Bile Duct Injury in Liver Transplantation

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  • University of Groningen

    Bile duct injury in liver transplantationDries, Sanna op den

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    Publication date:2013

    Link to publication in University of Groningen/UMCG research database

    Citation for published version (APA):Dries, S. O. D. (2013). Bile duct injury in liver transplantation: studies on etiology and the protective role ofmachine perfusion Groningen: s.n.

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  • Bile Duct Injury in Liver Transplantation

    Studies on Etiology and the Protective Role of Machine Perfusion

    Sanna op den Dries

    opdendries.indd 1 11-10-2013 9:50:02

  • Different parts of this thesis were funded by the Groningen University Institute for Drug Exploration

    (GUIDE), Junior Scientific Masterclass (JSM), Ubbo Emmius Foundation / JSM Talent Grant,

    grants from the Jan Kornelis de Cock Foundation, the Tekke Huizinga Foundation, Innovatief

    Actieprogramma Groningen (IAG-3) and the Astellas Transplantationele Research Prijs 2013.

    For the printing of this thesis, financial support of the following institutions and companies is

    gratefully acknowledged:

    Op den Dries, S.

    Bile duct injury in liver transplantation: Studies on etiology and the protective role of machine


    Dissertation University of Groningen, The Netherlands

    ISBN: 978-90-367-6446-9 (printed version)

    ISBN: 978-90-367-6445-2 (electronic version)

    Copyright 2013 S. op den Dries, The Netherlands

    All rights reserved. No part of this book may be reproduced, stored in a retrieval system or

    transmitted in any form or by any means, without the written permission of the author.

    Cover design and photo: Brett McManus and Sanna op den Dries

    Cover photo: Scanning Electron Microscopy (SEM) image of human bile duct


    Lay-out and Printed by: Gildeprint drukkerijen, Enschede, The Netherlands

    opdendries.indd 2 11-10-2013 9:50:02

  • Bile Duct Injury in Liver Transplantation

    Studies on Etiology and the Protective Role of Machine Perfusion


    ter verkrijging van het doctoraat in de

    Medische Wetenschappen

    aan de Rijksuniversiteit Groningen

    op gezag van de

    Rector Magnificus, dr. E. Sterken,

    in het openbaar te verdedigen op

    woensdag 13 november 2013

    om 16:15 uur


    Sanna op den Dries

    geboren op 29 april 1986

    te Dongeradeel

    opdendries.indd 3 11-10-2013 9:50:03

  • Promotores: Prof. dr. R.J. Porte

    Prof. dr. J.A. Lisman

    Beoordelingscommissie: Prof. dr. U. Beuers

    Prof. dr. E. Heineman

    Prof. dr. H.J. Verkade

    opdendries.indd 4 11-10-2013 9:50:03

  • Paranimfen: Drs. Negin Karimian

    Drs. Wieke G. Dalenberg

    opdendries.indd 5 11-10-2013 9:50:03

  • 6


    Part a: The Scope of Bile Duct Injury in Liver Transplantation

    Chapter 1 General Introduction and Aims of This Thesis 9

    Chapter 2 Biliary Complications Following Liver Transplantation 17

    In: Clavien PA, Trotter JF, editors. Medical Care of the Liver

    Transplant Patient. Wiley-Blackwell; 2012. p. 319-331.

    Chapter 3 Protection of Bile Ducts in Liver Transplantation: Looking Beyond Ischemia 39

    Transplantation 2011; 92: 373-379.

    Part B: Immune- and Ischemia-mediated Etiologies of Bile Duct Injury

    Chapter 4 Combination of Primary Sclerosing Cholangitis and CCR5-D32 in Recipients

    is Strongly Associated with the Development of Non-anastomotic Biliary

    Strictures after Liver Transplantation 55

    Liver Int 2011; 31: 1102-1109.

    Chapter 5 The Origin of Biliary Strictures afterLiverTransplantation: Is it the Amount

    of Epithelial Injury orInsufficient Regeneration that Counts? 71

    Adapted from: J Hepatol 2013; 58: 1065-1067.

    Chapter 6 Regeneration of Human Extrahepatic Biliary Epithelium: The Peribiliary

    Glands as Progenitor Cell Compartment 77

    Liver Int 2012; 32: 554-559.

    Chapter 7 Injury of Peribiliary Glands and Vascular Plexus before Liver Transplantation

    Predicts Formation of Non-anastomotic Biliary Strictures 89

    Submitted for publication.

    opdendries.indd 6 11-10-2013 9:50:03

  • Inhoudsopgave


    Part C: Machine Perfusion: aPotentialStrategytoPreventBileDuct Injury

    Chapter 8 Hypothermic Oxygenated Machine Perfusion Prevents Arteriolonecrosis of

    the Peribiliary Plexus in Pig Livers Donated after Cardiac Death 109

    Submitted for publication.

    Chapter 9 Normothermic Machine Perfusion Reduces Bile Duct Injury and Improves

    Biliary Epithelial Function in Rat Donor Livers 127

    Submitted for publication.

    Chapter 10 Ex-vivo Normothermic Machine Perfusion and Viability Testing of

    Discarded Human Donor Livers 147

    Am J Transplant. 2013; 13: 1327-1335.

    Chapter 11 Criteria for Viability Assessment of Discarded Human Donor Livers during

    Ex-Vivo Normothermic Machine Perfusion 163

    Submitted for publication.

    Part D: addendum

    Chapter 12 Shared Decision Making in Transplantation: HowPatients See Their Role in

    the DecisionProcess of Accepting a Donor Liver 181

    Submitted for publication.

    Chapter 13 An Ex-Vivo Oxygenated Normothermic Machine Perfusion System for Rat

    Livers 197

    Chapter 14 Summary, Discussion and Future Perspectives 211

    Nederlandse samenvatting 225

    List of publications 239

    List of contributing authors 241

    Acknowledgements 247

    Biography 253

    List of abbreviations cover

    opdendries.indd 7 11-10-2013 9:50:03

  • PaRT aThe Scope of Bile Duct Injury in Liver Transplantation

    opdendries.indd 8 11-10-2013 9:50:03

  • ChaPTER 1general Introduction and aims of This Thesis

    opdendries.indd 9 11-10-2013 9:50:04

  • Chapter 1


    Liver transplantation has proven to be a successful treatment for patients with end stage

    chronic or acute liver failure. Due to improved surgical techniques, enhanced intensive care, and

    effective immunosuppressant medications, excellent one- and five-year patient (around 90%

    and 80%, respectively) and graft survival rates (around 85% and 75%, respectively) are currently


    Nevertheless, liver transplant waiting lists are increasing more rapidly than the supply of donor

    organs, leaving many patients stranded without access to what is often a life-saving therapy.

    Efforts to increase the donor pool are being made by accepting more donors at the expense

    of diminished quality of their organs (i.e. extended criteria donors). An extended criteria donor

    (ECD) implies a higher donor-related risk in comparison with a standard criteria donor (SCD). This

    risk may manifest as increased incidence of postoperative complications, such as delayed graft

    function, graft failure, biliary complications or transmission of a donor-derived disease (3).

    Despite the good overall survival data, biliary complications are a major problem after liver

    transplantation. The incidence of biliary complications varies between 10% and 40% in different

    studies and these types of complications are associated with frequent hospital admissions, and

    high morbidity and mortality rates (4-6). Among the various biliary complications that can occur

    after OLT, bile duct strictures are of the greatest concern. Bile duct strictures can be classified as

    anastomotic strictures (AS) or non-anastomotic strictures (NAS). Solitary strictures at the biliary

    anastomosis have been reported in 9%-12% of the patients (7-9), and NAS have been reported

    in 1%-13% of patients receiving a liver from donation after brain death (DBD) and in 21%-33%

    of patients receiving a liver from donation after cardiac death (DCD) (10-13). NAS may occur in

    the extrahepatic donor bile duct as well as the intrahepatic bile ducts, but they are usually limited

    to the larger bile ducts.

    For many years researchers have been trying to understand the underlying mechanisms of AS and

    NAS. Current evidence suggests that AS are mainly related to the surgical technique and local

    ischemia of the distal bile duct stump, leading to fibrotic scarring of the anastomosis (4,9). The

    etiology of NAS is thought to be multifactorial and three relevant types of biliary injury have been

    identified as a potential cause of NAS: ischemia/reperfusion related injury; immune-mediated

    injury; and cytotoxic injury caused by hydrophobic bile salts (4,14). The etiologies of NAS are still