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Ferri F, Carotti S, Carpino G, Mischitelli M, Cantafora A, Molinaro A, Argenziano ME, Parisse S, Corsi A, Riminucci M, Lai Q, Mennini G, Spadetta G, Pugliese F, Rossi M, Morini S, Gaudio E, Ginanni Corradini S. The Propensity of the Human Liver to Form Large Lipid Droplets Is Associated with PNPLA3 Polymorphism, Reduced INSIG1 and NPC1L1 Expression and Increased Fibrogenetic Capacity. Int J Mol Sci 2021; 22:6100. [PMID: 34198853 PMCID: PMC8200978 DOI: 10.3390/ijms22116100] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2021] [Revised: 05/28/2021] [Accepted: 06/03/2021] [Indexed: 12/12/2022] Open
Abstract
In nonalcoholic steatohepatitis animal models, an increased lipid droplet size in hepatocytes is associated with fibrogenesis. Hepatocytes with large droplet (Ld-MaS) or small droplet (Sd-MaS) macrovesicular steatosis may coexist in the human liver, but the factors associated with the predominance of one type over the other, including hepatic fibrogenic capacity, are unknown. In pre-ischemic liver biopsies from 225 consecutive liver transplant donors, we retrospectively counted hepatocytes with Ld-MaS and Sd-MaS and defined the predominant type of steatosis as involving ≥50% of steatotic hepatocytes. We analyzed a donor Patatin-like phospholipase domain-containing protein 3 (PNPLA3) rs738409 polymorphism, hepatic expression of proteins involved in lipid metabolism by RT-PCR, hepatic stellate cell (HSC) activation by α-SMA immunohistochemistry and, one year after transplantation, histological progression of fibrosis due to Hepatitis C Virus (HCV) recurrence. Seventy-four livers had no steatosis, and there were 98 and 53 with predominant Ld-MaS and Sd-MaS, respectively. In linear regression models, adjusted for many donor variables, the percentage of steatotic hepatocytes affected by Ld-MaS was inversely associated with hepatic expression of Insulin Induced Gene 1 (INSIG-1) and Niemann-Pick C1-Like 1 gene (NPC1L1) and directly with donor PNPLA3 variant M, HSC activation and progression of post-transplant fibrosis. In humans, Ld-MaS formation by hepatocytes is associated with abnormal PNPLA3-mediated lipolysis, downregulation of both the intracellular cholesterol sensor and cholesterol reabsorption from bile and increased hepatic fibrogenesis.
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Affiliation(s)
- Flaminia Ferri
- Department of Translational and Precision Medicine, Sapienza University of Rome, 00185 Rome, Italy; (M.M.); (A.C.); (M.E.A.); (S.P.); (S.G.C.)
| | - Simone Carotti
- Laboratory of Microscopic and Ultrastructural Anatomy, CIR, University Campus Bio-Medico, 00128 Rome, Italy; (S.C.); (S.M.)
| | - Guido Carpino
- Department of Movement, Human and Health Sciences, Division of Health Sciences, University of Rome “Foro Italico”, 00135 Rome, Italy;
| | - Monica Mischitelli
- Department of Translational and Precision Medicine, Sapienza University of Rome, 00185 Rome, Italy; (M.M.); (A.C.); (M.E.A.); (S.P.); (S.G.C.)
| | - Alfredo Cantafora
- Department of Translational and Precision Medicine, Sapienza University of Rome, 00185 Rome, Italy; (M.M.); (A.C.); (M.E.A.); (S.P.); (S.G.C.)
| | - Antonio Molinaro
- Wallenberg Laboratory, Department of Molecular and Clinical Medicine/Wallenberg Laboratory, Institute of Medicine, University of Gothenburg and Sahlgrenska University Hospital, 413 45 Gothenburg, Sweden;
| | - Maria Eva Argenziano
- Department of Translational and Precision Medicine, Sapienza University of Rome, 00185 Rome, Italy; (M.M.); (A.C.); (M.E.A.); (S.P.); (S.G.C.)
| | - Simona Parisse
- Department of Translational and Precision Medicine, Sapienza University of Rome, 00185 Rome, Italy; (M.M.); (A.C.); (M.E.A.); (S.P.); (S.G.C.)
| | - Alessandro Corsi
- Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy; (A.C.); (M.R.)
| | - Mara Riminucci
- Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy; (A.C.); (M.R.)
| | - Quirino Lai
- General Surgery and Organ Transplantation Unit, Department of Surgery, Sapienza University of Rome, 00161 Rome, Italy; (Q.L.); (G.M.); (M.R.)
| | - Gianluca Mennini
- General Surgery and Organ Transplantation Unit, Department of Surgery, Sapienza University of Rome, 00161 Rome, Italy; (Q.L.); (G.M.); (M.R.)
| | - Gustavo Spadetta
- Department of Internal Anesthesiological and Cardiovascular Clinical Sciences, Sapienza University of Rome, 00185 Rome, Italy; (G.S.); (F.P.)
| | - Francesco Pugliese
- Department of Internal Anesthesiological and Cardiovascular Clinical Sciences, Sapienza University of Rome, 00185 Rome, Italy; (G.S.); (F.P.)
| | - Massimo Rossi
- General Surgery and Organ Transplantation Unit, Department of Surgery, Sapienza University of Rome, 00161 Rome, Italy; (Q.L.); (G.M.); (M.R.)
| | - Sergio Morini
- Laboratory of Microscopic and Ultrastructural Anatomy, CIR, University Campus Bio-Medico, 00128 Rome, Italy; (S.C.); (S.M.)
| | - Eugenio Gaudio
- Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza University of Rome, 00161 Rome, Italy;
| | - Stefano Ginanni Corradini
- Department of Translational and Precision Medicine, Sapienza University of Rome, 00185 Rome, Italy; (M.M.); (A.C.); (M.E.A.); (S.P.); (S.G.C.)
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Ivanics T, Abreu P, De Martin E, Sapisochin G. Changing Trends in Liver Transplantation: Challenges and Solutions. Transplantation 2021; 105:743-756. [PMID: 32910093 DOI: 10.1097/tp.0000000000003454] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Despite improvements in postliver transplant outcomes through refinements in perioperative management and surgical techniques, several changing trends in liver transplantation have presented challenges. Mortality on the waitlist remains high. In the United States, Europe, and the United Kingdom, there is an increasing need for liver transplantation, primarily as a result of increased incidence of nonalcoholic steatohepatitis-related cirrhosis and cancer indications. Meanwhile, donor suitability has decreased, as donors are often older and have more comorbidities. Despite a mismatch between organ need and availability, many organs are discarded. Notwithstanding this, many solutions have been developed to overcome these challenges. Innovative techniques in allograft preservation, viability assessment, and reconditioning have allowed the use of suboptimal organs with adequate results. Refinements in surgical procedures, including live donor liver transplantations, have increased the organ pool and are decreasing the time and mortality on the waitlist. Despite many challenges, a similar number of solutions and prospects are on the horizon. This review seeks to explore the changing trends and challenges in liver transplantation and highlight possible solutions and future directions.
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Affiliation(s)
- Tommy Ivanics
- Multi-Organ Transplant Program, University Health Network, Toronto, ON, Canada
| | - Phillipe Abreu
- Multi-Organ Transplant Program, University Health Network, Toronto, ON, Canada
| | - Eleonora De Martin
- APHP, Hôpital Paul Brousse, Centre Hépato-Biliaire, INSERM 1193, Université Paris-Sud, DHU Hepatinov, Villejuif, France
| | - Gonzalo Sapisochin
- Multi-Organ Transplant Program, University Health Network, Toronto, ON, Canada
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Sha M, Jeong S, Xia Q. Does Donor Allograft Microsteatosis Matter? Comparison of Outcomes in Liver Transplantation With a Propensity-Matched Cohort. Liver Transpl 2019; 25:1723-1724. [PMID: 31424625 DOI: 10.1002/lt.25624] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2019] [Accepted: 08/13/2019] [Indexed: 01/13/2023]
Affiliation(s)
- Meng Sha
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Seogsong Jeong
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Qiang Xia
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
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Ahmed EA, El-Badry AM, Mocchegiani F, Montalti R, Hassan AEA, Redwan AA, Vivarelli M. Impact of Graft Steatosis on Postoperative Complications after Liver Transplantation. Surg J (N Y) 2018; 4:e188-e196. [PMID: 30474065 PMCID: PMC6193803 DOI: 10.1055/s-0038-1675236] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2018] [Accepted: 08/30/2018] [Indexed: 02/07/2023] Open
Abstract
Background Steatotic grafts are more susceptible to ischemia-reperfusion injury than are normal grafts. Therefore, using steatotic grafts for liver transplantation (LT) is associated with high primary dysfunction and decreased survival rates. The aim of this study is to evaluate the impact of graft steatosis on post LT outcomes. Methods A retrospective cohort analysis of 271 LT recipients from 2005 to 2016 was performed and patients were classified based on two types of steatosis, macrosteatosis (MaS), and microsteatosis (MiS). Each category was subdivided into three groups according to the degree of steatosis: no (< 5%), mild (≥5 to < 30%), and moderate (≥30 to ≤60%). The primary hospital stays and 6-month postoperative complications were analyzed by the Clavien-Dindo classification system. Additionally, patient and graft survivals were studied. Results Significant differences were observed in grade III MaS ( p -value = 0.019) and grade V MiS ( p -value = 0.020). A high trend of early graft dysfunction was found in the moderate MaS and MiS groups; however, they were not statistically significant ( p -value = 0.199 and 0.282, respectively). Interestingly, the acute cellular rejection (ACR) rate was found to be inversely proportional to the degree of steatosis in both categories but it did not reach a significant level ( p -value = 0.161 and 0.111, respectively). Conclusion Excellent post LT long-term outcomes using grafts with mild and moderate steatosis were determined. Further studies are needed to evaluate the newly proposed relationship between ACR and steatosis.
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Affiliation(s)
- Emad Ali Ahmed
- Division of Hepatobiliary and Abdominal Transplantation Surgery, Department of Experimental and Clinical Medicine, Polytechnic University of Marche, Ancona, Italy
- Division of Hepatobiliary and Pancreatic Surgery Unit, Department of General Surgery, University of Sohag, Sohag, Egypt
| | - Ashraf Mohammad El-Badry
- Division of Hepatobiliary and Pancreatic Surgery Unit, Department of General Surgery, University of Sohag, Sohag, Egypt
| | - Federico Mocchegiani
- Division of Hepatobiliary and Abdominal Transplantation Surgery, Department of Experimental and Clinical Medicine, Polytechnic University of Marche, Ancona, Italy
| | - Roberto Montalti
- Division of Hepatobiliary and Abdominal Transplantation Surgery, Department of Experimental and Clinical Medicine, Polytechnic University of Marche, Ancona, Italy
| | - Asem Elsani Ali Hassan
- Division of Hepatobiliary and Pancreatic Surgery Unit, Department of General Surgery, University of Sohag, Sohag, Egypt
| | - Alaa Ahmed Redwan
- Division of Hepatobiliary and Pancreatic Surgery Unit, Department of General Surgery, University of Sohag, Sohag, Egypt
| | - Marco Vivarelli
- Division of Hepatobiliary and Abdominal Transplantation Surgery, Department of Experimental and Clinical Medicine, Polytechnic University of Marche, Ancona, Italy
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Abstract
Liver transplantation is the most effective treatment for selected patients with hepatocellular carcinoma. However, cancer recurrence, posttransplantation, remains to be the critical issue that affects the long-term outcome of hepatocellular carcinoma recipients. In addition to tumor biology itself, increasing evidence demonstrates that acute-phase liver graft injury is a result of hepatic ischemia reperfusion injury (which is an inevitable consequence during liver transplantation) and may promote cancer recurrence at late phase posttransplantation. The liver grafts from living donors, donors after cardiac death, and steatotic donors have been considered as promising sources of organs for liver transplantation and are associated with high incidence of liver graft injury. The acute-phase liver graft injury will trigger a series of inflammatory cascades, which may not only activate the cell signaling pathways regulating the tumor cell invasion and migration but also mobilize the circulating progenitor and immune cells to facilitate tumor recurrence and metastasis. The injured liver graft may also provide the favorable microenvironment for tumor cell growth, migration, and invasion through the disturbance of microcirculatory barrier function, induction of hypoxia and angiogenesis. This review aims to summarize the latest findings about the role and mechanisms of liver graft injury resulted from hepatic ischemia reperfusion injury on tumor recurrence posttransplantation, both in clinical and animal cohorts.
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Hori T, Onishi Y, Kamei H, Kurata N, Ishigami M, Ishizu Y, Ogura Y. Fibrosing cholestatic hepatitis C in post-transplant adult recipients of liver transplantation. Ann Gastroenterol 2016; 29:454-459. [PMID: 27708510 PMCID: PMC5049551 DOI: 10.20524/aog.2016.0069] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2016] [Accepted: 06/06/2016] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C recurrence continues to present a major challenge in liver transplantation (LT). Approximately 10% of hepatitis C virus (HCV)-positive recipients will develop fibrosing cholestatic hepatitis (FCH) after LT. FCH is clinically characterized as marked jaundice with cholestatic hepatic dysfunction and high titers of viremia. Pathologically, FCH manifests as marked hepatocyte swelling, cholestasis, periportal peritrabecular fibrosis and only mild inflammation. This progressive form usually involves acute liver failure, and rapidly results in graft loss. A real-time and precise diagnosis based on histopathological examination and viral measurement is indispensable for the adequate treatment of FCH. Typical pathological findings of FCH are shown. Currently, carefully selected combinations of direct-acting antivirals (DAAs) offer the potential for highly effective and safe regimens for hepatitis C, both in the pre- and post-transplant settings. Here, we review FCH caused by HCV in LT recipients, and current strategies for sustained virological responses after LT. Only a few cases of successfully treated FCH C after LT by DAAs have been reported. The diagnostic findings and therapeutic dilemma are discussed based on a literature review.
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Affiliation(s)
- Tomohide Hori
- Department of Transplant Surgery (Tohomide Hori, Yasuharu Onishi, Hideya Kamei, Nobuhiko Kurata, Yasuhiro Ogura), Nagoya University Hospital, Nagoya, Japan
| | - Yasuharu Onishi
- Department of Transplant Surgery (Tohomide Hori, Yasuharu Onishi, Hideya Kamei, Nobuhiko Kurata, Yasuhiro Ogura), Nagoya University Hospital, Nagoya, Japan
| | - Hideya Kamei
- Department of Transplant Surgery (Tohomide Hori, Yasuharu Onishi, Hideya Kamei, Nobuhiko Kurata, Yasuhiro Ogura), Nagoya University Hospital, Nagoya, Japan
| | - Nobuhiko Kurata
- Department of Transplant Surgery (Tohomide Hori, Yasuharu Onishi, Hideya Kamei, Nobuhiko Kurata, Yasuhiro Ogura), Nagoya University Hospital, Nagoya, Japan
| | - Masatoshi Ishigami
- Department of Gastroenterology and Hepatology (Masatoshi Ishigami), Nagoya University Hospital, Nagoya, Japan
| | - Yoji Ishizu
- Department of Gastroenterology and Hepatology (Masatoshi Ishigami), Nagoya University Hospital, Nagoya, Japan
| | - Yasuhiro Ogura
- Department of Transplant Surgery (Tohomide Hori, Yasuharu Onishi, Hideya Kamei, Nobuhiko Kurata, Yasuhiro Ogura), Nagoya University Hospital, Nagoya, Japan
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Hori T, Onishi Y, Kamei H, Kurata N, Ishigami M, Ishizu Y, Ogura Y. Fibrosing Cholestatic Hepatitis in a Complicated Case of an Adult Recipient After Liver Transplantation: Diagnostic Findings and Therapeutic Dilemma. AMERICAN JOURNAL OF CASE REPORTS 2016; 17:597-604. [PMID: 27545580 PMCID: PMC4994933 DOI: 10.12659/ajcr.898427] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2016] [Accepted: 05/27/2016] [Indexed: 01/06/2023]
Abstract
BACKGROUND Hepatitis C recurrence is a serious matter after liver transplantation (LT). Approximately 10% of hepatitis C virus (HCV) positive recipients develop fibrosing cholestatic hepatitis (FCH). FCH rapidly results in graft loss. Currently, direct-acting antivirals (DAAs) are effective and safe for hepatitis C, even after LT. However, only a few cases of successfully treated FCH after LT have been reported. We present FCH in a complicated case with sepsis and portal flow obstruction after LT. CASE REPORT A 66-year-old man underwent cadaveric LT. Liver function disorders were observed from post-operative day (POD) 22. Sepsis repeated on POD 38, 74, and 101. Steroid pulse therapy was given from POD 40 to 54. The infectious focus was surgically removed on POD 89. Interventional radiology for portal venous obstruction was completed on POD 96. To make a real-time diagnosis and to investigate the graft condition, repeat liver needle biopsies (LNBs) were taken. Although there was a combined impact of sepsis, portal flow decrease, and recurrent hepatitis C on graft failure, it was interesting that recurrent hepatitis C was consistently detectable from the first LNB. HCV-ribonucleic acid increased on POD 68. Liver function disorders peaked on POD 71 and 72. Jaundice peaked on POD 82. DAA induction was regrettably delayed because of a reluctance to introduce DAAs under conditions of graft dysfunction. DAAs were administered after hospital discharge. CONCLUSIONS A real-time and precise diagnosis based on histopathological examination and viral measurement is important for FCH treatment. Well-considered therapy with DAAs should be aggressively introduced for potentially fatal FCH after LT.
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Nemes B, Gámán G, Polak WG, Gelley F, Hara T, Ono S, Baimakhanov Z, Piros L, Eguchi S. Extended-criteria donors in liver transplantation Part II: reviewing the impact of extended-criteria donors on the complications and outcomes of liver transplantation. Expert Rev Gastroenterol Hepatol 2016; 10:841-59. [PMID: 26831547 DOI: 10.1586/17474124.2016.1149062] [Citation(s) in RCA: 74] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Extended-criteria donors (ECDs) have an impact on early allograft dysfunction (EAD), biliary complications, relapse of hepatitis C virus (HCV), and survivals. Early allograft dysfunction was frequently seen in grafts with moderate and severe steatosis. Donors after cardiac death (DCD) have been associated with higher rates of graft failure and biliary complications compared to donors after brain death. Extended warm ischemia, reperfusion injury and endothelial activation trigger a cascade, leading to microvascular thrombosis, resulting in biliary necrosis, cholangitis, and graft failure. The risk of HCV recurrence increased by donor age, and associated with using moderately and severely steatotic grafts. With the administration of protease inhibitors sustained virological response was achieved in majority of the patients. Donor risk index and EC donor scores (DS) are reported to be useful, to assess the outcome. The 1-year survival rates were 87% and 40% respectively, for donors with a DS of 0 and 3. Graft survival was excellent up to a DS of 2, however a DS >2 should be avoided in higher-risk recipients. The 1, 3 and 5-year survival of DCD recipients was comparable to optimal donors. However ECDs had minor survival means of 85%, 78.6%, and 72.3%. The graft survival of split liver transplantation (SLT) was comparable to that of whole liver orthotopic liver transplantation. SLT was not regarded as an ECD factor in the MELD era any more. Full-right-full-left split liver transplantation has a significant advantage to extend the high quality donor pool. Hypothermic oxygenated machine perfusion can be applied clinically in DCD liver grafts. Feasibility and safety were confirmed. Reperfusion injury was also rare in machine perfused DCD livers.
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Affiliation(s)
- Balázs Nemes
- a Department of Organ Transplantation, Faculty of Medicine, Institute of Surgery , University of Debrecen , Debrecen , Hungary
| | - György Gámán
- b Clinic of Transplantation and Surgery , Semmelweis University , Budapest , Hungary
| | - Wojciech G Polak
- c Department of Surgery, Division of Hepatopancreatobiliary and Transplant Surgery, Erasmus MC , University Medical Center Rotterdam , Rotterdam , The Netherlands
| | - Fanni Gelley
- d Dept of Internal medicine and Gastroenterology , Polyclinic of Hospitallers Brothers of St. John of God , Budapest , Hungary
| | - Takanobu Hara
- e Department of Surgery , Nagasaki University Graduate School of Biomedical Sciences , Nagasaki , Japan
| | - Shinichiro Ono
- e Department of Surgery , Nagasaki University Graduate School of Biomedical Sciences , Nagasaki , Japan
| | - Zhassulan Baimakhanov
- e Department of Surgery , Nagasaki University Graduate School of Biomedical Sciences , Nagasaki , Japan
| | - Laszlo Piros
- b Clinic of Transplantation and Surgery , Semmelweis University , Budapest , Hungary
| | - Susumu Eguchi
- e Department of Surgery , Nagasaki University Graduate School of Biomedical Sciences , Nagasaki , Japan
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Nemes B, Gámán G, Polak WG, Gelley F, Hara T, Ono S, Baimakhanov Z, Piros L, Eguchi S. Extended criteria donors in liver transplantation Part I: reviewing the impact of determining factors. Expert Rev Gastroenterol Hepatol 2016; 10:827-39. [PMID: 26838962 DOI: 10.1586/17474124.2016.1149061] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
The definition and factors of extended criteria donors have already been set; however, details of the various opinions still differ in many respects. In this review, we summarize the impact of these factors and their clinical relevance. Elderly livers must not be allocated for hepatitis C virus (HCV) positives, or patients with acute liver failure. In cases of markedly increased serum transaminases, donor hemodynamics is an essential consideration. A prolonged hypotension of the donor does not always lead to an increase in post-transplantation graft loss if post-OLT care is proper. Hypernatremia of less than 160 mEq/L is not an absolute contraindication to accept a liver graft per se. The presence of steatosis is an independent and determinant risk factor for the outcome. The gold standard of the diagnosis is the biopsy. This is recommended in all doubtful cases. The use of HCV+ grafts for HCV+ recipients is comparable in outcome. The leading risk factor for HCV recurrence is the actual RNA positivity of the donor. The presence of a proper anti-HBs level seems to protect from de novo HBV infection. A favourable outcome can be expected if a donation after cardiac death liver is transplanted in a favourable condition, meaning, a warm ischemia time < 30 minutes, cold ischemia time < 8-10 hours, and donor age 50-60 years. The pathway of organ quality assessment is to obtain the most relevant information (e.g. biopsy), consider the co-existing donor risk factors and the reserve capacity of the recipient, and avoid further technical issues.
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Affiliation(s)
- Balázs Nemes
- a Department of Organ Transplantation, Faculty of Medicine , Institute of Surgery, University of Debrecen , Debrecen , Hungary
| | - György Gámán
- b Clinic of Transplantation and Surgery , Semmelweis University , Budapest , Hungary
| | - Wojciech G Polak
- c Department of Surgery, Division of Hepatopancreatobiliary and Transplant Surgery, Erasmus MC , University Medical Center Rotterdam , Rotterdam , The Netherlands
| | - Fanni Gelley
- d Department of Internal medicine and Gastroenterology , Polyclinic of Hospitallers Brothers of St. John of God , Budapest , Hungary
| | - Takanobu Hara
- e Department of Surgery , Nagasaki University Graduate School of Biomedical Sciences , Nagasaki , Japan
| | - Shinichiro Ono
- e Department of Surgery , Nagasaki University Graduate School of Biomedical Sciences , Nagasaki , Japan
| | - Zhassulan Baimakhanov
- e Department of Surgery , Nagasaki University Graduate School of Biomedical Sciences , Nagasaki , Japan
| | - Laszlo Piros
- b Clinic of Transplantation and Surgery , Semmelweis University , Budapest , Hungary
| | - Susumu Eguchi
- e Department of Surgery , Nagasaki University Graduate School of Biomedical Sciences , Nagasaki , Japan
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Grąt M, Wronka KM, Patkowski W, Stypułkowski J, Grąt K, Krasnodębski M, Masior Ł, Lewandowski Z, Krawczyk M. Effects of Donor Age and Cold Ischemia on Liver Transplantation Outcomes According to the Severity of Recipient Status. Dig Dis Sci 2016; 61:626-635. [PMID: 26499986 PMCID: PMC4729807 DOI: 10.1007/s10620-015-3910-7] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2015] [Accepted: 09/28/2015] [Indexed: 02/07/2023]
Abstract
UNLABELLED BackgroundProlonged cold ischemic time (CIT) and increased donor age are well-known factors negatively influencing outcomes after liver transplantation (LT). AIMS The aim of this study was to evaluate whether the magnitude of their negative effects is related to recipient model for end-stage liver disease (MELD) score. METHODS This retrospective study was based on a cohort of 1402 LTs, divided into those performed in low-MELD (<10), moderate-MELD (10–20), and high-MELD (>20) recipients. RESULTS While neither donor age (p = 0.775) nor CIT (p = 0.561) was a significant risk factor for worse 5-year graft survival in low-MELD recipients, both were found to yield independent effects (p = 0.003 and p = 0.012, respectively) in moderate-MELD recipients, and only CIT (p = 0.004) in high-MELD recipients. However, increased donor age only triggered the negative effect of CIT in moderate-MELD recipients, which was limited to grafts recovered from donors aged ≥46 years (p = 0.019). Notably, utilization of grafts from donors aged ≥46 years with CIT ≥9 h in moderate-MELD recipients (p = 0.003) and those with CIT ≥9 h irrespective of donor age in high-MELD recipients (p = 0.031) was associated with particularly compromised outcomes. CONCLUSIONS In conclusion, the negative effects of prolonged CIT seem to be limited to patients with moderate MELD receiving organs procured from older donors and to high-MELD recipients, irrespective of donor age. Varying effects of donor age and CIT according to recipient MELD score should be considered during the allocation process in order to avoid high-risk matches.
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Affiliation(s)
- Michał Grąt
- />Department of General, Transplant, and Liver Surgery, Medical University of Warsaw, 1A Banacha Street, 02-097 Warsaw, Poland
| | - Karolina M. Wronka
- />Department of General, Transplant, and Liver Surgery, Medical University of Warsaw, 1A Banacha Street, 02-097 Warsaw, Poland
| | - Waldemar Patkowski
- />Department of General, Transplant, and Liver Surgery, Medical University of Warsaw, 1A Banacha Street, 02-097 Warsaw, Poland
| | - Jan Stypułkowski
- />Department of General, Transplant, and Liver Surgery, Medical University of Warsaw, 1A Banacha Street, 02-097 Warsaw, Poland
| | - Karolina Grąt
- />Second Department of Clinical Radiology, Medical University of Warsaw, 1A Banacha Street, 02-097 Warsaw, Poland
| | - Maciej Krasnodębski
- />Department of General, Transplant, and Liver Surgery, Medical University of Warsaw, 1A Banacha Street, 02-097 Warsaw, Poland
| | - Łukasz Masior
- />Department of General, Transplant, and Liver Surgery, Medical University of Warsaw, 1A Banacha Street, 02-097 Warsaw, Poland
| | - Zbigniew Lewandowski
- />Department of Epidemiology, Medical University of Warsaw, 3 Oczki Street, 02-007 Warsaw, Poland
| | - Marek Krawczyk
- />Department of General, Transplant, and Liver Surgery, Medical University of Warsaw, 1A Banacha Street, 02-097 Warsaw, Poland
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Burra P, De Martin E, Zanetto A, Senzolo M, Russo FP, Zanus G, Fagiuoli S. Hepatitis C virus and liver transplantation: where do we stand? Transpl Int 2016; 29:135-152. [PMID: 26199060 DOI: 10.1111/tri.12642] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2015] [Revised: 03/06/2015] [Accepted: 07/15/2015] [Indexed: 12/14/2022]
Abstract
The hepatitis C virus (HCV) infects more than 180 million people globally, with increasing incidence, especially in developing countries. HCV infection frequently progresses to liver cirrhosis leading to liver transplantation or death, and HCV recurrence still constitutes a major challenge for the transplant team. Antiviral therapy is the only available instrument to slow down this process, although its actual impact on liver histology, in responders and nonresponders, is still controversial. We are now facing a "new era" of direct antiviral agents that is already changing the approach to HCV burden both in the pre- and in the post-liver transplantation settings. Available data on sofosbuvir/ledipasvir and sofosbuvir/simeprevir in patients with decompensated cirrhosis sustain a SVR12 of 89% , but one-third of patients do not clinically improved. The sofosbuvir/ribavirin treatment in stable cirrhotic patients with HCC before liver transplantation is associated with 2% recurrence rate if liver transplantation is performed at least one month after undetectable HCV-RNA is achieved. The treatment of recurrence with the new antiviral drugs is associated with a SVR that ranges between 60 and 90%. In this review, we have focused on the evolution of antiviral therapy for HCV recurrence from the "old" interferon-based therapy to the "new" interferon-free regimens, highlighting useful information to aid the transplant hepatologist in the clinical practice.
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Affiliation(s)
- Patrizia Burra
- Multivisceral Transplant Unit, Gastroenterology, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, Padua, Italy
| | - Eleonora De Martin
- Multivisceral Transplant Unit, Gastroenterology, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, Padua, Italy
- Centre Hepato-Biliaire Paul Brousse, Villejuif, France
| | - Alberto Zanetto
- Multivisceral Transplant Unit, Gastroenterology, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, Padua, Italy
| | - Marco Senzolo
- Multivisceral Transplant Unit, Gastroenterology, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, Padua, Italy
| | - Francesco Paolo Russo
- Multivisceral Transplant Unit, Gastroenterology, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, Padua, Italy
| | - Giacomo Zanus
- Hepatobiliary Surgery and Liver Transplantation Unit, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, Padua, Italy
| | - Stefano Fagiuoli
- Gastroenterology and Transplant Hepatology, Papa Giovanni XXIII Hospital, Bergamo, Italy
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12
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Mitchell O, Gurakar A. Management of Hepatitis C Post-liver Transplantation: a Comprehensive Review. J Clin Transl Hepatol 2015; 3:140-8. [PMID: 26357641 PMCID: PMC4548349 DOI: 10.14218/jcth.2015.00005] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2015] [Revised: 03/19/2015] [Accepted: 03/22/2015] [Indexed: 02/07/2023] Open
Abstract
Infection with hepatitis C virus (HCV) is a common cause of chronic liver disease, and HCV-related cirrhosis and hepatocellular carcinoma are the leading causes for liver transplantation in the Western world. Recurrent infection of the transplanted liver allograft is universal in patients with detectable HCV viremia at the time of transplant and can cause a spectrum of disease, ranging from asymptomatic chronic infection to an aggressive fibrosing cholestatic hepatitis. Recurrent HCV is more aggressive in the post-transplant population and is a leading cause of allograft loss, morbidity, and mortality. Historically, treatment of recurrent HCV has been limited by low rates of treatment success and high side effect profiles. Over the past few years, promising new therapies have emerged for the treatment of HCV that have high rates of sustained virological response without the need for interferon based regimens. In addition to being highly effective, these treatments have higher rates of adherence and a lower side effect profile. The purpose of this review is to summarize current therapies in recurrent HCV infection, to review the recent advances in therapy, and to highlight areas of ongoing research.
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Affiliation(s)
- Oscar Mitchell
- Department of Transplant Hepatology, Division of Gastroenterology and Hepatology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Ahmet Gurakar
- Department of Transplant Hepatology, Division of Gastroenterology and Hepatology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
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13
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Xia W, Ke Q, Wang Y, Feng X, Guo H, Wang W, Zhang M, Shen Y, Wu J, Xu X, Yan S, Zheng S. Donation after cardiac death liver transplantation: Graft quality evaluation based on pretransplant liver biopsy. Liver Transpl 2015; 21:838-846. [PMID: 25824672 DOI: 10.1002/lt.24123] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2014] [Accepted: 03/18/2015] [Indexed: 02/05/2023]
Abstract
Donation after cardiac death (DCD) liver grafts are associated with inferior clinical outcomes and high discard rates because of poor graft quality. We investigated the predictive value of DCD liver biopsy for the pretransplant graft quality evaluation. DCD liver transplants that took place between October 2010 and April 2014 were included (n = 127). Histological features of graft biopsy samples were analyzed to assess risk factors for graft survival. Macrovesicular steatosis ≥ 20% [hazard ratio (HR) = 2.973; P = 0.045] and sinusoidal neutrophilic infiltrate (HR = 6.969; P = 0.005) were confirmed as independent risk factors for graft survival; hepatocellular swelling, vacuolation, and necrosis failed to show prognostic value. Additionally, a donor serum total bilirubin level ≥ 34.2 μmol/L was also associated with a lower probability of graft survival. Our analysis indicates that macrovesicular steatosis ≥ 20% and sinusoidal neutrophilic infiltrate are novel and useful histological markers for DCD liver grafts with unacceptable quality. This finding can be used by transplant surgeons to improve DCD liver acceptance protocols.
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Affiliation(s)
- Weiliang Xia
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Zhejiang University, Hangzhou, China
- Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Qinghong Ke
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Zhejiang University, Hangzhou, China
- Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Ye Wang
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Zhejiang University, Hangzhou, China
- Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Xiaowen Feng
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Zhejiang University, Hangzhou, China
- Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Haijun Guo
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Zhejiang University, Hangzhou, China
- Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Weilin Wang
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Zhejiang University, Hangzhou, China
- Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Min Zhang
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Zhejiang University, Hangzhou, China
- Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Yan Shen
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Zhejiang University, Hangzhou, China
- Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Jian Wu
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Zhejiang University, Hangzhou, China
- Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Xiao Xu
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Zhejiang University, Hangzhou, China
- Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Sheng Yan
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Zhejiang University, Hangzhou, China
- Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Shusen Zheng
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Zhejiang University, Hangzhou, China
- Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
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Kakati B, Seetharam A. Hepatitis C Recurrence after Orthotopic Liver Transplantation: Mechanisms and Management. J Clin Transl Hepatol 2014; 2:189-96. [PMID: 26355427 PMCID: PMC4521242 DOI: 10.14218/jcth.2014.00016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2014] [Revised: 06/06/2014] [Accepted: 07/07/2014] [Indexed: 12/04/2022] Open
Abstract
Chronic Hepatitis C (HCV) infection is the leading indication for orthotopic liver transplantation and recurrence is nearly universal. Chronic HCV infection is frequently established through evasion of the innate immune system. Priming of adaptive immune responses modulate the severity and rate of fibrosis progression. Those with demonstrable viremia entering the transplant period uniformly suffer recurrence post-transplant. Progression to cirrhosis is accelerated post-transplant secondary to systemic immunosuppression. In addition, a number of factors, including donor, host, and viral characteristics, influence severity and rate of fibrosis progression. Interferon-based therapy, the previous standard of care, in those with advanced cirrhosis or post-transplant has been limited by a number of issues. These include a relative lack of efficacy and poor tolerability with higher incidence of infection and anemia. Recently, approval of direct acting antivirals have ushered in a new era in HCV therapeutics and have applicability in these special populations. Their use immediately prior to or post-transplant is expected to improve both morbidity and mortality.
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Affiliation(s)
- Bobby Kakati
- Banner Transplant and Advanced Liver Disease Center, Phoenix, AZ, USA
| | - Anil Seetharam
- Banner Transplant and Advanced Liver Disease Center, Phoenix, AZ, USA
- University of Arizona College of Medicine-Phoenix, Phoenix, AZ, USA
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15
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Grassi A, Ballardini G. Post-liver transplant hepatitis C virus recurrence: an unresolved thorny problem. World J Gastroenterol 2014; 20:11095-11115. [PMID: 25170198 PMCID: PMC4145752 DOI: 10.3748/wjg.v20.i32.11095] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2013] [Revised: 02/15/2014] [Accepted: 05/29/2014] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV)-related cirrhosis represents the leading cause of liver transplantation in developed, Western and Eastern countries. Unfortunately, liver transplantation does not cure recipient HCV infection: reinfection universally occurs and disease progression is faster after liver transplant. In this review we focus on what happens throughout the peri-transplant phase and in the first 6-12 mo after transplantation: during this crucial period a completely new balance between HCV, liver graft, the recipient's immune response and anti-rejection therapy is achieved that will deeply affect subsequent outcomes. Nearly all patients show an early graft reinfection, with HCV viremia reaching and exceeding pre-transplant levels; in this setting, histological assessment is essential to differentiate recurrent hepatitis C from acute or chronic rejection; however, differentiating the two patterns remains difficult. The host immune response (mainly cellular mediated) appears to be crucial both in the control of HCV infection and in the genesis of rejection, and it is also strongly influenced by immunosuppressive treatment. At present no clear immunosuppressive strategy could be strongly recommended in HCV-positive recipients to prevent HCV recurrence, even immunotherapy appears to be ineffective. Nonetheless it seems reasonable that episodes of rejection and over-immunosuppression are more likely to enhance the risk of HCV recurrence through immunological mechanisms. Both complete prevention of rejection and optimization of immunosuppression should represent the main goals towards reducing the rate of graft HCV reinfection. In conclusion, post-transplant HCV recurrence remains an unresolved, thorny problem because many factors remain obscure and need to be better determined.
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16
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Vasuri F, Malvi D, Gruppioni E, Grigioni WF, D’Errico-Grigioni A. Histopathological evaluation of recurrent hepatitis C after liver transplantation: A review. World J Gastroenterol 2014; 20:2810-2824. [PMID: 24659874 PMCID: PMC3961976 DOI: 10.3748/wjg.v20.i11.2810] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2013] [Revised: 11/08/2013] [Accepted: 12/13/2013] [Indexed: 02/06/2023] Open
Abstract
Although the morphological features of hepatitis C virus (HCV) recurrence after orthotopic liver transplantation (OLT) have been well established in the last decades, the differential diagnosis still represents a challenge for the pathologist, especially early recurrent hepatitis C vs mild acute cellular rejection. The present review focuses on the role of the pathologist and the pathology laboratory in the management of recipients with recurrent hepatitis C, the usefulness of early and late post-OLT liver biopsies, and the potential role of ancillary techniques (immunohistochemistry and reverse transcription-polymerase chain reaction, RT-PCR). The English literature on the topic is reviewed, focusing on the histopathology, the immunohistochemistry and the use of RT-PCR on HCV-positive post-OLT biopsies. The different histopathological illustrations of early and chronic recurrent hepatitis C are presented, with special focus on the main differential diagnoses and those features with prognostic relevance (cholestasis above all). The usefulness of ancillary techniques are discussed, especially HCV RNA quantitation by RT-PCR. Finally, the usefulness of long-term protocol biopsies is addressed: their usefulness for the study of allograft disease progression is clear, but their meaning in the long term is still debated. The significance of plasma cell infiltrate in HCV-positive allografts, the prognostic weight of graft steatosis, and the impact of donor age in recurrent hepatitis C also represent additional open issues.
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17
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Subramanian V, Bharat A, Vachharajani N, Crippin J, Shenoy S, Mohanakumar T, Chapman WC. Perioperative blood transfusion affects hepatitis C virus (HCV)-specific immune responses and outcome following liver transplantation in HCV-infected patients. HPB (Oxford) 2014; 16:282-94. [PMID: 23869514 PMCID: PMC3945855 DOI: 10.1111/hpb.12128] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2012] [Accepted: 04/09/2013] [Indexed: 12/12/2022]
Abstract
OBJECTIVES Perioperative factors can affect outcomes of liver transplantation (LT) in recipients with hepatitis C virus (HCV) infection. This study was conducted to investigate whether the immunomodulatory effects of packed red blood cells (PRBC) and platelets administered in the perioperative period might affect immune responses to HCV and thus outcomes in LT recipients. METHODS Data for a total of 257 HCV LT recipients were analysed. Data on clinical demographics including perioperative transfusion (during and within the first 24 h), serum cytokine concentration, HCV-specific interferon-γ (IFN-γ) and interleukin-17 (IL-17) producing cells, and outcomes including graft and patient survival were analysed. RESULTS Patient survival was higher in HCV LT recipients who did not receive transfusions (Group 1, n = 65) than in those who did (Group 2, n = 192). One-year patient survival was 95% in Group 1 and 88% in Group 2 (P = 0.02); 5-year survival was 77% in Group 1 and 66% in Group 2 (P = 0.05). Group 2 had an increased post-transplant viral load (P = 0.032) and increased incidence of advanced fibrosis at 1 year (P = 0.04). After LT, Group 2 showed increased IL-10, IL-17, IL-1β and IL-6, and decreased IFN-γ, and a significantly increased rate of IL-17 production against HCV antigen. Increasing donor age (P = 0.02), PRBC transfusion (P < 0.01) and platelets administration were associated with worse survival. CONCLUSIONS Transfusion had a negative impact on LT recipients with HCV. The associated early increase in pro-HCV IL-17 and IL-6, with decreased IFN-γ, suggests that transfusion may be associated with the modulation of HCV-specific responses, increased fibrosis and poor transplant outcomes.
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Affiliation(s)
- Vijay Subramanian
- Department of Surgery, Washington University School of MedicineSt Louis, MO, USA
| | - Ankit Bharat
- Department of Surgery, Washington University School of MedicineSt Louis, MO, USA
| | - Neeta Vachharajani
- Department of Surgery, Washington University School of MedicineSt Louis, MO, USA
| | - Jeffrey Crippin
- Department of Medicine, Washington University School of MedicineSt Louis, MO, USA
| | - Surendra Shenoy
- Department of Surgery, Washington University School of MedicineSt Louis, MO, USA
| | - Thalachallour Mohanakumar
- Department of Surgery, Washington University School of MedicineSt Louis, MO, USA,Pathology and Immunology, Washington University School of MedicineSt Louis, MO, USA
| | - William C Chapman
- Department of Surgery, Washington University School of MedicineSt Louis, MO, USA,Correspondence William C. Chapman, Department of Surgery, Washington University School of Medicine, Box 8109, 6107 Queeny Tower, 660 South Euclid Avenue, St Louis, MO 63110, USA. Tel: + 1 314 362 7792. Fax: + 1 314 361 4197. E-mail:
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18
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Dunn W, O'Neil M, Zhao J, Wu CH, Roberts B, Chakraborty S, Sherman C, Weaver B, Taylor R, Olson J, Olyaee M, Gilroy R, Schmitt T, Wan YJY, Weinman SA. Donor PNPLA3 rs738409 genotype affects fibrosis progression in liver transplantation for hepatitis C. Hepatology 2014; 59:453-60. [PMID: 24123231 PMCID: PMC7224311 DOI: 10.1002/hep.26758] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2012] [Revised: 08/12/2013] [Accepted: 09/17/2013] [Indexed: 12/18/2022]
Abstract
UNLABELLED The rs738409 G>C single nucleotide polymorphism occurring in the patatin-like phospholipase 3 gene has been identified as a novel genetic marker for hepatic steatosis. Recent studies also associated rs738409 with fibrosis in hepatitis C (HCV). Therefore, we sought to determine the impact of donor and recipient rs738409 genotype on the progression of fibrosis after liver transplantation for HCV. This cohort study included 101 patients infected with HCV who underwent liver transplantation between January 2008, and June 2011. Donor and recipient rs738409 genotypes were determined from donor wedge biopsies and recipient explants. The time to Ishak stage 3 fibrosis, or HCV-related mortality/graft loss was analyzed by the Cox model adjusting for HCV-Donor Risk Index, warm ischemic time, pretransplant Model for Endstage Liver Disease (MELD) and viral load. The rs738409 CC variant was present in 56% of donors and 57% of recipients. The median follow-up period was 620 days. A total of 39 patients developed the primary outcome of ≥stage 3 fibrosis or HCV-related mortality/graft loss, the time to which differed by donor (P = 0.019) but not recipient (P = 0.89) genotype. In the multivariate model, donor GC or GG variants had 2.53 times the risk (95% confidence interval [CI] 1.25-5.02, P = 0.008) compared to CC variants. In the alternative endpoint: stage 3 fibrosis or all-cause mortality/graft loss, the effect of donor genotype was attenuated but remained significant at 1.98 (95% CI 1.11-3.53). CONCLUSIONS The rs738409 genotype is an important predictor of posttransplant outcome in HCV. Liver, and not adipocytes, is the site at which this effect occurs. Our finding may be useful in donor selection for liver transplantation with HCV, and may guide decisions regarding early antiviral treatment.
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Affiliation(s)
- Winston Dunn
- Department of Internal Medicine; University of Kansas Medical Center; Kansas City KS
| | - Maura O'Neil
- Department of Internal Medicine; University of Kansas Medical Center; Kansas City KS
| | - Jie Zhao
- Department of Internal Medicine; University of Kansas Medical Center; Kansas City KS
| | - Chuang Hong Wu
- Department of Internal Medicine; University of Kansas Medical Center; Kansas City KS
| | - Benjamin Roberts
- Department of Internal Medicine; University of Kansas Medical Center; Kansas City KS
| | - Shweta Chakraborty
- Department of Internal Medicine; University of Kansas Medical Center; Kansas City KS
| | - Craig Sherman
- Department of Internal Medicine; University of Kansas Medical Center; Kansas City KS
| | - Brandy Weaver
- Department of Internal Medicine; University of Kansas Medical Center; Kansas City KS
| | - Ryan Taylor
- Department of Internal Medicine; University of Kansas Medical Center; Kansas City KS
| | - Jody Olson
- Department of Internal Medicine; University of Kansas Medical Center; Kansas City KS
| | - Mojtaba Olyaee
- Department of Internal Medicine; University of Kansas Medical Center; Kansas City KS
| | - Richard Gilroy
- Department of Internal Medicine; University of Kansas Medical Center; Kansas City KS
| | - Timothy Schmitt
- Department of Internal Medicine; University of Kansas Medical Center; Kansas City KS
| | - Yu-Jui Yvonne Wan
- Department of Internal Medicine; University of Kansas Medical Center; Kansas City KS
| | - Steven A. Weinman
- Department of Internal Medicine; University of Kansas Medical Center; Kansas City KS
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19
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Howell J, Angus P, Gow P. Hepatitis C recurrence: the Achilles heel of liver transplantation. Transpl Infect Dis 2013; 16:1-16. [PMID: 24372756 DOI: 10.1111/tid.12173] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2013] [Revised: 06/12/2013] [Accepted: 08/03/2013] [Indexed: 12/18/2022]
Abstract
Hepatitis C virus (HCV) infection is the most common indication for liver transplantation worldwide; however, recurrence post transplant is almost universal and follows an accelerated course. Around 30% of patients develop aggressive HCV recurrence, leading to rapid fibrosis progression (RFP) and culminating in liver failure and either death or retransplantation. Despite many advances in our knowledge of clinical risks for HCV RFP, we are still unable to accurately predict those most at risk of adverse outcomes, and no clear consensus exists on the best approach to management. This review presents a critical overview of clinical factors shown to influence the course of HCV recurrence post transplant, with particular focus on recent data identifying the important role of metabolic factors, such as insulin resistance, in HCV recurrence. Emerging data for genetic markers of HCV recurrence and their usefulness for predicting adverse outcomes will also be explored.
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Affiliation(s)
- J Howell
- Liver Transplant Unit, Austin Hospital, Melbourne, Australia; Department of Medicine, University of Melbourne, Melbourne, Australia
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20
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Chavin KD, Taber DJ, Norcross M, Pilch NA, Crego H, McGillicuddy JW, Bratton CF, Lin A, Baliga PK. Safe use of highly steatotic livers by utilizing a donor/recipient clinical algorithm. Clin Transplant 2013; 27:732-41. [PMID: 23991646 DOI: 10.1111/ctr.12211] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/18/2013] [Indexed: 01/23/2023]
Abstract
The aim of this study was to assess the long-term safety and clinical outcomes associated with the utilization of highly steatotic donor livers utilizing a specific donor/recipient matching algorithm. This was a prospective, observational, single-center, 10-yr follow-up study. Highly steatotic livers were utilized according to a donor/recipient algorithm that guided the surgeon to use highly steatotic donor organs judiciously in low-risk recipients. This study initially compared fat assessment based on frozen-section Ehrlich's hematoxylin and eosin (H&E) to reperfusion biopsy fat assessment and demonstrated that H&E is an insensitive analysis to determine degree of steatosis. Patients were divided into three groups based on donor steatosis (group 1: <30% steatosis, group 2: 30-60% steatosis, group 3: >60% steatosis), and clinical outcomes were assessed. One hundred and sixteen patients were included in the analysis. Patients that received severely steatotic livers (>60% fat) showed increased reperfusion liver injury and delayed return of liver function in the early postoperative period, demonstrated by biochemical markers. However, there were no differences in primary non-function, postoperative complications, length of stay, and patient and graft survival. Using rigorous donor/recipient matching through a detailed algorithm, these data demonstrate that normal liver allograft outcomes are not superior to those in highly steatotic grafts.
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Affiliation(s)
- Kenneth D Chavin
- Division of Transplantation, Department of Surgery, Medical University of South Carolina, Charleston, SC, USA
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21
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Gelley F, Gámán G, Gerlei Z, Zádori G, Görög D, Kóbori L, Fehérvári I, Schuller J, Szőnyi L, Nagy P, Doros A, Fazakas J, Lengyel G, Schaff Z, Kiss A, Sárváry E, Nemes B. Hepatitis C virus recurrence after liver transplantation in Hungary. Trends over the past 10 years. Orv Hetil 2013; 154:1058-66. [DOI: 10.1556/oh.2013.29647] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Introduction: Management of hepatitis C virus recurrence is a challenge after liver transplantation. Aim: The aim of the authors was to analyse the outcome of liver transplantation performed in hepatitis C virus positive patients during the past ten years and to compare recent data with a previous report of the authors. Method: The authors retrospectively evaluated the data (donors, recipients, perioperative characteristics, patient and graft survival, serum titer of hepatitis C virus RNA, histology) of 409 patients who underwent liver transplantation between 2003 and 2012. Results: 156 patients were transplanted due to hepatitis C virus associated liver cirrhosis (38%). Worse outcome was observed in these patients in comparison to hepatitis C virus negative recipients. The cumulative patient survival rates at 1, 5, and 10 year were 80%, 61%, 51% in the hepatitis C virus positive group and 92%, 85%, 79% in the hepatitis C virus negative group, respectively (p<0.001). The cumulative graft survival rates at 1, 5 and 10 year were 79%, 59% and 50% in hepatitis C virus positive and 89%, 80% and 70% in hepatitis C virus negative patients (p<0.001). Hepatitis C virus recurrence was observed in the majority of the patients (132 patients, 85%), mainly within the first year (83%). The authors observed recurrence within 6 months in 71 patients (56%), and within 3 months in 26 patients (20%). The mean hepatitis C virus recurrence free survival was 243 days. Higher rate of de novo diabetes was detected in case of early recurrence. The cumulative patient survival rates at 1, 3, 5, 10 years were 98%, 89.5%, 81% and 65% when hepatitis C virus recurrence exceeded 3 months and 64%, 53%, 30.5% and 30.5% in patients with early recurrence (p<0.001). Conclusions: Poor outcome of liver transplantation in hepatitis C virus positive patients is still a challenge. Hepatitis C virus recurrence is observed earlier after liver transplantation in comparison with a previous report of the authors. De novo diabetes occurs more frequently in case of early recurrence. Despite an immediate start of antiviral treatment, early recurrence has a significant negative impact on the outcome of transplantation. Orv. Hetil., 2013, 154, 1058–1066.
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Affiliation(s)
- Fanni Gelley
- Semmelweis Egyetem, Általános Orvostudományi Kar Transzplantációs és Sebészeti Klinika Budapest
| | - György Gámán
- Semmelweis Egyetem, Általános Orvostudományi Kar Transzplantációs és Sebészeti Klinika Budapest
| | - Zsuzsanna Gerlei
- Semmelweis Egyetem, Általános Orvostudományi Kar Transzplantációs és Sebészeti Klinika Budapest
| | - Gergely Zádori
- Semmelweis Egyetem, Általános Orvostudományi Kar Transzplantációs és Sebészeti Klinika Budapest
| | - Dénes Görög
- Semmelweis Egyetem, Általános Orvostudományi Kar Transzplantációs és Sebészeti Klinika Budapest
| | - László Kóbori
- Semmelweis Egyetem, Általános Orvostudományi Kar Transzplantációs és Sebészeti Klinika Budapest
| | - Imre Fehérvári
- Semmelweis Egyetem, Általános Orvostudományi Kar Transzplantációs és Sebészeti Klinika Budapest
| | - János Schuller
- Egyesített Szent István és Szent László Kórház – Rendelőintézet Hepatológiai Osztály Budapest
| | - László Szőnyi
- Semmelweis Egyetem, Általános Orvostudományi Kar I. Gyermekgyógyászati Klinika, Általános Belgyógyászati és Gasztroenterológiai Osztály Budapest
| | - Péter Nagy
- Semmelweis Egyetem, Általános Orvostudományi Kar I. Patológiai és Kísérleti Rákkutató Intézet Budapest
| | - Attila Doros
- Semmelweis Egyetem, Általános Orvostudományi Kar Transzplantációs és Sebészeti Klinika Budapest
| | - János Fazakas
- Semmelweis Egyetem, Általános Orvostudományi Kar Transzplantációs és Sebészeti Klinika Budapest
| | - Gabriella Lengyel
- Semmelweis Egyetem, Általános Orvostudományi Kar II. Belgyógyászati Klinika Budapest
| | - Zsuzsa Schaff
- Semmelweis Egyetem, Általános Orvostudományi Kar II. Patológiai Intézet Budapest
| | - András Kiss
- Semmelweis Egyetem, Általános Orvostudományi Kar II. Patológiai Intézet Budapest
| | - Enikő Sárváry
- Semmelweis Egyetem, Általános Orvostudományi Kar Transzplantációs és Sebészeti Klinika Budapest
| | - Balázs Nemes
- Semmelweis Egyetem, Általános Orvostudományi Kar Transzplantációs és Sebészeti Klinika Budapest
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Gehrau RC, Mas VR, Villamil FG, Dumur CI, Mehta NK, Suh JL, Maluf DG. MicroRNA signature at the time of clinical HCV recurrence associates with aggressive fibrosis progression post-liver transplantation. Am J Transplant 2013; 13:729-37. [PMID: 23312020 DOI: 10.1111/ajt.12047] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2012] [Revised: 10/08/2012] [Accepted: 11/02/2012] [Indexed: 01/25/2023]
Abstract
Diagnosis and prediction of the severity of hepatitis C virus recurrence (HCVrec) after liver transplantation (LT) remain a challenge. MicroRNAs have been recently recognized as potential disease biomarkers. Archival liver biopsy samples from 43 HCV+ LT recipients were collected at clinical HCVrec time and at 3 years post-LT. Patients were classified as progressors (P = F0/F1) or nonprogressors (NP = F3/F4) according to the severity of fibrosis on the 3-year biopsy. Training (n = 27) and validation (n = 16) sets were defined. RNA was isolated from all biopsies at clinical HCVrec time, labeled and hybridized to miRNA-arrays. Progressors versus nonprogressors were compared using the two-sample t-test. A p-value ≤0.01 was considered significant. The ingenuity pathway analysis tool was used for microRNA and miRNA:mRNA ontology data integration. Nine microRNAs were differentially expressed between groups. A supervised cluster analysis separated samples in two well-defined groups (progressors vs. nonprogressors). Pathway analysis associated those microRNAs with hepatitis, steatosis, fibrosis, cirrhosis and T cell-related immune response. Data integration identified 17 genes from a previous genomic study as 9-microRNAs signature targets. Seven microRNAs were successfully validated in the validation set using QPCR. We have identified a 9-microRNA signature able to identify early post-LT patients at high risk of severe HCVrec during long-term follow-up.
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Affiliation(s)
- R C Gehrau
- Transplant Division, Department of Surgery, University of Virginia, Charlottesville, VA, USA
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Akamatsu N, Sugawara Y. Living-donor liver transplantation and hepatitis C. HPB SURGERY : A WORLD JOURNAL OF HEPATIC, PANCREATIC AND BILIARY SURGERY 2013; 2013:985972. [PMID: 23401640 PMCID: PMC3564275 DOI: 10.1155/2013/985972] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 05/17/2012] [Accepted: 01/01/2013] [Indexed: 12/19/2022]
Abstract
Hepatitis-C-virus- (HCV-) related end-stage cirrhosis is the primary indication for liver transplantation in many countries. Unfortunately, however, HCV is not eliminated by transplantation and graft reinfection is universal, resulting in fibrosis, cirrhosis, and finally graft decompression. In areas with low deceased-donor organ availability like Japan, living-donor liver transplantation (LDLT) is similarly indicated for HCV cirrhosis as deceased-donor liver transplantation (DDLT) in Western countries and accepted as an established treatment for HCV-cirrhosis, and the results are equivalent to those of DDLT. To prevent graft failure due to recurrent hepatitis C, antiviral treatment with pegylated-interferon and ribavirin is currently considered the most promising regimen with a sustained viral response rate of around 30% to 35%, although the survival benefit of this regimen remains to be investigated. In contrast to DDLT, many Japanese LDLT centers have reported modified treatment regimens as best efforts to secure first graft, such as aggressive preemptive antiviral treatment, escalation of dosages, and elongation of treatment duration.
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Affiliation(s)
- Nobuhisa Akamatsu
- Department of Hepato-Biliary-Pancreatic Surgery, Saitama Medical Center, Saitama Medical University, 1981 Tsujido-cho, Kamoda, Kawagoe, Saitama 350-8550, Japan
- Artificial Organ and Transplantation Division, Department of Surgery, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
| | - Yasuhiko Sugawara
- Artificial Organ and Transplantation Division, Department of Surgery, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
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Akamatsu N, Sugawara Y. Liver transplantation and hepatitis C. Int J Hepatol 2012; 2012:686135. [PMID: 22900194 PMCID: PMC3412106 DOI: 10.1155/2012/686135] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2012] [Accepted: 05/21/2012] [Indexed: 02/07/2023] Open
Abstract
Hepatitis-C-virus- (HCV-) related end-stage cirrhosis is the primary indication for liver transplantation in many countries. Unfortunately, however, HCV is not eliminated by transplantation and graft reinfection is universal, resulting in fibrosis, cirrhosis, and finally graft decompensation. The use of poor quality organs, particularly from older donors, has a highly negative impact on the severity of recurrence and patient/graft survival. Although immunosuppressive regimens have a considerable impact on the outcome, the optimal regimen after liver transplantation for HCV-infected patients remains unclear. Disease progression monitoring with protocol biopsy and new noninvasive methods is essential for predicting patient/graft outcome and starting antiviral treatment with the appropriate timing. Antiviral treatment with pegylated interferon and ribavirin is currently considered the most promising regimen with a sustained viral response rate of around 30% to 35%, although the survival benefit of this regimen remains to be investigated. Living-donor liver transplantation is now widely accepted as an established treatment for HCV cirrhosis and the results are equivalent to those of deceased donor liver transplantation.
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Affiliation(s)
- Nobuhisa Akamatsu
- Department of Hepato-Biliary-Pancreatic Surgery, Saitama Medical Center, Saitama Medical University, 1981 Tsujido-cho, Kamoda, Kawagoe, Saitama 350-8550, Japan
- Artificial Organ and Transplantation Division, Department of Surgery, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
| | - Yasuhiko Sugawara
- Artificial Organ and Transplantation Division, Department of Surgery, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
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Germani G, Tsochatzis E, Papastergiou V, Burroughs AK. HCV in liver transplantation. Semin Immunopathol 2012; 35:101-10. [PMID: 22829333 DOI: 10.1007/s00281-012-0329-5] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2012] [Accepted: 07/01/2012] [Indexed: 12/23/2022]
Abstract
HCV-related cirrhosis represents the leading indication for liver transplantation in the Western countries. HCV reinfection after liver transplantation occurs in virtually all patients transplanted for HCV-related liver disease Histological evidence of chronic HCV infection develops in 50 to 90 % of patients by 12 months after liver transplantation, and cirrhosis occurs in about 20 % of patients within 5 years after transplant. Several studies have evaluated host, viral, and transplant-related factors that might be associated with the severity of HCV recurrence. Among host factors, immunosuppression is one of the major factors that accounts for accelerated HCV recurrence and it has been an area of extensive research and controversy. Donor age, steatosis, and immunogenetic factors are also relevant in determining the outcome in patients transplanted for HCV-related cirrhosis. A major step to prevent complications of HCV recurrence related to the rapid fibrosis is the posttransplant antiviral treatment. Two strategies have been tried: pre-emptive or other strategies as soon as possible after liver transplantation or elective therapy once there is histological evidence of recurrent hepatitis C. Retransplantation due to graft failure from recurrent hepatitis C is rarely an option in the era of organ shortage as it is associated with poor outcome, but many case needs to be considered early in the evolution of disease. New antivirals may change the outcome dramatically of patients transplanted for HCV cirrhosis.
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Affiliation(s)
- Giacomo Germani
- The Royal Free Sheila Sherlock Liver Centre and University Department of Surgery, Royal Free Hospital and UCL, London, UK
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Shackel NA. When has the horse bolted? J Gastroenterol Hepatol 2012; 27:1133-4. [PMID: 22712704 DOI: 10.1111/j.1440-1746.2012.07164.x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
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