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Chouik Y, Corpechot C, Francoz C, De Martin E, Guillaud O, Abergel A, Altieri M, Barbier L, Besch C, Chazouillères O, Conti F, Dharancy S, Durand F, Duvoux C, Gugenheim J, Hardwigsen J, Hilleret MN, Houssel-Debry P, Kamar N, Minello A, Neau-Cransac M, Pageaux GP, Radenne S, Roux O, Saliba F, Samuel D, Vanlemmens C, Woehl-Jaegle ML, Leroy V, Duclos-Vallée JC, Dumortier J. Autoimmune hepatitis recurrence after liver transplantation: "Les jeux sont faits". Liver Transpl 2024; 30:395-411. [PMID: 37788303 DOI: 10.1097/lvt.0000000000000278] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2023] [Accepted: 08/30/2023] [Indexed: 10/05/2023]
Abstract
Autoimmune hepatitis (AIH) may recur after liver transplantation (LT). The aims of this study were to evaluate the incidence and risk factors for recurrent autoimmune hepatitis (rAIH). A multicenter retrospective French nationwide study, including all patients aged ≥16 transplanted for AIH, with at least 1 liver biopsy 1 year after LT, was conducted between 1985 and 2018. Risk factors for rAIH were identified using a multivariate Cox regression model. Three hundred and forty-four patients were included (78.8% women) with a median age at LT of 43.6 years. Seventy-six patients (22.1%) developed recurrence in a median time of 53.6 months (IQR, 14.1-93.2). Actuarial risk for developing rAIH was 41.3% 20 years after LT. In multivariate analysis, the strongest risk factor for rAIH was cytomegalovirus D+/R- mismatch status (HR=2.0; 95% CI: 1.1-3.6; p =0.03), followed by associated autoimmune condition. Twenty-one patients (27.6% of rAIH patients) developed liver graft cirrhosis after rAIH. Independent risk factors for these severe forms of rAIH were young age at LT, IgG levels >20.7 g/L, and LT in the context of (sub)fulminant hepatitis. Immunosuppression, especially long-term maintenance of corticosteroid therapy, was not significantly associated with rAIH. Recurrence of AIH after LT is frequent and may lead to graft loss. Recurrence is more frequent in young patients with active disease at the time of LT, yet systematic corticosteroid therapy does not prevent it.
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Affiliation(s)
- Yasmina Chouik
- Hospices civils de Lyon, Hôpital Edouard Herriot, Service d'Hépato-Gastroentérologie, and Université Claude Bernard Lyon 1, Lyon, France
- Hospices civils de Lyon, Hôpital de la Croix Rousse, Service d'Hépato-Gastroentérologie, Lyon, France
| | - Christophe Corpechot
- Hôpital Saint-Antoine, Centre de référence des maladies inflammatoires des voies biliaires et des hépatites auto-immunes, Filière de santé FILFOIE, Assistance Publique - Hôpitaux de Paris (AP-HP), INSERM UMRS 938, Centre de Recherche Saint-Antoine, Sorbonne Université, Paris
| | - Claire Francoz
- APHP, Hôpital Beaujon, Service d'Hépatologie et Transplantation Hépatique - Université Paris Diderot - INSERM U1149, Clichy
| | - Eleonora De Martin
- AP-HP Hôpital Paul-Brousse, Centre Hépato-Biliaire, Inserm Unité 1193, Université Paris-Saclay, FHU Hépatinov, Centre de Référence Maladies Inflammatoires des Voies Biliaires et Hépatites Auto-immunes, Villejuif
| | - Olivier Guillaud
- Hospices civils de Lyon, Hôpital Edouard Herriot, Service d'Hépato-Gastroentérologie, and Université Claude Bernard Lyon 1, Lyon, France
| | - Armand Abergel
- CHU Estaing, Médecine digestive, Institut Pascal, UMR 6602 UCA CNRS SIGMA, Clermont-Ferrand
| | - Mario Altieri
- Hôpital Côte de Nacre, Service d'Hépato-Gastroentérologie, Nutrition et Oncologie Digestive, Caen
| | - Louise Barbier
- CHU Tours, Hôpital Trousseau Service de chirurgie digestive, oncologique et endocrinienne, Transplantation hépatique, Tours
| | - Camille Besch
- CHRU Hautepierre, Service de chirurgie hépato-bilio-pancréatique et transplantation hépatique, Strasbourg
| | - Olivier Chazouillères
- Hôpital Saint-Antoine, Centre de référence des maladies inflammatoires des voies biliaires et des hépatites auto-immunes, Filière de santé FILFOIE, Assistance Publique - Hôpitaux de Paris (AP-HP), INSERM UMRS 938, Centre de Recherche Saint-Antoine, Sorbonne Université, Paris
| | - Filomena Conti
- Service de Chirurgie Digestive et Hépato-Biliaire, Transplantation Hépatique, AP-HP Hôpital Pitié Salpêtrière, Paris
| | | | - François Durand
- APHP, Hôpital Beaujon, Service d'Hépatologie et Transplantation Hépatique - Université Paris Diderot - INSERM U1149, Clichy
| | | | - Jean Gugenheim
- Hôpital universitaire de Nice, service de Chirurgie Digestive et de Transplantation Hépatique - Université de Nice-Sophia-Antipolis, Nice
| | - Jean Hardwigsen
- APHM, Hôpital La Timone, Service chirurgie générale et transplantation hépatique Marseille
| | - Marie-Noëlle Hilleret
- CHU Grenoble-Alpes, Service d'hépato-gastroentérologie- INSERM U1209-Université Grenoble-Alpes, La Tronche
| | - Pauline Houssel-Debry
- Hôpital Universitaire de Pontchaillou, Service d'Hépatologie et Transplantation hépatique, Rennes
| | - Nassim Kamar
- CHU Rangueil, Département de Néphrologie et Transplantation d'Organes, Toulouse
| | - Anne Minello
- CHU Dijon, Service d'Hépato-gastroentérologie et oncologie digestive, Inserm EPICAD LNC-UMR1231, Université de Bourgogne-Franche Comté, Dijon
| | - Martine Neau-Cransac
- CHU de Bordeaux, Hôpital Haut Lévêque, Service de Chirurgie hépatobiliaire et de transplantation hépatique, Bordeaux
| | | | - Sylvie Radenne
- Hospices civils de Lyon, Hôpital de la Croix Rousse, Service d'Hépato-Gastroentérologie, Lyon, France
| | - Olivier Roux
- APHP, Hôpital Beaujon, Service d'Hépatologie et Transplantation Hépatique - Université Paris Diderot - INSERM U1149, Clichy
| | - Faouzi Saliba
- AP-HP Hôpital Paul-Brousse, Centre Hépato-Biliaire, Inserm Unité 1193, Université Paris-Saclay, FHU Hépatinov, Centre de Référence Maladies Inflammatoires des Voies Biliaires et Hépatites Auto-immunes, Villejuif
| | - Didier Samuel
- AP-HP Hôpital Paul-Brousse, Centre Hépato-Biliaire, Inserm Unité 1193, Université Paris-Saclay, FHU Hépatinov, Centre de Référence Maladies Inflammatoires des Voies Biliaires et Hépatites Auto-immunes, Villejuif
| | - Claire Vanlemmens
- Hôpital Jean Minjoz, Service d'Hépatologie et Soins Intensifs Digestifs, Besançon, France
| | - Marie-Lorraine Woehl-Jaegle
- CHU Tours, Hôpital Trousseau Service de chirurgie digestive, oncologique et endocrinienne, Transplantation hépatique, Tours
| | - Vincent Leroy
- CHU Grenoble-Alpes, Service d'hépato-gastroentérologie- INSERM U1209-Université Grenoble-Alpes, La Tronche
| | - Jean-Charles Duclos-Vallée
- AP-HP Hôpital Paul-Brousse, Centre Hépato-Biliaire, Inserm Unité 1193, Université Paris-Saclay, FHU Hépatinov, Centre de Référence Maladies Inflammatoires des Voies Biliaires et Hépatites Auto-immunes, Villejuif
| | - Jérôme Dumortier
- Hospices civils de Lyon, Hôpital Edouard Herriot, Service d'Hépato-Gastroentérologie, and Université Claude Bernard Lyon 1, Lyon, France
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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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HLA-DR Mismatch and Black Race Are Associated With Recurrent Autoimmune Hepatitis After Liver Transplantation. Transplant Direct 2021; 7:e714. [PMID: 34131586 PMCID: PMC8196096 DOI: 10.1097/txd.0000000000001160] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Accepted: 03/30/2021] [Indexed: 01/02/2023] Open
Abstract
Supplemental Digital Content is available in the text. The predictors of recurrent autoimmune hepatitis (R-AIH) after liver transplantation (LT) are heterogeneous with limited data to guide immunosuppression, with little data on impact of race.
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Abstract
Autoimmune liver diseases are characterized by immune-mediated inflammation and eventual destruction of the hepatocytes and the biliary epithelial cells. They can progress to irreversible liver damage requiring liver transplantation. The post-liver transplant goals of treatment include improving the recipient’s survival, preventing liver graft-failure, and decreasing the recurrence of the disease. The keystone in post-liver transplant management for autoimmune liver diseases relies on identifying which would be the most appropriate immunosuppressive maintenance therapy. The combination of a steroid and a calcineurin inhibitor is the current immunosuppressive regimen of choice for autoimmune hepatitis. A gradual withdrawal of glucocorticoids is also recommended. On the other hand, ursodeoxycholic acid should be initiated soon after liver transplant to prevent recurrence and improve graft and patient survival in primary biliary cholangitis recipients. Unlike the previously mentioned autoimmune diseases, there are not immunosuppressive or disease-modifying agents available for patients with primary sclerosing cholangitis. However, colectomy and annual colonoscopy are key components during the post-liver transplant period.
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Tanaka A, Kono H, Leung PSC, Gershwin ME. Recurrence of disease following organ transplantation in autoimmune liver disease and systemic lupus erythematosus. Cell Immunol 2019; 347:104021. [PMID: 31767117 DOI: 10.1016/j.cellimm.2019.104021] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2019] [Revised: 11/01/2019] [Accepted: 11/15/2019] [Indexed: 12/15/2022]
Abstract
Disease recurrence after organ transplantation associated with graft failure is a major clinical challenge in autoimmune diseases. Primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC) and autoimmune Hepatitis (AIH) are the three most common (autoimmune liver diseases) ALD for which liver transplantation (LT) is the most effective treatment option for patients with end-stage diseases. Although the 5- and 10-year survival rates of post-LT patients are remarkable (80-84% and 71-79% in PBC, 73-87% and 58-83% in PSC, 76-79% and 67-77% respectively in AIH patients), post-LT disease recurrence is not uncommon. Here, we summarize literature findings on disease recurrence of these ALD with emphasis on the incidence, risk factors and impact on long-term outcome. We noted that the incidence of disease recurrence varies between studies, which ranges from 53% to 10.9% in PBC, 8.2% to 44.7% in PSC and 7% to 42% in AIH. The variations are likely due to differences in study design, such as sample size, duration of studies and follow up time. This is further compounded by the lack of precise clinical diagnosis criteria and biomarkers of disease recurrence in these ALD, variation in post-LT treatment protocols to prevent disease recurrence and a multitude of risk factors associated with these ALD. While recurrence of PBC and AIH does not significantly impact long term outcome including overall survival, recurrent PSC patients often require another LT. Renal transplantation, like LT, is the treatment of choice in patients with end-stage lupus nephritis. While calcineurin inhibitor (CNI) and immunosuppressive drugs have improved the survival rate, post-transplant recurrence of lupus nephritis from surveillance-biopsy proven lupus nephritis range from 30% to 44%. On the other hand, recurrence of post-transplant lupus nephritis from registry survey analysis were only 1.1% to 2.4%. In general, risk factors associated with an increased frequency of post-transplant recurrence of autoimmune diseases are not clearly defined. Large scale multi-center studies are needed to further define guidelines for the diagnosis and clinical management to minimize disease recurrence and improve outcomes of post-transplant patients.
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Affiliation(s)
- Atsushi Tanaka
- Department of Medicine, Teikyo University School of Medicine, Tokyo, Japan
| | - Hajime Kono
- Department of Medicine, Teikyo University School of Medicine, Tokyo, Japan
| | - Patrick S C Leung
- Division of Rheumatology Allergy and Clinical Immunology, University of California School of Medicine, Davis, CA, United States
| | - M Eric Gershwin
- Division of Rheumatology Allergy and Clinical Immunology, University of California School of Medicine, Davis, CA, United States.
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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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Visseren T, Darwish Murad S. Recurrence of primary sclerosing cholangitis, primary biliary cholangitis and auto-immune hepatitis after liver transplantation. Best Pract Res Clin Gastroenterol 2017. [PMID: 28624107 DOI: 10.1016/j.bpg.2017.04.004] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Liver transplantation is a well-accepted treatment for decompensated chronic liver disease due to primary sclerosing cholangitis (PSC), primary biliary cholangitis (PBC) and auto-immune hepatitis (AIH). Survival after liver transplantation is generally good with 1 and 5-year survival rates around 90% and 70-85%. After transplantation, however, these diseases recur in 8.6-27% (rPSC), 10.9-42.3% (rPBC) and 7-42% (rAIH), and this poses significant challenges in terms of management and graft outcome in these patients. In this review we discuss the incidence, clinical presentation, challenges in diagnosis, reported risk factors and impact on post-transplant outcomes of recurrence of PSC, PBC and AIH after liver transplantation. We also discuss some of the limitations of current investigations and formulate idea's for future research objectives.
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Affiliation(s)
- T Visseren
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands; Department of Surgery, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands.
| | - S Darwish Murad
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands.
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Bosch A, Dumortier J, Maucort-Boulch D, Scoazec JY, Wendum D, Conti F, Morard I, Rubbia-Brandt L, Terris B, Radenne S, Abenavoli L, Poupon R, Chazouillères O, Calmus Y, Boillot O, Giostra E, Corpechot C. Preventive administration of UDCA after liver transplantation for primary biliary cirrhosis is associated with a lower risk of disease recurrence. J Hepatol 2015; 63:1449-58. [PMID: 26282232 DOI: 10.1016/j.jhep.2015.07.038] [Citation(s) in RCA: 69] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2015] [Revised: 07/16/2015] [Accepted: 07/29/2015] [Indexed: 12/20/2022]
Abstract
BACKGROUND & AIMS Recurrence of primary biliary cirrhosis (PBC) after liver transplantation (LT) is not rare and can occasionally lead to severe graft dysfunction and retransplantation. Ursodeoxycholic acid (UDCA) is a safe and effective treatment for PBC. However, whether preventive administration of UDCA after LT could lower the incidence of PBC recurrence is unknown. METHODS Patients transplanted for PBC in five French and Swiss centers from 1988 to 2010 were included. Most patients from a single center received UDCA (10-15 mg/kg/d) preventively. Recurrence of PBC was histologically defined from biopsies routinely performed at 1, 5, 10, and 15 years of follow-up, and at any time when clinically indicated. RESULTS A total of 90 patients with a 1-year minimum follow-up were studied retrospectively, including 19 (21%) patients receiving preventive UDCA. The mean follow-up was 12 years. Recurrence was diagnosed in 48 (53%) patients. The recurrence rates at 5, 10, and 15 years were 27%, 47%, and 61%, respectively. In a multivariate proportional hazards model adjusted for potential confounders and risk factors, preventive UDCA was the only factor affecting the risk of recurrence significantly (HR=0.32; 95% CI: 0.11-0.91). The 5, 10, and 15-year rates of recurrence were 11%, 21%, and 40%, respectively, under preventive UDCA, and 32%, 53%, and 70%, respectively, without preventive UDCA. Seven patients with recurrence (15%) progressed to cirrhosis, requiring retransplantation in one. However, neither recurrence nor preventive UDCA had a significant impact on survival. CONCLUSIONS Preventive treatment with UDCA reduces the risk of PBC recurrence after LT.
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Affiliation(s)
- Alexie Bosch
- Unité de Transplantation Hépatique, Fédération des Spécialités Digestives, Hospices civils de Lyon, Hôpital Edouard Herriot, Lyon, France
| | - Jérôme Dumortier
- Unité de Transplantation Hépatique, Fédération des Spécialités Digestives, Hospices civils de Lyon, Hôpital Edouard Herriot, Lyon, France
| | - Delphine Maucort-Boulch
- Service de Biostatistique, Hospices civils de Lyon et CNRS UMR5558, Laboratoire de Biométrie et Biologie évolutive, Equipe biostatistique Santé, Université Claude-Bernard, Lyon, France
| | - Jean-Yves Scoazec
- Service Central d'Anatomie et de Cytologie Pathologiques, Hospices civils de Lyon, Hôpital Edouard Herriot, Lyon, France
| | - Dominique Wendum
- Service d'Anatomie et de Cytologie Pathologiques, Assistance Publique - Hôpitaux de Paris (APHP), Hôpital Saint-Antoine, Paris, France
| | - Filomena Conti
- Service de Transplantation Hépatique, APHP, Hôpital Saint-Antoine, Paris, France
| | - Isabelle Morard
- Centre des Affections Hépato-Biliaires et Pancréatiques, Service de Gastroentérologie et Hépatologie, Hôpitaux Universitaires de Genève, Genève, Switzerland
| | - Laura Rubbia-Brandt
- Service de Pathologie clinique, Hôpitaux Universitaires de Genève, Genève, Switzerland
| | - Benoit Terris
- Service d'Anatomie et de Cytologie Pathologiques, APHP, Hôpital Cochin, Paris, France
| | - Sylvie Radenne
- Service de Gastroentérologie et Hépatologie et INSERM U1052, Hospices civils de Lyon, Hôpital de la Croix-Rousse, Lyon, France
| | - Ludovico Abenavoli
- Dipartimento di Scienze della Salute, Università Magna Graecia, Catanzaro, Italy; Service d'Hépatologie, Centre de référence des Maladies Inflammatoires des Voies biliaires, APHP, Hôpital Saint-Antoine, Paris, France
| | - Raoul Poupon
- Service d'Hépatologie, Centre de référence des Maladies Inflammatoires des Voies biliaires, APHP, Hôpital Saint-Antoine, Paris, France
| | - Olivier Chazouillères
- Service d'Hépatologie, Centre de référence des Maladies Inflammatoires des Voies biliaires, APHP, Hôpital Saint-Antoine, Paris, France
| | - Yvon Calmus
- Service Central d'Anatomie et de Cytologie Pathologiques, Hospices civils de Lyon, Hôpital Edouard Herriot, Lyon, France
| | - Olivier Boillot
- Unité de Transplantation Hépatique, Fédération des Spécialités Digestives, Hospices civils de Lyon, Hôpital Edouard Herriot, Lyon, France
| | - Emiliano Giostra
- Centre des Affections Hépato-Biliaires et Pancréatiques, Service de Gastroentérologie et Hépatologie, Hôpitaux Universitaires de Genève, Genève, Switzerland
| | - Christophe Corpechot
- Service d'Hépatologie, Centre de référence des Maladies Inflammatoires des Voies biliaires, APHP, Hôpital Saint-Antoine, Paris, France.
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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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Akamatsu N, Sugawara Y. Primary biliary cirrhosis and liver transplantation. Intractable Rare Dis Res 2012; 1:66-80. [PMID: 25343075 PMCID: PMC4204562 DOI: 10.5582/irdr.2012.v1.2.66] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2012] [Revised: 04/28/2012] [Accepted: 05/11/2012] [Indexed: 12/13/2022] Open
Abstract
Primary biliary cirrhosis (PBC) is an immune-mediated chronic progressive inflammatory liver disease, predominantly affecting middle-aged women, characterized by the presence of antimitochondrial antibodies (AMAs), which can lead to liver failure. Genetic contributions, environmental factors including chemical and infectious xenobiotics, autoimmunity and loss of tolerance have been aggressively investigated in the pathogenesis of PBC, however, the actual impact of these factors is still controversial. Survival of PBC patients has been largely improved with the widespread use of ursodeoxycholic acid (UDCA), however, one third of patients still do not respond to the treatment and proceed to liver cirrhosis, requiring liver transplantation as a last resort for cure. The outcome of liver transplantation is excellent with 5- and 10-year survival rates around 80% and 70%, respectively, while along with long survival, the recurrence of the disease has become an important outcome after liver transplantation. Prevalence rates of recurrent PBC rage widely between 1% and 35%, and seem to increase with longer follow-up. Center-specific issues, especially the use of protocol biopsy, affect the variety of incidence, yet, recurrence itself does not affect patient and graft survival at present, and retransplantation due to recurrent disease is extremely rare. With a longer follow-up, recurrent disease could have an impact on patient and graft survival.
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Affiliation(s)
- Nobuhisa Akamatsu
- Department of Hepato-biliary-pancreatic Surgery, Saitama Medical Center, Saitama Medical University, Saitama, Japan
- Artificial Organ and Transplantation Division, Department of Surgery, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan
| | - Yasuhiko Sugawara
- Artificial Organ and Transplantation Division, Department of Surgery, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan
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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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Fosby B, Karlsen TH, Melum E. Recurrence and rejection in liver transplantation for primary sclerosing cholangitis. World J Gastroenterol 2012; 18:1-15. [PMID: 22228965 PMCID: PMC3251800 DOI: 10.3748/wjg.v18.i1.1] [Citation(s) in RCA: 102] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/23/2011] [Revised: 06/15/2011] [Accepted: 06/22/2011] [Indexed: 02/06/2023] Open
Abstract
Primary sclerosing cholangitis (PSC) is a chronic progressive inflammatory disease affecting the bile ducts, leading to fibrosis and eventually cirrhosis in most patients. Its etiology is unknown and so far no effective medical therapy is available. Liver transplantation (LTX) is the only curative treatment and at present PSC is the main indication for LTX in the Scandinavian countries. Close to half of the PSC patients experience one or more episodes of acute cellular rejection (ACR) following transplantation and approximately 1/5 of the transplanted patients develop recurrent disease in the graft. In addition, some reports indicate that ACR early after LTX for PSC can influence the risk for recurrent disease. For these important post-transplantation entities affecting PSC patients, we have reviewed the current literature on epidemiology, pathogenesis, treatment and the possible influence of rejection on the risk of recurrent disease in the allograft.
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Montano-Loza AJ, Mason AL, Ma M, Bastiampillai RJ, Bain VG, Tandon P. Risk factors for recurrence of autoimmune hepatitis after liver transplantation. Liver Transpl 2009; 15:1254-61. [PMID: 19790153 DOI: 10.1002/lt.21796] [Citation(s) in RCA: 78] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Autoimmune hepatitis has been reported to recur after liver transplantation. The aim of our study was to evaluate the risk factors associated with recurrence of autoimmune hepatitis. Forty-six patients that underwent liver transplantation because of end-stage liver disease secondary to autoimmune hepatitis were studied. Recurrence of autoimmune hepatitis was diagnosed in 11 of the 46 (24%) patients, and the overall 5-year probability of recurrence was 18%. By univariate Cox analysis, the features before liver transplantation associated with a higher risk of recurrence were concomitant autoimmune disease [hazard ratio (HR), 3.74; 95% confidence interval (CI), 1.05-13.36; P = 0.04], high aspartate aminotransferase (HR, 1.09; 95% CI, 1.03-1.14; P = 0.002), high alanine aminotransferase (HR, 1.09; 95% CI, 1.03-1.20; P = 0.003), and high immunoglobulin G (IgG; HR, 1.25; 95% CI, 1.11-1.41; P = 0.0003). Moreover, patients with recurrence had a higher frequency of moderate to severe inflammatory activity (HR, 5.3; 95% CI, 1.55-18.79; P = 0.008) and plasma cell infiltration in the liver explant (HR, 5.8; 95% CI, 1.52-22.43; P = 0.01). In the multivariate Cox analysis, only the presence of moderate to severe inflammation (HR, 6.9; 95% CI, 1.76-26.96; P = 0.006) and high IgG levels before liver transplantation (HR, 7.5; 95% CI, 1.45-38.45; P = 0.02) were independently associated with the risk of autoimmune hepatitis recurrence. In conclusion, patients with concomitant autoimmune disease, high aspartate aminotransferase, alanine aminotransferase, and IgG before the transplant, or moderate to severe inflammatory activity or plasma cell infiltration in the liver explant have a higher risk of recurrent disease. These findings suggest that recurrence of autoimmune hepatitis may reflect incomplete suppression of disease activity prior to liver transplantation.
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Affiliation(s)
- Aldo J Montano-Loza
- Division of Gastroenterology and Liver Unit, University of Alberta Hospital, Edmonton, Alberta, Canada.
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Kumagi T, Heathcote EJ. Primary biliary cirrhosis. Orphanet J Rare Dis 2008; 3:1. [PMID: 18215315 PMCID: PMC2266722 DOI: 10.1186/1750-1172-3-1] [Citation(s) in RCA: 84] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2007] [Accepted: 01/23/2008] [Indexed: 12/15/2022] Open
Abstract
Primary biliary cirrhosis (PBC) is a chronic and slowly progressive cholestatic liver disease of autoimmune etiology characterized by injury of the intrahepatic bile ducts that may eventually lead to liver failure. Affected individuals are usually in their fifth to seventh decades of life at time of diagnosis, and 90% are women. Annual incidence is estimated between 0.7 and 49 cases per million-population and prevalence between 6.7 and 940 cases per million-population (depending on age and sex). The majority of patients are asymptomatic at diagnosis, however, some patients present with symptoms of fatigue and/or pruritus. Patients may even present with ascites, hepatic encephalopathy and/or esophageal variceal hemorrhage. PBC is associated with other autoimmune diseases such as Sjogren's syndrome, scleroderma, Raynaud's phenomenon and CREST syndrome and is regarded as an organ specific autoimmune disease. Genetic susceptibility as a predisposing factor for PBC has been suggested. Environmental factors may have potential causative role (infection, chemicals, smoking). Diagnosis is based on a combination of clinical features, abnormal liver biochemical pattern in a cholestatic picture persisting for more than six months and presence of detectable antimitochondrial antibodies (AMA) in serum. All AMA negative patients with cholestatic liver disease should be carefully evaluated with cholangiography and liver biopsy. Ursodeoxycholic acid (UDCA) is the only currently known medication that can slow the disease progression. Patients, particularly those who start UDCA treatment at early-stage disease and who respond in terms of improvement of the liver biochemistry, have a good prognosis. Liver transplantation is usually an option for patients with liver failure and the outcome is 70% survival at 7 years. Recently, animal models have been discovered that may provide a new insight into the pathogenesis of this disease and facilitate appreciation for novel treatment in PBC.
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Affiliation(s)
- Teru Kumagi
- Department of Medicine, Toronto Western Hospital (University Health Network/University of Toronto), Toronto, Ontario, Canada.
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Abstract
As long-term graft survival and mortality after liver transplantation improve, recognition that allografts may be affected by the same disease process that resulted in the failure of the liver is of both clinical and academic importance. Recipients need to be counseled about recurrence and potential impact on graft function and graft survival; clinicians need to be aware of the potential of recurrence to interpret the clinical, laboratory, radiologic, and histologic findings and alter management. Understanding which conditions recur in the allograft and factors associated with recurrence may shed light on pathogenesis. This article discusses the recurrence of nonviral diseases after liver transplantation, diagnosis, and management.
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Affiliation(s)
- Ye Htun Oo
- Liver and Hepatobiliary Unit, Queen Elizabeth Hospital, Edgbaston, Birmingham, B15 2TH, United Kingdom
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Gautam M, Cheruvattath R, Balan V. Recurrence of autoimmune liver disease after liver transplantation: a systematic review. Liver Transpl 2006; 12:1813-24. [PMID: 17031826 DOI: 10.1002/lt.20910] [Citation(s) in RCA: 168] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Recurrence of autoimmune liver disease in allografts has long been a topic of debate. We conducted a systematic review of the literature to examine the reported incidence of recurrence after liver transplantation of primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), and autoimmune hepatitis (AIH). The MEDLINE, EMBASE, and Cochrane electronic databases were used to identify articles. The inclusion criteria used were articles on patients with at least 90 days of posttransplantation follow-up, histologic criteria for diagnosis of PBC and AIH recurrence, radiologic or histologic criteria or both for diagnosis of PSC recurrence, and exclusion of other causes of liver disease causing similar histologic findings. Incidence in individual studies was combined to calculate the overall recurrence. Risk factors were analyzed whenever crude data were available. Funnel plots were used to assess publication bias. Out of 90 articles identified, 43 met criteria for systematic review (PBC, 16; PSC, 14; AIH, 13). The calculated weighted recurrence rate was 18% for PBC, 11% for PSC, and 22% for AIH. No difference was found in PBC and AIH recurrence by type of primary immunosuppression. There were not enough data to assess this issue in PSC studies. There was evidence of publication bias among PSC and AIH studies but not among PBC studies. In conclusion, recurrence of autoimmune liver disease after liver transplantation appears to be a real concern. As these patients are followed long-term, recurrence of disease may become the primary cause of morbidity.
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Affiliation(s)
- Manjushree Gautam
- Division of Transplantation Medicine, Mayo Clinic, Scottsdale, AZ, USA
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Abstract
Long-term graft survival and mortality after liver transplantation continue to improve. However, disease recurrence remains a major stumbling block, especially among patients with hepatitis C. Chronic hepatitis C recurs to varying degrees in nearly all patients who undergo transplantation. Transplantation for hepatitis C is associated with higher rates of graft failure and death compared with transplantation for other indications, and retransplantation for hepatitis C related liver failure remains controversial. Recurrence of hepatitis B has been markedly reduced with improved prophylactic regimens. Further, rates of hepatocellular carcinoma recurrence have also decreased, as improved patient selection criteria have prioritized transplantation for those with a low risk of recurrence. Primary biliary cirrhosis recurs in some patients, but it is often relatively mild. Autoimmune liver disease has also been shown to have a relatively benign post-transplantation course, but some studies have indicated that it slowly progresses in most recipients. It has been recently reported that alcoholic liver disease liver transplant recipients who return to drinking have worsened mortality. In such patients worse outcomes are not due to graft failure, but instead to other comorbidities. Recurrences of other diseases, including nonalcoholic steatohepatitis and primary sclerosing cholangitis, are now being recognized as having potentially detrimental effects on graft survival and mortality. Expert clinical management may help prevent and treat complications associated with disease recurrence.
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Affiliation(s)
- David S Kotlyar
- University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA
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Abstract
The article focuses on diagnosis and management of allograft failure in four main categories: (1) ischemic-reperfusion injury (primary nonfunction), (2) technical complications (hepatic artery and portal vein thrombosis), (3) chronic rejection, and (4) recurrent disease. It also discusses the complex problems involved in retransplantation for allograft failure.
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Affiliation(s)
- James R Burton
- Division of Gastroenterology and Hepatology, University of Colorado Health Sciences Center, 4200 East Ninth Avenue, B154, Denver, CO 80262, USA.
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Mastropasqua M, Braga L, Kanematsu M, Vaidean G, Shrestha R, Leonardou P, Firat Z, Woosley JT, Semelka RC. Hepatic nodules in liver transplantation candidates: MR imaging and underlying hepatic disease. Magn Reson Imaging 2005; 23:557-62. [PMID: 15919601 DOI: 10.1016/j.mri.2005.02.001] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2004] [Accepted: 02/03/2005] [Indexed: 01/26/2023]
Abstract
OBJECTIVE To assess by MR imaging the frequency of hepatic nodules in patients waiting on the liver transplant list and to determine whether certain underlying hepatic diseases were more often associated with the development of such hepatic nodules. MATERIAL AND METHODS We reviewed the MR and clinical records in all patients seen by the liver transplant service at our center since its inception in January 1998 until September 2002. A total of 371 patients (207 men and 164 women, age range 18-68 years, mean 45 years) were included in the study. The presence of hepatic nodules, size, number and underlying hepatic diseases were determined in all patients. Magnetic resonance imaging was performed on a 1.5-T MR imager using T1-weighted, T2-weighted and multi-phase gadolinium-enhanced sequences. Odds ratio (OR) and 95% confidence intervals (CIs) were computed to evaluate the association between the underlying hepatic disease and the development of hepatic nodule. RESULTS Among 371 liver transplantation candidates, the most common underlying hepatic disease was hepatitis C virus (HCV) infection, either alone (n=93; 25%) or associated with other hepatic diseases (n=40; 10.8%). Of all patients, 33 (8.9%) had regenerative nodules (RNs), 40 (10.7%) dysplastic nodules (DNs) and 57 (15.3%) hepatocellular carcinomas (HCCs). Hepatocellular carcinoma was observed in 35.3% of patients with HCV infection and alcohol abuse combined, 24.5% with cryptogenic cirrhosis, 25% with hemochromatosis and 19% with alcohol abuse. Patients who had either DNs or HCC were 2.5 times more likely to have either alcohol abuse or HCV, alone or combined, as the substrate of their liver disease (OR 2.54, 95% CI 1.56-4.13). Our data suggest a supra-additive interaction between HCV infection and ethanol in their association with MR imaging detected lesions. CONCLUSION Patients with cryptogenic cirrhosis, alcohol abuse, HCV infection (alone or combined) and hemochromatosis had the greatest likelihood of having HCC, with the combination of HCV infection and alcohol abuse having the highest of all.
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Affiliation(s)
- Maria Mastropasqua
- Department of Radiology, University of North Carolina, Chapel Hill, NC 27599-7510, USA
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