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

Authors

  • Harm Hoekstra,

    1. Swiss HPB Center, Department of Visceral and Transplant Surgery, University Hospital Zurich, Switzerland
    2. Section of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, University Medical Center Groningen, University of Groningen, The Netherlands
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  • Robert J. Porte,

    1. Section of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, University Medical Center Groningen, University of Groningen, The Netherlands
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  • Yinghua Tian,

    1. Swiss HPB Center, Department of Visceral and Transplant Surgery, University Hospital Zurich, Switzerland
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  • Wolfram Jochum,

    1. Department of Pathology, University Hospital Zurich, Switzerland
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  • Bruno Stieger,

    1. Division of Clinical Pharmacology and Toxicology, Department of Internal Medicine, University Hospital Zurich, Switzerland
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  • Wolfgang Moritz,

    1. Swiss HPB Center, Department of Visceral and Transplant Surgery, University Hospital Zurich, Switzerland
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  • Maarten J.H. Slooff,

    1. Section of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, University Medical Center Groningen, University of Groningen, The Netherlands
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  • Rolf Graf,

    1. Swiss HPB Center, Department of Visceral and Transplant Surgery, University Hospital Zurich, Switzerland
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  • Pierre A. Clavien

    Corresponding author
    1. Swiss HPB Center, Department of Visceral and Transplant Surgery, University Hospital Zurich, Switzerland
    • University Hospital Zurich, Raemistrasse 100, 8091 Zürich, Switzerland
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    • fax: (4) 1-2554449


  • Potential conflict of interest: Nothing to report.

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.)

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