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1
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Chen C, Ke R, Yang F, Cai Q, Liu J, Huang X, Chen J, Xu F, Jiang Y. Risk factors for recurrent autoimmune liver diseases after liver transplantation: A meta-analysis. Medicine (Baltimore) 2020; 99:e20205. [PMID: 32443344 PMCID: PMC7253929 DOI: 10.1097/md.0000000000020205] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2020] [Revised: 04/04/2020] [Accepted: 04/09/2020] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND Autoimmune liver disease (ALD) is a chronic liver disease caused by immune dysfunction in the body. However, no causative or curative medical treatment with proven efficacy exists to cure ALDs, and liver transplantation (LT) remains the only effective treatment available. However, the problem of recurrence of ALDs (rALDs) still remains after LT, which seriously affects the survival rate of the patients. Therefore, clinicians need to be aware of the risk factors affecting rALDs after LT. Therefore, this meta-analysis aims to define the risk factors for rALDs, which include the recurrence of primary biliary cirrhosis, primary sclerosing cholangitis and autoimmune hepatitis. METHODS A systematic search in Pubmed, Embase, Cochrane library and Web of Science databases was performed from 1980 to 2019. The inclusion criteria were risk factors for developing rALDs after LT. However, case series, case reports, reviews, meta-analysis and studies only including human immunodeficiency virus cases, children, and pregnant patients were excluded. RESULTS The electronic database search yielded 1728 results. Sixty-three retrospective cohort studies met the inclusion criteria and 13 were included in the meta-analysis. The final cohort included 5077 patients, and among them, 21.96% developed rALDs. Colectomy before LT, HR 0.59 (95% confidence interval [CI]: 0.37-0.96), cholangiocarcinoma, HR 3.42 (95% CI: 1.88-6.21), multiple episodes of acute cellular rejection, HR 2.07 (95% CI: 1.27-3.37), model for end-stage liver disease score, HR 1.05 (95% CI: 1.02-1.08), use of mycophenolate mofetil, HR 1.46 (95% CI: 1.00-2.12) and the use of cyclosporin A, HR 0.69 (95% CI: 0.49-0.97) were associated with the risk of rprimary sclerosing cholangitis. In addition, the use of tacrolimus, HR 1.73 (95% CI: 1.00-2.99) and cyclosporin A, HR 0.59 (95% CI: 0.39-0.88) were associated with the risk of rALD. CONCLUSIONS Multiple risk factors for rALDs were identified, such as colectomy before LT, cholangiocacinoma, multiple episodes of acute cellular rejection, model for end-stage liver disease score, and especially the use of mycophenolate mofetil, cyclosporin A and tacrolimus.
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Affiliation(s)
- Chongfa Chen
- Department of Hepatobiliary Surgery, Dongfang Hospital, Xiamen University
| | - Ruisheng Ke
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Xiamen University
| | - Fang Yang
- Department of Hepatobiliary Surgery, 900 Hospital of the Joint Logistics Team, China
| | - Qiucheng Cai
- Department of Hepatobiliary Surgery, 900 Hospital of the Joint Logistics Team, China
| | - Jianyong Liu
- Department of Hepatobiliary Surgery, 900 Hospital of the Joint Logistics Team, China
| | - Xinghua Huang
- Department of Hepatobiliary Surgery, 900 Hospital of the Joint Logistics Team, China
| | - Jianwei Chen
- Department of Hepatobiliary Surgery, 900 Hospital of the Joint Logistics Team, China
| | - Fengfeng Xu
- Department of Hepatobiliary Surgery, Dongfang Hospital, Xiamen University
| | - Yi Jiang
- Department of Hepatobiliary Surgery, Dongfang Hospital, Xiamen University
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2
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Autoimmune Hepatitis-Immunologically Triggered Liver Pathogenesis-Diagnostic and Therapeutic Strategies. J Immunol Res 2019; 2019:9437043. [PMID: 31886312 PMCID: PMC6899271 DOI: 10.1155/2019/9437043] [Citation(s) in RCA: 82] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2019] [Revised: 09/15/2019] [Accepted: 09/21/2019] [Indexed: 12/20/2022] Open
Abstract
Autoimmune hepatitis (AIH) is a severe liver disease that arises in genetically predisposed male and female individuals worldwide. Diagnosis of AIH is made clinically applying diagnostic scores; however, the heterotopic disease phenotype often makes a rapid determination of disease challenging. AIH responds favorably to steroids and pharmacologic immunosuppression, and liver transplantation is only necessary in cases with acute liver failure or end-stage liver cirrhosis. Recurrence or development of de novo AIH after transplantation is possible, and treatment is similar to standard AIH therapy. Current experimental investigations of T cell-mediated autoimmune pathways and analysis of changes within the intestinal microbiome might advance our knowledge on the pathogenesis of AIH and trigger a spark of hope for novel therapeutic strategies.
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3
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Schiano TD, Florman S, Fiel MI. Recurrent Idiopathic Liver Allograft Failure. Am J Clin Pathol 2019; 152:369-376. [PMID: 31139817 DOI: 10.1093/ajcp/aqz044] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
OBJECTIVES Many transplant programs have had patients who develop idiopathic recurrent liver allograft failure, necessitating serial transplants, and are deemed to have refractory or recurrent rejection. The frequency and the etiology of this immunologic dysfunction have not been well characterized. METHODS Herein, we illustrate the case of a patient who required three retransplants over a period of 20 years for recurrent liver allograft failure. By extensively compiling the patient's many liver biopsy specimens and explants over time, we demonstrate that antibody-mediated rejection (AMR) was a major contributing factor from the outset. We conducted a review of the Scientific Registry for Transplant Recipients database to estimate the potential frequency of AMR. RESULTS As illustrated by this case, AMR has varied histologic findings in the setting of elevated donor-specific antibody titers. CONCLUSIONS The cause of recurrent allograft failure in this patient was likely a combination of acute cellular rejection and AMR, manifestations of likely underlying immune dysregulation. Pathologists and transplant physicians should recognize the variable histologic presentations of AMR, which is imperative for its timely intervention. This case demonstrates how difficult the diagnosis of AMR can be to make, highlighting the need for strong clinical suspicion in patients having difficult-to-treat rejection and recurrent allograft failure.
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Affiliation(s)
- Thomas D Schiano
- The Recanati-Miller Transplantation Institute, Icahn School of Medicine at Mount Sinai, New York, NY
- Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Sander Florman
- The Recanati-Miller Transplantation Institute, Icahn School of Medicine at Mount Sinai, New York, NY
| | - M Isabel Fiel
- Department of Pathology, Molecular and Cell Medicine, Icahn School of Medicine at Mount Sinai, New York, NY
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Krenzien F, Keshi E, Splith K, Griesel S, Kamali K, Sauer IM, Feldbrügge L, Pratschke J, Leder A, Schmelzle M. Diagnostic Biomarkers to Diagnose Acute Allograft Rejection After Liver Transplantation: Systematic Review and Meta-Analysis of Diagnostic Accuracy Studies. Front Immunol 2019; 10:758. [PMID: 31031758 PMCID: PMC6470197 DOI: 10.3389/fimmu.2019.00758] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2019] [Accepted: 03/21/2019] [Indexed: 12/19/2022] Open
Abstract
Objective: A systematic review and meta-analysis of diagnostic biomarkers for noninvasive diagnosis of acute allograft rejection following liver transplantation. Background: Noninvasive blood and urine markers have been widely explored in recent decades for diagnosing acute rejection after liver transplantation. However, none have been translated into routine clinical use so far due to uncertain diagnostic accuracy, and liver biopsy remains the gold standard. Methods: Systematic literature searches of Medline, Cochrane and Embase were conducted up to February 2019 to identify studies evaluating the use of noninvasive markers in diagnosing allograft rejection following liver transplantation. Meta-analysis was performed using a random effects model with DerSimonian–Laird weighting and the hierarchical summary receiver operating curve. Results: Of 560 identified studies, 15 studies (1,445 patients) met the inclusion criteria. The following markers were tested: acid labile nitroso-compounds (NOx), serum amyloid A protein, procalcitonin, peripheral blood eosinophil count, peripheral blood T-cell activation and interleukin 2 (IL-2) receptor, guanylate-binding protein-2 mRNA, graft-derived cell-free DNA, pi-glutathione S-transferase, alpha-glutathione S-transferase and serum HLA class I soluble antigens. Only eosinophil count was tested in multiple studies, and they demonstrated high heterogeneity (I2 = 72% [95% CI: 0.5–0.99]). IL-2 receptor demonstrated the highest sensitivity (89% [95% CI: 0.78–0.96]) and specificity (81% [95% CI: 0.69–0.89]). Conclusion: IL-2 receptor expression demonstrated the highest diagnostic accuracy, while the peripheral eosinophil count was the only marker tested in more than one study. Presently, liver biopsy remains superior to noninvasive diagnostic biomarkers as most studies exhibited inferior designs, hindering possible translation into clinical application.
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Affiliation(s)
- Felix Krenzien
- Department of Surgery, Charité-Universitätsmedizin Berlin, Campus Charité Mitte and Campus Virchow-Klinikum, Berlin, Germany.,Berlin Institute of Health Research, Berlin, Germany
| | - Eriselda Keshi
- Department of Surgery, Charité-Universitätsmedizin Berlin, Campus Charité Mitte and Campus Virchow-Klinikum, Berlin, Germany
| | - Katrin Splith
- Department of Surgery, Charité-Universitätsmedizin Berlin, Campus Charité Mitte and Campus Virchow-Klinikum, Berlin, Germany
| | - Silvan Griesel
- Department of Surgery, Charité-Universitätsmedizin Berlin, Campus Charité Mitte and Campus Virchow-Klinikum, Berlin, Germany
| | - Kaan Kamali
- Department of Surgery, Charité-Universitätsmedizin Berlin, Campus Charité Mitte and Campus Virchow-Klinikum, Berlin, Germany
| | - Igor M Sauer
- Department of Surgery, Charité-Universitätsmedizin Berlin, Campus Charité Mitte and Campus Virchow-Klinikum, Berlin, Germany
| | - Linda Feldbrügge
- Department of Surgery, Charité-Universitätsmedizin Berlin, Campus Charité Mitte and Campus Virchow-Klinikum, Berlin, Germany.,Berlin Institute of Health Research, Berlin, Germany
| | - Johann Pratschke
- Department of Surgery, Charité-Universitätsmedizin Berlin, Campus Charité Mitte and Campus Virchow-Klinikum, Berlin, Germany
| | - Annekatrin Leder
- Department of Surgery, Charité-Universitätsmedizin Berlin, Campus Charité Mitte and Campus Virchow-Klinikum, Berlin, Germany
| | - Moritz Schmelzle
- Department of Surgery, Charité-Universitätsmedizin Berlin, Campus Charité Mitte and Campus Virchow-Klinikum, Berlin, Germany
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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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6
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Satapathy SK, Jones OD, Vanatta JM, Kamal F, Kedia SK, Jiang Y, Nair SP, Eason JD. Outcomes of Liver Transplant Recipients With Autoimmune Liver Disease Using Long-Term Dual Immunosuppression Regimen Without Corticosteroid. Transplant Direct 2017; 3:e178. [PMID: 28706981 PMCID: PMC5498019 DOI: 10.1097/txd.0000000000000693] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2017] [Revised: 04/15/2017] [Accepted: 05/01/2017] [Indexed: 12/26/2022] Open
Abstract
BACKGROUND Liver transplant (LT) recipients with autoimmune liver disease (primary sclerosing cholangitis, primary biliary cholangitis, autoimmune hepatitis) are at increased risk of developing acute cellular rejection (ACR), and in many cases graft failure due to recurrent disease. We describe our experience with dual immunosuppression without steroid maintenance and analyze its effect on disease recurrence; ACR; patient and graft survivals; and complications, such as sepsis and de novo malignancy. METHODS We included 74 consecutive LT recipients (April 2006 to April 2013) with autoimmune liver disease (primary sclerosing cholangitis, 20; primary biliary cholangitis, 23; autoimmune hepatitis, 31) from a single transplant center. Immunosuppression protocol included rabbit antithymocyte globulin for induction and mycophenolate mofetil with tacrolimus or sirolimus/everolimus indefinitely for maintenance. RESULTS Overall 1-, 3-, 5-, and 7-year patient survival was 95.9%, 90.4%, 82,2% and 74.9%, re-graft-free survival was 93.2%, 86.3%, 79.9%, and 72.8%, respectively (median follow-up, 5.5 years). In a multivariate Cox regression analysis, sepsis during post-LT period (P = 0.040; hazard ratio [HR], 2.52; 95% confidence interval [CI], 1.04-6.11), steroid use for ACR (P = 0.037; HR, 2.60; 95% CI, 1.06-6.34), and younger age (<40 years) at LT (P = 0.038; HR, 2.53; 95% CI, 1.05-6.10) predicted graft survival, whereas steroid use for ACR was the only variable that was predictive of overall patient survival (P = 0.004; HR, 4.10; 95% CI, 1.59-10.52). Overall, 34 biopsy-proven ACR was noted in 22 LT recipients (30%), 13 (17.5%) had disease recurrence, and 34 episodes of sepsis occurred in 19 patients. CONCLUSIONS Dual immunosuppression protocol in LT recipients with autoimmune liver disease without corticosteroid maintenance had acceptable rates of survival and ACR without predisposing patients to the adverse effects of long-term steroid therapy.
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Affiliation(s)
- Sanjaya K. Satapathy
- Methodist University Hospital Transplant Institute, University of Tennessee Health Sciences Center, Memphis, TN
| | - Ollie D. Jones
- Department of Gastroenterology, University of Tennessee Health Sciences Center, Memphis, TN
| | - Jason M. Vanatta
- Methodist University Hospital Transplant Institute, University of Tennessee Health Sciences Center, Memphis, TN
| | - Faisal Kamal
- Department of Internal Medicine, University of Tennessee Health Sciences Center, Memphis, TN
| | | | - Yu Jiang
- School of Public Health, University of Memphis, Memphis, TN
| | - Satheesh P. Nair
- Methodist University Hospital Transplant Institute, University of Tennessee Health Sciences Center, Memphis, TN
| | - James D. Eason
- Methodist University Hospital Transplant Institute, University of Tennessee Health Sciences Center, Memphis, TN
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7
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Abstract
Primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC) are the most common cholestatic liver diseases (CLD) in adults. Liver transplant (LT) is desirable for those who progress to end-stage liver disease. CLD have become an uncommon indication for LT. PSC and PBC accounted for 7.1% of all adult LT in 2015. CLD have the best post-LT outcomes compared with other indications for LT. Disease recurrence of PSC and PBC after LT is reported in up to 37% and 43% of LT recipients, respectively. Although recurrent PBC does not affect post-LT outcomes, recurrent PSC is associated with worse post-LT survival.
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Affiliation(s)
- Nathalie A Pena Polanco
- Division of Internal Medicine, Miller School of Medicine, University of Miami, 1611 Northwest 12th Avenue, Suite Central 600-D, Miami, FL 33136, USA
| | - Cynthia Levy
- Division of Hepatology, Miller School of Medicine, University of Miami, 1120 Northwest 14th Street, Suite 1112, Miami, FL 33136, USA
| | - Eric F Martin
- Division of Hepatology, Miller School of Medicine, University of Miami, 1120 Northwest 14th Street, Suite 1112, Miami, FL 33136, USA.
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8
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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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9
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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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10
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Abstract
Liver transplantation (LT) is an established lifesaving therapy for patients with cholestatic liver diseases, including primary cholestatic diseases, namely primary sclerosing cholangitis and primary biliary cirrhosis, as well as secondary forms of cholestatic liver disease, including those with cholestatic complications of LT needing a retransplant. Patients with cholestatic liver diseases can be transplanted for complications of end-stage liver disease or for disease-specific symptoms before the onset of end-stage liver disease. These patients should be regularly assessed. Patient survival after LT for cholestatic liver diseases is generally better than for other indications.
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Affiliation(s)
- Vandana Khungar
- Division of Gastroenterology, University of Pennsylvania, 3400 Spruce Street, 2 Dulles, Philadelphia, PA 19104, USA
| | - David Seth Goldberg
- Division of Gastroenterology, University of Pennsylvania, Blockley Hall, 423 Guardian Drive, Room 730, Philadelphia, PA 19104, USA.
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11
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Abstract
Liver transplantation (LT) is the most effective treatment modality for end stage liver disease caused by many etiologies including autoimmune processes. That said, the need for transplantation for autoimmune hepatitis (AIH) and primary biliary cirrhosis (PBC), but not for primary sclerosing cholangitis (PSC), has decreased over the years due to the availability of effective medical treatment. Autoimmune liver diseases have superior transplant outcomes than those of other etiologies. While AIH and PBC can recur after LT, recurrence is of limited clinical significance in most, but not all cases. Recurrent PSC, however, often progresses over years to a stage requiring re-transplantation. The exact incidence and the predisposing factors of disease recurrence remain debated. Better understanding of the pathogenesis and the risk factors of recurrent autoimmune liver diseases is required to develop preventive measures. In this review, we discuss the current knowledge of incidence, diagnosis, risk factors, clinical course, and treatment of recurrent autoimmune liver disease (AIH, PBC, PSC) following LT.
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12
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Vierling JM. Autoimmune Hepatitis and Overlap Syndromes: Diagnosis and Management. Clin Gastroenterol Hepatol 2015; 13:2088-108. [PMID: 26284592 DOI: 10.1016/j.cgh.2015.08.012] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2015] [Revised: 08/11/2015] [Accepted: 08/11/2015] [Indexed: 12/14/2022]
Affiliation(s)
- John M Vierling
- Departments of Medicine and Surgery, Baylor College of Medicine, Baylor-St Luke's Medical Center, Houston, Texas.
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13
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14
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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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15
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Sakai H, Ishiyama K, Tanaka Y, Ide K, Ohira M, Tahara H, Abe T, Hirata F, Morimoto H, Hashimoto S, Tanimine N, Saeki Y, Shimizu S, Yano T, Kobayashi T, Tashiro H, Ohdan H. Potential Benefit of Mixed Lymphocyte Reaction Assay-based Immune Monitoring After Living Donor Liver Transplantation for Recipients With Autoimmune Hepatitis. Transplant Proc 2014; 46:785-9. [DOI: 10.1016/j.transproceed.2013.11.123] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2013] [Accepted: 11/07/2013] [Indexed: 12/22/2022]
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16
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Guidelines for the management of primary biliary cirrhosis: The Intractable Hepatobiliary Disease Study Group supported by the Ministry of Health, Labour and Welfare of Japan. Hepatol Res 2014; 44 Suppl S1:71-90. [PMID: 24397841 DOI: 10.1111/hepr.12270] [Citation(s) in RCA: 78] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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17
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Poupon R, Corpechot C. Treatment of primary biliary cirrhosis. Expert Opin Orphan Drugs 2013. [DOI: 10.1517/21678707.2014.870031] [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: 11/05/2022]
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18
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Abstract
Autoimmune hepatitis (AIH) was the first chronic liver disease in which remission was achieved by immunosuppression. Prognosis is poor when left untreated. Since the original description in 1950 by Waldenström, the initially reported treatment option has remained until today and is the core of the basic therapeutic strategy of inducing remission with steroids and azathioprine. Immunosuppression as a treatment concept spans different situations including the induction and maintenance of remission, treatment of nonresponders, avoidance of side effects, perioperative treatment of liver transplantation candidates and the issue of withdrawal. Alternative immunosuppressive drugs such as transplantation immunosuppressants have been administered and reported in small series. In an attempt to optimize side effect management, a recent large multicenter prospective treatment trial suggests that budesonide may offer an alternative for noncirrhotic AIH patients with lower steroid side effects. With an early diagnosis and effective therapy, only 4% of transplant candidates are transplanted for AIH. After liver transplantation there is a considerable risk for graft loss because of recurrent AIH, and lifelong vigilance and therapeutic attention is important.
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Affiliation(s)
- Christian P Strassburg
- Medizinische Klinik und Polikklinik I, University of Bonn Medical Center, Bonn, Germany.
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19
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Dbouk N, Parekh S. Impact of pretransplant antinuclear antibody and antismooth muscle antibody titers on disease recurrence and graft survival following liver transplantation in autoimmune hepatitis patients. J Gastroenterol Hepatol 2013; 28:537-42. [PMID: 22432792 PMCID: PMC3388173 DOI: 10.1111/j.1440-1746.2012.07125.x] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
BACKGROUND AND AIMS Disease recurrence following transplantation occurs in 20-45% of patients with autoimmune hepatitis (AIH). Factors associated with an increased risk of recurrence include human leukocyte antigen (HLA) DR3 and HLA DR4 positivity, inadequate immunosuppression, and severity of inflammation in the native liver. Titers of several autoantibodies can be elevated in patients with AIH, including antinuclear antibody (ANA) and antismooth muscle antibody (SMA); however, it is unclear whether or not the degree of elevation influences the risk of disease recurrence following transplantation. METHODS We conducted a retrospective study to evaluate the potential impact of pretransplant titers on post-transplant outcomes for patients with AIH. Sixty-three patients with AIH who underwent 72 liver transplants between 1 January 1989 and 1 January 2009 were included, with a median follow up of 10 months. Patients were divided into group A (ANA or SMA ≥ 1:160) and group B (titers ≤ 1:160). RESULTS There was no significant difference in the recurrence rates or death between patients in groups A and B, respectively. Only race appeared to impact outcomes, with African American patients having a higher incidence of death and recurrent disease post-transplant compared to other ethnicities. CONCLUSIONS Based on our findings, pretransplant ANA and SMA levels do not appear to impact recurrence rates or outcomes following liver transplantation for AIH.
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Affiliation(s)
- Nader Dbouk
- Division of Digestive Diseases, Department of Internal Medicine, Emory University School of Medicine, Atlanta, GA, Emory Transplant Center
| | - Samir Parekh
- Division of Digestive Diseases, Department of Internal Medicine, Emory University School of Medicine, Atlanta, GA, Emory Transplant Center
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20
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Bhanji RA, Mason AL, Girgis S, Montano-Loza AJ. Liver transplantation for overlap syndromes of autoimmune liver diseases. Liver Int 2013; 33:210-9. [PMID: 23146117 DOI: 10.1111/liv.12027] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2012] [Accepted: 10/04/2012] [Indexed: 12/22/2022]
Abstract
BACKGROUND/AIMS The term overlap syndrome describes variant forms of autoimmune hepatitis (AIH) that present in combination with either characteristics of primary biliary cirrhosis (PBC), or primary sclerosing cholangitis (PSC). This study analysed the outcomes and evidence of recurrent liver disease after liver transplantation in patients with overlap syndromes compared with patients transplanted for single autoimmune liver disease. METHODS We evaluated 231 adult patients who received a liver transplant as a result of autoimmune liver diseases; including 103 with PBC, 84 with PSC, 32 with AIH and 12 with overlap syndrome (7 AIH-PBC and 5 AIH-PSC). RESULTS Patients with overlap syndromes had a higher probability of recurrence than patients with a single autoimmune liver disease (5 years: 53% vs. 17%; 10 years 69% vs. 29%, P = 0.001). Furthermore, median time for recurrence in overlap syndrome was shorter when compared with patients with single autoimmune liver disease (67 ± 20 vs. 172 ± 9 months, P = 0.001). The diagnosis of overlap syndrome was independently associated with a higher risk to develop recurrent disease than patients transplanted with a single disease (HR 3.39, P = 0.007). Median graft survival for overlap syndrome was 123 ± 16 months and 180 ± 8 months in patients with single autoimmune liver diseases (P = 0.9), and median patient survival for overlap syndrome was 135 ± 13 months and 193 ± 8 months in patients with single autoimmune liver disease (P = 0.6). CONCLUSIONS Patients that received an allograft for end-stage liver disease secondary to overlap syndrome had a higher rate of disease recurrence when compared with transplant recipients with single autoimmune liver disorders, but the overall survival was comparable.
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Affiliation(s)
- Rahima A Bhanji
- Division of Gastroenterology & Liver Unit, Zeidler Ledcor Centre, Edmonton, Alberta, Canada
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21
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Abstract
Primary biliary cirrhosis (PBC) is a chronic inflammatory autoimmune disease that mainly targets the cholangiocytes of the interlobular bile ducts in the liver. It is a rare disease with prevalence of less than one in 2000. Its prevalence in developing countries is increasing presumably because of growth in recognition and knowledge of the disease. PBC is thought to result from a combination of multiple genetic factors and superimposed environmental triggers. The contribution of the genetic predisposition is evidenced by familial clustering. Several risk factors, including exposure to infectious agents and chemical xenobiotics, have been suggested. Common symptoms of the disease are fatigue and pruritus, but most patients are asymptomatic at first presentation. The prognosis of PBC has improved because of early diagnosis and use of ursodeoxycholic acid, the only established medical treatment for this disorder. When administered at adequate doses of 13–15 mg/kg/day, up to two out of three patients with PBC may have a normal life expectancy without additional therapeutic measures. However, some patients do not respond adequately to ursodeoxycholic acid and might need alternative therapeutic approaches.
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Affiliation(s)
- Nadya Al-Harthy
- Gastroenterology and Hepatology, Royal Hospital, Muscat, Oman
| | - Teru Kumagi
- Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Ehime, Japan
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22
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Czaja AJ. Diagnosis, pathogenesis, and treatment of autoimmune hepatitis after liver transplantation. Dig Dis Sci 2012; 57:2248-66. [PMID: 22562533 DOI: 10.1007/s10620-012-2179-3] [Citation(s) in RCA: 62] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2012] [Accepted: 04/12/2012] [Indexed: 02/06/2023]
Abstract
Autoimmune hepatitis can recur or appear de novo after liver transplantation, and it can result in hepatic fibrosis, graft loss, and re-transplantation. The goals of this review are to describe the prevalence, manifestations, putative pathogenic mechanisms, outcomes, and management of these occurrences. Autoimmune hepatitis recurs in 8-12 % of transplanted patients at 1 year and 36-68 % at 5 years. Recurrence may be asymptomatic and detected only by surveillance liver test abnormalities or protocol liver tissue examination. Autoantibodies that characterized the original disease, hypergammaglobulinemia, increased serum immunoglobulin G level, and histological findings of interface hepatitis, lymphoplasmacytic infiltration, perivenular hepatocyte necrosis, pseudo-rosetting, and acidophil bodies typify recurrence. Premature corticosteroid withdrawal and pre-transplant severity of the original disease are possible risk factors. De novo autoimmune hepatitis occurs in 1-7 % of patients 0.1-9 years after transplantation, especially in children. The appearance of autoantibodies may herald its emergence, and antibodies to glutathione-S-transferase T1 have been predictive of the disease. Recurrent disease may reflect recruitment of residual memory T lymphocytes and host-specific genetic predispositions, whereas de novo disease may reflect an allo-antigenic immune response and molecular mimicries that override self-tolerance. Treatment should be appropriate for autoimmune hepatitis and not based on anti-rejection drugs. Corticosteroid therapy alone or combined with azathioprine is the essential treatment. The substitution of mycophenolate mofetil for azathioprine and switch of the calcineurin inhibitor or its replacement with rapamycin have also been used for refractory disease. Re-transplantation has been necessary in 8-23 %.
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Affiliation(s)
- Albert J Czaja
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, 200 First Street S.W., Rochester, MN 55905, USA.
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23
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Abstract
Autoimmune hepatitis is a chronic liver disease characterized by elevated aminotransferase levels, autoantibodies, increased γ-globulin or IgG levels and biopsy evidence of interface hepatitis. Recent advances include new practice guidelines that redefine criteria for remission to require complete biochemical and histological normalization on therapy; comparisons between the revised original and simplified diagnostic scoring systems; refined characterization of autoantibodies and their diagnostic performance parameters; proof of the safety and efficacy of combination budesonide and azathioprine therapy for non-cirrhotic patients; scrutiny of overlap syndromes; further analyses of the outcomes of orthotopic liver transplantation and the diagnosis and treatment of recurrent and de novo autoimmune hepatitis after transplantation. Anticipated consequences of the application of the new definition of therapeutic remission include a reduction in the proportion of patients achieving remission with conventional immunosuppression regimens and a corresponding increase in the need for alternative therapies.
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24
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Kahraman A, Fingas CD, Syn WK, Gerken G, Canbay A. Role of stress-induced NKG2D ligands in liver diseases. Liver Int 2012; 32:370-82. [PMID: 22097967 DOI: 10.1111/j.1478-3231.2011.02608.x] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2011] [Accepted: 06/15/2011] [Indexed: 12/24/2022]
Abstract
Cell death by apoptosis is a prominent feature in a variety of liver diseases. It is likely that apoptosis is the initial cellular response to hepatocyte and biliary injury, which then leads to the initiation of cellular and cytokine cascades culminating in hepatocyte death with subsequent fibrosis and cirrhosis. This sequence of events is of paramount clinical importance. Recently, soluble forms of the major histocompatibility complex class I-related chains A and closely related B (MIC A and B) were reported to be increased in patients with a variety of liver diseases. MIC A and B are cell surface glycoproteins that function as indicators for cellular stress and thus activate circulating cytotoxic natural killer (NK) cells. The interaction between MIC A and B with their cognate receptor natural killer group 2 member D (NKG2D) culminates in enhanced liver cell death, which is mediated in part by apoptotic mechanisms. The present overview focuses on the role of the stress-induced NKG2D ligands MIC A and B in diverse liver diseases. Critical insights into these complex relations may help to promote rationally based therapies in liver diseases. Importantly, we hope that this overview will help to stimulate further studies into mechanisms by which stress ligands mediate cell death and its sequale.
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Affiliation(s)
- Alisan Kahraman
- University Clinic Essen, University of Duisburg-Essen, Essen, Germany
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25
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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: 106] [Impact Index Per Article: 8.2] [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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26
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Ishibashi H, Nakanuma Y, Ueno Y, Egawa H, Koike K, Komori A, Sakisaka S, Shimoda S, Shirabe K, Zeniya M, Soejima Y, Takeyama Y, Tanaka A, Nakamuta M, Nakamura M, Harada K, Fukushima N, Maehara Y, Morizane T, Tsubouchi H. Clinical Guideline of Primary Biliary Cirrhosis 2012 The Intractable Hepato-Biliary Disease Study Group supported by the Ministry of Health, Labour and Welfare of Japan. ACTA ACUST UNITED AC 2012. [DOI: 10.2957/kanzo.53.633] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Affiliation(s)
- Hiromi Ishibashi
- International University of Health and Welfare/Fukuoka Sanno Hospital, Fukuoka, Japan
- Clinical Research Center, National Hospital Organization Nagasaki Medical Center, Omura, Japan
- Chairman of the Working Group
| | - Yasuni Nakanuma
- Department of Pathology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan
- Chairman of the Subcommittee Meeting of PBC
| | - Yoshiyuki Ueno
- Department of Gastroenterology, Yamagata University Faculty of Medicine, Yamagata, Japan
| | - Hiroto Egawa
- Department of Surgery, Institute of Gastroenterology, Tokyo Women's Medical University, Tokyo, Japan
| | - Kazuhiko Koike
- Gastroenterology, Jikei University Graduate School of Medicine, Tokyo, Japan
| | - Atsumasa Komori
- Clinical Research Center, National Hospital Organization Nagasaki Medical Center, Omura, Japan
| | - Shotaro Sakisaka
- Department of Medicine and Gastroenterology, Fukuoka University Faculty of Medicine, Fukuoka, Japan
| | - Shinji Shimoda
- Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan
| | - Ken Shirabe
- Department of Surgery and Science, Kyushu University, Fukuoka, Japan
| | - Mikio Zeniya
- Gastroenterology, Jikei University Graduate School of Medicine, Tokyo, Japan
| | - Yuji Soejima
- Department of Surgery and Science, Kyushu University, Fukuoka, Japan
| | - Yasuaki Takeyama
- Department of Medicine and Gastroenterology, Fukuoka University Faculty of Medicine, Fukuoka, Japan
| | - Atsushi Tanaka
- Department of Medicine, Teikyo University School of Medicine, Tokyo, Japan
| | - Makoto Nakamuta
- Department of Gastroenterology, National Hospital Organization Kyushu Medical Center, Fukuoka, Japan
| | - Minoru Nakamura
- Clinical Research Center, National Hospital Organization Nagasaki Medical Center, Omura, Japan
- Department of Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Kenichi Harada
- Department of Pathology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan
| | - Nobuyoshi Fukushima
- Department of Gastroenterology, National Hospital Organization Kyushu Medical Center, Fukuoka, Japan
| | - Yoshihiko Maehara
- Department of Surgery and Science, Kyushu University, Fukuoka, Japan
| | | | - Hirohito Tsubouchi
- Digestive Disease and Life-style Related Disease, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
- Chairman of the Intractable Hepato-Biliary Disease Study Group
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27
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Ilyas JA, O'Mahony CA, Vierling JM. Liver transplantation in autoimmune liver diseases. Best Pract Res Clin Gastroenterol 2011; 25:765-82. [PMID: 22117641 DOI: 10.1016/j.bpg.2011.09.008] [Citation(s) in RCA: 61] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2011] [Accepted: 09/30/2011] [Indexed: 01/31/2023]
Abstract
Liver transplantation is indicated for terminal phases of autoimmune hepatitis, primary biliary cirrhosis and primary sclerosing cholangitis. Indications for transplantation in autoimmune liver diseases are similar to those used in other acute or chronic liver diseases. Therapeutic advances have reduced the need for transplantation for autoimmune hepatitis and primary biliary cirrhosis but not for primary sclerosing cholangitis. Overall, outcomes of transplantation for autoimmune liver diseases are excellent. However, recurrence of autoimmune liver diseases in the allograft has variable impacts on graft and patient survivals. Treatment of recurrent diseases requires changes in immunosuppression or addition of ursodeoxycholic acid. Among autoimmune liver diseases, only autoimmune hepatitis occurs de novo in recipients transplanted for other diseases. Patients transplanted for autoimmune hepatitis or primary sclerosing cholangitis are at risk for reactivation or de novo onset of ulcerative colitis. Better understanding of the pathogenesis of recurrent autoimmune liver diseases is needed to devise effective means of prevention and treatment.
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Affiliation(s)
- Jawad A Ilyas
- Fellow in Hepatology and Liver Transplantation, Liver Center, Baylor College of Medicine and St. Luke's Episcopal Hospital, 1709 Dryden, Suite 1500, Houston, TX 77030, USA
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28
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Strassburg CP, Manns MP. Therapy of autoimmune hepatitis. Best Pract Res Clin Gastroenterol 2011; 25:673-87. [PMID: 22117634 DOI: 10.1016/j.bpg.2011.08.003] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/17/2011] [Accepted: 08/18/2011] [Indexed: 01/31/2023]
Abstract
Autoimmune hepatitis was the first chronic liver disease with a favourable response to drug therapy and a dismal prognosis when left untreated. Since its original description in 1950 and first treatment studies the basic therapeutic strategy of inducing remission with steroids and azathioprine has not been modified in principle. A timely diagnosis before cirrhosis develops, the avoidance of immunosuppressant side effect, non-responders to standard induction therapy, and adherence to therapy are the greatest challenges. Alternative immunosuppressive drugs have been tested in small series and include transplant immunosuppressants. A recent large multicenter prospective treatment trial suggests that budesonide may offer an alternative in non-cirrhotic AIH patients capable of minimizing unwanted steroid effects. The ultimate treatment approach upon drug treatment failure is liver transplantation. Only four percent of transplant candidates are transplanted for AIH but the risk for graft loss because of recurrence has to be considered and recurrent AIH treated after transplantation.
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Affiliation(s)
- Christian P Strassburg
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany.
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29
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Smyk DS, Mytilinaiou MG, Milkiewicz P, Rigopoulou EI, Invernizzi P, Bogdanos DP. Towards systemic sclerosis and away from primary biliary cirrhosis: the case of PTPN22. AUTOIMMUNITY HIGHLIGHTS 2011; 3:1-9. [PMID: 26000122 PMCID: PMC4389021 DOI: 10.1007/s13317-011-0023-y] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 07/16/2011] [Accepted: 07/29/2011] [Indexed: 12/12/2022]
Abstract
Primary biliary cirrhosis (PBC) is a chronic cholestatic liver disease characterized by immune-mediated destruction of the small and medium size intrahepatic bile ducts. PBC patients often have concomitant autoimmune diseases, which are most often autoimmune thyroid disease, as well as Sicca syndrome. Occasionally, some PBC patients will also have systemic sclerosis of the limited cutaneous type (lcSSc). Conversely, up to one-fourth of SSc patients are positive for antimitochondrial antibody, the serologic hallmark of PBC. It is also common for SSc patients to have concomitant autoimmune disease, which may include PBC in rare cases. This has led to speculation of shared environmental and/or genetic factors, which lead to the development of PBC in SSc patients and vice versa. Recent genetic studies have revealed associations with several genes in both SSc and PBC. PTPN22 is one gene that has been associated with SSc, but not with PBC. It may be argued that some SSc patients with a particular genotype, which shares genes found in both conditions may develop PBC. Likewise, particular genes such as PTPN22 may infer susceptibility to SSc alone. The presence of PTPN22 may also contribute to the development of SSc in PBC patients. The lack of a large number of overlapping genes may, in part, explain the relative rarity of PBC with SSc and vice versa. This review will examine the literature surrounding the genetic associations of PBC and SSc, and the role of PTPN22 in particular.
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Affiliation(s)
- Daniel S. Smyk
- Institute of Liver Studies, King’s College London School of Medicine at King’s College Hospital, Denmark Hill Campus, London, SE5 9RS UK
| | - Maria G. Mytilinaiou
- Institute of Liver Studies, King’s College London School of Medicine at King’s College Hospital, Denmark Hill Campus, London, SE5 9RS UK
| | - Piotr Milkiewicz
- Liver Unit, Liver Unit and Liver Research Laboratories, Pomeranian Medical University, SPSK2, Powstancow Wlkp, 7270-111 Szczecin, Poland
| | - Eirini I. Rigopoulou
- Department of Medicine and Research Laboratory of Internal Medicine, University of Thessaly Medical School, Thessaly, Mezourlo, Larissa, 41222 Greece
| | - Pietro Invernizzi
- Center for Autoimmune Liver Diseases, Division of Internal Medicine, IRCCS Istituto Clinico Humanitas, Rozzano, Italy
- Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, Davis, CA USA
| | - Dimitrios P. Bogdanos
- Institute of Liver Studies, King’s College London School of Medicine at King’s College Hospital, Denmark Hill Campus, London, SE5 9RS UK
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30
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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: 96] [Impact Index Per Article: 6.9] [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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31
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Kemmer N, Neff G. Recipient-based approach to tailoring immunosuppression in liver transplantation. Transplant Proc 2010; 42:1731-7. [PMID: 20620512 DOI: 10.1016/j.transproceed.2010.02.076] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2009] [Accepted: 02/02/2010] [Indexed: 01/05/2023]
Abstract
Improvements in the field of transplant immunosuppression (IS) have led to significant advances in long-term survival of liver transplant recipients. Despite this progress, survival rates vary depending on recipient, donor and/or perioperative factors. Tailoring IS based on recipient factors is of growing interest among health care providers involved in the care of organ transplant recipients. To date there is no consensus document addressing individualized IS therapy for liver transplant recipients. This review will discuss the information available on the effect of the various IS drugs on recipient-based factors such as age, ethnicity, and liver disease etiology.
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Affiliation(s)
- N Kemmer
- Department of Internal Medicine, University of Cincinnati, Cincinnati, Ohio, USA
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32
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Strassburg CP. Autoimmune hepatitis. Best Pract Res Clin Gastroenterol 2010; 24:667-82. [PMID: 20955969 DOI: 10.1016/j.bpg.2010.07.011] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2010] [Revised: 07/22/2010] [Accepted: 07/22/2010] [Indexed: 01/31/2023]
Abstract
Autoimmune hepatitis is a chronic inflammatory disease of the liver with a dismal prognosis when left untreated. Key for the improvement of prognosis is a timely diagnosis before cirrhosis has developed. This is reached by the exclusion of other causes of hepatitis, elevated immunoglobulin G, autoantibody profile and histological assessment. Treatment achieves remission rates in 80% of individuals and consists of immunosuppression with corticosteroids and azathioprine. A recent randomised controlled multicenter trial has added budesonide to the effective treatment options in non-cirrhotic patients and leads to a reduction of unwanted steroid side effects. Autoimmune hepatitis is an autoimmune disease of unknown aetiology. Association studies of major histocompatibility complex and other genes demonstrate an influence of immunogenetics. However, apart from the autoimmune polyglandular syndrome type 1, in which 10% of patients suffer from an autoantibody-positive autoimmune hepatitis linked to mutations of the autoimmune regulator gene, there is no clear evidence for a hereditary aetiology of this disease.
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Affiliation(s)
- Christian P Strassburg
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany.
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33
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Nguyen DL, Juran BD, Lazaridis KN. Primary biliary cirrhosis. Best Pract Res Clin Gastroenterol 2010; 24:647-54. [PMID: 20955967 PMCID: PMC2958170 DOI: 10.1016/j.bpg.2010.07.006] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2010] [Accepted: 07/14/2010] [Indexed: 01/31/2023]
Abstract
Primary biliary cirrhosis (PBC) is an idiopathic chronic autoimmune liver disease that primarily affects women. It is believed that the aetiology for PBC is a combination between environmental triggers in genetically vulnerable persons. The diagnosis for PBC is made when two of the three criteria are fulfilled and they are: (1) biochemical evidence of cholestatic liver disease for at least 6 month's duration; (2) anti-mitochondrial antibody (AMA) positivity; and (3) histologic features of PBC on liver biopsy. Ursodeoxycholic acid (UDCA) is the only FDA-approved medical treatment for PBC and should be administered at a recommended dose of 13-15 mg/kg/day. Unfortunately despite adequate dosing of UDCA, approximately one-third of patients does not respond adequately and may require liver transplantation. Future studies are necessary to elucidate the role of environmental exposures and overall genetic impact not only in the development of PBC, but on disease progression and variable clinical response to therapy.
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Affiliation(s)
- Douglas L Nguyen
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, 200 First St. SW, Rochester, MN 55905, USA.
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34
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Kashyap R, Safadjou S, Chen R, Mantry P, Sharma R, Patil V, Maloo M, Ryan C, Marroquin C, Barry C, Ramaraju G, Maliakkal B, Orloff M. Living donor and deceased donor liver transplantation for autoimmune and cholestatic liver diseases--an analysis of the UNOS database. J Gastrointest Surg 2010; 14:1362-9. [PMID: 20617395 DOI: 10.1007/s11605-010-1256-1] [Citation(s) in RCA: 56] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2010] [Accepted: 06/07/2010] [Indexed: 02/06/2023]
Abstract
INTRODUCTION Autoimmune hepatitis and cholestatic liver diseases have more favorable outcomes after liver transplantation as compared to viral hepatitis and alcoholic liver diseases. However, there are only few reports comparing outcomes of both living donor liver transplants (LDLT) and deceased donor liver transplants (DDLT) for these conditions. AIM We aim to study the survival outcomes of patients undergoing LT for autoimmune and cholestatic diseases and to identify possible risk factors influencing survival. Survival outcomes for LDLT vs. DDLT are also to be compared for these diseases. PATIENTS AND METHODS A retrospective analysis of the UNOS database for patients transplanted between February 2002 until October 2006 for AIH, PSC, and PBC was performed. Survival outcomes for LDLT and DDLT patients were analyzed and factors influencing survival were identified. RESULTS Among all recipients the estimated patient survival at 1, 3, and 5 years for LDLT was 95.5%, 93.6%,and 92.5% and for DDLT was 90.9%, 86.5%, and 84.9%, respectively (p = 0.002). The estimated graft survival at 1, 3, and 5 years for LDLT was 87.9%, 85.4%, and 84.3% and for DDLT 85.9%, 80.3%, and 78.6%, respectively (p = 0.123). On multivariate proportional hazard regression analysis after adjusting for age and MELD score, the effect of donor type was not found to be significant. CONCLUSION The overall survival outcomes of LDLT were similar to DDLT in our patients with autoimmune and cholestatic liver diseases. It appears from our study that after adjusting for age and MELD score donor type does not significantly affect the outcome.
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Affiliation(s)
- Randeep Kashyap
- Department of Surgery, Division of Solid Organ Transplantation, University of Rochester Medical Center, P.O. Box SURG, 601 Elmwood Avenue, Rochester, NY 14642, USA.
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35
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Wallace K, Cowie DE, Konstantinou DK, Hill SJ, Tjelle TE, Axon A, Koruth M, White SA, Carlsen H, Mann DA, Wright MC. The PXR is a drug target for chronic inflammatory liver disease. J Steroid Biochem Mol Biol 2010; 120:137-48. [PMID: 20416375 PMCID: PMC2937210 DOI: 10.1016/j.jsbmb.2010.04.012] [Citation(s) in RCA: 65] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2010] [Revised: 04/13/2010] [Accepted: 04/16/2010] [Indexed: 12/17/2022]
Abstract
UNLABELLED PXR activators are used to treat pruritus in chronic inflammatory liver diseases such as primary biliary cirrhosis (PBC). The aims of this study were to determine whether PXR activators could have an additional benefit of inhibiting inflammation in the liver, and determine whether cyclosporin A - which more effectively prevents PBC recurrence in transplanted patients than FK506 - is a PXR activator. In SJL/J mice (which have constitutively high levels of hepatic portal tract inflammatory cell recruitment), feeding a PXR activator inhibited inflammation, TNFalpha and Il-1alpha mRNA expression in SJL/J-PXR(+/+), but not SJL/J-PXR(-/-). Monocytic cells - a major source of inflammatory mediators such as TNFalpha - expressed the PXR and PXR activators inhibited endotoxin-induced NF-kappaB activation and TNFalpha expression. PXR activation also inhibited endotoxin-stimulated TNFalpha secretion from liver monocytes/macrophages isolated from PXR(+/+) mice, but not from cells isolated from PXR(-/-) mice. To confirm that PXR activation inhibits NF-kappaB in vivo, 3x-kappaB-luc fibrotic mice (which express a luciferase gene regulated by NF-kappaB) were imaged after treatment with the hepatotoxin CCl(4). PXR activator inhibited the induction of hepatic NF-kappaB activity without affecting CCl(4) toxicity/hepatic damage. Using a PXR reporter gene assay, cyclosporin A - but not FK506 - was shown to be a direct PXR activator, and also to induce expression of the classic PXR-regulated CYP3A4 gene in human hepatocytes and in a cell line null for the FXR, a nuclear receptor with similar properties to the PXR. CONCLUSION PXR activation is anti-inflammatory in the liver and the effects of cyclosporin A in PBC disease recurrence may be mediated in part via the PXR. Since PXR activation promotes hepatocyte growth and is also anti-fibrogenic, the PXR may be an excellent drug target for the treatment of chronic inflammatory liver disease.
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Key Words
- alt, alanine aminotransferase
- csa, cyclosporin a
- gt, gliotoxin
- gapdh, glyceradehyde 3 phosphate dehydrogenase
- hyp, hyperforin
- ikk2-in, iκb kinase 2 inhibitor
- lps, lipopolysaccharide
- metyr, metyrapone
- mts, ([3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2h-tetrazolium salt
- pbc, primary biliary cirrhosis
- pcn, pregnenolone 16α carbonitrile
- pti, portal tract inflammation
- pparγ, peroxiome proliferator activated receptor γ
- pxr, pregnane x receptor
- rif, rifampicin
- sulf, sulfasalazine
- tlr4, toll-like receptor 4
- tnfα, tumour necrosis factor-α
- pregnane x receptor
- sxr
- nf-κb
- rifampicin
- hyperforin
- tnfα
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MESH Headings
- Animals
- Cell Line
- Cyclosporine/therapeutic use
- Female
- Gene Expression Regulation
- Hepatitis, Chronic/drug therapy
- Hepatitis, Chronic/genetics
- Hepatitis, Chronic/metabolism
- Humans
- Liver Cirrhosis, Biliary/drug therapy
- Liver Cirrhosis, Biliary/genetics
- Liver Cirrhosis, Biliary/metabolism
- Mice
- Mice, Knockout
- NF-kappa B/metabolism
- Pregnane X Receptor
- Receptors, Steroid/deficiency
- Receptors, Steroid/genetics
- Receptors, Steroid/metabolism
- Tumor Necrosis Factor-alpha/genetics
- Tumor Necrosis Factor-alpha/metabolism
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Affiliation(s)
- Karen Wallace
- Institute of Cellular Medicine, University of Newcastle, Newcastle, Upon Tyne, UK
| | - David E. Cowie
- Institute of Cellular Medicine, University of Newcastle, Newcastle, Upon Tyne, UK
| | | | - Stephen J. Hill
- Institute of Cellular Medicine, University of Newcastle, Newcastle, Upon Tyne, UK
| | | | - Andrew Axon
- Institute of Cellular Medicine, University of Newcastle, Newcastle, Upon Tyne, UK
| | - Matthew Koruth
- Institute Medical Sciences, University of Aberdeen, Aberdeen, UK
| | - Steven A. White
- Institute of Cellular Medicine, University of Newcastle, Newcastle, Upon Tyne, UK
| | | | - Derek A. Mann
- Institute of Cellular Medicine, University of Newcastle, Newcastle, Upon Tyne, UK
| | - Matthew C. Wright
- Institute of Cellular Medicine, University of Newcastle, Newcastle, Upon Tyne, UK
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36
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Oo YH, Hubscher SG, Adams DH. Autoimmune hepatitis: new paradigms in the pathogenesis, diagnosis, and management. Hepatol Int 2010; 4:475-93. [PMID: 20827405 PMCID: PMC2900560 DOI: 10.1007/s12072-010-9183-5] [Citation(s) in RCA: 88] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2010] [Accepted: 03/13/2010] [Indexed: 02/06/2023]
Abstract
Autoimmune hepatitis (AIH), primary biliary cirrhosis, and primary sclerosing cholangitis are the three major autoimmune diseases affecting the liver, and of these three, AIH is the most typical autoimmune disease being characterized by a T-cell-rich infiltrate, raised circulating γ-globulins, autoantibodies, HLA associations, and links with other autoimmune diseases. It is the only one, of the three diseases, that responds well to immunosuppressive therapy. AIH is caused by dysregulation of immunoregulatory networks and the consequent emergence of autoreactive T cells that orchestrate a progressive destruction of hepatocytes leading untreated to liver failure. T cells play a major role in the immunopathogenesis, and both CD4(+) and CD8(+) T cells are involved together with effector responses mediated by NK cells, γδ T cells, and macrophages. A number of triggering factors have been proposed including viruses, xenobiotics, and drugs, but none have been conclusively shown to be involved in pathogenesis.
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Affiliation(s)
- Ye H. Oo
- Centre for Liver Research, NIHR Biomedical Research Unit, University of Birmingham, Edgbaston, Birmingham, B15 2TT UK
| | - Stefan G. Hubscher
- Department of Pathology, University of Birmingham Medical School, Wolfson Drive, Edgbaston, Birmingham, B15 2TT UK
| | - David H. Adams
- Centre for Liver Research, NIHR Biomedical Research Unit, University of Birmingham, Edgbaston, Birmingham, B15 2TT UK
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37
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Poupon R. Primary biliary cirrhosis: a 2010 update. J Hepatol 2010; 52:745-58. [PMID: 20347176 DOI: 10.1016/j.jhep.2009.11.027] [Citation(s) in RCA: 200] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2009] [Revised: 11/27/2009] [Accepted: 11/30/2009] [Indexed: 12/14/2022]
Abstract
Primary biliary cirrhosis (PBC) is a chronic inflammatory autoimmune disease that mainly targets the cholangiocytes of the interlobular bile ducts in the liver. The condition primarily affects middle-aged women. Without treatment, PBC generally progresses to cirrhosis and eventually liver failure over a period of 10-20 years. PBC is a rare disease with prevalence of less than 1/2000. PBC is thought to result from a combination of multiple genetic factors and superimposed environmental triggers. The contribution of the genetic predisposition is evidenced by the familial clustering. Several risk factors, including exposure to infectious agents and chemical xenobiotics, have been suggested. Ursodeoxycholic acid (UDCA) is currently the only FDA-approved medical treatment for PBC. When administered at doses of 13-15 mg/kg/day, a majority of patients with PBC have a normal life expectancy without additional therapeutic measures. One out of three patients does not adequately respond to UDCA therapy and may need additional medical therapy and/or liver transplantation. This review summarises current knowledge on the epidemiology, ethiopathogenesis, clinical, and therapeutic aspects of PBC.
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Affiliation(s)
- Raoul Poupon
- UPMC Univ Paris 06, France; INSERM, UMR_S 938, Paris, France.
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38
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Hytiroglou P, Gutierrez JA, Freni M, Odin JA, Stanca CM, Merati S, Schiano TD, Branch AD, Thung SN. Recurrence of primary biliary cirrhosis and development of autoimmune hepatitis after liver transplant: A blind histologic study. Hepatol Res 2009; 39:577-84. [PMID: 19207586 PMCID: PMC3127546 DOI: 10.1111/j.1872-034x.2008.00483.x] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
AIM This long-term study aimed to evaluate recurrence and evolution of primary biliary cirrhosis (PBC) after orthotopic liver transplantation (OLT). METHODS We reviewed "blindly" allograft biopsy specimens of women who underwent transplantation for PBC (n = 84), and women who received a transplant for chronic hepatitis C virus infection (CHCV ) (n = 108). All needle liver biopsy specimens obtained more than 6 months post-OLT were examined, including 83 specimens from 44 PBC patients and 152 specimens from 58 CHCV patients. RESULTS Granulomatous destructive cholangitis was found in five biopsies from four PBC patients (P = 0.0048). Non-necrotizing epithelioid cell granulomas were present in four biopsies from four PBC patients, and in two biopsies from one CHCV patient. Piecemeal necrosis (P = 0.0002), lobular necroinflammatory activity (P < 0.0001), steatosis (P < 0.0001) and fibrosis (P < 0.0001) were more prevalent in CHCV patients than PBC patients. Four PBC patients developed histologic evidence of autoimmune hepatitis (AIH), at a mean time of 3.66 years post-OLT. One of these patients had histologic features of AIH/PBC overlap syndrome. All four patients developed bridging fibrosis (n = 2) or cirrhosis (n = 2). No other PBC patient had evidence of cirrhosis after OLT. CONCLUSIONS Histologic findings indicative of recurrent PBC were present in 15.9% of the PBC patients undergoing biopsy in this series. However, this group of patients did not suffer significant bile duct loss or fibrosis, as compared to the control group, suggesting that recurrent PBC is a mild or slowly progressive disease. Histologic evidence of AIH was observed in allograft biopsies of some PBC patients.
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Affiliation(s)
- Prodromos Hytiroglou
- Lillian and Henry M. Stratton-Hans Popper Department of Pathology, The Mount Sinai Medical Center, New York, NY, USA
| | - Julio A. Gutierrez
- Recanati-Miller Transplant Institute, The Mount Sinai Medical Center, New York, NY, USA
| | - Maria Freni
- Recanati-Miller Transplant Institute, The Mount Sinai Medical Center, New York, NY, USA
| | - Joseph A. Odin
- Division of Liver Diseases, Department of Medicine, The Mount Sinai Medical Center, New York, NY, USA
| | - Carmen M. Stanca
- Division of Liver Diseases, Department of Medicine, The Mount Sinai Medical Center, New York, NY, USA
| | - Sukma Merati
- Lillian and Henry M. Stratton-Hans Popper Department of Pathology, The Mount Sinai Medical Center, New York, NY, USA
| | - Thomas D. Schiano
- Division of Liver Diseases, Department of Medicine, The Mount Sinai Medical Center, New York, NY, USA
| | - Andrea D. Branch
- Recanati-Miller Transplant Institute, The Mount Sinai Medical Center, New York, NY, USA
| | - Swan N. Thung
- Lillian and Henry M. Stratton-Hans Popper Department of Pathology, The Mount Sinai Medical Center, New York, NY, USA
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39
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Hirschfield GM, Al-Harthi N, Heathcote EJ. Current status of therapy in autoimmune liver disease. Therap Adv Gastroenterol 2009; 2:11-28. [PMID: 21180531 PMCID: PMC3002506 DOI: 10.1177/1756283x08098966] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Therapeutic strategies for autoimmune liver diseases are increasingly established. Although proportionately uncommon, specialist centers have with time refined the best approaches for each disease, based on an improved understanding of the spectrum of presentation. The major treatment aims are to prevent end-stage liver disease and its associated complications. As a result of drugs such as ursodeoxycholic acid, predniso(lo)ne and azathioprine, both primary biliary cirrhosis and autoimmune hepatitis are now less commonly indications for liver transplantation. Unfortunately, the same inroads in treatment efficacy have as yet not been made for primary sclerosing cholangitis, although the recognition that a subset of patients may have a treatable secondary sclerosing cholangitis (IgG4 related) is helping a proportion. With better biological understanding, more specific interventions are expected that will benefit all those with autoimmune liver diseases.
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