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Kumar N, Choudhary NS. Managing HBV and HCV Infection Pre- and Post-liver Transplant. J Clin Exp Hepatol 2024; 14:101287. [PMID: 38076445 PMCID: PMC10709521 DOI: 10.1016/j.jceh.2023.09.008] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/26/2022] [Accepted: 09/19/2023] [Indexed: 03/03/2025] Open
Abstract
Hepatitis B and C are common causes of end-stage liver disease and etiologies of liver transplantation. It is important to prevent recurrence in cases of hepatitis B. Nucleos(t)ide analogs are the mainstay of HBV treatment before (in patients with decompensated cirrhosis) and after liver transplantation. After the introduction of direct-acting antivirals, the treatment of HCV has become considerably easy. In patients with advanced HCV-related cirrhosis, it is better to do transplantation first and treat them after liver transplantation. The sustained virological response rates have improved from 8 to 50% in the interferon era to 90% in the direct-acting antivirals era. In the current review, we discuss the treatment of HBV and HCV before and after liver transplantation.
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Affiliation(s)
- Naveen Kumar
- Hepatology and Gastroenterology, Narayana Hospital Delhi, India
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2
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Saimaier K, Han S, Lv J, Zhuang W, Xie L, Liu G, Wang C, Zhang R, Hua Q, Shi C, Du C. Manganese Exacerbates ConA-Induced Liver Inflammation via the cGAS-STING Signaling Pathway. Inflammation 2024; 47:333-345. [PMID: 37805951 DOI: 10.1007/s10753-023-01912-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2023] [Revised: 09/21/2023] [Accepted: 09/22/2023] [Indexed: 10/10/2023]
Abstract
There is a potential association between the dysregulation of trace elements and impaired liver function. Elevated levels of manganese, an essential metal ion, have been observed in liver-related diseases, and excessive intake of manganese can worsen liver damage. However, the specific mechanisms underlying manganese-induced liver injury are not well understood. The aim of our study was to investigate the effects of excess manganese on autoimmune hepatitis (AIH) and elucidate its mechanisms. Our findings revealed that manganese exacerbates liver damage under ConA-induced inflammatory conditions. Transcriptomic and experimental data suggested that manganese enhances inflammatory signaling and contributes to the inflammatory microenvironment in the liver of AIH mice. Further investigations demonstrated that manganese exacerbates liver injury by activating the cGAS-STING signaling pathway and its downstream pro-inflammatory factors such as IFN[Formula: see text], IFN[Formula: see text], TNF[Formula: see text], and IL-6 in the liver of AIH mice. These results suggest that manganese overload promotes the progression of AIH by activating cGAS-STING-mediated inflammation, providing a new perspective for the treatment and prognosis of AIH.
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Affiliation(s)
- Kaidireya Saimaier
- Putuo People's Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai, China
| | - Sanxing Han
- Putuo People's Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai, China
| | - Jie Lv
- Putuo People's Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai, China
| | - Wei Zhuang
- Putuo People's Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai, China
- Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China
- College of Life Sciences, University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Ling Xie
- Putuo People's Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai, China
| | - Guangyu Liu
- Putuo People's Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai, China
| | - Chun Wang
- Putuo People's Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai, China
| | - Ru Zhang
- Putuo People's Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai, China
| | - Qiuhong Hua
- Putuo People's Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai, China
| | - Changjie Shi
- Putuo People's Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai, China
| | - Changsheng Du
- Putuo People's Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai, China.
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3
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Kelly C, Zen Y, Heneghan MA. Post-Transplant Immunosuppression in Autoimmune Liver Disease. J Clin Exp Hepatol 2023; 13:350-359. [PMID: 36950491 PMCID: PMC10025678 DOI: 10.1016/j.jceh.2022.07.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Revised: 06/10/2022] [Accepted: 07/04/2022] [Indexed: 02/17/2023] Open
Abstract
Autoimmune liver diseases (AILDs) are a group of conditions where immune-mediated liver damage can lead to the need for transplantation. Collectively, they account for almost a quarter of all liver transplants. Outcomes in terms of graft and patient survival for all liver transplants have improved markedly over decades with improvements in patient selection, surgical techniques and longer-term care and this is also seen in patients with AILDs. The current five- and ten-year survival rates post-transplant in autoimmune disease are excellent, at 88% and 78%, respectively. A key factor in maintaining good outcomes post liver transplant for these autoimmune conditions is the immunosuppression strategy. These patients have increased the rates of rejection, and autoimmune conditions can all recur in the graft ranging from 12 to 60% depending on the population studied. Immunosuppressive regimens are centred on calcineurin inhibitors, often combined with low dose corticosteroids, with or without the addition of antimetabolite therapy. There is no clear evidence-based immunosuppressive regimen for these conditions, and a tailored approach balancing the individuals' immunological profile against the risks of immunosuppression is often used. There are disease-specific considerations to optimised graft function including the role of ursodeoxycholic acid in both primary biliary cholangitis and primary sclerosing cholangitis and the role and timing of colectomy in primary sclerosing cholangitis in inflammatory bowel disease patients. However, unmet needs still exist in the management of AILDs post liver transplantation particularly in building the evidence base for optimal immunosuppression as well as mitigating the risk of recurrent disease.
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Key Words
- AIH, Autoimmune hepatitis
- AILD, Autoimmune liver disease
- CNI, Calcineurin inhibitors
- IBD, Inflammatory bowel disease
- LT, Liver transplantation
- PBC, Primary biliary cholangitis
- PSC, Primary sclerosing cholangitis
- autoimmune liver disease
- immunosuppression
- rAIH, Recurrent autoimmune hepatitis
- rPBC, Recurrent primary biliary cholangitis
- rPSC, Recurrent primary sclerosing cholangitis
- transplantation
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Affiliation(s)
- Claire Kelly
- Institute of Liver Studies, Kings College Hospital, London, UK
| | - Yoh Zen
- Institute of Liver Studies, Kings College Hospital, London, UK
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4
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Ismail B, Benrajab KM, Bejarano P, Ruiz P, Sears D, Tzakis A, Zervos XB. Benign course of residual inflammation at end of treatment of liver transplant recipients after sofosbuvir based therapy. World J Hepatol 2022; 14:602-611. [PMID: 35582292 PMCID: PMC9055203 DOI: 10.4254/wjh.v14.i3.602] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2021] [Revised: 12/16/2021] [Accepted: 02/16/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Persistent inflammation on histology after successful hepatitis C (HCV) treatment has been reported. However, data regarding the long-term impact in liver transplant recipients is limited, particularly after using direct-acting antiviral (DAA) therapies.
AIM To evaluate the impact of successful treatment with DAAs on histological changes and occult HCV and to describe the clinical course of residual inflammation in liver transplant recipients.
METHODS We conducted a case series of 13 chronic HCV infected liver transplant recipients successfully treated with DAAs between December 2013 and May 2014. All patients were treated for 24 wk and had non-detectable serum HCV RNA by the time of biopsy. Only patients with at least one liver biopsy at or after treatment were included. We examined liver biopsies for evidence of residual inflammation and the presence of intrahepatic HCV RNA.
RESULTS Persistent inflammation was seen in 12/13 patients on end of treatment biopsy. Inflammation was still seen in the available five follow-up biopsies (range 38-48 wk after the end of treatment). Intrahepatic HCV RNA was undetectable in all biopsies. All patients had preserved graft function for a mean follow-up of 2.5 years, except one that developed chronic rejection.
CONCLUSION After successful HCV treatment with DAAs, liver transplant recipients may have persistent inflammation on biopsy without evidence of intracellular RNA. The clinical outcome remained favorable in most patients. Further studies with a larger number and longer follow-up are needed to establish the implication of this finding on long-term graft function.
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Affiliation(s)
- Bahaaeldeen Ismail
- Division of Digestive Diseases and Nutrition, University of Kentucky College of Medicine, Lexington, KY 40536, United States
| | - Karim M Benrajab
- Division of Digestive Diseases and Nutrition, University of Kentucky College of Medicine, Lexington, KY 40536, United States
| | - Pablo Bejarano
- Department of Pathology, Cleveland Clinic Florida, Weston, FL 33331, United States
| | - Phillip Ruiz
- Department of Pathology, University of Miami Miller School of Medicine, Miami, FL 33136, United States
| | - Debbie Sears
- Department of Liver Transplant, Cleveland Clinic Florida, Weston, FL 33331, United States
| | - Andreas Tzakis
- Department of Liver Transplant, Cleveland Clinic Florida, Weston, FL 33331, United States
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5
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GPX4-Regulated Ferroptosis Mediates S100-Induced Experimental Autoimmune Hepatitis Associated with the Nrf2/HO-1 Signaling Pathway. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:6551069. [PMID: 34966478 PMCID: PMC8712167 DOI: 10.1155/2021/6551069] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/25/2021] [Revised: 10/05/2021] [Accepted: 11/03/2021] [Indexed: 12/17/2022]
Abstract
Autoimmune hepatitis (AIH) is an inflammatory autoimmune disease of the liver. Oxidative stress triggered by reactive oxygen radicals is a common pathophysiological basis for the pathogenesis of many liver diseases, and ferroptosis is associated with the toxic accumulation of reactive oxygen species. The signaling transduction pathways responsible for iron processing and lipid-peroxidation mechanisms are believed to drive ferroptosis. However, the specific mechanisms regulating ferroptosis remain unclear. The aims of this investigation were to identify the possible effector functions of ferroptosis, based on glutathione peroxidase 4 (GPX4) regulation in an S100-induced autoimmune hepatitis mouse model and hepatocyte injury models. The S100 liver antigen-induced AIH mouse model was used to detect ferroptotic biomarkers using western blotting. Upregulated levels of cyclooxygenase2 (COX2) and Acyl-Coenzyme A synthase long-chain family member 4 (ACSL4) were observed in the S100-induced AIH model group, while levels of GPX4 and ferritin heavy chain 1 (FTH1) were downregulated (P < 0.05). The expression profiles of COX2, ACSL4, GPX4, and FTH1 were restored following the administration of ferrostatin-1. In addition, Nrf2 and HO-1 levels in the S100-induced AIH model mice after treatment with ferrostatin-1 were downregulated compared to the nonferrostatin-1-treated S100-induced AIH model mice (P < 0.05). Moreover, COX2 and ACSL4 levels were significantly upregulated, with significant FTH1 downregulation, in the AIH model mice when liver-specific GPX4 was silenced using AAV8 constructs. These data indicate that inhibition of ferroptosis significantly ameliorated the influence of AIH on the Nuclear factor E2-related factor 2 (Nrf2)/Heme oxygenase-1 (HO-1) signaling pathway, and that ferroptosis may act as an initiator or intermediate mediator leading to AIH.
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6
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Sirbe C, Simu G, Szabo I, Grama A, Pop TL. Pathogenesis of Autoimmune Hepatitis-Cellular and Molecular Mechanisms. Int J Mol Sci 2021; 22:13578. [PMID: 34948375 PMCID: PMC8703580 DOI: 10.3390/ijms222413578] [Citation(s) in RCA: 55] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2021] [Revised: 12/09/2021] [Accepted: 12/14/2021] [Indexed: 02/05/2023] Open
Abstract
Pediatric autoimmune liver disorders include autoimmune hepatitis (AIH), autoimmune sclerosing cholangitis (ASC), and de novo AIH after liver transplantation. AIH is an idiopathic disease characterized by immune-mediated hepatocyte injury associated with the destruction of liver cells, causing inflammation, liver failure, and fibrosis, typically associated with autoantibodies. The etiology of AIH is not entirely unraveled, but evidence supports an intricate interaction among genetic variants, environmental factors, and epigenetic modifications. The pathogenesis of AIH comprises the interaction between specific genetic traits and molecular mimicry for disease development, impaired immunoregulatory mechanisms, including CD4+ T cell population and Treg cells, alongside other contributory roles played by CD8+ cytotoxicity and autoantibody production by B cells. These findings delineate an intricate pathway that includes gene to gene and gene to environment interactions with various drugs, viral infections, and the complex microbiome. Epigenetics emphasizes gene expression through hereditary and reversible modifications of the chromatin architecture without interfering with the DNA sequence. These alterations comprise DNA methylation, histone transformations, and non-coding small (miRNA) and long (lncRNA) RNA transcriptions. The current first-line therapy comprises prednisolone plus azathioprine to induce clinical and biochemical remission. Further understanding of the cellular and molecular mechanisms encountered in AIH may depict their impact on clinical aspects, detect biomarkers, and guide toward novel, effective, and better-targeted therapies with fewer side effects.
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Affiliation(s)
- Claudia Sirbe
- 2nd Pediatric Discipline, Department of Mother and Child, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania; (C.S.); (T.L.P.)
- 2nd Pediatric Clinic, Emergency Clinical Hospital for Children, 400177 Cluj-Napoca, Romania
| | - Gelu Simu
- Cardiology Department, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania;
- Cardiology Department, Rehabilitation Hospital, 400066 Cluj-Napoca, Romania
| | - Iulia Szabo
- Department of Rheumatology, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania;
| | - Alina Grama
- 2nd Pediatric Discipline, Department of Mother and Child, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania; (C.S.); (T.L.P.)
- 2nd Pediatric Clinic, Emergency Clinical Hospital for Children, 400177 Cluj-Napoca, Romania
| | - Tudor Lucian Pop
- 2nd Pediatric Discipline, Department of Mother and Child, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania; (C.S.); (T.L.P.)
- 2nd Pediatric Clinic, Emergency Clinical Hospital for Children, 400177 Cluj-Napoca, Romania
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7
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Mack CL, Adams D, Assis DN, Kerkar N, Manns MP, Mayo MJ, Vierling JM, Alsawas M, Murad MH, Czaja AJ. Diagnosis and Management of Autoimmune Hepatitis in Adults and Children: 2019 Practice Guidance and Guidelines From the American Association for the Study of Liver Diseases. Hepatology 2020; 72:671-722. [PMID: 31863477 DOI: 10.1002/hep.31065] [Citation(s) in RCA: 548] [Impact Index Per Article: 109.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2019] [Accepted: 11/25/2019] [Indexed: 02/06/2023]
Affiliation(s)
- Cara L Mack
- Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO
| | - David Adams
- Centre for Liver Research, University of Birmingham, Birmingham, UK
| | - David N Assis
- Department of Internal Medicine, Yale School of Medicine, New Haven, CT
| | - Nanda Kerkar
- Golisano Children's Hospital at Strong, University of Rochester Medical Center, New York, NY
| | - Michael P Manns
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Marlyn J Mayo
- Division of Digestive and Liver Diseases, University of Texas SW Medical Center, Dallas, TX
| | - John M Vierling
- Medicine and Surgery, Baylor College of Medicine, Houston, TX
| | | | - Mohammad H Murad
- Mayo Knowledge and Encounter Research Unit, Mayo Clinic College of Medicine, Rochester, MN
| | - Albert J Czaja
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN
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8
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Webb GJ, Hirschfield GM, Krawitt EL, Gershwin ME. Cellular and Molecular Mechanisms of Autoimmune Hepatitis. ANNUAL REVIEW OF PATHOLOGY-MECHANISMS OF DISEASE 2019; 13:247-292. [PMID: 29140756 DOI: 10.1146/annurev-pathol-020117-043534] [Citation(s) in RCA: 96] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Autoimmune hepatitis is an uncommon idiopathic syndrome of immune-mediated destruction of hepatocytes, typically associated with autoantibodies. The disease etiology is incompletely understood but includes a clear association with human leukocyte antigen (HLA) variants and other non-HLA gene variants, female sex, and the environment. Pathologically, there is a CD4+ T cell-rich lymphocytic inflammatory infiltrate with variable hepatocyte necrosis and subsequent hepatic fibrosis. Attempts to understand pathogenesis are informed by several monogenetic syndromes that may include autoimmune liver injury, by several drug and environmental agents that have been identified as triggers in a minority of cases, by human studies that point toward a central role for CD4+ effector and regulatory T cells, and by animal models of the disease. Nonspecific immunosuppression is the current standard therapy. Further understanding of the disease's cellular and molecular mechanisms may assist in the design of better-targeted therapies, aid the limitation of adverse effects from therapy, and inform individualized risk assessment and prognostication.
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Affiliation(s)
- G J Webb
- National Institute for Health Research Liver Biomedical Research Centre, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham B15 2TT, United Kingdom; ,
| | - G M Hirschfield
- National Institute for Health Research Liver Biomedical Research Centre, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham B15 2TT, United Kingdom; ,
| | - E L Krawitt
- Department of Medicine, University of Vermont, Burlington, Vermont 05405, USA; .,Department of Medicine, Dartmouth College, Hanover, New Hampshire 03755, USA
| | - M E Gershwin
- Division of Rheumatology, Allergy, and Clinical Immunology, School of Medicine, University of California, Davis, California 95817, USA;
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9
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Stirnimann G, Ebadi M, Czaja AJ, Montano-Loza AJ. Recurrent and De Novo Autoimmune Hepatitis. Liver Transpl 2019; 25:152-166. [PMID: 30375180 DOI: 10.1002/lt.25375] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2018] [Accepted: 10/23/2018] [Indexed: 02/07/2023]
Abstract
Clinical indications for liver transplantation (LT) in patients with autoimmune hepatitis (AIH) are identical to those of patients with other chronic liver diseases that end in acute or semiacute liver failure, decompensated cirrhosis, or hepatocellular carcinoma. Recurrent disease after LT has been reported in 10%-50% of patients with AIH, and the frequency of detection is influenced in part by the use of protocol or clinically indicated liver biopsy. De novo AIH connotes the development of AIH in patients transplanted for liver diseases other than AIH, and it has been reported in 5%-10% of pediatric and 1%-2% of adult recipients. Recurrent disease can negatively impact on graft and patient survival, and retransplantation has been required in 8%-23%. De novo AIH is within the spectrum of graft dysfunction that includes plasma cell-rich rejection, and it can also progress to cirrhosis and graft failure. Treatment for recurrent or de novo disease is based on the conventional regimens for AIH, and corticosteroid therapy alone or combined with azathioprine is standard. Better control of disease activity prior to LT has been associated with less recurrence, and maintenance corticosteroid treatment after LT can reduce its frequency. In conclusion, recurrent AIH is far more frequent than de novo AIH. Both may have negative impacts on graft and patient survival, and early detection and treatment are key objectives. Future investigations must codify the diagnostic criteria for each graft dysfunction, seek diagnostic biomarkers, and evaluate treatments that improve outcomes without increasing the risk of pre- and post-LT infections.
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Affiliation(s)
- Guido Stirnimann
- Department of Visceral Surgery and Medicine, Inselspital Bern, Bern University Hospital and University of Bern, Bern, Switzerland.,Division of Gastroenterology and Liver Unit, University of Alberta Hospital, Edmonton, Alberta, Canada
| | - Maryam Ebadi
- Division of Gastroenterology and Liver Unit, University of Alberta Hospital, Edmonton, Alberta, Canada
| | - Albert J Czaja
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, MN
| | - Aldo J Montano-Loza
- Division of Gastroenterology and Liver Unit, University of Alberta Hospital, Edmonton, Alberta, Canada
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10
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Chan C, Schiano T, Agudelo E, Paul Haydek J, Hoteit M, Laurito MP, Norvell JP, Terrault N, Verna EC, Yang A, Levitsky J. Immune-mediated graft dysfunction in liver transplant recipients with hepatitis C virus treated with direct-acting antiviral therapy. Am J Transplant 2018; 18:2506-2512. [PMID: 30075485 DOI: 10.1111/ajt.15053] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2018] [Revised: 07/10/2018] [Accepted: 07/29/2018] [Indexed: 01/25/2023]
Abstract
Interferon treatment of hepatitis C virus (HCV) infection after liver transplantation (LT) can result in immune-mediated graft dysfunction (IGD). The occurrence of, risk factors for, and outcomes of IGD with direct-acting antiviral (DAA) therapy have not been reported. We conducted a multicenter study of HCV+LT recipients who did or did not develop DAA-IGD (1 case: 2 controls-33 vs 66). Among all treated between 2014 and 2016, DAA-IGD occurred in 3.4% (33/978). IGD occurred only after treatment completion (76.0 [IQR, 47.0;176]). Among those treated, 48% had plasma cell hepatitis, 36% acute cellular rejection, 6% chronic rejection, and 9% combined findings. Median time to liver enzyme resolution was 77.5 days (IQR, 31.5;126). After diagnosis, hospitalizations, steroid-induced hyperglycemia, and infection occurred in a higher percentage of cases vs controls (33% vs 7.5%, 21% vs 1.5%, 9% vs 0%; all P < .05). Only one IGD patient died and none required retransplant. A multivariate regression analysis found that liver enzyme elevations during and soon after DAA therapy completion correlated with subsequent IGD. In conclusion, while DAA-IGD is uncommon, liver enzyme elevations during or after DAA therapy may be a sign of impending IGD. These indicators should guide clinicians to diagnose and treat IGD early before the more deleterious later clinical presentation.
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Affiliation(s)
- Christine Chan
- Division of Gastroenterology and Hepatology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Thomas Schiano
- Recanati/ Miller Transplantation Institute and the Division of Liver Diseases, Mount Sinai Medical Center, New York, NY, USA
| | - Eliana Agudelo
- UCSF Medical Center Division of Liver Transplant, San Francisco, CA, USA
| | - John Paul Haydek
- Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA
| | - Maarouf Hoteit
- Division of Gastroenterology and Hepatology, Penn Transplant Institute, University of Pennsylvania, Philadelphia, PA, USA
| | - Marcela P Laurito
- Department of Medicine, Center for Liver Disease and Transplantation, Columbia University, New York, NY, USA
| | - John P Norvell
- Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA
| | - Norah Terrault
- UCSF Medical Center Division of Liver Transplant, San Francisco, CA, USA
| | - Elizabeth C Verna
- Department of Medicine, Center for Liver Disease and Transplantation, Columbia University, New York, NY, USA
| | - Amy Yang
- Division of Gastroenterology and Hepatology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Josh Levitsky
- Division of Gastroenterology and Hepatology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
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11
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Saxena V, Terrault NA. Recurrent Primary Disease After Liver Transplantation. ZAKIM AND BOYER'S HEPATOLOGY 2018:784-815.e14. [DOI: 10.1016/b978-0-323-37591-7.00053-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
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12
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Abstract
Recurrent autoimmune hepatitis (AIH) and de novo AIH are 2 important causes of late graft failure after liver transplantation (LT). Recurrent AIH occurs in patients who undergo LT for AIH. De novo AIH occurs in patients who are transplanted for etiologies other than AIH. Although typically treated with standard treatment for AIH, including corticosteroids and azathioprine, both recurrent and de novo AIH may progress to end-stage liver disease requiring retransplantation.
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Affiliation(s)
- Eliza W Beal
- Division of Transplantation, Department of Surgery, The Ohio State University Wexner Medical Center, 395 West 12th Avenue, Suite 100, Columbus, OH 43210, USA
| | - Sylvester M Black
- Division of Transplantation, Department of Surgery, The Ohio State University Wexner Medical Center, 395 West 12th Avenue, Suite 100, Columbus, OH 43210, USA
| | - Anthony Michaels
- Division of Gastroenterology, Hepatology and Nutrition, The Ohio State University Wexner Medical Center, 395 West 12th Avenue, Suite 200, Columbus, OH 43210, USA.
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13
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Ibáñez-Samaniego L, Salcedo M, Vaquero J, Bañares R. De novo autoimmune hepatitis after liver transplantation: A focus on glutathione S-transferase theta 1. Liver Transpl 2017; 23:75-85. [PMID: 27712026 DOI: 10.1002/lt.24652] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2016] [Accepted: 09/13/2016] [Indexed: 02/07/2023]
Abstract
De novo autoimmune hepatitis (DAIH) is a rare clinical condition with features that resemble those of autoimmune hepatitis (AIH) in patients undergoing liver transplantation (LT) for nonautoimmune liver disease. The diagnosis of this entity has been based on the presence of biochemical and histological patterns similar to those observed in the primary AIH, although several considerations must be taken into account. The impact of DAIH on graft survival is relevant, and early diagnosis and treatment is associated with a good longterm outcome. Although glutathione S-transferase theta 1 (GSTT1) alloimmune recognition has been shown to be involved in the pathogenesis of DAIH, further studies are necessary to fully determine its pathogenic mechanisms and risk factors. We review the pathophysiology, the most common histological patterns, the treatment strategies, and the longterm outcomes of DAIH after LT with a special focus on GSTT1. Liver Transplantation 23:75-85 2017 AASLD.
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Affiliation(s)
- Luis Ibáñez-Samaniego
- Digestive Disease Department and Liver Transplantation Unit, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria del Hospital Gregorio Marañón, Madrid, Spain
| | - Magdalena Salcedo
- Digestive Disease Department and Liver Transplantation Unit, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria del Hospital Gregorio Marañón, Madrid, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Madrid, Spain
| | - Javier Vaquero
- Digestive Disease Department and Liver Transplantation Unit, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria del Hospital Gregorio Marañón, Madrid, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Madrid, Spain
| | - Rafael Bañares
- Digestive Disease Department and Liver Transplantation Unit, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria del Hospital Gregorio Marañón, Madrid, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Madrid, Spain.,Facultad de Medicina, Universidad Complutense, Madrid, Spain
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14
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Autoimmune Liver Disease Post-Liver Transplantation: A Summary and Proposed Areas for Future Research. Transplantation 2016; 100:515-24. [PMID: 26447505 PMCID: PMC4764021 DOI: 10.1097/tp.0000000000000922] [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] [Indexed: 01/10/2023]
Abstract
Autoimmune liver diseases (AILD) are rare diseases with a reported prevalence of less than 50 per 100 000 population. As the research landscape and our understanding of AILDs and liver transplantation evolves, there remain areas of unmet needs. One of these areas of unmet needs is prevention of disease recurrence after liver transplantation. Disease recurrence is not an insignificant event because allograft loss with the need for retransplantation can occur. Patients transplanted for AILD are more likely to experience acute rejection compared to those transplanted for non-AILD, and the reason(s) behind this observation is unclear. Tasks for the future include a better understanding of the pathogenesis of AILD, definition of the precise pathogenetic mechanisms of recurrent AILD, and development of strategies that can identify recipients at risk for disease recurrence. Importantly, the role of crosstalk between alloimmune responses and autoimmune responses in AILD is an important area that needs further study. This article reviews the relevant literature of de novo autoimmune hepatitis, recurrent autoimmune hepatitis, recurrent primary sclerosing cholangitis, and recurrent primary biliary cirrhosis in terms of the clinical entity, the scientific advancements, and future scientific goals to enhance our understanding of these diseases. A review of the relevant literature of de novo autoimmune hepatitis, recurrent autoimmune hepatitis, recurrent primary sclerosing cholangitis, and recurrent primary biliary cirrhosis in terms of the clinical entity, the scientific advancements and future scientific goals to enhance our understanding of these diseases.
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Vukotic R, Vitale G, D’Errico-Grigioni A, Muratori L, Andreone P. De novo autoimmune hepatitis in liver transplant: State-of-the-art review. World J Gastroenterol 2016; 22:2906-2914. [PMID: 26973387 PMCID: PMC4779914 DOI: 10.3748/wjg.v22.i10.2906] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2015] [Revised: 11/06/2015] [Accepted: 12/30/2015] [Indexed: 02/06/2023] Open
Abstract
In the two past decades, a number of communications, case-control studies, and retrospective reports have appeared in the literature with concerns about the development of a complex set of clinical, laboratory and histological characteristics of a liver graft dysfunction that is compatible with autoimmune hepatitis. The de novo prefix was added to distinguish this entity from a pre-transplant primary autoimmune hepatitis, but the globally accepted criteria for the diagnosis of autoimmune hepatitis have been adopted in the diagnostic algorithm. Indeed, de novo autoimmune hepatitis is characterized by the typical liver necro-inflammation that is rich in plasma cells, the presence of interface hepatitis and the consequent laboratory findings of elevations in liver enzymes, increases in serum gamma globulin and the appearance of non-organ specific auto-antibodies. Still, the overall features of de novo autoimmune hepatitis appear not to be attributable to a univocal patho-physiological pathway because they can develop in the patients who have undergone liver transplantation due to different etiologies. Specifically, in subjects with hepatitis C virus recurrence, an interferon-containing antiviral treatment has been indicated as a potential inception of immune system derangement. Herein, we attempt to review the currently available knowledge about de novo liver autoimmunity and its clinical management.
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Stanca CM, Aloman C, Fiel MI, Raja K, Uskudar O, Florman S, Schiano TD. The dynamic and clinical significance of autoantibodies and immunoglobulins in liver transplant recipients. Clin Transplant 2016; 30:241-6. [DOI: 10.1111/ctr.12682] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/07/2015] [Indexed: 01/03/2023]
Affiliation(s)
| | | | | | - Kaiser Raja
- The Mount Sinai Medical Center; New York NY USA
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17
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Kerkar N, Yanni G. ‘De novo’ and ‘recurrent’ autoimmune hepatitis after liver transplantation: A comprehensive review. J Autoimmun 2016; 66:17-24. [DOI: 10.1016/j.jaut.2015.08.017] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2015] [Accepted: 08/23/2015] [Indexed: 02/08/2023]
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18
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Dhanasekaran R, Sanchez W, Mounajjed T, Wiesner RH, Watt KD, Charlton MR. Impact of fibrosis progression on clinical outcome in patients treated for post-transplant hepatitis C recurrence. Liver Int 2015; 35:2433-41. [PMID: 26058570 DOI: 10.1111/liv.12890] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2015] [Accepted: 06/03/2015] [Indexed: 12/24/2022]
Abstract
BACKGROUND & AIMS Patients who achieve sustained virological response (SVR) following the treatment of post-liver transplant (LT) recurrence of hepatitis C virus (HCV) infection have improved outcomes. The full impact of eradication of HCV on allograft histology is, however, not clearly known. METHODS We studied allograft histology in protocol-based paired liver biopsies in consecutive LT recipients who underwent post-LT treatment of recurrence of HCV. RESULTS A total of 116 patients were treated with interferon-based therapy for recurrent HCV. Paired pre-treatment baseline biopsies and post-treatment biopsies were available in 83.2% of patients. SVR was achieved in 37.9% of patients. Among the patients who achieved SVR, 20.5% had progression of fibrosis on post-treatment biopsies vs. 65.5% of patients with non-response/relapse (P < 0.001). The impact of virological response on fibrosis progression was sustained and a similar outcome was observed in the subset of patients who had 4-5 year post-treatment biopsies available. In the SVR group, 12.8% progressed to fibrosis stage ≥3 on post-treatment biopsies vs. 37.9% in the non-response/relapse group (P = 0.001). The 5-year survival in patients with progression of fibrosis 86% vs. 98% among patients who had improvement/stable fibrosis [P = 0.003; HR 3.8 (1.2-11.8)]. A small subset of patients who achieve SVR unfortunately still experience progression of fibrosis, most commonly associated with plasma cell hepatitis. CONCLUSIONS In post-transplant patients treated for HCV, SVR is associated with improved graft survival and also with sustained and significant improvement in histological outcome. Importantly, progression of fibrosis still occurred in a small subset of patients who achieved SVR.
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Affiliation(s)
| | - William Sanchez
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Taofic Mounajjed
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
| | - Russell H Wiesner
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Kymberly D Watt
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Michael R Charlton
- Intermountain Transplant Center, Intermountain Medical Center, Murray, UT, USA
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19
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Abstract
INTRODUCTION Pegylated interferon and ribavirin (PEGIFN/RBV) therapy for recurrent hepatitis C after liver transplantation (LT) is associated with a lower sustained virological response (SVR) rate as well as more frequent side effects compared to non-transplant patients. We aimed to determine the incidence and clinical characteristics of LT recipients with recurrent hepatitis C who developed immunological dysfunction (ID) during or after PEG-IFN/RBV therapy and to assess its impact on patient and graft survival. METHODS Seventy-four deceased donor LT recipients with histological recurrence of hepatitis C were treated with PEG-IFN/RBV from 1/00 to 12/08. ID was defined as biopsy-proven rejection or moderate plasma cell hepatitis. Patients were followed up until death, re-LT or 30 September 2011. RESULTS Twelve patients (16 %) had ID, 8 (10.7 %) had cholestasis without ID, while 54 had no ID/cholestasis during or after discontinuation of PEG-IFN/RBV therapy. Biopsy-proven acute cellular rejection prior to (hazard ratio = 4.87, p = 0.009) and type of immunosuppression at the time of initiation of PEG-IFN/RBV were the only independent predictors of ID. Patients who were on tacrolimus at the time of initiation of PEG-IFN/RBV had a significantly lower risk of ID compared to those who were on cyclosporine (HR 0.254, p = 0.023). Patients with ID had a trend toward a lower SVR rate (25 vs. 54 %, p = 0.18) and a significantly higher rate of graft failure (33 vs. 4 %, p = 0.004) compared to patients with no ID/cholestasis. CONCLUSIONS ID is common during or after PEG-IFN/RBV therapy for recurrent hepatitis C and frequently associated with decreased graft survival, trending toward low rates of SVR. Careful monitoring of liver biochemistries during or after PEG-IFN/RBV therapy with a low threshold to biopsy patients and particularly those receiving cyclosporine-based immunosuppression may improve outcomes in these patients.
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20
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Tanaka T, Sugawara Y, Kokudo N. Liver transplantation and autoimmune hepatitis. Intractable Rare Dis Res 2015; 4:33-38. [PMID: 25674386 PMCID: PMC4322593 DOI: 10.5582/irdr.2014.01034] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2014] [Accepted: 01/13/2015] [Indexed: 12/11/2022] Open
Abstract
Liver Transplantation (LT) is an effective treatment for patients with end-stage liver disease including autoimmune hepatitis (AIH). Indication for LT for AIH does not differ basically from other liver diseases including both acute and chronic types of disease progression, although it is reported to be an infrequent indication for LT worldwide due to the therapeutic advances of immunosuppression. The outcome following LT is feasible, with current patient and graft survival exceeding 75% at 5 years. Recurrent and de-novo AIH posttranslant has also been reported; and this seems to have important clinical implications because its management differs from the standard treatment for allograft rejection. In this review, we discuss the characteristics of AIH, focusing on the indication for LT and issues raised following LT.
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Affiliation(s)
- Tomohiro Tanaka
- Organ Transplantation Service, The University of Tokyo Hospital, Tokyo, Japan
| | - Yasuhiko Sugawara
- Artificial Organ and Transplantation Division, Department of Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Norihiro Kokudo
- Artificial Organ and Transplantation Division, Department of Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
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21
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Ueda Y, Yoshizawa A, Ogura Y, Miyagawa-Hayashino A, Haga H, Chiba T, Uemoto S. Plasma cell hepatitis induced by the termination of antiviral therapy for recurrent hepatitis C after living donor liver transplantation. Hepatol Res 2014; 44:E279-83. [PMID: 24112365 DOI: 10.1111/hepr.12243] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/13/2013] [Revised: 09/12/2013] [Accepted: 09/13/2013] [Indexed: 02/08/2023]
Abstract
Plasma cell hepatitis (PCH) is an idiopathic disorder characterized by plasma cell infiltration in the allografts of patients who have undergone liver transplantation. Although an increasing number of cases of PCH have been reported in liver transplant recipients with hepatitis C recurrence treated with interferon, it is unclear whether PCH is induced by interferon itself. Here, we describe the cases of two patients who developed PCH just after the termination of antiviral therapy for recurrent hepatitis C after living donor liver transplantation. Liver dysfunction appeared at 1 month in one patient and 2 months in the other patient after pegylated interferon plus ribavirin therapy, and liver histology showed interface hepatitis with plasma cell-rich lymphoid aggregates. Both patients recovered after steroid therapy and achieved sustained virological response. These cases suggest that PCH could be induced by the alteration of the immune condition resulting from the termination of antiviral therapy. PCH should be considered when the transaminase levels increase after antiviral therapy, and it should be carefully distinguished from hepatitis C relapse.
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Affiliation(s)
- Yoshihide Ueda
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
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22
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Shetty S, Adams DH, Hubscher SG. Post-transplant liver biopsy and the immune response: lessons for the clinician. Expert Rev Clin Immunol 2014; 8:645-61. [DOI: 10.1586/eci.12.65] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
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23
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Yu E. Histopathological Features of Late Liver Allograft Dysfunction. KOREAN JOURNAL OF TRANSPLANTATION 2013. [DOI: 10.4285/jkstn.2013.27.4.153] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Affiliation(s)
- Eunsil Yu
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
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24
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Ikegami T, Wang H, Yoshizumi T, Toshima T, Aishima S, Fukuhara T, Furusyo N, Kotoh K, Shimoda S, Shirabe K, Maehara Y. Strategies to treat interferon-induced graft dysfunction after living donor liver transplantation for hepatitis C. Hepatol Int 2013. [DOI: 10.1007/s12072-013-9496-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
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25
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Castillo-Rama M, Sebagh M, Sasatomi E, Randhawa P, Isse K, Salgarkar AD, Ruppert K, Humar A, Demetris AJ. "Plasma cell hepatitis" in liver allografts: identification and characterization of an IgG4-rich cohort. Am J Transplant 2013; 13:2966-77. [PMID: 24011021 DOI: 10.1111/ajt.12413] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2013] [Revised: 05/22/2013] [Accepted: 05/23/2013] [Indexed: 01/25/2023]
Abstract
Plasma cell hepatitis (PCH), also known as "de novo autoimmune" hepatitis, is an increasingly recognized, but suboptimally named and poorly understood, category of late allograft dysfunction strongly resembling autoimmune hepatitis (AIH): They share plasma-cell-rich necro-inflammatory activity on biopsy, autoantibodies and steroid responsiveness, but overlap with rejection is problematic. A retrospective study of clinical, serological, histopathological and IgG4 immunohistological features of PCH (n = 20) in liver allograft recipients, native liver AIH (n = 19) and plasma-cell-rich renal allograft rejection (n = 20) showed: (1) high frequency (44%) of HLA-DR15; (2) less female predominance (p = 0.03) and (3) n = 9/20 PCH recipients showed >25 IgG4+ plasma cells/high-power field (IgG4+ PCH) versus AIH (n = 1/19, p = 0.008) or plasma-cell-rich kidney rejection (n = 2/20, p = 0.03). The IgG4+ PCH (n = 9) subgroup showed lower alanine transaminase (ALT) (p < 0.01) and aspartate transaminase (AST) (p < 0.05) at index biopsy but (a) higher plasma cell number/percentage, (b) more aggressive-appearing portal/periportal and perivenular necro-inflammatory activity and (c) more severe portal/periportal fibrosis than IgG4- PCH (n = 11). Significant demographic, histopathologic and plasma cell phenotype differences between PCH and AIH suggest distinct pathogenic mechanisms for at least the IgG4+ PCH subgroup likely representing an overlap between allo- and auto-immunity. IgG4+ PCH was associated with fibrosis, but also highly responsive to increased immunosuppression.
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Affiliation(s)
- M Castillo-Rama
- Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA; Department of Pathology, Division of Liver and Transplantation Pathology, Thomas E Starzl Transplantation, University of Pittsburgh, Pittsburgh, PA
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26
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Abstract
Autoimmune hepatitis is a disease of the hepatic parenchyma that can present in acute or chronic forms. In common with many autoimmune diseases, autoimmune hepatitis is associated with non-organ-specific antibodies in the context of hepatic autoimmunity. This dichotomy has made definition of a unifying hypothesis in the pathophysiology of the disease difficult, although data from the past 8 years have drawn attention to the role of regulatory T cells. Several triggers have been identified, and the disease arises in genetically susceptible individuals. Clinical and biochemical remission is achievable in up to 85% of cases. For the remaining patients, alternative immunosuppression strategies are an option. Liver transplantation provides an excellent outcome for patients with acute liver failure or complications of end-stage liver disease, including hepatocellular carcinoma. Variant or overlapping syndromes are worthy of consideration when unexpected disease features arise.
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Affiliation(s)
- Michael A Heneghan
- Institute of Liver Studies, King's College Hospital NHS Foundation Trust, Denmark Hill, London, UK.
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27
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The prediction of immunological dysfunction during antiviral therapy for HCV after liver transplantation: can we improve outcomes? Hepatol Int 2013. [PMID: 26202024 DOI: 10.1007/s12072-013-9474-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
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28
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Zhao XY, Rakhda MIA, Wang TI, Jia JD. Immunoglobulin G4-associated de novo autoimmune hepatitis after liver transplantation for chronic hepatitis B- and C-related cirrhosis and hepatocellular carcinoma: a case report with literature review. Transplant Proc 2013; 45:824-7. [PMID: 23498828 DOI: 10.1016/j.transproceed.2012.02.049] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2011] [Accepted: 02/28/2012] [Indexed: 12/14/2022]
Abstract
Immunoglobulin G4 (IgG4)-associated autoimmune hepatitis (AIH) was recognized as a new disease entity; however, IgG4-associated de novo AIH after the liver transplantation had not been reported yet. Herein we have described a 56-year-old man who developed IgG4 de novo AIH as 1 year-post liver transplantation after receiving pegylated interferon alpha-2a and ribavirin therapy for hepatitis C virus recurrence. The histopathologic evidence showed an aggressive lymphoplasmacytic interface hepatitis with centrilobular necrosis (plasma cells > 30%) and IgG4-positive plasma cells (>10 per high power field). Serum IgG (9220 mg/dL) and IgG4 (3289 mg/dL) were also elevated. Improvement of liver function tests (LFTs) by prednisone and azathioprine therapy are manifested as normalized alanine aminotransferase and IgG levels. IgG4 relates to more severe histological activity; however, it is believed to be a good prognostic predictor of a response to prednisone plus azathioprine therapy especially with early diagnosis and timely management.
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Affiliation(s)
- X-y Zhao
- Liver Research Center, Beijing Friendship Hospital, Beijing, PR China; Capital Medical University, Beijing, PR China.
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29
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Tamè M, Buonfiglioli F, Del Gaudio M, Lisotti A, Cecinato P, Colecchia A, Azzaroli F, D’Errico A, Arena R, Calvanese C, Quarneti C, Ballardini G, Pinna AD, Mazzella G. Long-term leukocyte natural α-interferon and ribavirin treatment in hepatitis C virus recurrence after liver transplantation. World J Gastroenterol 2013; 19:5278-5285. [PMID: 23983430 PMCID: PMC3752561 DOI: 10.3748/wjg.v19.i32.5278] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2013] [Revised: 06/11/2013] [Accepted: 07/04/2013] [Indexed: 02/06/2023] Open
Abstract
AIM To evaluate the effect of long-term treatment with leukocyte natural α-interferon (ln-α-IFN) plus ribavirin (RBV). METHODS Forty-six patients with hepatitis C virus (HCV) recurrence received 3 MU three times a week of ln-α-IFN plus RBV for 1 mo; then, patients with good tolerability (n = 30) were switched to daily IFN administration, while the remaining were treated with the same schedule. Patients have been treated for 12 mo after viral clearance while non-responders (NR) entered in the long-term treatment group. Liver biopsies were planned at baseline, 1 year after sustained virological response (SVR) and at 36 mo after start of therapy in NR. MedCalc software package was used for statistical analysis. RESULTS About 16.7% of genotype 1-4 and 70% of genotype 2-3 patients achieved SVR. Nine patients withdrew therapy because of non-tolerance or non-compliance. A significant improvement in serum biochemistry and histological activity was observed in all SVR patients and long-term treated; 100% of patients with SVR achieved a histological response (fibrosis stabilization or improvement) with a significant reduction in mean staging value (from 2.1 to 1.0; P = 0.0031); histological response was observed in 84% of long-term treated patients compared to 57% of drop-out. Six patients died during the entire study period (follow-up 40.6 ± 7.7 mo); of them, 5 presented with severe HCV recurrence on enrollment. Diabetes (OR = 0.38, 95%CI: 0.08-0.59, P = 0.01), leukopenia (OR = 0.54, 95%CI: 0.03-0.57, P = 0.03) and severe HCV recurrence (OR = 0.51, 95%CI: 0.25-0.69, P = 0.0003) were variables associated to survival. Long-term treatment was well tolerated; no patients developed rejection or autoimmune disease. CONCLUSION Long-term treatment improves histology in SVR patients and slows disease progression also in NR, leading to a reduction in liver decompensation, graft failure and liver-related death.
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30
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Naini BV, Lassman CR. Liver Transplant Pathology: Review of Challenging Diagnostic Situations. Surg Pathol Clin 2013; 6:277-93. [PMID: 26838975 DOI: 10.1016/j.path.2013.03.004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Abstract
Histopathologic assessment of allograft liver biopsies has an important role in managing patients who have undergone liver transplantation. In this review, several topics are discussed that create diagnostic problems in transplant pathology, with emphasis on pathologic features and differential diagnosis. The topics discussed are acute cellular rejection, late acute rejection (centrizonal/parenchymal rejection), chronic rejection, plasma cell hepatitis, idiopathic posttransplant chronic hepatitis, fibrosing cholestatic hepatitis, selected viral infections (cytomegalovirus, Epstein-Barr virus, and hepatitis E), and acute antibody-mediated rejection.
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Affiliation(s)
- Bita V Naini
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, 10833 Le Conte Avenue, 1P-172 CHS, Los Angeles, CA 90095-1732, USA.
| | - Charles R Lassman
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, 10833 Le Conte Ave, 13-145 CHS, Los Angeles, CA 90095-1732, USA
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31
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Ueda Y, Kaido T, Ogura Y, Ogawa K, Yoshizawa A, Hata K, Fujimoto Y, Miyagawa-Hayashino A, Haga H, Marusawa H, Teramukai S, Uemoto S, Chiba T. Pretransplant serum hepatitis C virus RNA levels predict response to antiviral treatment after living donor liver transplantation. PLoS One 2013; 8:e58380. [PMID: 23505497 PMCID: PMC3591322 DOI: 10.1371/journal.pone.0058380] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2012] [Accepted: 02/04/2013] [Indexed: 12/24/2022] Open
Abstract
Background Given the limited efficacy and high adverse event rate associated with treatment of recurrent hepatitis C after liver transplantation, an individualized treatment strategy should be considered. The aim of this study was to identify predictors of response to antiviral therapy for hepatitis C after living donor liver transplantation (LDLT) and to study the associated adverse events. Methods A retrospective chart review was performed on 125 hepatitis C virus (HCV)-positive LDLT recipients who received interferon plus ribavirin and/or peginterferon plus ribavirin therapy at Kyoto University between January 2001 and June 2011. Results Serum HCV RNA reached undetectable levels within 48 weeks in 77 (62%) of 125 patients, and these patients were defined as showing virological response (VR). Of 117 patients, 50 (43%) achieved sustained VR (SVR). Predictive factors associated with both VR and SVR by univariate analysis included low pretransplant serum HCV RNA levels, a non-1 HCV genotype, and low pretreatment serum HCV RNA levels. In addition, LDLT from ABO-mismatched donors was significantly associated with VR, and white cell and neutrophil counts before interferon therapy were associated with SVR. Multivariate analysis showed that 2 variables–pretransplant serum HCV RNA level less than 500 kIU/mL and a non-1 HCV genotype–remained in models of both VR and SVR and that an ABO mismatch was associated with VR. No variables with a significant effect on treatment withdrawal were found. Conclusions Virological response to antiviral therapy in patients with hepatitis C recurring after LDLT can be predicted prior to transplant, based on pretransplant serum HCV-RNA levels and HCV genotype. LDLT from ABO-mismatched donors may contribute to more efficacious interferon therapy. Trial Registration UMIN-CTR
UMIN000003286
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Affiliation(s)
- Yoshihide Ueda
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
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32
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Kallwitz ER. Recurrent hepatitis C virus after transplant and the importance of plasma cells on biopsy. World J Gastroenterol 2013; 19:158-160. [PMID: 23345937 PMCID: PMC3547566 DOI: 10.3748/wjg.v19.i2.158] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2012] [Revised: 11/17/2012] [Accepted: 12/27/2012] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV) is the leading indication for liver transplantation in the United States. It recurs universally after transplant but the rate of fibrosis and the development of graft failure is variable. Different donor and recipient features have been demonstrated to impact fibrosis. Plasma cell hepatitis, a histologic finding, is one feature associated with poor graft and patient outcomes. The pathogenic mechanism resulting in plasma cell hepatitis is poorly understood, with evidence suggesting a role for both the HCV and the immune system.A recent publication described plasma cell hepatitis in a larger context of immune medicated graft dysfunction in transplant recipients receiving interferon based therapy. This manuscript will highlight the topic of plasma cell hepatitis and provide commentary on the lack of recognition, the data regarding pathophysiologic mechanisms and the potential management options.
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33
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Anagnostis P, Efstathiadou ZA, Akriviadis E, Hytiroglou P, Kita M. De novo autoimmune hepatitis associated with PTH(1-34) and PTH(1-84) administration for severe osteoporosis in a liver transplant patient. Osteoporos Int 2012; 23:2387-91. [PMID: 22120908 DOI: 10.1007/s00198-011-1848-y] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2011] [Accepted: 11/10/2011] [Indexed: 11/29/2022]
Abstract
De novo autoimmune hepatitis (AIH) is a rare graft dysfunction occurring in patients having undergone liver transplantation (LT) for causes other than AIH. We describe for the first time a case of de novo AIH associated with the administration of parathyroid hormone 1-34 [PTH(1-34)] and PTH(1-84) for severe osteoporosis. A 61-year-old woman was referred to our metabolic bone clinic due to severe osteoporosis, 3 years after LT for primary biliary cirrhosis. Initial treatment with PTH(1-34) led to asymptomatic hypertransaminasemia (two-fold the upper limit of normal), which normalized after drug discontinuation. A new flare of transaminases (three-fold the upper limit of normal) along with elevated alkaline phosphatase was observed after administration of PTH(1-84), which did not resolve after PTH(1-84) withdrawal. Subsequently, after exclusion of common causes of liver enzyme elevation, a liver biopsy was performed. Histological findings showed de novo AIH, which responded rapidly to treatment with methylprednisolone.
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Affiliation(s)
- P Anagnostis
- Department of Endocrinology, Hippokration Hospital, 49 Konstantinoupoleos Str., Thessaloniki, Greece.
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34
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Abstract
Recurrent HCV disease is the most common cause of graft loss and patient mortality in HCV-infected liver transplant (LT) recipients. Risk factors for more severe recurrence that are potentially modifiable are older donor age, prolonged cold ischaemia time, prior treated acute rejection, CMV hepatitis, IL28B donor genotype, and post-LT insulin resistance. The most effective means of preventing HCV recurrence is eradicating HCV prior to LT. Select wait-list candidates with compensated or mildly decompensated disease can be considered for antiviral treatment with peginterferon, ribavirin (and protease inhibitor if genotype 1). For the majority of LT patients, HCV treatment must be delayed until post-transplant. Treatment is generally undertaken if histologic severity reaches grade 3 or 4 necroinflammation or stage ≥2 fibrosis, or if cholestatic hepatitis. Achievement of sustained viral response (SVR) post-LT is associated with stabilization of fibrosis and improved graft survival. SVR is attained in ~30% of patients treated with peginterferon and ribavirin. Poor tolerability of therapy is a limitation. Combination therapy with telaprevir or boceprevir added to peginterferon and ribavirin is anticipated to increase efficacy but with higher rates of adverse effects and challenges in managing drug-drug interactions between the protease inhibitors and calcineurin inhibitors/sirolimus.
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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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Levitsky J, Fiel MI, Norvell JP, Wang E, Watt KD, Curry MP, Tewani S, McCashland TM, Hoteit MA, Shaked A, Saab S, Chi AC, Tien A, Schiano TD. Risk for immune-mediated graft dysfunction in liver transplant recipients with recurrent HCV infection treated with pegylated interferon. Gastroenterology 2012; 142:1132-1139.e1. [PMID: 22285805 DOI: 10.1053/j.gastro.2012.01.030] [Citation(s) in RCA: 70] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2011] [Revised: 01/09/2012] [Accepted: 01/15/2012] [Indexed: 01/07/2023]
Abstract
BACKGROUND & AIMS Patients with recurrent hepatitis C virus infection treated with pegylated interferon (PEG) after liver transplantation can develop severe immune-mediated graft dysfunction (IGD) characterized by plasma cell hepatitis or rejection. METHODS We conducted a multicenter case-control study of 52 liver transplant recipients with hepatitis C to assess the incidence of, risk factors for, and outcomes of PEG-IGD. Data from each patient were compared with those from 2 matched patients who did not develop PEG-IGD (n = 104). We performed a multivariate analysis of risk factors and analyzed treatment and outcomes of graft dysfunction subtypes. RESULTS Overall incidence of PEG-IGD during a 10-year study period was 7.2%. Risk factors included no prior PEG therapy (odds ratio = 5.3; P < .0001), therapy with PEGα-2a (odds ratio = 4.7; P = .03), and immune features (mainly plasma cell hepatitis) on pre-PEG therapy liver biopsies (odds ratio = 3.9; P = .005). The PEG-IGD group had lower long-term patient (61.5% vs 91.3% of controls) and graft (38.5% vs 85.6% of controls) survival and higher rates of retransplantation (34.6% vs 6.7% of controls) (all, P < .0001), without increases in sustained virologic response. Variables associated with increased mortality included acute rejection as the PEG-IGD sub-type (hazard ratio [HR] = 2.4; P = .002), a high level of alkaline phosphatase at PEG initiation (HR = 1.003; P = .005), and lack of a sustained virologic response (HR = 3.3; P = .04). Variables associated with graft failure included a high level of alkaline phosphatase at PEG initiation (HR = 1.002; P = .04) and lack of a sustained virologic response (HR = 2.1; P = .04). CONCLUSIONS PEG-IGD has high morbidity and mortality and is not associated with increased rates of virologic response. It is important to avoid PEG therapy in liver transplant recipients with specific clinical, biochemical, and histologic risk factors for PEG-IGD.
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Affiliation(s)
- Josh Levitsky
- Northwestern University Feinberg School of Medicine, Northwestern Memorial Hospital, Chicago, Illinois 60611, USA.
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Berenguer M, Charco R, Manuel Pascasio J, Ignacio Herrero J. Spanish society of liver transplantation (SETH) consensus recommendations on hepatitis C virus and liver transplantation. Liver Int 2012; 32:712-31. [PMID: 22221843 DOI: 10.1111/j.1478-3231.2011.02731.x] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2011] [Accepted: 11/23/2011] [Indexed: 02/06/2023]
Abstract
In November 2010, the Spanish Society of Liver Transplantation (Sociedad Española de Trasplante Hepático, SETH) held a consensus conference. One of the topics of debate was liver transplantation in patients with hepatitis C. This document reviews (i) the natural history of post-transplant hepatitis C, (ii) factors associated with post-transplant prognosis in patients with hepatitis C, (iii) the role of immunosuppression in the evolution of recurrent hepatitis C and response to antiviral therapy, (iv) antiviral therapy, both before and after transplantation, (v) follow-up of patients with recurrent hepatitis C and (vi) the role of retransplantation.
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Affiliation(s)
- Marina Berenguer
- Spanish Society of Liver Transplantation (Sociedad Española de Trasplante Hepático, SETH)
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38
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Liberal R, Longhi MS, Grant CR, Mieli-Vergani G, Vergani D. Autoimmune hepatitis after liver transplantation. Clin Gastroenterol Hepatol 2012; 10:346-53. [PMID: 22056300 DOI: 10.1016/j.cgh.2011.10.028] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2011] [Revised: 10/10/2011] [Accepted: 10/20/2011] [Indexed: 02/07/2023]
Abstract
Liver transplantation is an effective treatment for patients with end-stage acute and chronic autoimmune hepatitis. However, despite the good outcomes reported, disease recurrence is relatively common in the allograft. In addition, autoimmunity and autoimmune liver disease can arise de novo after transplantation for non-autoimmune liver disorders. Little is known about the mechanisms by which autoimmune diseases develop after liver transplantation, but genetic factors, molecular mimicry, impaired regulatory T-cell responses, and exposures to new alloantigens might be involved. Regardless of the pathogenic mechanisms, it is important to remain aware of the existence of recurrent and de novo autoimmune hepatitis after liver transplantation; these disorders are similar to classic autoimmune hepatitis and are therefore not treated with standard antirejection strategies.
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Affiliation(s)
- Rodrigo Liberal
- Institute of Liver Studies, King's College London School of Medicine at King's College Hospital, Denmark Hill, London, United Kingdom
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39
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Mizokami M. Discovery of critical host factor, IL-28B, associated with response to hepatitis C virus treatment. J Gastroenterol Hepatol 2012; 27:425-9. [PMID: 22168813 DOI: 10.1111/j.1440-1746.2011.07054.x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Chronic hepatitis C affects 2.2-3.0% of the world population (130 million-170 million). Pegylated interferon-α (PEG-IFN-α) in combination with ribavirin (RBV), the approved and standard therapy, leads to viral eradication in about 50% of treated patients. In 2009, genome-wide association studies (GWAS) identified host genetic variation to be critical for predicting treatment response and spontaneous clearance in patients infected with hepatitis C virus (HCV). A correlated set of polymorphisms in the region of the interleukin-28B (IL-28B) gene on chromosome 19, coding for interferon (IFN)-λ3 were associated with clearance of genotype 1 hepatitis C virus (HCV) in patients treated with PEG-IFN-α and RBV. The same polymorphisms were subsequently associated with spontaneous clearance of HCV in untreated patients. In addition, prediction of viral response to PEG-IFN-α and RBV therapy of patients with recurrent HCV infection after orthotopic liver transplantation depends on the IL-28B genotype of both recipient and donor tissues. Diagnosis of a patient's IL-28B genotype is likely to aid in clinical decision making with standard-of-care regimens. Future studies will investigate the possibility of individualizing treatment duration and novel regimens according to IL-28B genotype. As GWAS yield unexpected data, this approach could lead to the development of novel drug therapy, such as already appears promising with IFN-λ. In this Okuda lecture, I present the current understanding in regard to the relationship between host variations and clinical outcome of hepatitis C.
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Affiliation(s)
- Masashi Mizokami
- The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa, Japan.
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40
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Abstract
Liver disease caused by the hepatitis C virus is the main indication for liver transplantation in Western countries. However, HCV re-infection post-transplantation is constant and recent data confirm that it significantly impairs patient and graft survival. Chronic HCV infection develops in 75-90% of patients, and 5-30% ultimately progress to cirrhosis within 5 years. Because of the impact of HCV recurrence on graft and patient survival, several treatment strategies have been evaluated. Antiviral therapy could be administered before transplantation to suppress viral replication and reduce the risk of recurrence. However, this approach is applicable in around 50% of patients and tolerance is poor, particularly in patients with decompensated cirrhosis. Pre-emptive therapy in the early post-transplant period is limited by the high rate of side effects. Frequently, antiviral therapy is initiated when HCV recurs to obtain viral eradication and/or reduce disease progression. Treatment of established graft lesions with Pegylated Interferon (PEG-IFN) and Ribavirin (RBV) combination therapy results in a sustained virological response (SVR) in around 30% of patients. The new classes of potent and direct antiviral agents (DAA) will certainly improve the results of pre- and post-transplant antiviral therapy. However, at the present time, no data are available on the use of these drugs in patients with decompensated cirrhosis or post-transplant hepatitis.
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Affiliation(s)
- Bruno Roche
- Centre Hepato-Biliaire, AP-HP Hopital Paul Brousse, Villejuif, France. France
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41
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Casanovas T, Argudo A, Peña-Cala MC. Effectiveness and safety of everolimus in the treatment of autoimmune hepatitis related to anti-hepatitis C virus therapy after liver transplant: three case reports. Transplant Proc 2012; 43:2233-6. [PMID: 21839242 DOI: 10.1016/j.transproceed.2011.05.028] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Treatment of recurrent hepatitis C after liver transplantation is indicated in selected cases. During the combined treatment with pegylated interferon and ribavirin, some patients develop immune-mediated liver dysfunction similar to the previously described "de novo" autoimmune hepatitis. Herein we have presented three liver transplant patients who during or after combined antiviral treatment were diagnosed as autoimmune hepatitis related to interferon based on their clinical, biochemical, and liver histology features. There were two women and one man, of ages 49, 52, and 49 years who were transplanted due to cirrhosis related to hepatitis C virus genotype 1. In two patients, elevated liver enzymes occurred during antiviral therapy and in the third, after the therapy. The diagnosis of autoimmune hepatitis was reached after excluding other possible causes. One patient had a sustained viral response; and two cases were nonresponders. Antinuclear antibodies were present in two subjects and antinuclear antibodies and anti-smooth muscle antibodies in the other case. First-line treatment of autoimmune hepatitis with prednisone and azathioprine stabilized clinical and biochemical parameters'. In order to avoid the long-term use of prednisone, everolimus was introduced in the three patients. Interestingly, hepatitis C did not progress and clinical, biochemical, as well as histological parameters stabilized. In one patient, the liver fibrosis stage as assessed by histology showed improvement. However, one subject experienced repeated cerebral hemorrhage and died. Although this is heterogeneous population with partially known characteristics, with a difficult differential diagnosis, the objectives of preserving liver function and avoiding recurrent progressive hepatitis C seemed to be achieved by adding everolimus. In addition, we totally stopped prednisone therapy. In conclusion, treatment with everolimus in combination with cyclosporine achieved a partial remission in two liver transplan cases of autoimmune hepatitis related to interferon therapy.
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Affiliation(s)
- T Casanovas
- Unitat de Trasplantament Hepàtic, Hospital Universitari de Bellvitge, Hospitalet de Llobregat, IDIBELL (Institut d'Investigació Biomèdica de Bellvitge), Barcelona, Spain.
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42
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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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43
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Abstract
1. Despite highly potent immunosuppression regimens, there is a small cohort of patients at risk of graft failure due to rejection. 2. Steroid-resistant rejection is managed by the escalation of immunosuppression, but only one-third of patients with chronic rejection respond to this approach. 3. Interferon therapy for recurrent hepatitis C may induce an immunoreactive state and increase rejection rates. 4. Cyclosporine reduces the risk of recurrence of primary biliary cirrhosis but does not alter survival rates. 5. Patterns of primary sclerosing cholangitis recurrence are not affected by immunosuppression. 6. Autoimmune hepatitis recurrence and de novo autoimmune hepatitis are corticosteroid-responsive in most cases.
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Affiliation(s)
- John O'Grady
- Institute of Liver Studies, King's College Hospital, London, United Kingdom. john.o'
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44
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De Martin E, Rodriguez-Castro KI, Vitale A, Zanus G, Senzolo M, Russo FP, Burra P. Antiviral Treatment for HCV Recurrence after Liver Transplantation: When, how Much and for How Long? Future Virol 2011; 6:1179-1186. [DOI: 10.2217/fvl.11.89] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Affiliation(s)
- Eleonora De Martin
- Multivisceral Transplant Unit, Department of Surgical & Gastroenterological Sciences, Padua University Hospital. Via Giustiniani 2, 35128 Padua, Padua, Italy
| | - Kryssia I Rodriguez-Castro
- Multivisceral Transplant Unit, Department of Surgical & Gastroenterological Sciences, Padua University Hospital. Via Giustiniani 2, 35128 Padua, Padua, Italy
| | - Alessandro Vitale
- Department of General Surgery & Organ Transplantation, Hepatobiliary Surgery & Liver Transplant Unit, Padua University Hospital, Via Giustiniani 2, 35128Padua, Italy
| | - Giacomo Zanus
- Department of General Surgery & Organ Transplantation, Hepatobiliary Surgery & Liver Transplant Unit, Padua University Hospital, Via Giustiniani 2, 35128Padua, Italy
| | - Marco Senzolo
- Multivisceral Transplant Unit, Department of Surgical & Gastroenterological Sciences, Padua University Hospital. Via Giustiniani 2, 35128 Padua, Padua, Italy
| | - Francesco Paolo Russo
- Multivisceral Transplant Unit, Department of Surgical & Gastroenterological Sciences, Padua University Hospital. Via Giustiniani 2, 35128 Padua, Padua, Italy
| | - Patrizia Burra
- Multivisceral Transplant Unit, Department of Surgical & Gastroenterological Sciences, Padua University Hospital. Via Giustiniani 2, 35128 Padua, Padua, Italy
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45
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What is the long-term outcome of the liver allograft? J Hepatol 2011; 55:702-717. [PMID: 21426919 DOI: 10.1016/j.jhep.2011.03.005] [Citation(s) in RCA: 93] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2010] [Revised: 03/11/2011] [Accepted: 03/13/2011] [Indexed: 12/11/2022]
Abstract
With improved long-term survival following liver transplantation (LT), issues relating to the assessment of the liver allograft in long-term survivors are becoming increasingly relevant. Histological abnormalities are commonly present in late post-transplant biopsies, including protocol biopsies from patients who appear to be well with good graft function. Recurrent disease is the commonest recognised cause of abnormal graft histology, but may be modified by the effects of immunosuppression or interactions with other graft complications, resulting in complex or atypical changes. Other abnormalities seen in late post-transplant biopsies include rejection (which often has different appearances to those seen in the post-transplant period), de novo disease, "idiopathic" post-transplant hepatitis (IPTH) and nodular regenerative hyperplasia. In many cases graft dysfunction has more than one cause and liver biopsy may help to identify the predominant cause of graft damage. Problems exist with the terminology used to describe less well understood patterns of graft injury, but there is emerging evidence to suggest that late rejection, de novo autoimmune hepatitis and IPTH may all be part of an overlapping spectrum of immune-mediated injury occurring in the late post-transplant liver allograft. Careful clinico-pathological correlation is very important and the wording of the biopsy report should take into account therapeutic implications, particularly whether changes in immunosuppression may be indicated. This article will provide an overview of the main histological changes occurring in long-term survivors post-LT, focusing on areas where the assessment of late post-transplant biopsies is most relevant clinically.
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46
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Yasui S, Fujiwara K, Yokosuka O. Autoimmune fulminant hepatic failure in chronic hepatitis C during Peg-interferon-alpha 2b plus ribavirin treatment showing histological heterogeneity. Dig Liver Dis 2011; 43:666-7. [PMID: 21435960 DOI: 10.1016/j.dld.2011.02.014] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2010] [Revised: 02/07/2011] [Accepted: 02/16/2011] [Indexed: 12/11/2022]
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47
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Takeishi K, Shirabe K, Toshima T, Ikegami T, Morita K, Fukuhara T, Motomura T, Mano Y, Uchiyama H, Soejima Y, Taketomi A, Maehara Y. De novo autoimmune hepatitis subsequent to switching from type 2b to type 2a alpha-pegylated interferon treatment for recurrent hepatitis C after liver transplantation: report of a case. Surg Today 2011; 41:1016-9. [PMID: 21748625 DOI: 10.1007/s00595-010-4392-z] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2009] [Accepted: 03/24/2010] [Indexed: 02/05/2023]
Abstract
Interferon (IFN), which is the only possible agent for recurrent hepatitis C after liver transplantation, may cause serious immune-related disorders. We report a case of de novo autoimmune hepatitis (AIH), which developed subsequent to switching from 2b pegylated interferon-α (peg-IFN) to 2a peg-IFN after living donor liver transplantation (LDLT). A 51-year-old man with hepatitis C-associated liver cirrhosis underwent LDLT. About 13 months after the initiation of antiviral therapy, in the form of type 2b peg-IFN with ribavirin, a negative serum hepatitis C virus (HCV)-RNA titer was confirmed. Thereafter, the 2b peg-IFN was switched to 2a peg-IFN, 3 months after which severe liver dysfunction developed, despite a constantly negative HCV-RNA. Liver biopsy showed portal and periportal inflammatory infiltrates including numerous plasma cells, indicating AIH. He was treated with steroid pulse treatment, followed by high-level immunosuppression maintenance, but eventually died of Pneumocystis pneumonitis 4 months after the diagnosis of de novo AIH.
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Affiliation(s)
- Kazuki Takeishi
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
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48
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Sebagh M, Azoulay D, Roche B, Hoti E, Karam V, Teicher E, Bonhomme-Faivre L, Saliba F, Duclos-Vallée JC, Samuel D. Significance of isolated hepatic veno-occlusive disease/sinusoidal obstruction syndrome after liver transplantation. Liver Transpl 2011; 17:798-808. [PMID: 21351239 DOI: 10.1002/lt.22282] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
After liver transplantation (LT), hepatic veno-occlusive disease (VOD), which is also known as sinusoidal obstruction syndrome (SOS), has been reported initially in relation to azathioprine use and subsequently in relation to acute rejection (AR). Isolated veno-occlusive disease (iVOD)/SOS raises some questions about its significance and especially its treatment. From the post-LT biopsy samples of 1364 patients (2000-2008), 31 patients with index biopsy samples showing VOD/SOS (2.3%) were identified. After a review of the index biopsy samples and previous biopsy samples, those patients not exposed to azathioprine therapy were subdivided into 2 groups according to the absence or presence of AR. Fifteen of the 31 patients had no previous evidence of AR, whereas 16 experienced episodes of AR (before or concurrently with VOD). The 2 groups were similar in terms of demographic and clinical data and the range of histological centrilobular changes. AR episodes were characterized by an endothelial predilection. iVOD/SOS occurred later than acute rejection-related veno-occlusive disease (AR-VOD)/SOS (mean times of 65 and 4.4 months, respectively, P = 0.0098). There was a tendency for iVOD/SOS to progress less frequently to chronic rejection in comparison with AR-VOD/SOS (3/15 versus 9/15, P = 0.06). The histological resolution of iVOD/SOS was significantly more frequent in patients who benefited from increased immunosuppression in comparison with those who did not (5/7 versus 2/8, P = 0.05). When the groups were considered together, the same result was obtained (14/18 versus 4/12, P = 0.024). In conclusion, despite a constant overall prevalence of VOD/SOS, the proportion of iVOD/SOS has increased. The histological resolution of iVOD/SOS after increase in immunosuppression suggests an immune-mediated origin. Better optimization of immunosuppression may be a curative treatment.
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Affiliation(s)
- Mylène Sebagh
- Laboratoire d'Anatomie Pathologique, Assistance Publique-Hôpitaux de Paris, Villejuif, France.
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49
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Selzner N, Guindi M, Renner EL, Berenguer M. Immune-mediated complications of the graft in interferon-treated hepatitis C positive liver transplant recipients. J Hepatol 2011; 55:207-17. [PMID: 21145865 DOI: 10.1016/j.jhep.2010.11.012] [Citation(s) in RCA: 86] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/17/2010] [Revised: 11/23/2010] [Accepted: 11/23/2010] [Indexed: 02/07/2023]
Abstract
Hepatitis C virus (HCV) re-infection of the graft is universal and interferon based antiviral therapy remains at present the treatment of choice in HCV liver transplant recipients. Apart from the antiviral effects, interferon and ribavirin have both potent immunomodulatory properties resulting in a broad range of immune-related disorders including acute cellular rejection and chronic ductopenic rejection as well as de novo autoimmune hepatitis. Further complicating the picture, HCV infection per se is associated with a variety of autoimmune phenomena. We discuss here the immune-mediated complications and their relationship to chronic HCV and interferon based antiviral therapy.
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Affiliation(s)
- Nazia Selzner
- University Health Network, University of Toronto, Toronto, Canada.
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50
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Ponziani FR, Gasbarrini A, Pompili M, Burra P, Fagiuoli S. Management of hepatitis C virus infection recurrence after liver transplantation: an overview. Transplant Proc 2011; 43:291-5. [PMID: 21335208 DOI: 10.1016/j.transproceed.2010.09.102] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Hepatitis C virus (HCV) infection is the major indication for liver transplantation worldwide. Its recurrence is virtually universal. Once reinfection is established, progression to cirrhosis occurs in 25%-30% of recipients within 5 years. Several studies have attempted to identify the ideal antiviral treatment for liver transplant recipients. At present, the management of recurrent HCV infection in liver transplant recipients is based on widely accepted indications, which represent a reliable guide to identify the "ideal" candidate for therapy, when therapy should be started, and what is to be expected in terms of side effects and response to treatment.
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Affiliation(s)
- F R Ponziani
- Department of Internal Medicine, Catholic University, Rome, Italy.
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