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Liu X, Wang J, Li F, Timchenko N, Tsai RYL. Transcriptional control of a stem cell factor nucleostemin in liver regeneration and aging. PLoS One 2024; 19:e0310219. [PMID: 39259742 PMCID: PMC11389944 DOI: 10.1371/journal.pone.0310219] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2024] [Accepted: 08/27/2024] [Indexed: 09/13/2024] Open
Abstract
Nucleostemin (NS) plays a role in liver regeneration, and aging reduces its expression in the baseline and regenerating livers following 70% partial hepatectomy (PHx). Here we interrogate the mechanism controlling NS expression during liver regeneration and aging. The NS promoter was analyzed by TRANSFAC. Functional studies were performed using cell-based luciferase assay, endogenous NS expression in Hep3B cells, mouse livers with a gain-of-function mutation of C/EBPα (S193D), and mouse livers with C/EBPα knockdown. We found a CAAT box with four C/EBPα binding sites (-1216 to -735) and a GC box with consensus binding sites for c-Myc, E2F1, and p300-associated protein complex (-633 to -1). Age-related changes in NS expression correlated positively with the expression of c-Myc, E2F1, and p300, and negatively with that of C/EBPα and C/EBPβ. PHx upregulated NS expression at 1d, coinciding with an increase in E2F1 and a decrease in C/EBPα. C/EBPα bound to the consensus sequences found in the NS promoter in vitro and in vivo, inhibited its transactivational activity in a binding site-dependent manner, and decreased the expression of endogenous NS in Hep3B cells. In vivo activation of C/EBPα by the S193D mutation resulted in a 4th-day post-PHx reduction of NS, a feature shared by 16-m/o livers. Finally, C/EBPα knockdown increased its expression in aged (24-m/o) livers under both baseline and regeneration conditions. This study reports the C/EBPα suppression of NS expression in aged livers, providing a new perspective on the mechanistic orchestration of tissue homeostasis in aging.
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Affiliation(s)
- Xiaoqin Liu
- Institute of Biosciences and Technology, Texas A&M Health, Houston, TX, United States of America
- Department of Translational Medical Sciences, Texas A&M University School of Medicine, Bryan, TX, United States of America
| | - Junying Wang
- Institute of Biosciences and Technology, Texas A&M Health, Houston, TX, United States of America
| | - Fang Li
- Institute of Biosciences and Technology, Texas A&M Health, Houston, TX, United States of America
| | - Nikolai Timchenko
- Department of Surgery, Cincinnati Children Hospital Medical Center, University of Cincinnati, Cincinnati, OH, United States of America
| | - Robert Y L Tsai
- Institute of Biosciences and Technology, Texas A&M Health, Houston, TX, United States of America
- Department of Translational Medical Sciences, Texas A&M University School of Medicine, Bryan, TX, United States of America
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Wang J, Zhang W, Liu X, Kim M, Zhang K, Tsai RYL. Epigenome-wide analysis of aging effects on liver regeneration. BMC Biol 2023; 21:30. [PMID: 36782243 PMCID: PMC9926786 DOI: 10.1186/s12915-023-01533-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2022] [Accepted: 02/01/2023] [Indexed: 02/15/2023] Open
Abstract
BACKGROUND Aging is known to exert an effect on liver regeneration, with the ability of liver to regenerate displaying a significant decline over time. Liver physiological parameters such as liver volume, blood flow, and metabolism, as well as the ability to regenerate after injury have all been shown to decrease at old age in humans and model systems, with a number of molecular mechanisms proposed to be involved, including DNA methylation-dependent genome remodeling. To address how changes in DNA methylation mediate the adverse aging effect on liver regeneration, we searched for differentially methylated genomic regions (DMRs) in mouse livers co-regulated by aging and regeneration and determined their associated genes and enriched pathways. RESULTS DMRs were identified using whole-genome bisulfite sequencing (WGBS). Pathway analysis of aging DMR-mapped genes revealed two distinct phases of aging, 2-to-8 and 8-to-16 months old (m/o). Regenerative DMR-mapped differentially expressed genes (DEGs) were enriched in pathways controlling cell proliferation and differentiation. Most DMRs shared by both aging and regeneration changed in the same methylation direction between 2 and 8 m/o but in the opposite direction between 8 and 16 m/o. Regenerative DMRs inversely affected by aging during 8-to-16 m/o were found in the promoter/gene regions of 12 genes. Four regenerative DEGs were synchronously regulated by early aging and inversely regulated by mid-to-late aging DMRs. Lead DMR-mapped genes were validated by their expression profiles in liver aging and regeneration. CONCLUSIONS Our study has uncovered new DMRs and gene targets inversely affected by liver aging and regeneration to explain the adverse aging effect on liver regeneration. These findings will be of fundamental importance to understand the epigenomic changes underlying the biology of aging on liver regeneration.
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Affiliation(s)
- Junying Wang
- grid.412408.bInstitute of Biosciences and Technology, Texas A&M Health Science Center, 2121 W. Holcombe Blvd, Houston, TX 77030 USA
| | - Wen Zhang
- grid.412408.bInstitute of Biosciences and Technology, Texas A&M Health Science Center, 2121 W. Holcombe Blvd, Houston, TX 77030 USA
| | - Xiaoqin Liu
- grid.412408.bInstitute of Biosciences and Technology, Texas A&M Health Science Center, 2121 W. Holcombe Blvd, Houston, TX 77030 USA
| | - Minjee Kim
- grid.412408.bInstitute of Biosciences and Technology, Texas A&M Health Science Center, 2121 W. Holcombe Blvd, Houston, TX 77030 USA
| | - Ke Zhang
- grid.412408.bInstitute of Biosciences and Technology, Texas A&M Health Science Center, 2121 W. Holcombe Blvd, Houston, TX 77030 USA ,grid.412408.bDepartment of Translational Medical Sciences, Texas A&M Health Science Center, 2121 W. Holcombe Blvd, Houston, TX 77030 USA
| | - Robert Y. L. Tsai
- grid.412408.bInstitute of Biosciences and Technology, Texas A&M Health Science Center, 2121 W. Holcombe Blvd, Houston, TX 77030 USA ,grid.412408.bDepartment of Translational Medical Sciences, Texas A&M Health Science Center, 2121 W. Holcombe Blvd, Houston, TX 77030 USA
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Lyu N, Yi JZ, Zhao M. Immunotherapy in older patients with hepatocellular carcinoma. Eur J Cancer 2021; 162:76-98. [PMID: 34954439 DOI: 10.1016/j.ejca.2021.11.024] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2021] [Revised: 10/31/2021] [Accepted: 11/21/2021] [Indexed: 02/06/2023]
Abstract
Hepatocellular carcinoma (HCC) is one of the most common types of cancer globally and is currently the third leading cause of cancer-related deaths. Recently, immunotherapy using immune checkpoint inhibitors (ICIs) has been shown with encouraging anticancer activity and safety in clinical trials. To reverse the phenomenon of tumours evading immune response, ICIs can be used to stimulate the natural antitumour potential of cancer cells by blocking the relevant checkpoints to activate T cells. However, the components and functions of the immune system may undergo a series of changes with ageing, known as 'immunosenescence,' potentially affecting the antitumour effect and safety of immunotherapy. In the current phase III clinical trials of ICIs including nivolumab, pembrolizumab and atezolizumab, the proportion of patients with HCC older than 65 years in CheckMate 459, KEYNOTE-240 and IMbrave150 is 51%, 58% and 50%, respectively, which is less than 70%-73% of epidemiological investigation. Therefore, the elderly population recruited in clinical trials may not accurately represent the real-world elderly patients with HCC, which affects the extrapolation of the efficacy and safety profile obtained in clinical trials to the elderly population in the real world. This review provides the latest advances in ICIs immuno-treatment available for HCC and relevant information about their therapeutic effects and safety on elderly patients. We discuss the benefits of ICIs for older HCC patients, and relevant recommendations about conducting further clinical trials are proposed for more complete answers to this clinical issue.
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Affiliation(s)
- Ning Lyu
- Department of Minimally Invasive Interventional Therapy, Liver Cancer Study and Service Group, Sun Yat-sen University Cancer Center, Guangzhou, China; State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, China; Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Jun-Zhe Yi
- Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Ming Zhao
- Department of Minimally Invasive Interventional Therapy, Liver Cancer Study and Service Group, Sun Yat-sen University Cancer Center, Guangzhou, China; State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, China; Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.
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METİN O, ŞİMŞEK C, GÜRAKAR A. Update on liver transplantation-newer aspects. Turk J Med Sci 2020; 50:1642-1650. [PMID: 32222125 PMCID: PMC7672347 DOI: 10.3906/sag-2002-17] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2020] [Accepted: 03/22/2020] [Indexed: 12/12/2022] Open
Abstract
Liver transplantation (LT) remains the only therapeutic option offering gold standard treatment for end-stage liver disease (ESLD) and acute liver failure (ALF), as well as for certain early-stage liver tumors. Currently, the greatest challenge facing LT is the simple fact that there are not enough adequate livers for all the potential patients that could benefit from LT. Despite efforts to expand the donor pool to include living and deceased donors, organ shortage is still a major problem in many countries. To solve this problem, the use of marginal liver grafts has become an inevitable choice. Although the definition of marginal grafts or criteria for expanded donor selection has not been clarified yet, they are usually defined as grafts that may potentially cause primary nonfunction, impaired function, or late loss of function. These include steatotic livers, older donors, donors with positive viral serology, split livers, and donation after cardiac death (DCD). Therefore, to get the best outcome from these liver grafts, donor-recipient selection should be vigilant. Alcohol- related liver disease (ALD) is one of the most common indications for LT in Europe and North America. Traditionally, LT for alcoholic liver disease was kept limited for patients who have achieved 6 months of abstinence, in part due to social and ethical concerns regarding the use of a limited resource. However, the majority of patients with severe alcoholic hepatitis who fail medical therapy will not live long enough to meet this requirement. Besides, the initial results of early liver transplantation (ELT) without waiting for 6 months of abstinence period are satisfactory in severe alcoholic hepatitis (SAH). It will be important to take care of these patients from a newer perspective.
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Affiliation(s)
- Olga METİN
- Department of Internal Medicine, Okmeydanı Training and Research Hospital, İstanbulTurkey
| | - Cem ŞİMŞEK
- Department of Gastroenterology, School of Medicine, Hacettepe University, AnkaraTurkey
| | - Ahmet GÜRAKAR
- Division of Gastroenterology and Hepatology, Johns Hopkins University School of Medicine Liver Transplant Program Baltimore, MarylandUSA
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Caso-Maestro O, Jiménez-Romero C, Justo-Alonso I, Calvo-Pulido J, Lora-Pablos D, Marcacuzco-Quinto A, Cambra-Molero F, García-Sesma A, Pérez-Flecha M, Muñoz-Arce C, Loinaz-Segurola C, Manrique-Municio A. Analyzing predictors of graft survival in patients undergoing liver transplantation with donors aged 70 years and over. World J Gastroenterol 2018; 24:5391-5402. [PMID: 30598583 PMCID: PMC6305532 DOI: 10.3748/wjg.v24.i47.5391] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/03/2018] [Revised: 11/24/2018] [Accepted: 12/01/2018] [Indexed: 02/06/2023] Open
Abstract
AIM To increase the number of available grafts.
METHODS This is a single-center comparative analysis performed between April 1986 and May 2016. Two hundred and twelve liver transplantation (LT) were performed with donors ≥ 70 years old (study group). Then, we selected the first cases that were performed with donors < 70 years old immediately after the ones that were performed with donors ≥ 70 years old (control group).
RESULTS Graft and patient survivals were similar between both groups without increasing the risk of complications, especially primary non-function, vascular complications and biliary complications. We identified 5 risk factors as independent predictors of graft survival: recipient hepatitis C virus (HCV)-positivity [hazard ratio (HR) = 2.35; 95% confidence interval (CI): 1.55-3.56; P = 0.00]; recipient age (HR = 1.04; 95%CI: 1.02-1.06; P = 0.00); donor age X model for end-stage liver disease (D-MELD) (HR = 1.00; 95%CI: 1.00-1.00; P = 0.00); donor value of serum glutamic-pyruvic transaminase (HR = 1.00; 95%CI: 1.00-1.00; P = 0.00); and donor value of serum sodium (HR = 0.96; 95%CI: 0.94-0.99; P = 0.00). After combining D-MELD and recipient age we obtained a new scoring system that we called DR-MELD (donor age X recipient age X MELD). Graft survival significantly decreased in patients with a DR-MELD score ≥ 75000, especially in HCV patients (77% vs 63% at 5 years in HCV-negative patients, P = 0.00; and 61% vs 25% at 5 years in HCV-positive patients; P = 0.00).
CONCLUSION A DR-MELD ≥ 75000 must be avoided in order to obtain the best results in LT with donors ≥ 70 years old.
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Affiliation(s)
- Oscar Caso-Maestro
- Unit of HBP Surgery and Abdominal Organs Transplantation, Department of General Surgery, “12 de octubre” University Hospital, Madrid 28041, Spain
| | - Carlos Jiménez-Romero
- Unit of HBP Surgery and Abdominal Organs Transplantation, Department of General Surgery, “12 de octubre” University Hospital, Madrid 28041, Spain
| | - Iago Justo-Alonso
- Unit of HBP Surgery and Abdominal Organs Transplantation, Department of General Surgery, “12 de octubre” University Hospital, Madrid 28041, Spain
| | - Jorge Calvo-Pulido
- Unit of HBP Surgery and Abdominal Organs Transplantation, Department of General Surgery, “12 de octubre” University Hospital, Madrid 28041, Spain
| | - David Lora-Pablos
- Clinical Research Department, Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), “12 de octubre” University Hospital, Madrid 28041, Spain
| | - Alberto Marcacuzco-Quinto
- Unit of HBP Surgery and Abdominal Organs Transplantation, Department of General Surgery, “12 de octubre” University Hospital, Madrid 28041, Spain
| | - Félix Cambra-Molero
- Unit of HBP Surgery and Abdominal Organs Transplantation, Department of General Surgery, “12 de octubre” University Hospital, Madrid 28041, Spain
| | - Alvaro García-Sesma
- Unit of HBP Surgery and Abdominal Organs Transplantation, Department of General Surgery, “12 de octubre” University Hospital, Madrid 28041, Spain
| | - Marina Pérez-Flecha
- Unit of HBP Surgery and Abdominal Organs Transplantation, Department of General Surgery, “12 de octubre” University Hospital, Madrid 28041, Spain
| | - Carlos Muñoz-Arce
- Unit of HBP Surgery and Abdominal Organs Transplantation, Department of General Surgery, “12 de octubre” University Hospital, Madrid 28041, Spain
| | - Carmelo Loinaz-Segurola
- Unit of HBP Surgery and Abdominal Organs Transplantation, Department of General Surgery, “12 de octubre” University Hospital, Madrid 28041, Spain
| | - Alejandro Manrique-Municio
- Unit of HBP Surgery and Abdominal Organs Transplantation, Department of General Surgery, “12 de octubre” University Hospital, Madrid 28041, Spain
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6
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Badawy A, Kaido T, Uemoto S. Current Status of Liver Transplantation Using Marginal Grafts. J INVEST SURG 2018; 33:553-564. [PMID: 30457408 DOI: 10.1080/08941939.2018.1517197] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Affiliation(s)
- Amr Badawy
- Division of Hepato-Biliary-Pancreatic and Transplant Surgery, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
- Department of General Surgery, Alexandria University, Alexandria, Egypt
| | - Toshimi Kaido
- Division of Hepato-Biliary-Pancreatic and Transplant Surgery, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Shinji Uemoto
- Division of Hepato-Biliary-Pancreatic and Transplant Surgery, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
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7
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8
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Blay C, Planes S, Ky CL. Optimal age of the donor graft tissue in relation to cultured pearl phenotypes in the mollusc, Pinctada margaritifera. PLoS One 2018; 13:e0198505. [PMID: 29912963 PMCID: PMC6005463 DOI: 10.1371/journal.pone.0198505] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2017] [Accepted: 05/21/2018] [Indexed: 12/21/2022] Open
Abstract
Ageing is defined as the progressive decline in tissue and organ functions over time. This study aims to evaluate the ageing effect on cultured pearl quality phenotypes (including size and quality traits) in the graft-recipient animal model: Pinctada margaritifera. For this, eight uniform grafting experiments were designed using two hatchery-produced pearl oyster families as donors, which were followed through time, between 7 and 30 months in age. For each age category, 20 donors were studied for each culture site giving a total of 2400 grafted oysters. Several phenotypic measurements were made: 1) donor family growth performance from shell size records, 2) pearl size and corresponding quality traits, and 3) expression of some genes related to biomineralization processes on both the mantle graft and on pearl sac tissues. Results showed that: 1) donor age has an impact on pearl size, with grafts coming from the youngest donors yielding the biggest pearls; and 2) grafts from donors between 12 and 18 months in age produced pearls of the highest quality (grade and surface quality), a result supported by an analysis where the level of expression for a panel of genes associated with biomineralization was greatest in donors within the 12 to 18 months age group. These results indicate that donors aged between 12 and 18 months have high potential for biomineralisation and nacre deposition, and likely produce larger and higher quality cultured pearls than older donors.
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Affiliation(s)
- Carole Blay
- Ifremer, UMR 241, EIO, Labex Corail, Centre du Pacifique, Taravao, Tahiti, Polynésie Française
- PSL Research University, EPHE-UPVD-CNRS, USR 3278 CRIOBE, Labex Corail, Université de Perpignan, Perpignan, France
| | - Serge Planes
- PSL Research University, EPHE-UPVD-CNRS, USR 3278 CRIOBE, Labex Corail, Université de Perpignan, Perpignan, France
| | - Chin-Long Ky
- Ifremer, UMR 241, EIO, Labex Corail, Centre du Pacifique, Taravao, Tahiti, Polynésie Française
- * E-mail:
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9
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Short-term Results of Liver Transplantation With Octogenarian Donors. Transplant Proc 2018; 50:184-191. [DOI: 10.1016/j.transproceed.2017.12.002] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2017] [Accepted: 12/04/2017] [Indexed: 02/06/2023]
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10
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Cepeda-Franco C, Bernal-Bellido C, Barrera-Pulido L, Álamo-Martínez JM, Ruiz-Matas JH, Suárez-Artacho G, Marín-Gómez LM, Tinoco-González J, Díaz-Aunión C, Padillo-Ruiz FJ, Gómez-Bravo MÁ. Survival Outcomes in Liver Transplantation With Elderly Donors: Analysis of Andalusian Transplant Register. Transplant Proc 2017; 48:2983-2986. [PMID: 27932125 DOI: 10.1016/j.transproceed.2016.09.026] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2016] [Revised: 08/16/2016] [Accepted: 09/01/2016] [Indexed: 02/08/2023]
Abstract
Recently, there has been a large discrepancy between the number of patients on the waiting list for a liver transplant and the availability of deceased donors, with an increase in annual wait list mortality rates. Elderly donor livers are thought to be marginal grafts; however, in recent years, their utilization has constantly increased. The aim of this study is to evaluate the utilization of elderly donors in Andalusia and post-transplant outcomes. This retrospective observational study of 2408 liver transplants, performed in Andalusia between 2000 and 2014, analyzes the outcomes from donors aged 70 plus (n = 423) in terms of survival rates of the graft and the recipient, the type of transplant, donor age, and D-MELD score (product of donor age and preoperative Model for End-stage Liver Disease score). The most frequent indications for transplant were alcoholic cirrhosis (49.2%), hepatitis C cirrhosis (13%), and hepatocellular carcinoma (12.5%). The overall survival at 5 years was 64%, with a significant fall in survival for recipients with a D-MELD greater than 1500 (57%; P = .045). In the 70-year-old-plus donor group, the overall patient survival was 58.4%. The retransplant rate increased proportionately with donor age. In the alcoholic cirrhosis recipient subgroup, the overall survival at 5 years was 67.6% (P < .05) compared with 33.5% in patients with hepatitis C. Use of elderly donors is a safe strategy to reduce the scarcity of donors, provided that a D-MELD score below 1500 is obtained. Retransplant rates increase progressively with donor age. It is necessary to carefully screen recipients of older organs, taking into account that the best results are obtained for alcoholic cirrhosis, negative viral load hepatitis C, and a D-MELD score below 1500.
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Affiliation(s)
- C Cepeda-Franco
- Liver Transplant Unit, Virgen del Rocío University Hospital, Seville, Spain.
| | - C Bernal-Bellido
- Liver Transplant Unit, Virgen del Rocío University Hospital, Seville, Spain
| | - L Barrera-Pulido
- Liver Transplant Unit, Virgen del Rocío University Hospital, Seville, Spain
| | - J M Álamo-Martínez
- Liver Transplant Unit, Virgen del Rocío University Hospital, Seville, Spain
| | | | - G Suárez-Artacho
- Liver Transplant Unit, Virgen del Rocío University Hospital, Seville, Spain
| | - L M Marín-Gómez
- Liver Transplant Unit, Virgen del Rocío University Hospital, Seville, Spain
| | - J Tinoco-González
- Liver Transplant Unit, Virgen del Rocío University Hospital, Seville, Spain
| | | | - F J Padillo-Ruiz
- Liver Transplant Unit, Virgen del Rocío University Hospital, Seville, Spain
| | - M Á Gómez-Bravo
- Liver Transplant Unit, Virgen del Rocío University Hospital, Seville, Spain
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11
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Echeverri J, Selzner M. "In 10 years" debate: Con-machine perfusion will be limited to specific situations (Steatotic, donation after circulatory death). Liver Transpl 2016; 22:29-32. [PMID: 27588758 DOI: 10.1002/lt.24622] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2016] [Accepted: 08/30/2016] [Indexed: 12/31/2022]
Affiliation(s)
- Juan Echeverri
- Department of Surgery, Multi Organ Transplant Program, Toronto General Hospital, Toronto, ON, Canada
| | - Markus Selzner
- Department of Surgery, Multi Organ Transplant Program, Toronto General Hospital, Toronto, ON, Canada.
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12
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The Kupffer Cell Number Affects the Outcome of Living Donor Liver Transplantation from Elderly Donors. Transplant Direct 2016; 2:e94. [PMID: 27819035 PMCID: PMC5082997 DOI: 10.1097/txd.0000000000000608] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2016] [Accepted: 06/03/2016] [Indexed: 01/09/2023] Open
Abstract
Background There have been no previous reports how Kupffer cells affect the outcome of living donor liver transplantation (LDLT) with an elderly donor. The aim of this study was to elucidate the influence of Kupffer cells on LDLT. Methods A total of 161 adult recipients underwent LDLT. The graft survival, prognostic factors for survival, and graft failure after LDLT were examined between cases with a young donor (<50, n = 112) and an elderly donor (≥50, N = 49). The Kupffer cells, represented by CD68-positive cell in the graft, were examined in the young and elderly donors. Results In a multivariable analysis, a donor older than 50 years, sepsis, and diabetes mellitus were significant predictors of graft failure after LDLT. The CD68 in younger donors was significantly more expressed than that in elderly donors. The group with a less number of CD68-positive cells in the graft had a significantly poor survival in the elderly donor group and prognostic factor for graft failure. Conclusions The worse outcome of LDLT with elderly donors might be related to the lower number of Kupffer cells in the graft, which can lead to impaired recovery of the liver function and may predispose patients to infectious diseases after LDLT.
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13
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Lipopolysaccharide and Tumor Necrosis Factor Alpha Inhibit Interferon Signaling in Hepatocytes by Increasing Ubiquitin-Like Protease 18 (USP18) Expression. J Virol 2016; 90:5549-5560. [PMID: 27009955 PMCID: PMC4886784 DOI: 10.1128/jvi.02557-15] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2015] [Accepted: 02/29/2016] [Indexed: 12/22/2022] Open
Abstract
Inflammation may be maladaptive to the control of viral infection when it impairs interferon (IFN) responses, enhancing viral replication and spread. Dysregulated immunity as a result of inappropriate innate inflammatory responses is a hallmark of chronic viral infections such as, hepatitis B virus and hepatitis C virus (HCV). Previous studies from our laboratory have shown that expression of an IFN-stimulated gene (ISG), ubiquitin-like protease (USP)18 is upregulated in chronic HCV infection, leading to impaired hepatocyte responses to IFN-α. We examined the ability of inflammatory stimuli, including tumor necrosis factor alpha (TNF-α), lipopolysaccharide (LPS), interleukin-6 (IL-6) and IL-10 to upregulate hepatocyte USP18 expression and blunt the IFN-α response. Human hepatoma cells and primary murine hepatocytes were treated with TNF-α/LPS/IL-6/IL-10 and USP18, phosphorylated (p)-STAT1 and myxovirus (influenza virus) resistance 1 (Mx1) expression was determined. Treatment of Huh7.5 cells and primary murine hepatocytes with LPS and TNF-α, but not IL-6 or IL-10, led to upregulated USP18 expression and induced an IFN-α refractory state, which was reversed by USP18 knockdown. Liver inflammation was induced in vivo using a murine model of hepatic ischemia/reperfusion injury. Hepatic ischemia/reperfusion injury led to an induction of USP18 expression in liver tissue and promotion of lymphocytic choriomeningitis replication. These data demonstrate that certain inflammatory stimuli (TNF-α and LPS) but not others (IL-6 and IL-10) target USP18 expression and thus inhibit IFN signaling. These findings represent a new paradigm for how inflammation alters hepatic innate immune responses, with USP18 representing a potential target for intervention in various inflammatory states. IMPORTANCE Inflammation may prevent the control of viral infection when it impairs the innate immune response, enhancing viral replication and spread. Blunted immunity as a result of inappropriate innate inflammatory responses is a common characteristic of chronic viral infections. Previous studies have shown that expression of certain interferon-stimulated genes is upregulated in chronic HCV infection, leading to impaired hepatocyte responses. In this study, we show that multiple inflammatory stimuli can modulate interferon stimulated gene expression and thus inhibit hepatocyte interferon signaling via USP18 induction. These findings represent a new paradigm for how inflammation alters hepatic innate immune responses, with the induction of USP18 representing a potential target for intervention in various inflammatory states.
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14
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Tanemura A, Mizuno S, Kato H, Murata Y, Kuriyama N, Azumi Y, Kishiwada M, Usui M, Sakurai H, Isaji S. D-MELD, the Product of Donor Age and Preoperative MELD, Predicts Surgical Outcomes After Living Donor Liver Transplantation, Especially in the Recipients With HCV-positive and Smaller Grafts. Transplant Proc 2016; 48:1025-1031. [PMID: 27320548 DOI: 10.1016/j.transproceed.2015.12.090] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2015] [Accepted: 12/30/2015] [Indexed: 12/12/2022]
Abstract
BACKGROUND Appropriate donor-recipient match has not been explored well in living-donor liver transplantation (LDLT) unlike deceased-donor liver transplantation. In this study, we evaluate the donor-recipient match using D-MELD (donor age × recipient Modified for End-stage Liver Disease [MELD] score) as a predictor of surgical outcomes in LDLT, paying attention to graft size and hepatitis C virus (HCV) status. PATIENT AND METHODS The 120 consecutive recipients who received adult-to-adult LDLT from March 2002 to December 2014 were divided into the two groups according to D-MELD score: D-MELD <1000 (low-D-MELD: n = 101) and D-MELD ≥1000 (high-D-MELD: n = 19). RESULTS The 90-day mortality rate was significantly higher in the high-DM group than in low-DM group: 36.8% versus 14.9% (P = .046). In the HCV-positive recipients, the 90-day mortality rate was significantly higher in high-DM group (n = 6) than in low-DM group (n = 37): 66.7% versus 13.5% (P = .012), and the 3-year survival rate was significantly lower in high-DM group than in the low-DM group: 33.3% versus 56.8% (P = .01). In the recipients with left graft, the 90-day mortality rate was significantly higher in the high-DM group (n = 8) than in the low-DM group (n = 41): 50% versus 14.6% (P = .044), and total bilirubin level on postoperative day 14 was significantly higher in the high-DM group than in the low-DM group: 17.4 mg/dL versus 9.2 mg/dL (P = .018). CONCLUSIONS It was clarified that D-MELD could predict early and long-term surgical outcomes in the recipients who were HCV-positive and who had smaller grafts.
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Affiliation(s)
- A Tanemura
- Department of Hepatobiliary Pancreatic and Transplant Surgery, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie, Japan
| | - S Mizuno
- Department of Hepatobiliary Pancreatic and Transplant Surgery, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie, Japan.
| | - H Kato
- Department of Hepatobiliary Pancreatic and Transplant Surgery, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie, Japan
| | - Y Murata
- Department of Hepatobiliary Pancreatic and Transplant Surgery, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie, Japan
| | - N Kuriyama
- Department of Hepatobiliary Pancreatic and Transplant Surgery, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie, Japan
| | - Y Azumi
- Department of Hepatobiliary Pancreatic and Transplant Surgery, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie, Japan
| | - M Kishiwada
- Department of Hepatobiliary Pancreatic and Transplant Surgery, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie, Japan
| | - M Usui
- Department of Hepatobiliary Pancreatic and Transplant Surgery, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie, Japan
| | - H Sakurai
- Department of Hepatobiliary Pancreatic and Transplant Surgery, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie, Japan
| | - S Isaji
- Department of Hepatobiliary Pancreatic and Transplant Surgery, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie, Japan
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Kamo N, Kaido T, Hammad A, Ogawa K, Fujimoto Y, Uemura T, Mori A, Hatano E, Okajima H, Uemoto S. Impact of elderly donors for liver transplantation: A single-center experience. Liver Transpl 2015; 21:591-8. [PMID: 25641778 DOI: 10.1002/lt.24086] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2014] [Accepted: 01/18/2015] [Indexed: 12/20/2022]
Abstract
Elderly donor grafts for liver transplantation (LT) are recognized to be marginal grafts. The present study investigated the impact of using elderly donors for LT. Between June 1990 and August 2012, 1631 patients received LT at Kyoto University Hospital. Out of 1631 patients, 1597 patients received living donor liver transplantation (LDLT), whereas the other 34 patients underwent deceased donor liver transplantation (DDLT). Seventy-five grafts that were used came from individuals who were ≥60 years old. We retrospectively analyzed the recipients' survival rates according to donor age. The overall survival rates of the recipients of all LDLT (P < 0.001), adult-to-adult LDLT (P = 0.007), all DDLT (P = 0.026), and adult-to-adult DDLT (P = 0.011) were significantly lower for the elderly donor group versus the younger group and especially for those who were hepatitis C-positive. A multivariate analysis revealed that donor age, ABO incompatibility, and preoperative intensive care unit stay were independent risk factors for poor patient survival in adult-to-adult LDLT. However, no significant differences existed between the 2 groups among those who received adult-to-adult LDLT in and after April 2006. No significant association was found between donor age and incidence of acute cellular rejection. In conclusion, donor age was closely related to the survival rate for LDLT and DDLT, although the impact of donor age was not shown in the recent cases.
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Affiliation(s)
- Naoko Kamo
- Division of Hepato-Biliary-Pancreatic and Transplant Surgery, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
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Abstract
BACKGROUND With the increase in average life expectancy in recent decades, the proportion of elderly patients requiring liver surgery is rising. The aim of the meta-analysis reported here was to evaluate the safety and efficacy of hepatectomy in elderly patients. METHODS An extensive electronic search was performed for relevant articles that compare the outcomes of hepatectomy in patients ≥70 years of age with those in younger patients prior to October 2012. Analysis of pooled data was performed with RevMan 5.0. RESULTS Twenty-eight observational studies involving 15,480 patients were included in the analysis. Compared with the younger patients, elderly patients experienced more complications (31.8 vs 28.7 %; P = 0.002), mainly as a result of increased cardiac complications (7.5 vs 1.9 %; P < 0.001) and delirium (11.7 vs 4.5 %; P < 0.001). Postoperative major surgical complications (12.6 vs 11.3 %; P = 0.55) and mortality (3.6 vs 3.3 %; P = 0.68) were comparable between elderly and younger patients. For patients with malignancies, both the 5-year disease-free survival (26.5 vs 26.3 %; P = 0.60) and overall survival (39.5 vs 40.7 %; P = 0.29) did not differ significantly between the two groups. CONCLUSIONS Postoperative major surgical complications, mortality, and long-term results in elderly patients seem to be comparable with those in younger patients, suggesting that age alone should not be considered a contraindication for hepatectomy.
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17
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Andreou A, Gül S, Pascher A, Schöning W, Al-Abadi H, Bahra M, Klein F, Denecke T, Strücker B, Puhl G, Pratschke J, Seehofer D. Patient and tumour biology predict survival beyond the Milan criteria in liver transplantation for hepatocellular carcinoma. HPB (Oxford) 2015; 17:168-75. [PMID: 25263399 PMCID: PMC4299391 DOI: 10.1111/hpb.12345] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2014] [Accepted: 08/22/2014] [Indexed: 12/12/2022]
Abstract
BACKGROUND Patients with hepatocellular carcinoma (HCC) beyond the Milan criteria are not considered for liver transplantation (LT) in many centres; however, LT may be the only treatment able to achieve long-term survival in patients with unresectable HCC. The aim of this study was to assess the role of recipient age and tumour biology expressed by the DNA index in the selection of HCC patients for LT. PATIENTS Clinicopathological data of 364 patients with HCC who underwent LT between 1989 and 2010 were evaluated. Overall survival (OS) was analysed by patient age, tumour burden based on Milan criteria and the DNA index. RESULTS After a median follow-up time of 78 months, the median survival was 100 months. Factors associated with OS on univariate analysis included Milan criteria, patient age, hepatitis C infection, alpha-fetoprotein (AFP) level, the DNA index, number of HCC, diameter of HCC, bilobar HCC, microvascular tumour invasion and tumour grading. On multivariate analysis, HCC beyond Milan criteria and the DNA index >1.5 independently predicted a worse OS. When stratifying patients by both age and Milan criteria, patients ≤ 60 years with HCC beyond Milan criteria had an OS comparable to that of patients >60 years within Milan criteria (10-year OS: 33% versus 37%, P = 0.08). Patients ≤ 60 years with HCC beyond Milan criteria but a favourable DNA index ≤ 1.5 achieved excellent long-term outcomes, comparable with those of patients within Milan criteria. CONCLUSIONS Patients ≤ 60 years may undergo LT for HCC with favourable outcomes independently of their tumour burden. Additional assessment of tumour biology, e.g. using the DNA index, especially in this subgroup of patients can support the selection of LT candidates who may derive the most long-term survival benefit, even if Milan criteria are not fulfilled.
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Affiliation(s)
- Andreas Andreou
- Department of General, Visceral and Transplant Surgery, CharitéBerlin, Germany,Correspondence, Andreas Andreou, Department of General, Visceral and Transplant Surgery, Charité, Campus Virchow-Klinikum, Augustenburger Platz 1, 13353 Berlin, Germany. Tel: 30 450 652274. Fax: 450 552900. E-mail:
| | - Safak Gül
- Department of General, Visceral and Transplant Surgery, CharitéBerlin, Germany
| | - Andreas Pascher
- Department of General, Visceral and Transplant Surgery, CharitéBerlin, Germany
| | - Wenzel Schöning
- Department of General, Visceral and Transplant Surgery, CharitéBerlin, Germany
| | - Hussein Al-Abadi
- Department of General, Visceral and Transplant Surgery, CharitéBerlin, Germany
| | - Marcus Bahra
- Department of General, Visceral and Transplant Surgery, CharitéBerlin, Germany
| | - Fritz Klein
- Department of General, Visceral and Transplant Surgery, CharitéBerlin, Germany
| | - Timm Denecke
- Department of Diagnostic and Interventional Radiology, CharitéBerlin, Germany
| | - Benjamin Strücker
- Department of General, Visceral and Transplant Surgery, CharitéBerlin, Germany
| | - Gero Puhl
- Department of General, Visceral and Transplant Surgery, CharitéBerlin, Germany
| | - Johann Pratschke
- Department of General, Visceral and Transplant Surgery, CharitéBerlin, Germany
| | - Daniel Seehofer
- Department of General, Visceral and Transplant Surgery, CharitéBerlin, Germany
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18
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Wang K, Jiang WT, Deng YL, Pan C, Shen ZY. Effect of donor age on graft function and long-term survival of recipients undergoing living donor liver transplantation. Hepatobiliary Pancreat Dis Int 2015; 14:50-5. [PMID: 25655290 DOI: 10.1016/s1499-3872(15)60334-4] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
BACKGROUND Donor shortage is the biggest obstacle in organ transplantation. Living donor liver transplantation (LDLT) has been considered as a valuable approach to shortening waiting time. The objectives of this study were to investigate the feasibility of utilizing donors older than 50 years in LDLT and to evaluate the graft function and recipient survival. METHODS All LDLT cases (n=159) were divided into the older (donor age≥50 years, n=10) and younger (donor age<50 years, n=149) donor groups. Donor graft and recipient condition pre-, intra- and post-operation were compared between the two groups. In particular, graft functions and recipient survivals were analyzed. RESULTS The median donor age was 58.5 (52.5-60.0) years in the older donor group and 25.0 (23.0-32.0) in the younger donor group. There was no significant difference in cold ischemic time, anhepatic phase and operation time between the older and younger donor groups (P>0.05). However, the volume of red blood cell transfused in operation was greater in the older donor group than in the younger donor group (1900 vs 1200 mL, P=0.023). The 1-, 3- and 5-year graft survival rates were 90%, 80% and 80% for the older donor group, and 92%, 87% and 87% for the younger donor group, respectively (P=0.459). The 1-, 3- and 5-year survival rates were 100%, 90% and 90% for recipients with older grafts, and 93%, 87% and 87% for those with younger grafts, respectively (P=0.811). CONCLUSION It is safe for a LDLT recipient to receive liver from donors older than 50 years, and there is no significant adverse effect on graft function and long-term patients' survival.
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Affiliation(s)
- Kai Wang
- Department of Transplant Surgery, Tianjin First Center Hospital, Key Laboratory of Organ Transplantation of Tianjin, Tianjin 300192, China.
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19
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Lüthold SC, Kaseje N, Jannot AS, Mentha G, Majno P, Toso C, Belli DC, McLin VA, Wildhaber BE. Risk factors for early and late biliary complications in pediatric liver transplantation. Pediatr Transplant 2014; 18:822-30. [PMID: 25263826 DOI: 10.1111/petr.12363] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/14/2014] [Indexed: 12/14/2022]
Abstract
BC are a common source of morbidity after pediatric LT. Knowledge about risk factors may help to reduce their incidence. Retrospective analysis of BC in 116 pediatric patients (123 LT) (single institution, 05/1990-12/2011, medium follow-up 7.9 yr). One-, five-, and 10-yr survival was 91.1%, no patient died of BC. Prevalence and risk factors for anastomotic and intrahepatic BC were examined. There were 29 BC in 123 LT (23.6%), with three main categories: 10 (8.1%) primary anastomotic strictures, eight (6.5%) anastomotic leaks, and three (2.4%) intrahepatic strictures. Significant risk factors for anastomotic leaks were total operation time (increase 1.26-fold) and early HAT (<30 days post-LT; increase 5.87-fold). Risk factor for primary anastomotic stricture was duct-to-duct choledochal anastomosis (increase 5.96-fold when compared to biliary-enteric anastomosis). Risk factors for intrahepatic strictures were donor age >48 yr (increase 1.09-fold) and MELD score >30 (increase 1.2-fold). To avoid morbidity from anastomotic BC in pediatric LT, the preferred biliary anastomosis appears to be biliary-enteric. Operation time should be kept to a minimum, and HAT must by all means be prevented. Children with a high MELD score or receiving livers from older donors are at increased risk for intrahepatic strictures.
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Affiliation(s)
- Samuel C Lüthold
- Division of Pediatric Surgery, Geneva University Hospitals, Geneva, Switzerland
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20
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Poujol-Robert A, Boëlle PY, Conti F, Durand F, Duvoux C, Wendum D, Paradis V, Mackiewicz V, Chazouillères O, Corpechot C, Poupon R. Aspirin may reduce liver fibrosis progression: Evidence from a multicenter retrospective study of recurrent hepatitis C after liver transplantation. Clin Res Hepatol Gastroenterol 2014; 38:570-6. [PMID: 25130796 DOI: 10.1016/j.clinre.2014.07.004] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2014] [Accepted: 07/09/2014] [Indexed: 02/07/2023]
Abstract
BACKGROUND AND AIMS There is evidence for an association between thrombosis in the hepatic microcirculation and liver fibrosis. The aim of this study was to evaluate the role of daily low-dose aspirin (75 or 100mg, given for prevention of hepatic artery thrombosis) in fibrosis progression to ≥ F2 fibrosis score in liver-transplant recipients with recurrent hepatitis C virus (HCV). METHODS All HCV-positive patients who had undergone liver transplantation (LT) between 2000 and 2010 were included. Exclusion criteria were negative HCV RNA, previous LT or death within a year of LT. Liver fibrosis was assessed by histological evaluation. Data were censored at the date of the last histological evaluation before starting anti HCV therapy. Progression to fibrosis F ≥ 2 was analyzed with a multistate model with time-dependent covariables. RESULTS One hundred and eighty-eight patients were included. In univariate analysis, older recipient and donor age, male donor gender, activity score ≥ A2 after LT, number of steroid boluses and aspirin intake (HR: 0.75 [0.57-0.97]; P=0.03) influenced the risk of progression to fibrosis ≥ F2. In multivariate analysis, adjusted on site, older donor age, male donor gender, activity score ≥ A2 and number of steroids boluses, remained independent predictors of fibrosis progression, while younger recipient age and aspirin intake (HR: 0.65 [0.47-0.91]; P=0.01) were associated with a slower fibrosis progression. CONCLUSION Low-dose aspirin treatment might be associated with a lower risk of liver fibrosis progression in patients with HCV recurrence after LT.
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Affiliation(s)
- Armelle Poujol-Robert
- Service d'hépatologie, hôpital Saint-Antoine, 184, rue du faubourg Saint-Antoine, 75012 Paris, France.
| | | | - Filomena Conti
- Centre de transplantation hépatique, hôpital Saint-Antoine, AP-HP, Paris, France
| | - François Durand
- Service d'hépatologie et réanimation hépatodigestive, hôpital Beaujon, AP-HP, Clichy, France
| | - Christophe Duvoux
- Service d'hépato-gastroentérologie, hôpital Henri-Mondor, AP-HP, Créteil, France
| | - Dominique Wendum
- Service d'anatomie et de cytologie pathologiques, hôpital Saint-Antoine, AP-HP, Paris, France
| | - Valérie Paradis
- Département d'anatomie pathologique, hôpital Beaujon, AP-HP, Clichy, France
| | - Vincent Mackiewicz
- Secteur de virologie, service de microbiologie, hôpital Beaujon, AP-HP, Clichy, France
| | - Olivier Chazouillères
- Service d'hépatologie, hôpital Saint-Antoine, 184, rue du faubourg Saint-Antoine, 75012 Paris, France; UMR S938, faculté de médecine Pierre-et-Marie-Curie, site Saint-Antoine, Paris, France; Université Pierre-et-Marie-Curie (UPMC) Paris 6, Paris, France
| | - Christophe Corpechot
- Service d'hépatologie, hôpital Saint-Antoine, 184, rue du faubourg Saint-Antoine, 75012 Paris, France
| | - Raoul Poupon
- Service d'hépatologie, hôpital Saint-Antoine, 184, rue du faubourg Saint-Antoine, 75012 Paris, France
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21
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Chedid MF, Rosen CB, Nyberg SL, Heimbach JK. Excellent long-term patient and graft survival are possible with appropriate use of livers from deceased septuagenarian and octogenarian donors. HPB (Oxford) 2014; 16:852-858. [PMID: 24467292 PMCID: PMC4159459 DOI: 10.1111/hpb.12221] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2013] [Accepted: 12/17/2013] [Indexed: 12/12/2022]
Abstract
BACKGROUND Although increasing donor age adversely affects survival after liver transplantation, livers have been used from selected deceased donors older than 70 years. Although there are reports of excellent short-term results, long-term results are unknown. Our experience was reviewed with septuagenarian and octogenarian deceased donors to determine long-term outcomes. METHODS All primary deceased donor liver transplants performed at our institution between July 1998 and December 2010 were reviewed. Recipients of livers procured after circulatory arrest, split and reduced-size livers and multiple organ transplants were excluded from the study. Patient and graft survival were calculated using the Kaplan-Meier method, and survival comparisons were made with the log-rank test. RESULTS In total, 780 patients met inclusion criteria, and 109 patients received livers from donors older than 70 years (range = 70-86). There were no differences in long-term patient (P = 0.67) or graft (P = 0.42) survival between hepatitis C negative recipients of livers from older compared with younger donors. In contrast, 7-year survival for HCV-positive recipients of older donor livers was less than half that of HCV-negative recipients. DISCUSSION Transplantation of livers from septua- and octogenarian donors can achieve excellent long-term patient and graft survival for selected HCV-negative patients.
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Affiliation(s)
- Marcio F Chedid
- Division of Transplantation Surgery, Department of Surgery and William J. von Liebig Transplant Center, Mayo ClinicRochester, MN, USA
| | - Charles B Rosen
- Division of Transplantation Surgery, Department of Surgery and William J. von Liebig Transplant Center, Mayo ClinicRochester, MN, USA
| | - Scott L Nyberg
- Division of Transplantation Surgery, Department of Surgery and William J. von Liebig Transplant Center, Mayo ClinicRochester, MN, USA
| | - Julie K Heimbach
- Division of Transplantation Surgery, Department of Surgery and William J. von Liebig Transplant Center, Mayo ClinicRochester, MN, USA
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22
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Dumortier J, Boillot O, Scoazec JY. Natural history, treatment and prevention of hepatitis C recurrence after liver transplantation: Past, present and future. World J Gastroenterol 2014; 20:11069-11079. [PMID: 25170196 PMCID: PMC4145750 DOI: 10.3748/wjg.v20.i32.11069] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2013] [Revised: 03/07/2014] [Accepted: 06/23/2014] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV)-related liver disease, including cirrhosis and hepatocellular carcinoma is the main indication for liver transplantation (LT) worldwide. Post-transplant HCV re-infection is almost universal and results in accelerated progression from acute hepatitis to chronic hepatitis, and liver cirrhosis. Comprehension and treatment of recurrent HCV infection after LT have been major issues for all transplant hepatologists and transplant surgeons for the last decades. The aim of this paper is to review the evolution of our knowledge on the natural history of HCV recurrence after LT, including risk factors for disease progression, and antiviral therapy. We will focus our attention on possible ways (present and future) to improve the final long-term results of LT for HCV-related liver disease.
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23
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Zavaglia C, Silini E, Mangia A, Airoldi A, Piazzolla V, Vangeli M, Stigliano R, Foschi A, Mazzarelli C, Tinelli C. Prognostic factors of hepatic decompensation and hepatocellular carcinoma in patients with transfusion-acquired HCV infection. Liver Int 2014; 34:e308-16. [PMID: 24529078 DOI: 10.1111/liv.12502] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2013] [Accepted: 02/08/2014] [Indexed: 12/20/2022]
Abstract
AIMS Aim of this study was to assess if host (immunogenetic traits, age, sex), exogenous (alcohol) or viral factors (viral type, past HBV infection) might affect the progression of chronic hepatitis C to liver decompensation or the development of HCC in a cohort of patients exposed to a single blood transfusion prior to the introduction of anti-HCV screening. METHODS Two hundred and forty-eight patients with a history of a single exposure to blood or blood products prior to 1990 were retrospectively considered. Patients were devoid of other risk factors of liver disease or immunosuppression and naïve to antiviral therapies. Eight baseline variables were assessed: age at transfusion, sex, HBV core antibody, immunogenetic profile (DRB1*11, DRB1*1104, DRB1*07), HCV genotype and alcohol consumption. RESULTS The follow-up was 22 (SD: 11) years. Sixty-eight patients (27%) progressed to hepatic decompensation over a median period of 22.5 years (IQR: 14-30) and 41 patients (16%) developed HCC over a median period of 31 years (IQR: 24-38). The cumulative incidence of liver failure was 0.4% (95% CI: 0.1-3.1), 4.9% (95% CI: 2.6-9.3) and 16.2% (95% CI: 10.4-24.7) at 10, 20 and 30 years after blood transfusion respectively. By univariate analysis, only age at transfusion was correlated with the risk of decompensation. Stratifying the age of transfusion by tertiles, the incidence of hepatic decompensation was 0.7% per year in patients transfused at ≤24 years of age as compared to 1.2% and 1.9% per year in those transfused at 25-35 and >36 years of age respectively (HR: 5.5, 95% CI: 2.78-10.7, P<0.001). The risk of HCC development was correlated by univariate analysis with age at transfusion (as continuous variable, HR: 1.12, 95% CI: 1.08-1.16 per year of age, P<0.001, >36 compared to ≤24 years, HR: 10.3, 95% CI: 3.9-26.9, P<0.001) and male sex (HR: 4.2, 95% CI: 1.7-10, P=0.001). Multivariate analysis confirmed age at transfusion and male sex as independent predictors of HCC development [HR: 1.12 per year (95% CI: 1.08-1.16), P<0.001 and HR: 5.4 (95% CI: 2.2-13.2), P<0.001 respectively]. CONCLUSIONS In patients with transfusion-acquired HCV infection, age at transfusion affects the risk for hepatic decompensation. Age at transfusion and male sex are independent risk factors for HCC development.
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Affiliation(s)
- Claudio Zavaglia
- Struttura Complessa di Gastroenterologia ed Epatologia 'Crespi', Ospedale Niguarda, piazza Ospedale Maggiore 3, 20162, Milano, Italy
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24
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Dumortier J, Salamé E, Roche B, Hurtova M, Conti F, Radenne S, Vanlemmens C, Pageaux GP, Saliba F, Samuel D, Compagnon P, Neau-Cransac M, Calmus Y, Guillaud O, Gugenheim J, Altieri M, Durand F, Hardwigsen J, Lorho R, Dharancy S, Leroy V, Di Giambattista F, Duvoux C. Severe fibrosis in patients with recurrent hepatitis C after liver transplantation: a French experience on 250 patients over 15 years (the Orfèvre study). Clin Res Hepatol Gastroenterol 2014; 38:292-9. [PMID: 24685602 DOI: 10.1016/j.clinre.2014.02.007] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2013] [Revised: 01/27/2014] [Accepted: 02/18/2014] [Indexed: 02/04/2023]
Abstract
BACKGROUND AND AIMS Recurrent hepatitis C after liver transplantation (LT) is associated with rapid fibrosis progression. The aim of this study was to evaluate the cumulative risk for severe fibrosis and the factors influencing it. PATIENTS AND METHODS Two hundred and fifty LT patients were included 1 to 15years after LT. Recurrence of chronic hepatitis C on liver graft was classified according to Metavir score. RESULTS Kaplan-Meyer estimates for actuarial progression to severe fibrosis (Metavir>F3) showed a probability of 15.2% and 44.5% at 5 and 10years, respectively. Predictive factors for progression to severe fibrosis were: use of tacrolimus as main CNI, recipient age at time of biopsy<55, donor age ≥45, graft HCV re-infection<3months, biologically suspected graft re-infection and lack of response to antiviral treatment after LT. Multivariate analysis disclosed that only donor age ≥45 (hazard ratio 2.243, 95%CI 1.264-3.983, P=0.0058) and lack of response to antiviral treatment (hazard ratio 2.816, 95%CI 1.227-6.464, P=0.0146) were associated to severe fibrosis. CONCLUSIONS Our study confirms that donor age ≥45 and lack of response to antiviral treatment after LT are major predictive factors of progression of HCV recurrence on liver graft.
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Affiliation(s)
- Jérôme Dumortier
- Unité de transplantation hépatique-fédération des spécialités digestives, HCL, pavillon D, hôpital Edouard-Herriot, 69437 Lyon cedex 03, France.
| | - Ephrem Salamé
- Service de chirurgie digestive et transplantation hépatique, hôpital Trousseau, 37170 Chambray-lès-Tours, France
| | - Bruno Roche
- Centre hépato-biliaire, hôpital Paul-Brousse, AP-HP, 94804 Villejuif, France
| | - Monika Hurtova
- Service d'hépatologie, hôpital Henri-Mondor, AP-HP, 94000 Créteil, France
| | - Filomena Conti
- Service de chirurgie, hôpital Cochin, AP-HP, 75014 Paris, France
| | - Sylvie Radenne
- Service d'hépatologie, HCL, hôpital de la Croix-Rousse, 69205 Lyon, France
| | - Claire Vanlemmens
- Service d'hépatologie, hôpital Jean-Minjoz, CHU de Besançon, 25030 Besançon, France
| | - Georges-Philippe Pageaux
- Fédération médico-chirurgicale des maladies de l'appareil digestif, hôpital Saint-Eloi, 34295 Montpellier, France
| | - Faouzi Saliba
- Centre hépato-biliaire, hôpital Paul-Brousse, AP-HP, 94804 Villejuif, France
| | - Didier Samuel
- Centre hépato-biliaire, hôpital Paul-Brousse, AP-HP, 94804 Villejuif, France
| | - Philippe Compagnon
- Service de chirurgie digestive et hépato-biliaire - transplantation hépatique, hôpital Henri-Mondor, AP-HP, 94000 Créteil, France
| | | | - Yvon Calmus
- Service de chirurgie, hôpital Cochin, AP-HP, 75014 Paris, France
| | - Olivier Guillaud
- Unité de transplantation hépatique-fédération des spécialités digestives, HCL, pavillon D, hôpital Edouard-Herriot, 69437 Lyon cedex 03, France
| | - Jean Gugenheim
- Service de chirurgie digestive, hôpital L'Archet 2, CHU de Nice, 06202 Nice, France
| | - Mario Altieri
- Service de chirurgie digestive, CHU de Côte de Nacre, 14033 Caen, France
| | - François Durand
- Service d'hépatologie, hôpital Beaujon, AP-HP, 92118 Clichy, France
| | - Jean Hardwigsen
- Service de chirurgie digestive, hôpital la Conception, 13385 Marseille, France
| | - Richard Lorho
- Service de chirurgie hépato-biliaire et digestive, hôpital de Pontchaillou, 35033 Rennes, France
| | | | - Vincent Leroy
- Service d'hépato-gastro-entérologie, hôpital A.-Michallon, 38700 La Tronche, France
| | | | - Christophe Duvoux
- Service d'hépatologie, hôpital Henri-Mondor, AP-HP, 94000 Créteil, France
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25
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Shin M, Moon HH, Kim JM, Park JB, Kwon CHD, Kim SJ, Joh JW. Importance of donor-recipient age gradient to the prediction of graft outcome after living donor liver transplantation. Transplant Proc 2014; 45:3005-12. [PMID: 24157024 DOI: 10.1016/j.transproceed.2013.08.018] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
PURPOSE Advanced donor age is a well-known risk factor for poor graft function after living donor liver transplantation (LDLT). In addition, advanced recipient age has a significant impact because of the high prevalence of comorbidities. We investigated the relationship between donor-recipient age gradient (DRAG) and the posttransplant outcomes in LDLT. METHODS We included 821 consecutive adult recipients who underwent LDLT from June 1997 to May 2011. According to the value of DRAG, they were divided into 2 groups: Negative years (the donor was younger than the recipient) and positive years (the donor was older than the recipient). These groups were further divided into subgroups (≤-21, -20 to -1, 0 to 20, and ≥21 years). We collected retrospectively patient characteristics, laboratory results, medical and surgical complications, and graft loss. RESULTS The positive DRAG group had higher level of posttransplant alkaline phosphatase, but a lower incidence of biliary complications. The negative DRAG group, particularly DRAG ≤ -21 years was associated with the superior 1-, 3-, 5-, and 10-year graft survivals. Recipients with DRAG ≥ 21 showed persistently inferior graft survival during the observation period. In cases of young donors, transplants utilizing lower DRAG seen between young donors and older recipients showed more favorable graft survival than that of young-to-young transplants. CONCLUSION This study demonstrated that DRAG and a fixed donor age limit could be significant factors to predict graft survival after LDLT. Patients should carefully consider the worse graft survival if the donor is older than the recipient by ≥20.
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Affiliation(s)
- M Shin
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
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26
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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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27
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Results of Liver Transplants From Donors Aged 70 Plus: Analysis of Andalusian Transplant Register. Transplant Proc 2013; 45:3647-9. [DOI: 10.1016/j.transproceed.2013.10.024] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
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28
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Martins PN, Markmann JF. Age-related differences in hepatic ischemia/reperfusion: gene activation, liver injury, and protective effect of melatonin. J Surg Res 2013; 185:e19-21. [DOI: 10.1016/j.jss.2012.08.023] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2012] [Revised: 08/09/2012] [Accepted: 08/09/2012] [Indexed: 10/27/2022]
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29
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Shin M, Kim J, Park J, Kwon C, Kim SJ, Joh JW. Effect of Donor–Recipient Age Gradient on Graft Outcomes in Deceased Donor Liver Transplantation. Transplant Proc 2013; 45:3013-8. [DOI: 10.1016/j.transproceed.2013.08.019] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
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30
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Nishikawa H, Kimura T, Kita R, Osaki Y. Treatment for hepatocellular carcinoma in elderly patients: a literature review. J Cancer 2013; 4:635-43. [PMID: 24155775 PMCID: PMC3805991 DOI: 10.7150/jca.7279] [Citation(s) in RCA: 84] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2013] [Accepted: 09/07/2013] [Indexed: 02/06/2023] Open
Abstract
An aging society means that the number of elderly patients with cancer is predicted to rise in the future. Hepatocellular carcinoma (HCC) usually develops in patients with hepatitis B virus infection, hepatitis C virus infection, or alcoholic liver disease. The risk of developing HCC is also known to be age-dependent and elderly patients sometimes present with HCC. The increased longevity of the population thus means that more elderly HCC patients are to be expected in the coming years. In general, many elderly patients are not receiving optimal therapy for malignancies, because it is often withheld from them because of perceived minimal survival advantage and the fear of potential toxicity. Comprehensive data with regard to treatment of elderly patients with HCC are currently limited. Furthermore, current guidelines for the management of HCC do not satisfy strategies according to age. Thus, there is urgent need for investigation of safety and clinical outcomes in elderly patients who receive therapy for HCC. In this review, we primarily refer to current knowledge of clinical characteristics and outcome in elderly patients with HCC who underwent different treatment approaches (i.e., surgical resection, liver transplantation, locoregional therapies, and molecular-targeting therapy).
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Affiliation(s)
- Hiroki Nishikawa
- Department of Gastroenterology and Hepatology, Osaka Red Cross Hospital, Osaka, Japan
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31
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Howell J, Sawhney R, Angus P, Fink M, Jones R, Wang BZ, Visvanathan K, Crowley P, Gow P. Identifying the superior measure of rapid fibrosis for predicting premature cirrhosis after liver transplantation for hepatitis C. Transpl Infect Dis 2013; 15:588-99. [PMID: 24028328 DOI: 10.1111/tid.12134] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2013] [Accepted: 03/24/2013] [Indexed: 01/06/2023]
Abstract
BACKGROUND Hepatitis C virus (HCV) recurrence post liver transplant is universal, with a subgroup of patients developing rapid hepatic fibrosis. Various clinical definitions of rapid fibrosis (RF) have been used to identify risks for rapid progression, but their comparability and efficacy at predicting adverse outcomes has not been determined. METHODS Retrospective data analysis was conducted on 100 adult patients with HCV who underwent liver transplantation at a single center. We measured year 1 fibrosis progression (RF defined as METAVIR F score ≥ 1 at 1-year liver biopsy), time to METAVIR F2-stage fibrosis, and fibrosis rate (calculated using liver biopsies graded by METAVIR scoring F0-4; fibrosis rate = fibrosis stage/year post transplant). RF was defined as ≥ 0.5 units/year. RESULTS Multivariate analysis revealed that donor age and peak HCV viral load were significant risks for RF, when fibrosis rate was used to define RF. Advanced donor age was a risk for rapid progression to F2-stage fibrosis, whereas genotype 2 or 3 HCV infection was protective. Fibrosis rate had the strongest correlation with time to cirrhosis development (P < 0.0001, r = -0.76) and was the most accurate predictor of rapid graft cirrhosis (P < 0.0001, area under the curve 0.979, sensitivity 100%, specificity 94%). CONCLUSION Different measures of RF progression identify different risks for RF and are not directly comparable. Fibrosis rate was the most accurate predictor of rapid graft cirrhosis.
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Affiliation(s)
- J Howell
- Victorian Liver Transplant Unit, Austin Hospital, Melbourne, VIC, Australia; Department of Medicine, University of Melbourne, Melbourne, VIC, Australia
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32
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Norvell JP, Levitsky J. Donor and recipient effects on graft and patient survival. Clin Liver Dis (Hoboken) 2013; 2:152-155. [PMID: 30992851 PMCID: PMC6448645 DOI: 10.1002/cld.223] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2013] [Revised: 05/15/2013] [Accepted: 05/18/2013] [Indexed: 02/04/2023] Open
Affiliation(s)
- JP Norvell
- Division of Digestive Diseases, Emory Transplant Center, Emory University, Atlanta, GA
| | - Josh Levitsky
- Department of Medicine, Kovler Organ Transplantation Center, Northwestern Memorial Hospital, Northwestern University, Chicago, IL
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Karnik GS, Shetty K. Management of recurrent hepatitis C in orthotopic liver transplant recipients. Infect Dis Clin North Am 2013; 27:285-304. [PMID: 23714341 DOI: 10.1016/j.idc.2013.02.003] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
End-stage liver disease and hepatocellular carcinoma from chronic hepatitis C are the most common indications for orthotopic liver transplantation and the incidence of both are projected to increase over the next decade. Recurrent hepatitis C virus infection of the allograft is associated with an accelerated progression to cirrhosis, graft loss, and death. This article presents an overview of the natural history of hepatitis C virus recurrence in liver transplant recipients and guidance on optimal management strategies.
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Affiliation(s)
- Geeta S Karnik
- Department of Infectious Diseases, Georgetown University Hospital, Washington, DC 20007, USA.
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34
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Freeman RB. Deceased donor risk factors influencing liver transplant outcome. Transpl Int 2013; 26:463-70. [PMID: 23414069 DOI: 10.1111/tri.12071] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2012] [Revised: 11/27/2012] [Accepted: 01/07/2013] [Indexed: 12/14/2022]
Abstract
As the pressure for providing liver transplantation to more and more candidates increases, transplant programs have begun to consider deceased donor characteristics that were previously considered unacceptable. With this trend, attention has focused on better defining those donor factors that can impact the outcome of liver transplantation. This review examines deceased donor factors that have been associated with patient or graft survival as well as delayed graft function and other liver transplant results.
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Affiliation(s)
- Richard B Freeman
- Department of Surgery, Dartmouth Hitchcock Medical Center, Geisel School of Medicine a Dartmouth, 1 Medical Center Drive, Lebanon, NH 03756, USA.
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35
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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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36
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Carbone M, Lenci I, Baiocchi L. Prevention of hepatitis C recurrence after liver transplantation: An update. World J Gastrointest Pharmacol Ther 2012; 3:36-48. [PMID: 22966482 PMCID: PMC3437445 DOI: 10.4292/wjgpt.v3.i4.36] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2011] [Revised: 06/20/2012] [Accepted: 06/28/2012] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C related liver failure and hepatocarcinoma are the most common indications for liver transplantation in Western countries. Recurrent hepatitis C infection of the allograft is universal and immediate following liver transplantation, being associated with accelerated progression to cirrhosis, graft loss and death. Graft and patient survival is reduced in liver transplant recipients with recurrent Hepatitis C virus (HCV) infection compared to HCV-negative recipients. Many variables may impact on recurrent HCV liver disease. Overall, excess immunosuppression is believed to be a key factor; however, no immunosuppressive regimen has been identified to be more beneficial or less harmful. Donor age limitations, exclusion of moderately to severely steatotic livers and minimization of ischemic times could be a potential strategy to minimize the severity of HCV disease in transplanted subjects. After transplantation, antiviral therapy based on pegylated IFN alpha with or without ribavirin is associated with far less results than that reported for immunocompetent HCV-infected patients. New findings in the field of immunotherapy and genomic medicine applied to this context are promising.
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Affiliation(s)
- Marco Carbone
- Marco Carbone, Liver Unit, Queen Elizabeth Hospital, Birmingham, B15 2TH, United Kingdom
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37
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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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38
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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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Ydreborg M, Westin J, Lagging M, Castedal M, Friman S. Impact of donor histology on survival following liver transplantation for chronic hepatitis C virus infection: a Scandinavian single-center experience. Scand J Gastroenterol 2012; 47:710-7. [PMID: 22452366 DOI: 10.3109/00365521.2012.672592] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVE Survival following liver transplantation for hepatitis C virus (HCV) infection is affected by several factors. The aims of this single-center study were to evaluate survival from 1992 to 2006 in HCV-infected liver transplant recipients and to identify factors influencing patient and graft survival, with particular focus on donor liver histopathology. MATERIAL AND METHODS Survival among 84 patients transplanted for HCV-related liver disease at the Sahlgrenska University Hospital during the above period was evaluated. Median follow-up time was 57 months (range 28-87). A perioperative liver biopsy from the donor liver graft was available in 68 cases. Biopsies were assessed for fibrosis, necroinflammatory activity, and degree of steatosis. Patient and graft survival according to relevant factors including donor histopathology were analyzed by Kaplan-Meier analysis. RESULTS We found an association between donor liver fibrosis and patient survival (p = 0.016) as well as between graft survival and portal inflammation in the donor liver (p = 0.026). Both these associations remained significant in multivariate analysis (p = 0.007 and 0.017 respectively). Moreover, recipient age over 60 was found predictive of patient survival and repeated steroid boluses or steroid-resistant rejection of graft survival. Donor age was high throughout the study period. CONCLUSION Histopathological features, especially portal inflammation and stage of fibrosis, in the donor liver may deleteriously affect graft and patient survival following HCV-related liver transplantation. Thus, pretransplant evaluation of donor histopathology may be of value in the selection of donors for transplantation of HCV-positive individuals, especially among donors older than 60 years.
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Affiliation(s)
- Magdalena Ydreborg
- Department of Infectious Diseases/Clinical Virology, Institute of Biomedicine, University of Gothenburg, Sweden.
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40
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Tanemura A, Mizuno S, Wada H, Yamada T, Nobori T, Isaji S. Donor age affects liver regeneration during early period in the graft liver and late period in the remnant liver after living donor liver transplantation. World J Surg 2012; 36:1102-1111. [PMID: 22374540 DOI: 10.1007/s00268-012-1496-1] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
BACKGROUND The aim of the present study was to evaluate the influence of donor age on liver regeneration and surgical outcomes in recipients and donors. PATIENTS AND METHODS Among 101 cases of adult-to-adult living donor liver transplantation (LDLT) between March 2002 and March 2011, according to donor age: younger (Y) <50 years of age or older (O) ≥ 50 years of age, the donors and recipients using right (R) or left (L) graft were divided into groups Y/R (n = 51) and O/R (n = 17), and groups Y/L (n = 26) and O/L (n = 7), respectively. Remnant liver volume (RemLV) and graft liver volume (GLV) were estimated by computed tomography (CT) volumetry. A disintegrin and metalloprotease with thrombospondin type I domain 13 (ADAMTS13) activities and von Willebrand factor (vWF) antigen levels were measured as factors reflecting thrombotic microangiopathy. RESULTS Among the donors, RemLV/total liver volume (TLV) was lower in group O/R than in group Y/R, although there were no significant differences by t-test with the Bonferroni correction (rough p value = 0.02 at 6 months and rough p value > 0.05 at 1, 3, and 12 months). Donor age (≥ 50 years) was independently correlated with impaired remnant liver regeneration at 6 months in right lobe LDLT (p = 0.04). Among the recipients, GLV/standard liver volume (SLV) was lower during the first month, although there were no significant differences between the two groups by t-test with the Bonferroni correction (rough p value = 0.03 at 1 week and rough p value >0.05 at 2 weeks and 1 and 3 months). Donor age (≥ 50 years) was independently correlated with impaired graft liver regeneration at 1 week in both right and left lobe LDLT (p < 0.05). ADAMTS13 activities were lower in group O/R than in group Y/R, although there were no significant differences by t-test with the Bonferroni correction (rough p value = 0.049 on postoperative days (POD) 1 and 28 and rough p value >0.05 on POD 7 and 14). vWF/ADAMTW13 ratios were higher on POD 14, although there were no significant differences between the two groups by t-test with the Bonferroni correction (rough p value = 0.044 on POD 14 and rough p value >0.05 on POD 1, 7, 14, and 28). CONCLUSIONS The surgical outcomes using older donor livers for LDLT were comparable to those using younger donor livers. When using older donor livers, however, we should pay attention to the liver volume for recipients as well as donors, because older donor livers might have impaired regenerative ability.
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Affiliation(s)
- Akihiro Tanemura
- Department of Hepatobiliary-Pancreatic and Transplant Surgery, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie, 514-0001, Japan
| | - Shugo Mizuno
- Department of Hepatobiliary-Pancreatic and Transplant Surgery, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie, 514-0001, Japan.
| | - Hideo Wada
- Department of Molecular and Laboratory Medicine, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie, 514-0001, Japan
| | - Tomomi Yamada
- Department of Translational Medical Science, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie, 514-0001, Japan
| | - Tsutomu Nobori
- Department of Molecular and Laboratory Medicine, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie, 514-0001, Japan
| | - Shuji Isaji
- Department of Hepatobiliary-Pancreatic and Transplant Surgery, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie, 514-0001, Japan
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41
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Uemura T, Nikkel LE, Hollenbeak CS, Ramprasad V, Schaefer E, Kadry Z. How can we utilize livers from advanced aged donors for liver transplantation for hepatitis C? Transpl Int 2012; 25:671-9. [DOI: 10.1111/j.1432-2277.2012.01474.x] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
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Rubín A, Aguilera V, Berenguer M. Liver transplantation and hepatitis C. Clin Res Hepatol Gastroenterol 2011; 35:805-12. [PMID: 21963086 DOI: 10.1016/j.clinre.2011.04.009] [Citation(s) in RCA: 53] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2011] [Accepted: 04/20/2011] [Indexed: 02/04/2023]
Abstract
Hepatitis C virus (HCV)-related end-stage cirrhosis with/without hepatocellular carcinoma is the primary indication for liver transplantation in many countries. Unfortunately, HCV is not eliminated by transplantation and graft re-infection is the rule, resulting in HCV-related graft disease. The natural history of recurrent hepatitis is variable; overall, progression to cirrhosis occurs in 20-30% and allograft failure in 10% after 5-10 years from transplantation. The use of poor quality organs, particularly from old donors, has a significant negative impact on disease severity and transplant outcome. In contrast, antiviral therapy, particularly if it results in permanent eradication of the virus, is associated with improved histology, reduced rate of graft decompensation and enhanced outcome. Disease monitoring, through protocol liver biopsies and new non-invasive tools, is essential to select patients at need of antiviral therapy. Peginterferon with ribavirin, used similarly to what is done in the non-transplant setting, is currently the treatment of choice; sustained viral response is achieved in about 35% of cases. Side effects, particularly anemia, are extremely frequent and sometimes severe (rejection, de novo autoimmune hepatitis). Retransplantation (RT) is the last option for the small subset of patients with allograft failure due to HCV recurrence who fulfil minimum criteria based on RT survival models.
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Affiliation(s)
- A Rubín
- Hepatology-liver transplantation unit, Digestive medicine service, and Ciberehd, National network center for hepatology and gastroenterology research, Hospital Universitari i Politècnic La Fe, Instituto de Salud Carlos III, Bulevar Sur s/n, 46026 Valencia, Spain
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44
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Selzner N, Boehnert M, Selzner M. Preconditioning, postconditioning, and remote conditioning in solid organ transplantation: basic mechanisms and translational applications. Transplant Rev (Orlando) 2011; 26:115-24. [PMID: 22000660 DOI: 10.1016/j.trre.2011.07.003] [Citation(s) in RCA: 64] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2011] [Revised: 05/06/2011] [Accepted: 07/05/2011] [Indexed: 02/07/2023]
Abstract
Ischemia and reperfusion (I/Rp) injury is inherent to solid organ transplantation and can result in primary nonfunction or delayed function of grafts, which is associated with a significant morbidity and mortality posttransplantation. It is also a major obstacle for the use of marginal grafts to increase the donor pool, as these grafts are prone to a higher degree of I/Rp injury. Pre-, post-, and remote conditioning are protective strategies against I/Rp injury, which can be applied in the transplant setting. These strategies hold the potential to reduce graft injury and to safely expand the donor pool. However, despite convincing experimental data, the protective effects of the "conditioning" protocols remain unclear, and only few have translated to clinical practice. This review summarizes pre-, post-, and remote conditioning strategies in clinical use in solid organ transplantation and discusses an overview of the mechanistic pathways involved in each strategy.
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Affiliation(s)
- Nazia Selzner
- Multi Organ Transplant Program, University Health Network, University of Toronto, Toronto, Canada
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Liver regeneration and aging: a current perspective. Curr Gerontol Geriatr Res 2011; 2011:526379. [PMID: 21912543 PMCID: PMC3170699 DOI: 10.1155/2011/526379] [Citation(s) in RCA: 109] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2011] [Accepted: 07/06/2011] [Indexed: 12/22/2022] Open
Abstract
Many organ systems exhibit significant age-related deficits, but,
based on studies in old rodents and elderly humans, the liver
appears to be relatively protected from such changes. A
remarkable feature of the liver is its capacity to regenerate its
mass following partial hepatectomy. Reports suggests that aging
compromises the liver's regenerative capacity, both in the
rate and to the extent the organ's original volume is
restored. There has been modest definitive information as to which
cellular and molecular mechanisms regulating hepatic regeneration
are affected by aging. Changes in hepatic sensitivity to growth
factors, for example, epidermal growth factor (EGF), appear to influence
regeneration in old animals. Studies have demonstrated (a) a 60%
decline in EGF binding to hepatocyte plasma membranes, (b) reduced
expression of the hepatic high affinity EGF receptor and (c) a
block between G1 and S-phases of the cell cycle in old rats
following EGF stimulation. Recent studies suggest that reduced
phosphorylation and dimerization of the EGF receptor, critical
steps in the activation of the extracellular signal-regulated
kinase pathway and subsequent cell proliferation are responsible.
Other studies have demonstrated that aging affects the
upregulation of a Forkhead Box transcription factor, FoxM1B, which
is essential for growth hormone-stimulated liver regeneration in
hepatectomized mice. Aging appears to compromise liver
regeneration by influencing several pathways, the result of which
is a reduction in the rate of regeneration, but not in the
capacity to restore the organ to its original volume.
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Máthé Z, Paul A, Molmenti EP, Vernadakis S, Klein CG, Beckebaum S, Treckmann JW, Cicinnati VR, Kóbori L, Sotiropoulos GC. Liver transplantation with donors over the expected lifespan in the model for end-staged liver disease era: is Mother Nature punishing us? Liver Int 2011; 31:1054-61. [PMID: 21733096 DOI: 10.1111/j.1478-3231.2011.02546.x] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
BACKGROUND The lack of sufficient donors to satisfy the waiting list requirements has prompted many to expand the acceptance criteria. The purpose of this study was to evaluate our liver transplantation (LT) experience with donors beyond the average lifespan. PATIENTS AND METHODS From January 2008 to December 2009, we received 75 liver offers involving donors ≥ 75 years of age. Donor and recipient data were analysed by both uni- and multivariate Cox proportional hazard model analyses. RESULTS We performed 32 adult liver transplants (43%). Half of the patients received organs through rescue allocations. Seven recipients (22%) developed initial poor function. Two had primary graft non-function (PNF). Four recipients were re-transplanted (two PNF and two ischaemic-type bile lesions). One- and 3-year cumulative survival was 62 and 51% respectively. PNF, lab model for end-staged liver disease (MELD), post-LT haemodialysis, post-LT re-operations and post-LT sepsis were significant predictors by univariate analysis. Only PNF reached multivariate significance (P = 0.0307). Rescue offer allocation reached significance as a predictor of PNF by general linear model forward analysis. One- and 3-year 'MELD based allocation' (n = 16) vs 'rescue allocation' (n = 16) survival rates were 44 and 29% vs 82 and 76% respectively (P = 0.0197). CONCLUSIONS Although grafts from donors ≥ 75 years allow for an expansion of the donor pool, long-term recipient survival is inferior to that encountered with younger donors. Acceptable results could be obtained by identifying 'preferred' recipients for rescue allocations.
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Affiliation(s)
- Zoltan Máthé
- Department of General, Visceral, and Transplantation Surgery, University Hospital Essen, Essen, Germany
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