treatment of PBC. [17][18][19][20]39,43 Increasing evidence supports the view that cholangiocyte apoptosis is a driving force in the pathogenesis of PBC: It has long been demonstrated that cholangiocyte apoptosis is associated with ductular inflammation in PBC, but not PSC.…”

Increasing Cycles of Intermittent Ischemia Can Effectively Maintain Liver Function during the Acute Phase of Ischemia Reperfusion Injury by Promotion of Bile Flow and Reduction in Bile Salt Toxicity

“…The substantial decrease observed in the phospholipid:bile salt ratio in the CC group indicates an increase in the cytotoxicity of the bile fluid [28,29,31,32]. This may be partly responsible for subsequent hepatocyte injury and impaired liver function [cf.…”