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Ge XL, Zhang X, Li CH, Pan K, He L, Ren WZ. Bile Acid Overload Induced by Bile Duct and Portal Vein Ligation Improves Survival after Staged Hepatectomy in Rats. Curr Med Sci 2023; 43:1013-1022. [PMID: 37837571 DOI: 10.1007/s11596-023-2779-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2022] [Accepted: 06/26/2023] [Indexed: 10/16/2023]
Abstract
OBJECTIVE Compared to portal vein ligation (PVL), simultaneous bile duct and portal vein ligation (BPL) can significantly enhance hypertrophy of the intact liver. This study aimed to investigate whether BPL could improve survival after extended hepatectomy independently of an increased remnant liver. METHODS We adopted rat models of 90% BPL or 90% PVL. To investigate the role of bile acids (BAs) the BA pools in the PVL and BPL groups were altered by the diet. Staged resection preserving 10% of the estimated liver weight was performed 3 days after BPL; PVL; or sham operation. Histology, canalicular network (CN) continuity; and hepatocyte polarity were evaluated. RESULTS At 3 days after BPL; PVL; or sham operation when the volumetric difference of the intended liver remained insignificant, the survival rates after extended hepatectomy were 86.7%, 47%, and 23.3%, respectively (P<0.01). BPL induced faster restoration of canalicular integrity along with an intensive but transient BA overload. Staged hepatectomy after BPL shortened the duration of the bile CN disturbance and limited BA retention. Decreasing the BA pools in the rats that underwent BPL could compromise these effects, whereas increasing the BA pools of rats that underwent PVL could induce similar effects. The changes in CN restoration were associated with activation of LKB1. CONCLUSION In addition to increasing the future remnant liver, BPL shortened the duration of the spatial disturbance of the CN and could significantly improve the tolerance of the hypertrophied liver to staged resection. BPL may be a safe and efficient future option for patients with an insufficient remnant liver.
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Affiliation(s)
- Xin-Lan Ge
- Faculty of Hepato-Pancreato-Biliary Surgery, First Medical Center, Chinese PLA General Hospital, Beijing, 100853, China
- Institute of Hepatobiliary Surgery of Chinese PLA, Beijing, 100853, China
- Key Laboratory of Digital Hepatobiliary Surgery, PLA, Beijing, 100853, China
| | - Xuan Zhang
- Faculty of Hepato-Pancreato-Biliary Surgery, First Medical Center, Chinese PLA General Hospital, Beijing, 100853, China
- Institute of Hepatobiliary Surgery of Chinese PLA, Beijing, 100853, China
- Key Laboratory of Digital Hepatobiliary Surgery, PLA, Beijing, 100853, China
| | - Chong-Hui Li
- Faculty of Hepato-Pancreato-Biliary Surgery, First Medical Center, Chinese PLA General Hospital, Beijing, 100853, China
- Institute of Hepatobiliary Surgery of Chinese PLA, Beijing, 100853, China
- Key Laboratory of Digital Hepatobiliary Surgery, PLA, Beijing, 100853, China
| | - Ke Pan
- Faculty of Hepato-Pancreato-Biliary Surgery, First Medical Center, Chinese PLA General Hospital, Beijing, 100853, China
- Institute of Hepatobiliary Surgery of Chinese PLA, Beijing, 100853, China
- Key Laboratory of Digital Hepatobiliary Surgery, PLA, Beijing, 100853, China
| | - Lei He
- Faculty of Hepato-Pancreato-Biliary Surgery, First Medical Center, Chinese PLA General Hospital, Beijing, 100853, China.
- Institute of Hepatobiliary Surgery of Chinese PLA, Beijing, 100853, China.
- Key Laboratory of Digital Hepatobiliary Surgery, PLA, Beijing, 100853, China.
| | - Wei-Zheng Ren
- Faculty of Hepato-Pancreato-Biliary Surgery, First Medical Center, Chinese PLA General Hospital, Beijing, 100853, China.
- Institute of Hepatobiliary Surgery of Chinese PLA, Beijing, 100853, China.
- Key Laboratory of Digital Hepatobiliary Surgery, PLA, Beijing, 100853, China.
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Czigany Z, Lurje I, Schmelzle M, Schöning W, Öllinger R, Raschzok N, Sauer IM, Tacke F, Strnad P, Trautwein C, Neumann UP, Fronek J, Mehrabi A, Pratschke J, Schlegel A, Lurje G. Ischemia-Reperfusion Injury in Marginal Liver Grafts and the Role of Hypothermic Machine Perfusion: Molecular Mechanisms and Clinical Implications. J Clin Med 2020; 9:E846. [PMID: 32244972 PMCID: PMC7141496 DOI: 10.3390/jcm9030846] [Citation(s) in RCA: 84] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2020] [Revised: 03/09/2020] [Accepted: 03/11/2020] [Indexed: 12/19/2022] Open
Abstract
Ischemia-reperfusion injury (IRI) constitutes a significant source of morbidity and mortality after orthotopic liver transplantation (OLT). The allograft is metabolically impaired during warm and cold ischemia and is further damaged by a paradox reperfusion injury after revascularization and reoxygenation. Short-term and long-term complications including post-reperfusion syndrome, delayed graft function, and immune activation have been associated with IRI. Due to the current critical organ shortage, extended criteria grafts are increasingly considered for transplantation, however, with an elevated risk to develop significant features of IRI. In recent years, ex vivo machine perfusion (MP) of the donor liver has witnessed significant advancements. Here, we describe the concept of hypothermic (oxygenated) machine perfusion (HMP/HOPE) approaches and highlight which allografts may benefit from this technology. This review also summarizes clinical applications and the main aspects of ongoing randomized controlled trials on hypothermic perfusion. The mechanistic aspects of IRI and hypothermic MP-which include tissue energy replenishment, optimization of mitochondrial function, and the reduction of oxidative and inflammatory damage following reperfusion-will be comprehensively discussed within the context of current preclinical and clinical evidence. Finally, we highlight novel trends and future perspectives in the field of hypothermic MP in the context of recent findings of basic and translational research.
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Affiliation(s)
- Zoltan Czigany
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, 52074 Aachen, Germany; (Z.C.); (U.P.N.)
| | - Isabella Lurje
- Department of Surgery, Campus Charité Mitte | Campus Virchow-Klinikum—Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany; (I.L.); (M.S.); (W.S.); (R.Ö.); (N.R.); (I.M.S.); (J.P.)
| | - Moritz Schmelzle
- Department of Surgery, Campus Charité Mitte | Campus Virchow-Klinikum—Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany; (I.L.); (M.S.); (W.S.); (R.Ö.); (N.R.); (I.M.S.); (J.P.)
| | - Wenzel Schöning
- Department of Surgery, Campus Charité Mitte | Campus Virchow-Klinikum—Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany; (I.L.); (M.S.); (W.S.); (R.Ö.); (N.R.); (I.M.S.); (J.P.)
| | - Robert Öllinger
- Department of Surgery, Campus Charité Mitte | Campus Virchow-Klinikum—Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany; (I.L.); (M.S.); (W.S.); (R.Ö.); (N.R.); (I.M.S.); (J.P.)
| | - Nathanael Raschzok
- Department of Surgery, Campus Charité Mitte | Campus Virchow-Klinikum—Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany; (I.L.); (M.S.); (W.S.); (R.Ö.); (N.R.); (I.M.S.); (J.P.)
| | - Igor M. Sauer
- Department of Surgery, Campus Charité Mitte | Campus Virchow-Klinikum—Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany; (I.L.); (M.S.); (W.S.); (R.Ö.); (N.R.); (I.M.S.); (J.P.)
| | - Frank Tacke
- Department of Hepatology and Gastroenterology, Campus Charité Mitte | Campus Virchow-Klinikum—Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany;
| | - Pavel Strnad
- Department of Gastroenterology, Metabolic Disorders and Intensive Care, University Hospital RWTH Aachen, 52074 Aachen, Germany; (P.S.); (C.T.)
| | - Christian Trautwein
- Department of Gastroenterology, Metabolic Disorders and Intensive Care, University Hospital RWTH Aachen, 52074 Aachen, Germany; (P.S.); (C.T.)
| | - Ulf Peter Neumann
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, 52074 Aachen, Germany; (Z.C.); (U.P.N.)
| | - Jiri Fronek
- Department of Transplant Surgery, Institute for Clinical and Experimental Medicine, 140 21 Prague, Czech Republic;
| | - Arianeb Mehrabi
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, 69120 Heidelberg, Germany;
| | - Johann Pratschke
- Department of Surgery, Campus Charité Mitte | Campus Virchow-Klinikum—Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany; (I.L.); (M.S.); (W.S.); (R.Ö.); (N.R.); (I.M.S.); (J.P.)
| | - Andrea Schlegel
- The Liver Unit, Queen Elizabeth Hospital Birmingham, Birmingham B15 2TH, UK;
| | - Georg Lurje
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, 52074 Aachen, Germany; (Z.C.); (U.P.N.)
- Department of Surgery, Campus Charité Mitte | Campus Virchow-Klinikum—Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany; (I.L.); (M.S.); (W.S.); (R.Ö.); (N.R.); (I.M.S.); (J.P.)
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Abstract
Primary hepatocytes form spheroids under some culture conditions. These spheroids exhibit many tissuelike ultrastructures and retain many liver-specific functions over a long period of time. They are attractive for many applications employing liver cells. The ability to maintain their viability and functions at a reduced temperature to allow for transportation to the site of their application will facilitate their use. Furthermore, with their structural and functional similarity, they could possibly be used as a model system for studying various liver ischemias. The effect of hypothermic treatment was assessed by oxygen consumption rate, ATP, H2O2, and caspase 8 content, as well as albumin and urea synthesis, during and posttreatment. No single outcome variable gives a superlative quantification of hypothermic damage. Taken together, the hypothermic treatment can be seen as increasingly damaging as the temperature decreases from 21°C to 15°C and 4°C. The addition of the chemical protectants glutathione, N-acetyl-L-cystein (NAC), and tauroursodeoxycholic acid (TUDCA) decreased the damaging effect of hypothermic treatment. This protection effect was even more profound when spheroids were preincubated with the protectant for 24 h, and was most prominent at 4°C. The viability of the hypothermically treated hepatocyte spheroids was confirmed by laser scanning confocal microscopy. The method reported provides a means of maintaining spheroids' viability and may allow for their distribution to application sites at a distance.
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Affiliation(s)
- Pamela H Lai
- Department of Chemical Engineering and Materials Science, University of Minnesota, Minneapolis, MN 55455-0132, USA
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Khan Z, Yokota S, Ono Y, Bell AW, Oertel M, Stolz DB, Michalopoulos GK. Bile Duct Ligation Induces ATZ Globule Clearance in a Mouse Model of α-1 Antitrypsin Deficiency. Gene Expr 2017; 17:115-127. [PMID: 27938510 PMCID: PMC5296240 DOI: 10.3727/105221616x692991] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
α-1 Antitrypsin deficiency (A1ATD) can progress to cirrhosis and hepatocellular carcinoma; however, not all patients are susceptible to severe liver disease. In A1ATD, a toxic gain-of-function mutation generates insoluble ATZ "globules" in hepatocytes, overwhelming protein clearance mechanisms. The relationship between bile acids and hepatocytic autophagy is less clear but may involve altered gene expression pathways. Based on previous findings that bile duct ligation (BDL) induces autophagy, we hypothesized that retained bile acids may have hepatoprotective effects in PiZZ transgenic mice, which model A1ATD. We performed BDL and partial BDL (pBDL) in PiZZ mice, followed by analysis of liver tissues. PiZZ liver subjected to BDL showed up to 50% clearance of ATZ globules, with increased expression of autophagy proteins. Analysis of transcription factors revealed significant changes. Surprisingly nuclear TFEB, a master regulator of autophagy, remained unchanged. pBDL confirmed that ATZ globule clearance was induced by localized stimuli rather than diet or systemic effects. Several genes involved in bile metabolism were overexpressed in globule-devoid hepatocytes, compared to globule-containing cells. Retained bile acids led to a dramatic reduction of ATZ globules, with enhanced hepatocyte regeneration and autophagy. These findings support investigation of synthetic bile acids as potential autophagy-enhancing agents.
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Affiliation(s)
- Zahida Khan
- *Department of Pediatrics, Children’s Hospital of Pittsburgh of UPMC, Pittsburgh, PA, USA
- †Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- ‡McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA, USA
| | - Shinichiro Yokota
- §Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- ¶Department of Surgery, Jichi Medical University, Shimotsuke, Japan
| | - Yoshihiro Ono
- §Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Aaron W. Bell
- †Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Michael Oertel
- †Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Donna B. Stolz
- ‡McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA, USA
- #Department of Cell Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - George K. Michalopoulos
- †Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- ‡McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA, USA
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Bruinsma B, Yeh H, Özer S, Martins P, Farmer A, Wu W, Saeidi N, op den Dries S, Berendsen T, Smith R, Markmann J, Porte R, Yarmush M, Uygun K, Izamis M. Subnormothermic machine perfusion for ex vivo preservation and recovery of the human liver for transplantation. Am J Transplant 2014; 14:1400-9. [PMID: 24758155 PMCID: PMC4470578 DOI: 10.1111/ajt.12727] [Citation(s) in RCA: 157] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2013] [Revised: 02/25/2014] [Accepted: 02/26/2014] [Indexed: 01/25/2023]
Abstract
To reduce widespread shortages, attempts are made to use more marginal livers for transplantation. Many of these grafts are discarded for fear of inferior survival rates or biliary complications. Recent advances in organ preservation have shown that ex vivo subnormothermic machine perfusion has the potential to improve preservation and recover marginal livers pretransplantation. To determine the feasibility in human livers, we assessed the effect of 3 h of oxygenated subnormothermic machine perfusion (21°C) on seven livers discarded for transplantation. Biochemical and microscopic assessment revealed minimal injury sustained during perfusion. Improved oxygen uptake (1.30 [1.11-1.94] to 6.74 [4.15-8.16] mL O2 /min kg liver), lactate levels (4.04 [3.70-5.99] to 2.29 [1.20-3.43] mmol/L) and adenosine triphosphate content (45.0 [70.6-87.5] pmol/mg preperfusion to 167.5 [151.5-237.2] pmol/mg after perfusion) were observed. Liver function, reflected by urea, albumin and bile production, was seen during perfusion. Bile production increased and the composition of bile (bile salts/phospholipid ratio, pH and bicarbonate concentration) became more favorable. In conclusion, ex vivo subnormothermic machine perfusion effectively maintains liver function with minimal injury and sustains or improves various hepatobiliary parameters postischemia.
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Affiliation(s)
- B.G. Bruinsma
- Center for Engineering in Medicine, Department of Surgery, Massachusetts General Hospital, Boston, MA, USA,Department of Surgery (Surgical Laboratory), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - H. Yeh
- Transplant Center, Massachusetts General Hospital, Boston, MA, USA
| | - S Özer
- Center for Engineering in Medicine, Department of Surgery, Massachusetts General Hospital, Boston, MA, USA
| | - P.N. Martins
- Organ Transplant Surgery, UMass Memorial Medical Center, Boston, MA, USA
| | - A. Farmer
- Center for Engineering in Medicine, Department of Surgery, Massachusetts General Hospital, Boston, MA, USA
| | - W. Wu
- Center for Engineering in Medicine, Department of Surgery, Massachusetts General Hospital, Boston, MA, USA
| | - N. Saeidi
- Center for Engineering in Medicine, Department of Surgery, Massachusetts General Hospital, Boston, MA, USA
| | - S. op den Dries
- Section of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - T.A. Berendsen
- Center for Engineering in Medicine, Department of Surgery, Massachusetts General Hospital, Boston, MA, USA
| | - R.N. Smith
- Department of Pathology, Massachusetts General Hospital, Boston, MA, USA
| | - J.F. Markmann
- Transplant Center, Massachusetts General Hospital, Boston, MA, USA
| | - R. Porte
- Section of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - M.L. Yarmush
- Center for Engineering in Medicine, Department of Surgery, Massachusetts General Hospital, Boston, MA, USA,Department of Biomedical Engineering, Rutgers University, Piscataway, NJ, USA
| | - K. Uygun
- Center for Engineering in Medicine, Department of Surgery, Massachusetts General Hospital, Boston, MA, USA,Corresponding authors Korkut Uygun, PhD , Maria-Louisa Izamis, PhD
| | - M.L. Izamis
- Center for Engineering in Medicine, Department of Surgery, Massachusetts General Hospital, Boston, MA, USA,Corresponding authors Korkut Uygun, PhD , Maria-Louisa Izamis, PhD
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Mourad MM, Algarni A, Liossis C, Bramhall SR. Aetiology and risk factors of ischaemic cholangiopathy after liver transplantation. World J Gastroenterol 2014; 20:6159-6169. [PMID: 24876737 PMCID: PMC4033454 DOI: 10.3748/wjg.v20.i20.6159] [Citation(s) in RCA: 85] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2013] [Revised: 01/26/2014] [Accepted: 03/19/2014] [Indexed: 02/06/2023] Open
Abstract
Liver transplantation (LT) is the best treatment for end-stage hepatic failure, with an excellent survival rates over the last decade. Biliary complications after LT pose a major challenge especially with the increasing number of procured organs after circulatory death. Ischaemic cholangiopathy (IC) is a set of disorders characterized by multiple diffuse strictures affecting the graft biliary system in the absence of hepatic artery thrombosis or stenosis. It commonly presents with cholestasis and cholangitis resulting in higher readmission rates, longer length of stay, repeated therapeutic interventions, and eventually re-transplantation with consequent effects on the patient’s quality of life and increased health care costs. The pathogenesis of IC is unclear and exhibits a higher prevalence with prolonged ischaemia time, donation after circulatory death (DCD), rejection, and cytomegalovirus infection. The majority of IC occurs within 12 mo after LT. Prolonged warm ischaemic times predispose to a profound injury with a subsequently higher prevalence of IC. Biliary complications and IC rates are between 16% and 29% in DCD grafts compared to between 3% and 17% in donation after brain death (DBD) grafts. The majority of ischaemic biliary lesions occur within 30 d in DCD compared to 90 d in DBD grafts following transplantation. However, there are many other risk factors for IC that should be considered. The benefits of DCD in expanding the donor pool are hindered by the higher incidence of IC with increased rates of re-transplantation. Careful donor selection and procurement might help to optimize the utilization of DCD grafts.
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Luo Y, Ji WB, Duan WD, Ye S, Dong JH. Graft cholangiopathy: etiology, diagnosis, and therapeutic strategies. Hepatobiliary Pancreat Dis Int 2014; 13:10-7. [PMID: 24463074 DOI: 10.1016/s1499-3872(14)60001-1] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND Graft cholangiopathy has been recognized as a significant cause of morbidity, graft loss, and even mortality in patients after orthotopic liver transplantation. The aim of this review is to analyze the etiology, pathogenesis, diagnosis and therapeutic strategies of graft cholangiopathy after liver transplantation. DATA SOURCE A PubMed database search was performed to identify articles relevant to liver transplantation, biliary complications and cholangiopathy. RESULTS Several risk factors for graft cholangiopathy after liver transplantation have been identified, including ischemia/reperfusion injury, cytomegalovirus infection, immunological injury and bile salt toxicity. A number of strategies have been attempted to prevent the development of graft cholangiopathy, but their efficacy needs to be evaluated in large clinical studies. Non-surgical approaches may offer good results in patients with extrahepatic lesions. For most patients with complex hilar and intrahepatic biliary abnormalities, however, surgical repair or re-transplantation may be required. CONCLUSIONS The pathogenesis of graft cholangiopathy after liver transplantation is multifactorial. In the future, more efforts should be devoted to the development of more effective preventative and therapeutic strategies against graft cholangiopathy.
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Affiliation(s)
- Ying Luo
- Department of Hepatobiliary Surgery, Chinese PLA General Hospital, Beijing 100853, China.
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Seehofer D, Eurich D, Veltzke-Schlieker W, Neuhaus P. Biliary complications after liver transplantation: old problems and new challenges. Am J Transplant 2013; 13:253-65. [PMID: 23331505 DOI: 10.1111/ajt.12034] [Citation(s) in RCA: 211] [Impact Index Per Article: 17.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2012] [Revised: 10/01/2012] [Accepted: 10/23/2012] [Indexed: 01/25/2023]
Abstract
Due to a vulnerable blood supply of the bile ducts, biliary complications are a major source of morbidity after liver transplantation (LT). Manifestation is either seen at the anastomotic region or at multiple locations of the donor biliary system, termed as nonanastomotic biliary strictures. Major risk factors include old donor age, marginal grafts and prolonged ischemia time. Moreover, partial LT or living donor liver transplantation (LDLT) and donation after cardiac death (DCD) bear a markedly higher risk of biliary complications. Especially accumulation of several risk factors is critical and should be avoided. Prophylaxis is still a major issue; however no gold standard is established so far, since many risk factors cannot be influenced directly. The diagnostic workup is mostly started with noninvasive imaging studies namely MRI and MRCP, but direct cholangiography still remains the gold standard. Especially nonanastomotic strictures require a multidisciplinary treatment approach. The primary management of anastomotic strictures is mainly interventional. However, surgical revision is finally indicated in a significant number of cases. Using adequate treatment algorithms, a very high success rate can be achieved in anastomotic complications, but in nonanastomotic strictures a relevant number of graft failures are still inevitable.
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Affiliation(s)
- D Seehofer
- Department of General-, Visceral and Transplantation Surgery, Charité Campus Virchow, Berlin, Germany.
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Izamis ML, Berendsen T, Uygun K, Yarmush M. Addressing the Donor Liver Shortage withEX VIVOMachine Perfusion. JOURNAL OF HEALTHCARE ENGINEERING 2012. [DOI: 10.1260/2040-2295.3.2.279] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
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10
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Ischemia-Reperfusion Injury and Ischemic-Type Biliary Lesions following Liver Transplantation. J Transplant 2012; 2012:164329. [PMID: 22530107 PMCID: PMC3316988 DOI: 10.1155/2012/164329] [Citation(s) in RCA: 71] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2011] [Revised: 12/19/2011] [Accepted: 12/23/2011] [Indexed: 12/14/2022] Open
Abstract
Ischemia-reperfusion (I-R) injury after liver transplantation (LT) induces intra- and/or extrahepatic nonanastomotic ischemic-type biliary lesions (ITBLs). Subsequent bile duct stricture is a significant cause of morbidity and even mortality in patients who underwent LT. Although the pathogenesis of ITBLs is multifactorial, there are three main interconnected mechanisms responsible for their formation: cold and warm I-R injury, injury induced by cytotoxic bile salts, and immunological-mediated injury. Cold and warm ischemic insult can induce direct injury to the cholangiocytes and/or damage to the arterioles of the peribiliary vascular plexus, which in turn leads to apoptosis and necrosis of the cholangiocytes. Liver grafts from suboptimal or extended-criteria donors are more susceptible to cold and warm I-R injury and develop more easily ITBLs than normal livers. This paper, focusing on liver I-R injury, reviews the risk factors and mechanisms leading to ITBLs following LT.
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11
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Lladó L, Fabregat J, Ramos E, Baliellas C, Torras J, Rafecas A. Complicaciones biliares tras el trasplante hepático. Cir Esp 2012; 90:4-10. [DOI: 10.1016/j.ciresp.2011.10.007] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2011] [Revised: 09/11/2011] [Accepted: 10/03/2011] [Indexed: 12/14/2022]
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13
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Lladó L, Fabregat J, Ramos E, Baliellas C, Torras J, Julià D, Berrozpe A, Jorba R, Rafecas A. Papel de la cirugía en el manejo de las complicaciones biliares tras el trasplante hepático. Cir Esp 2010; 87:364-71. [DOI: 10.1016/j.ciresp.2010.03.010] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2009] [Revised: 03/12/2010] [Accepted: 03/12/2010] [Indexed: 01/01/2023]
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Multifactorial biological modulation of warm ischemia reperfusion injury in liver transplantation from non-heart-beating donors eliminates primary nonfunction and reduces bile salt toxicity. Ann Surg 2009; 250:808-17. [PMID: 19826248 DOI: 10.1097/sla.0b013e3181bdd787] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
OBJECTIVE To design a multifactorial biological modulation approach targeting ischemia reperfusion injury to augment viability of porcine liver grafts from non-heart-beating donors (NHBD). BACKGROUND DATA Liver Transplantation (LTx) from NHBD is associated with an increased risk of primary nonfunction (PNF) and biliary complications. In porcine NHBD-LTx, we previously reported a 50% risk of PNF and toxic bile formation in grafts exposed to > or =30' warm ischemia (WI). METHODS Porcine livers exposed to 45' WI were cold stored, transplanted and either modulated (n = 6) or not (controls, n = 9). In the modulation group, donor livers were flushed with warm Ringers (avoiding cold-induced vasoconstriction), streptokinase (eliminating stagnating thrombi), and epoprostenol (vasodilator, platelet aggregation inhibitor) prior to cold storage. In recipients, glycine (Kupffer cell stabilizer), alpha1-acid-glycoprotein (anti-inflammatory protein), MAPKinase-inhibitor (pro-inflammatory cytokine generation inhibitor), alpha-tocopherol and glutathione (anti-oxidants), and apotransferrin (iron chelator) were administrated intravenously. PNF, survival, lactate, transaminase, TNF-alpha, redox-active iron, and biliary bile salt-to-phospholipid ratio were monitored. RESULTS No PNF was observed in modulated versus 55% in control pigs (P = 0.025). Survival was 83% in modulated versus 22% in control pigs (P = 0.02). At 180' postreperfusion, lactate was lower in modulated (5.4 +/- 1.9 mmol/L) versus control pigs (9.4 +/- 2.2 mmol/L; P = 0.011). At 60' postreperfusion, there was a trend for lower AST in modulated versus control pigs at 60' (939 +/- 578 vs. 1683 +/- 873 IU/L; P = 0.089). Postreperfusion, TNF-alpha remained stable in modulated pigs (49 +/- 27 pg/mL at 15' and 85 +/- 26 pg/mL at 180'; P = 0.399) but increased in control pigs (107 +/- 36 pg/mL at 15' and 499 +/- 216 pg/mL at 180'; P = 0.023). At 180' postreperfusion, redox-active iron was higher in control pigs versus modulated pigs (0.21+/-0.18 vs. 0.042+/-0.062 mum; P = 0.038). Biliary bile salt-to-phospholipid ratio post-LTx was lower in modulated versus control pigs (1128 +/- 447 vs. 4836 +/- 4619; P = 0.05). CONCLUSIONS A multifactorial biological modulation eliminates PNF, improves liver function and increases survival. Biochemically, TNF-alpha and redox-active iron are suppressed and biliary bile salt toxicity is reduced. Translating this strategy clinically may lead to wider and safer use of NHBD.
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Abstract
After liver transplantation, the prevalence of complications related to the biliary system is 6-35%. In recent years, the diagnosis and treatment of biliary problems has changed markedly. The two standard methods of biliary reconstruction in liver transplant recipients are the duct-to-duct choledochocholedochostomy and the Roux-en-Y-hepaticojejunostomy. Biliary leakage occurs in approximately 5-7% of transplant cases. Leakage from the site of anastomosis, the T-tube exit site and donor or recipient remnant cystic duct is well described. Symptomatic bile leakage should be treated by stenting of the duct by endoscopic retrograde cholangiopancreatography (ERCP) or percutaneous transhepatic cholangiography (PTCD). Biliary strictures can occur at the site of the anastomosis (anastomotic stricture; AS) or at other locations in the biliary tree (non-anastomotic strictures; NAS). AS occur in 5-10% of cases and are due to fibrotic healing. Treatment by ERCP or PTCD with dilatation and progressive stenting is successful in the majority of cases. NAS can occur in the context of a hepatic artery thrombosis, or with an open hepatic artery (ischaemic type biliary lesions or ITBL). The incidence is 5-10%. NAS has been associated with various types of injury, e.g. macrovascular, microvascular, immunological and cytotoxic injury by bile salts. Treatment can be attempted with multiple sessions of dilatation and stenting of stenotic areas by ERCP or PTCD. In cases of localized diseased and good graft function, biliary reconstructive surgery is useful. However, a significant number of patients will need a re-transplant. When biliary strictures or ischaemia of the graft are present, stones, casts and sludge can develop.
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Affiliation(s)
- Robert C Verdonk
- Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center Groningen, The Netherlands.
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Chen G, Wang S, Bie P, Li X, Dong J. Endogenous bile salts are associated with bile duct injury in the rat liver transplantation model. Transplantation 2009; 87:330-339. [PMID: 19202437 DOI: 10.1097/tp.0b013e3181954fee] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
BACKGROUND Nonanastomotic biliary strictures are a serious complication after orthotopic liver transplantation (OLT) and are difficult to cure. We examined the role of endogenous bile salt toxicity in the pathogenesis of bile duct injury after OLT. MATERIALS AND METHODS A total of 90 Sprague-Dawley rats were divided into three groups: Sham-operated group (Sham, n=30), OLT group with 1 hr donor liver preservation (OLT-1h, n=30), and OLT group with 12 hr donor liver preservation (OLT-12h, n=30). Bile was collected and analyzed biochemically. The histopathologic study was performed to determine the intrahepatic bile duct morphologic changes. Hepatic expressions of bile transporters Ntcp, Bsep, Mdr2, and Oatps were detected. RESULTS During the first 2 weeks after transplantation, bile salt secretion was not parallel with phospholipid secretion, resulting in high biliary bile salt-to-phospholipid (BS:PL) ratio. The expression of bile transporters was consistent with the change of bile composition. Bile duct injury correlated significantly with bile salt secretion and BS:PL ratio. Moreover, OLT group with longer donor liver preservation time (OLT-12h) had significantly lower Mdr2 messenger RNA/protein level, higher BS:PL ratio, and better correlation between BS:PL ratio and bile duct injury compared with those of OLT-1h. CONCLUSIONS The unparallel secretion of bile salts and phospholipids results in cytotoxic bile formation with high BS:PL ratio after liver transplantation. Longer donor liver preservation time will increase graft bile cytotoxicity. The results of this study suggest that endogenous bile salts play a role in the pathogenesis of bile duct injury after OLT.
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Affiliation(s)
- Geng Chen
- Institute of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University, Chongqing, China
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Buis CI, Geuken E, Visser DS, Kuipers F, Haagsma EB, Verkade HJ, Porte RJ. Altered bile composition after liver transplantation is associated with the development of nonanastomotic biliary strictures. J Hepatol 2009; 50:69-79. [PMID: 19012987 DOI: 10.1016/j.jhep.2008.07.032] [Citation(s) in RCA: 80] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2008] [Revised: 07/08/2008] [Accepted: 07/09/2008] [Indexed: 12/12/2022]
Abstract
BACKGROUND/AIMS Nonanastomotic biliary strictures are troublesome complications after liver transplantation. The pathogenesis of NAS is not completely clear, but experimental studies suggest that bile salt toxicity is involved. METHODS In one hundred and eleven adult liver transplants, bile samples were collected daily posttransplantation for determination of bile composition. Expression of bile transporters was studied perioperatively. RESULTS Nonanastomotic biliary strictures were detected in 14 patients (13%) within one year after transplantation. Patient and donor characteristics and postoperative serum liver enzymes were similar between patients who developed nonanastomotic biliary strictures and those who did not. Secretions of bile salts, phospholipids and cholesterol were significantly lower in patients who developed strictures. In parallel, biliary phospholipids/bile salt ratio was lower in patients developing strictures, suggestive for increased bile cytotoxicity. There were no differences in bile salt pool composition or in hepatobiliary transporter expression. CONCLUSIONS Although patients who develop nonanastomotic biliary strictures are initially clinically indiscernible from patients who do not develop nonanastomotic biliary strictures, the biliary bile salts and phospholipids secretion, as well as biliary phospholipids/bile salt ratio in the first week after transplantation, was significantly lower in the former group. This supports the concept that bile cytotoxicity is involved in the pathogenesis of nonanastomotic biliary strictures.
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Affiliation(s)
- Carlijn I Buis
- Section of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, University Medical Center Groningen, University of Groningen, P.O. Box 30.001, 9700 RB Groningen, The Netherlands
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18
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Zheng S, Feng X, Qing D, Chen M, Dong J. The tolerance time limits of biliary tracts of liver grafts subjected to warm ischemia and cold preservation: an experimental study in swine. Transplant Proc 2008; 40:1629-34. [PMID: 18589163 DOI: 10.1016/j.transproceed.2008.01.072] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2007] [Accepted: 01/16/2008] [Indexed: 11/18/2022]
Abstract
OBJECTIVE The objective of this study was to investigate the tolerance time limits of liver grafts and biliary tracts with warm ischemia to cold preservation providing experimental data to the prevent primary graft nonfunction and biliary necrosis after orthotopic liver transplantation (OLT). METHODS OLTs were performed in Bama miniature swine. Morphological and functional changes in the liver graft and biliary tracts were investigated after 10 minutes of warm ischemia and various durations of cold preservation. RESULTS When grafts were subjected to 10 minutes of warm ischemia followed by less than 16 hours of cold preservation, all animals survived 1 week; no animal died of biliary necrosis. However, when the cold preservation time exceeded 16 hours, the incidence of biliary necrosis increased significantly (P < .05) with deaths due to bile leaks. As cold preservation persisted, primary graft nonfunction and intraoperative or early postoperative deaths occurred, and all surviving animals developed biliary necrosis. When compared with the group undergoing less than 16 hours of cold preservation, the morphological scores and apoptosis index of epithelial cells of graft bile ducts were significantly increased among the group subjected to more than 16 hours of cold preservation after reperfusion (P < .05), whereas the activity of Na+-K+-ATPase and Ca2+-ATPase of graft bile ducts were reduced significantly (P < .05). Liver function tests showed the concentrations of alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma glutamyl transpeptidase, and alkaline phosphatase (ALP) decreased more slowly among the group undergoing more than 16 hours of cold preservation after operation. CONCLUSIONS We concluded that given 10 minutes of warm ischemia, cold preservation should be less than 16 hours to avoid early biliary necrosis; the corresponding tolerance time limit of the liver to cold preservation was less than 20 hours.
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Affiliation(s)
- S Zheng
- Institute of Hepatobiliary Surgery, Southwest Hospital, The Third Military Medical University, Chongqing, China
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Baiocchi L, Tisone G, Russo MA, Longhi C, Palmieri G, Volpe A, Almerighi C, Telesca C, Carbone M, Toti L, De Leonardis F, Angelico M. TUDCA prevents cholestasis and canalicular damage induced by ischemia-reperfusion injury in the rat, modulating PKCalpha-ezrin pathway. Transpl Int 2008; 21:792-800. [PMID: 18435680 DOI: 10.1111/j.1432-2277.2008.00682.x] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Cholestasis, induced by liver ischemia-reperfusion injury (IRI), is characterized by dilatation of bile canaliculi and loss of microvilli. Tauroursodeoxycholic acid (TUDCA) is an anti-cholestatic agent, modulating protein kinase C (PKC) alpha pathway. PKC reduces ischemic damage in several organs, its isoform alpha modulates ezrin, a key protein in the maintenance of cell lamellipoidal extensions. We evaluated the effects of TUDCA on cholestasis, canalicular changes and PKCalpha-ezrin expression in a rat model of liver IRI. Livers flushed and stored with Belzer solution or Belzer + 10 mm TUDCA (4 degrees C for 6 h) were reperfused (37 degrees C with O(2)) with Krebs-Ringer bicarbonate + 2.5 micromol/min of Taurocholate or TUDCA. Bile was harvested for bile flow assessment. Liver tissue was employed for Electron Microscopy (EM) and for PKCalpha and ezrin immunoblot and immunofluorescence. The same experiments were conducted with the PKCalpha inhibitor Go-6976. TUDCA-treated livers showed increased bile flow (0.25+/-0.17 vs. 0.042+/-0.02 microl/min/g liver, P<0.05) and better preservation of microvilli and bile canalicular area at EM. These effects were associated with increased PKCalpha and ezrin expression (P=0.03 and P=0.04 vs. control respectively), as also confirmed by immunofluorescence data. PKCalpha inhibition abolished these TUDCA effects. TUDCA administration during IRI reduces cholestasis and canalicular damage in the liver modulating PKCalpha-ezrin pathway.
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The role of bile salt toxicity in the pathogenesis of bile duct injury after non-heart-beating porcine liver transplantation. Transplantation 2008; 85:1625-31. [PMID: 18551070 DOI: 10.1097/tp.0b013e318170f5f7] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
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.
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Buis CI, Hoekstra H, Verdonk RC, Porte RJ. Causes and consequences of ischemic-type biliary lesions after liver transplantation. ACTA ACUST UNITED AC 2006; 13:517-24. [PMID: 17139425 DOI: 10.1007/s00534-005-1080-2] [Citation(s) in RCA: 166] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2005] [Accepted: 11/25/2005] [Indexed: 02/06/2023]
Abstract
Biliary complications are a major source of morbidity, graft loss, and even mortality after liver transplantation. The most troublesome are the so-called ischemic-type biliary lesions (ITBL), with an incidence varying between 5% and 15%. ITBL is a radiological diagnosis, characterized by intrahepatic strictures and dilatations on a cholangiogram, in the absence of hepatic artery thrombosis. Several risk factors for ITBL have been identified, strongly suggesting a multifactorial origin. The main categories of risk factors for ITBL include ischemia-related injury; immunologically induced injury; and cytotoxic injury, induced by bile salts. However, in many cases no specific risk factor can be identified. Ischemia-related injury comprises prolonged ischemic times and disturbance in blood flow through the peribiliary vascular plexus. Immunological injury is assumed to be a risk factor based on the relationship of ITBL with ABO incompatibility, polymorphism in genes coding for chemokines, and pre-existing immunologically mediated diseases such as primary sclerosing cholangitis and autoimmune hepatitis. The clinical presentation of patients with ITBL is often not specific; symptoms may include fever, abdominal complaints, and increased cholestasis on liver function tests. Diagnosis is made by imaging studies of the bile ducts. Treatment starts with relieving the symptoms of cholestasis and dilatation by endoscopic retrograde cholangiopancreaticography (ERCP) or percutaneous transhepatic cholangiodrainage (PTCD), followed by stenting if possible. Eventually up to 50% of the patients with ITBL will require a retransplantation or may die. In selected patients, a retransplantation can be avoided or delayed by resection of the extra-hepatic bile ducts and construction of a hepaticojejunostomy. More research on the pathogenesis of ITBL is needed before more specific preventive or therapeutic strategies can be developed.
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Affiliation(s)
- Carlijn I Buis
- Section of Hepatobiliary Surgery and Liver Transplantation, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
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Hoekstra H, Porte RJ, Tian Y, Jochum W, Stieger B, Moritz W, Slooff MJH, Graf R, Clavien PA. Bile salt toxicity aggravates cold ischemic injury of bile ducts after liver transplantation in Mdr2+/- mice. Hepatology 2006; 43:1022-31. [PMID: 16628673 DOI: 10.1002/hep.21169] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
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.
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Affiliation(s)
- Harm Hoekstra
- Swiss HPB Center, Department of Visceral and Transplant Surgery, University Hospital Zurich, Switzerland
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Nowak G, Norén UG, Wernerson A, Marschall HU, Möller L, Ericzon BG. Enteral donor pre-treatment with ursodeoxycholic acid protects the liver against ischaemia-reperfusion injury in rats. Transpl Int 2005; 17:804-9. [PMID: 15815896 DOI: 10.1007/s00147-004-0703-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2003] [Revised: 09/30/2003] [Accepted: 10/20/2003] [Indexed: 10/25/2022]
Abstract
Liver donor pre-treatment with ursodeoxycholic acid (UDCA) may protect against injury during transplantation. In the present study we evaluated whether enteral administration of UDCA has an effect on bile flow and protects the liver from injury related to transplantation. Wistar rats were used in liver perfusion (LP) and transplantation (LTx) models. Rats were enterally administered UDCA (800 mg/kg) 3 h before cold perfusion. In LP, bile flow and bile acid composition were analysed. In LTx, serum ALT and liver histology were analysed. LP showed biliary UDCA enrichment up to 36+/-13% in pre-treated rats, causing higher bile flow (P = 0.026) compared with control rats. LTx showed lower ALT and TUNEL positive hepatocytes in the UDCA group (P < 0.02 and P < 0.05). In conclusion, augmented bile salt-dependent bile flow is preserved in the liver after cold storage. Enteral donor pre-treatment with UDCA protects the liver against ischaemia-reperfusion injury.
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Affiliation(s)
- Grzegorz Nowak
- Department of Transplantation Surgery, Karolinska Institute, Huddinge University Hospital B56, 141 86 Stockholm, Sweden.
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Geuken E, Visser D, Kuipers F, Blokzijl H, Leuvenink HGD, de Jong KP, Peeters PMJG, Jansen PLM, Slooff MJH, Gouw ASH, Porte RJ. Rapid increase of bile salt secretion is associated with bile duct injury after human liver transplantation. J Hepatol 2004; 41:1017-25. [PMID: 15582136 DOI: 10.1016/j.jhep.2004.08.023] [Citation(s) in RCA: 84] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/01/2004] [Revised: 08/17/2004] [Accepted: 08/18/2004] [Indexed: 12/26/2022]
Abstract
BACKGROUND/AIMS Biliary strictures are a serious cause of morbidity after liver transplantation. We have studied the role of altered bile composition as a mechanism of bile duct injury after human liver transplantation. METHODS In 28 liver transplant recipients, bile samples were collected daily posttransplantation for determination of bile composition. Hepatic expression of bile transporters was studied before and after transplantation. Histopathological criteria as well as biliary concentrations of alkaline phosphatase (ALP) and gamma-glutamyltransferase (gamma-GT) were used to quantify bile duct injury. RESULTS Early after transplantation, bile salt secretion increased more rapidly than phospholipid secretion, resulting in high biliary bile salt/phospholipid ratio (BA/PL). In parallel with this, mRNA levels of the bile salt transporters NTCP and BSEP increased significantly after transplantation, whereas phospholipid translocator MDR3 mRNA levels remained unchanged. Bile duct injury correlated significantly with bile salt secretion and was associated with a high biliary BA/PL ratio. CONCLUSIONS Bile salt secretion after human liver transplantation recovers more rapidly than phospholipid secretion. This results in cytotoxic bile formation and correlates with bile duct injury. These findings suggest that endogenous bile salts have a role in the pathogenesis of bile duct injury after liver transplantation.
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Affiliation(s)
- Erwin Geuken
- Section of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, University Hospital Groningen, P.O. Box 30.001, 9700 RB Groningen, The Netherlands
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25
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Abstract
Cholestasis is a common sequela of liver transplantation. Although the majority of cases remain subclinical, severe cholestasis may be associated with irreversible liver damage, requiring retransplantation. Therefore, it is essential that clinicians be able to identify and treat the syndromes associated with cholestasis. In this review, we consider causes of intrahepatic cholestasis. These may be categorized by time of occurrence, namely, within 6 months of liver transplantation (early) and thereafter (late), although there may be an overlap in their causes. The causes of intrahepatic cholestasis include ischemia/reperfusion injury, bacterial infection, acute cellular rejection, cytomegalovirus infection, small-for-size graft, drugs for hepatotoxicity, intrahepatic biliary strictures, chronic rejection, hepatic artery thrombosis, ABO blood group incompatibility, and recurrent disease. The mechanisms of cholestasis in each category and the clinical presentation, diagnosis, treatment, and outcome are discussed in detail.
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Affiliation(s)
- Ziv Ben-Ari
- Liver Institute and Department of Medicine D, Rabin Medical Center, Beilinson Campus, Petah Tikva, Israel.
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26
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Calmus Y, Podevin P. Tauroursodeoxycholic acid for the cytoprotection of liver grafts during cold storage: a new aspect of its anti-apoptotic properties? Transplantation 2001; 71:1205-1206. [PMID: 11408962 DOI: 10.1097/00007890-200105150-00002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Affiliation(s)
- Y Calmus
- Hĵpital Cochin Université Paris V, France
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Falasca L, Tisone G, Palmieri G, Anselmo A, Di Paolo D, Baiocchi L, Torri E, Orlando G, Casciani CU, Angelico M. Protective role of tauroursodeoxycholate during harvesting and cold storage of human liver: a pilot study in transplant recipients. Transplantation 2001; 71:1268-1276. [PMID: 11397961 DOI: 10.1097/00007890-200105150-00015] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
BACKGROUND Ischemia-reperfusion injury is a major cause of early graft dysfunction after liver transplantation. Tauroursodeoxycholic acid (TUDCA), a natural amidated hydrophilic bile salt, protects from cholestasis and hepatocellular damage in a variety of experimental models, as well as from ischemia-reperfusion injury. We investigated in the human liver transplantation setting the effect of the addition of TUDCA at time of liver harvesting and cold storage on the intra- and postoperative enzyme release and liver histopathology at the end of cold storage, at reperfusion, and 7 days after transplantation. METHODS Eighteen patients undergoing elective liver transplantation were studied, including 6 serving as controls. In six patients, TUDCA was added to the University of Wisconsin solution used during harvesting and cold storage, to reach final concentrations of 2 mM. In three of these patients, TUDCA (3 g) was infused in the portal vein of the donor before organ explantation; in the other three cases, TUDCA was given through both routes. RESULTS The use of TUDCA did not cause adverse events. The release of aspartate aminotransferase in the inferior vena cava blood during liver flushing was significantly lower (P=0.05) in TUDCA-treated than in control grafts, as were cytolytic enzyme levels in peripheral blood during the first postoperative week (P<0.02). At electron microscopy, an overt endothelial damage (cytoplasmic vacuolization, cell leakage, and destruction with exposure of hepatocytes to the sinusoidal lumen) was invariably found in control grafts, both at reperfusion and at day 7 after transplant. These features were significantly ameliorated by TUDCA (P<0.001). Several ultrastructural cytoplasmic abnormalities of hepatocytes were seen. Among these, damage to mitochondria matrix and crystae was significantly reduced in TUDCA-treated versus control grafts (P<0.01). Mild to severe damage of bile canaliculi was a constant feature in control biopsies, with dilatation of canalicular lumen and loss of microvilli. Both these abnormalities were markedly ameliorated (P<0.001 by TUDCA). The best preservation was observed when TUDCA was given through both routes. CONCLUSIONS The use of TUDCA during harvesting and cold storage of human liver is associated with significant protection from ischemia-reperfusion injury. The clinical significance of this findings must be studied.
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Affiliation(s)
- L Falasca
- Department of Surgery, University of Rome Tor Vergata, Italy
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Kukan M, Haddad PS. Role of hepatocytes and bile duct cells in preservation-reperfusion injury of liver grafts. Liver Transpl 2001; 7:381-400. [PMID: 11349258 DOI: 10.1053/jlts.2001.23913] [Citation(s) in RCA: 63] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
In liver transplantation, it is currently hypothesized that nonparenchymal cell damage and/or activation is the major cause of preservation-related graft injury. Because parenchymal cells (hepatocytes) appear morphologically well preserved even after extended cold preservation, their injury after warm reperfusion is ascribed to the consequences of nonparenchymal cell damage and/or activation. However, accumulating evidence over the past decade indicated that the current hypothesis cannot fully explain preservation-related liver graft injury. We review data obtained in animal and human liver transplantation and isolated perfused animal livers, as well as isolated cell models to highlight growing evidence of the importance of hepatocyte disturbances in the pathogenesis of normal and fatty graft injury. Particular attention is given to preservation time-dependent decreases in high-energy adenine nucleotide levels in liver cells, a circumstance that (1) sensitizes hepatocytes to various stimuli and insults, (2) correlates well with graft function after liver transplantation, and (3) may also underlie the preservation time-dependent increase in endothelial cell damage. We also review damage to bile duct cells, which is increasingly being recognized as important in the long-lasting phase of reperfusion injury. The role of hydrophobic bile salts in that context is particularly assessed. Finally, a number of avenues aimed at preserving hepatocyte and bile duct cell integrity are discussed in the context of liver transplantation therapy as a complement to reducing nonparenchymal cell damage and/or activation.
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Affiliation(s)
- M Kukan
- Laboratory of Perfused Organs, Slovak Centre for Organ Transplantation, Institute of Preventive and Clinical Medicine, Bratislava, Slovakia
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Vajdová K, Smreková R, Kukan M, Lutterová M, Wsólová L. Bile analysis as a tool for assessing integrity of biliary epithelial cells after cold ischemia--reperfusion of rat livers. Cryobiology 2000; 41:145-52. [PMID: 11034793 DOI: 10.1006/cryo.2000.2276] [Citation(s) in RCA: 42] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Previous morphological studies failed to show appreciable injury of biliary epithelial cells (BEC) after cold ischemia of rat liver, although recent evidence indicated that BEC integrity and function were impaired in this model. We tested the hypothesis that analysis of bile for enzymes, such as lactate dehydrogenase (LDH), alanine transaminase (ALT), and aspartate transaminase (AST), can be used for assessing cold ischemic injury of BEC. Furthermore, we examined whether biliary gamma-glutamyltransferase (GGT) reflects warm ischemic injury of BEC and whether normothermic reperfusion aggravates the negative effect of cold ischemia on BEC integrity and function. Rat livers were reperfused after different periods of cold or warm ischemia using a blood-free perfusion model. Compared with controls, perfusate LDH, ALT, and AST levels and parameters of hepatocyte function, including hepatocyte tight junction permeability, were not significantly altered by 18-h cold ischemia. On the other hand, 9-h cold ischemia markedly increased biliary LDH, ALT, and AST levels. However, only LDH release into the bile was strongly dependent on the time of cold storage. Biliary GGT, LDH, and glucose levels decreased during the reperfusion period following 18-h cold ischemia. The results suggest that biliary LDH can be used for assessing injury of BEC in cold-preserved livers and that normothermic reperfusion does not aggravate preservation-induced injury of BEC after cold ischemic storage.
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Affiliation(s)
- K Vajdová
- Laboratory of Perfused Organs, SCOT, Institute of Preventive and Clinical Medicine, 83301 Bratislava, Slovakia
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Hertl M, Hertl MC, Kluth D, Broelsch CE. Hydrophilic bile salts protect bile duct epithelium during cold preservation: a scanning electron microscopy study. Liver Transpl 2000; 6:207-12. [PMID: 10719022 DOI: 10.1002/lt.500060201] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
Prolonged graft preservation is associated with postoperative bile duct strictures after liver transplantation. We previously showed that hydrophilic bile salts mitigate bile duct preservation injury in a pig model. Because this injury occurs at the epithelial level, scanning electron microscopy was performed to further characterize this effect in vitro. Swine livers were harvested after the intravenous infusion of 1 of 3 solutions: saline (n = 7), tauroursodeoxycholate ([TUDC] hydrophilic; n = 4), or taurodeoxycholate ([TDC] hydrophobic; n = 4). Livers were perfused with University of Wisconsin solution. The bile ducts were flushed retrograde, and the liver was stored at 0 degrees C to 1 degrees C for 20 hours. Bile duct samples were obtained at the time of harvest and 8, 12, 16, and 20 hours thereafter. In saline-infused controls at time 0, the epithelium was intact and composed of uniform cuboidal cells covered with fine regular microvilli. There were no spaces between individual cells. After 8 to 12 hours of preservation, cells were more irregular in shape, with loss of cell-cell contact. The cell surfaces showed fewer microvilli. Surface erosions suggested loss of cell-wall integrity. TUDC was protective, evidenced by normal-appearing cells with uniform microvilli after 16 hours. In contrast, TDC accelerated the injury process, causing cell-surface erosions, blebs, and loss of microvilli as early as time 0. Scanning electron microscopy is an excellent tool to study injury to bile duct epithelium. This study supports the hypothesis that hydrophilic bile salts protect bile ducts during preservation. To determine whether treatment with hydrophilic bile salts can prevent postoperative stricture, in vivo transplantation studies are needed.
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Affiliation(s)
- M Hertl
- Departments of General Surgery, University Hospital Hamburg, Germany
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HertI M, Hertl MC, Kunkel P, Schilling S, Prevot B, Kluth D, Malagó M, Broelsch CE. Tauroursodeoxycholate ameliorates reperfusion injury after pig liver transplantation. Transpl Int 1999. [DOI: 10.1111/j.1432-2277.1999.tb00774.x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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Stiehl A, Benz C, Sauer P. Mechanism of hepatoprotective action of bile salts in liver disease. Gastroenterol Clin North Am 1999; 28:195-209, viii. [PMID: 10198785 DOI: 10.1016/s0889-8553(05)70050-9] [Citation(s) in RCA: 24] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Ursodeoxycholic acid (UDCA) improves liver enzymes and in many instances liver histology in cholestatic liver diseases such as primary biliary cirrhosis and primary sclerosing cholangitis. Besides classic cholestatic diseases, UDCA also improves liver biochemistry in alcoholic liver disease and in chronic viral hepatitis C. The main target of UDCA treatment, however, is cholestasis, and consequently the mechanisms responsible for the beneficial effects in these diseases are of interest, and are discussed in detail in this article.
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Affiliation(s)
- A Stiehl
- Department of Medicine, University of Heidelberg, Germany
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Morgan WA, Kaler B, Bach PH. The role of ursodeoxycholic acid in bile acid-mediated kidney fragment toxicity. EXPERIMENTAL AND TOXICOLOGIC PATHOLOGY : OFFICIAL JOURNAL OF THE GESELLSCHAFT FUR TOXIKOLOGISCHE PATHOLOGIE 1999; 51:35-9. [PMID: 10048711 DOI: 10.1016/s0940-2993(99)80057-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Elevated levels of bile acids are thought to play an important role in the renal failure of patients with obstructive jaundice undergoing surgery. In contrast, ursodeoxycholic acid (UDA) is widely used to improve cholestasis and has been proposed as protective bile acids and antioxidant. The present study employs kidney fragments to determine the role of reactive oxygen species (ROS) in the mechanism of toxicity of hydrophobic bile acids and to determine the nephroprotectant properties of UDA against the hydrophobic bile acids. The hydrophobic bile acids chenodeoxycholic (200 microM) and deoxycholic acid (200 microM) significantly (P<0.05) increased lactate dehydrogenase leakage (LDH) from glomerular fragments from 2.7+/-0.4 to 5.03+/-0.23 and 4.66+/-0.37 (micromol NADH consumed/min/mg protein) for chenodeoxycholic and deoxycholic acid respectively. Preincubating the fragments with UDA (500 microM) did not prevent the leakage of LDH caused by the bile acids. The level of lipid peroxidation was not increased in fragments exposed to either ursodeoxycholic (0-500 microM), lithocholic (0-100 microM), chenodeoxycholic (0-500 microM) or deoxycholic acid (0-500 microM). Furthermore UDA (500 microM) did not prevent the increase in lipid peroxidation caused by tert-butyl hydroperoxide (0-1000 microM) in the fragments. These results suggest that hydrophobic bile acids do not cause lipid peroxidation in kidney fragments and that UDA is neither capable of preventing the loss of membrane integrity induced by hydrophobic bile acids or acting as an antioxidant in kidney fragments.
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Affiliation(s)
- W A Morgan
- Department of Life Sciences, Faculty of Science and Health, University of East London, UK. W.A.Morgan@.UEL.AC.UK
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Koeppel TA, Trauner M, Mennone A, Arrese M, Rios-Velez L, Boyer JL. Role of glutathione in hepatic bile formation during reperfusion after cold ischemia of the rat liver. J Hepatol 1998; 28:812-9. [PMID: 9625316 DOI: 10.1016/s0168-8278(98)80231-6] [Citation(s) in RCA: 21] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND/AIMS Liver reperfusion following cold ischemia is frequently associated with diminished bile flow in patients undergoing liver transplantation. Glutathione is a major determinant of bile-acid independent bile flow, and the effects of cold ischemia on biliary glutathione excretion are unknown. METHODS We examined the effects of cold ischemia (University of Wisconsin solution (4 degrees C), 24 h) with subsequent reperfusion (100 min) on biliary glutathione excretion in a recirculating system. Since glutathione might represent an important antioxidant within the biliary tract and oxidative stress in the biliary tract during reperfusion could contribute to the pathogenesis of bile duct injury after liver transplantation, we also assessed bile duct morphology in reperfused livers of mutant TR- -rats, in whom biliary excretion of glutathione is already impaired. RESULTS Hepatic bile formation was diminished in reperfused Wistar rat livers after cold ischemia. Biliary glutathione concentrations and output were significantly decreased and correlated with postischemic changes in bile secretion. An increased biliary oxidized glutathione/glutathione ratio, indicating oxidative stress, was detected only immediately after the onset of reperfusion. Basal bile flow rates in TR- -rat livers which were already markedly reduced in control-perfused livers, decreased further during the early but not the later reperfusion period. Reperfusion of both Wistar and TR- -rat livers was not associated with electron microscopic evidence of bile duct damage. CONCLUSIONS We conclude that impaired biliary excretion of glutathione contributes to decreased bile flow after cold ischemia. The absence of biliary glutathione does not appear to promote ultrastructural evidence of bile duct injury during reperfusion in the isolated perfused rat liver.
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Affiliation(s)
- T A Koeppel
- Department of Internal Medicine and Liver Center, Yale University School of Medicine, New Haven, CT 06520-8019, USA
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Balistreri WF. Bile acid therapy in pediatric hepatobiliary disease: the role of ursodeoxycholic acid. J Pediatr Gastroenterol Nutr 1997; 24:573-89. [PMID: 9161955 DOI: 10.1097/00005176-199705000-00016] [Citation(s) in RCA: 72] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Affiliation(s)
- W F Balistreri
- Division of Pediatric Gastroenterology and Nutrition, Children's Hospital Medical Center, Cincinnati, Ohio 45229-3039, USA
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Hertl M, Clausnitzer N, Rogiers X, Jung R, Broelsch CE. Infusion of hydrophilic bile salts protects the liver from reperfusion injury in the rat. Transplant Proc 1997; 29:386-7. [PMID: 9123048 DOI: 10.1016/s0041-1345(96)00130-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Affiliation(s)
- M Hertl
- Department of General Surgery, University Hospital Eppendorf, Hamburg, Germany
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37
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Hertl M, Engelhard O, Vollmers B, Rogiers X, Jung R, Broelsch CE. Donor pretreatment with hydrophilic bile salts protects the liver from preservation and reperfusion injury in the rat. Transplant Proc 1997; 29:388-9. [PMID: 9123049 DOI: 10.1016/s0041-1345(96)00131-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Affiliation(s)
- M Hertl
- Department of General Surgery, University Hospital Eppendorf, Hamburg, Germany
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Stefanini GF, Foschi FG, Marsigli L, Fumelli C, Grazi GL. Shortage of organs with a consequent increase in stand-by time and patient deaths. LIVER TRANSPLANTATION AND SURGERY : OFFICIAL PUBLICATION OF THE AMERICAN ASSOCIATION FOR THE STUDY OF LIVER DISEASES AND THE INTERNATIONAL LIVER TRANSPLANTATION SOCIETY 1996; 2:332-333. [PMID: 9346671 DOI: 10.1002/lt.500020420] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/22/2023]
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