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Chen Y, Chen R, Li H, Shuai Z. Clinical management of autoimmune liver diseases: juncture, opportunities, and challenges ahead. Immunol Res 2025; 73:67. [PMID: 40195209 PMCID: PMC11976385 DOI: 10.1007/s12026-025-09622-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2024] [Accepted: 03/14/2025] [Indexed: 04/09/2025]
Abstract
The three major autoimmune liver diseases are autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), and primary sclerosing cholangitis (PSC).These conditions are assumed to result from a breakdown in immunological tolerance, which leads to an inflammatory process that causes liver damage.The self-attack is started by T-helper cell-mediated identification of liver autoantigens and B-cell production of autoantibodies,and it is maintained by a reduction in the number and activity of regulatory T-cells.Infections and environmental factors have been explored as triggering factors for these conditions, in addition to a genetic predisposition.Allelic mutations in the HLA locus have been linked to vulnerability, as have relationships with single nucleotide polymorphisms in non-HLA genes.Despite the advances in the management of these diseases, there is no curative treatment for these disorders, and a significant number of patients eventually progress to an end-stage liver disease requiring liver transplantation.In this line, tailored immune-therapeutics have emerged as possible treatments to control the disease.In addition, early diagnosis and treatment are pivotal for reducing the long-lasting effects of these conditions and their burden on quality of life.Herein we present a review of the etiology, clinical presentation, diagnosis, and challenges on ALDs and the feasible solutions for these complex diseases.
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MESH Headings
- Humans
- Hepatitis, Autoimmune/therapy
- Hepatitis, Autoimmune/diagnosis
- Hepatitis, Autoimmune/immunology
- Hepatitis, Autoimmune/etiology
- Cholangitis, Sclerosing/therapy
- Cholangitis, Sclerosing/diagnosis
- Cholangitis, Sclerosing/immunology
- Liver Cirrhosis, Biliary/therapy
- Liver Cirrhosis, Biliary/diagnosis
- Liver Cirrhosis, Biliary/immunology
- Animals
- Immunotherapy/methods
- Autoimmune Diseases/therapy
- Autoimmune Diseases/diagnosis
- Disease Management
- Genetic Predisposition to Disease
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Affiliation(s)
- Yangfan Chen
- Department of Rheumatology and Immunology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China
| | - Ruofei Chen
- Department of Rheumatology and Immunology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China
| | - Haiyan Li
- Department of Rheumatology and Immunology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China
| | - Zongwen Shuai
- Department of Rheumatology and Immunology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China.
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, 230032, China.
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Nauffal V, Klarqvist MDR, Hill MC, Pace DF, Di Achille P, Choi SH, Rämö JT, Pirruccello JP, Singh P, Kany S, Hou C, Ng K, Philippakis AA, Batra P, Lubitz SA, Ellinor PT. Noninvasive assessment of organ-specific and shared pathways in multi-organ fibrosis using T1 mapping. Nat Med 2024; 30:1749-1760. [PMID: 38806679 DOI: 10.1038/s41591-024-03010-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2023] [Accepted: 04/22/2024] [Indexed: 05/30/2024]
Abstract
Fibrotic diseases affect multiple organs and are associated with morbidity and mortality. To examine organ-specific and shared biologic mechanisms that underlie fibrosis in different organs, we developed machine learning models to quantify T1 time, a marker of interstitial fibrosis, in the liver, pancreas, heart and kidney among 43,881 UK Biobank participants who underwent magnetic resonance imaging. In phenome-wide association analyses, we demonstrate the association of increased organ-specific T1 time, reflecting increased interstitial fibrosis, with prevalent diseases across multiple organ systems. In genome-wide association analyses, we identified 27, 18, 11 and 10 independent genetic loci associated with liver, pancreas, myocardial and renal cortex T1 time, respectively. There was a modest genetic correlation between the examined organs. Several loci overlapped across the examined organs implicating genes involved in a myriad of biologic pathways including metal ion transport (SLC39A8, HFE and TMPRSS6), glucose metabolism (PCK2), blood group antigens (ABO and FUT2), immune function (BANK1 and PPP3CA), inflammation (NFKB1) and mitosis (CENPE). Finally, we found that an increasing number of organs with T1 time falling in the top quintile was associated with increased mortality in the population. Individuals with a high burden of fibrosis in ≥3 organs had a 3-fold increase in mortality compared to those with a low burden of fibrosis across all examined organs in multivariable-adjusted analysis (hazard ratio = 3.31, 95% confidence interval 1.77-6.19; P = 1.78 × 10-4). By leveraging machine learning to quantify T1 time across multiple organs at scale, we uncovered new organ-specific and shared biologic pathways underlying fibrosis that may provide therapeutic targets.
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Affiliation(s)
- Victor Nauffal
- Cardiovascular Division, Brigham and Women's Hospital, Boston, MA, USA
- Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | | | - Matthew C Hill
- Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA
| | - Danielle F Pace
- Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Data Sciences Platform, Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Paolo Di Achille
- Data Sciences Platform, Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Seung Hoan Choi
- Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Joel T Rämö
- Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - James P Pirruccello
- Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Cardiology Division, Massachusetts General Hospital, Boston, MA, USA
- Division of Cardiology, University of California, San Francisco, San Francisco, CA, USA
| | - Pulkit Singh
- Data Sciences Platform, Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Shinwan Kany
- Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Department of Cardiology, University Heart and Vascular Center Hamburg-Eppendorf, Hamburg, Germany
| | - Cody Hou
- Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Kenney Ng
- Center for Computational Health, IBM Research, Cambridge, MA, USA
| | - Anthony A Philippakis
- Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Data Sciences Platform, Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Eric and Wendy Schmidt Center, Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Puneet Batra
- Data Sciences Platform, Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Steven A Lubitz
- Demoulas Center for Cardiac Arrhythmias, Massachusetts General Hospital, Boston, MA, USA
| | - Patrick T Ellinor
- Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
- Demoulas Center for Cardiac Arrhythmias, Massachusetts General Hospital, Boston, MA, USA.
- Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA.
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Gorbatyuk O, Kurylo H. Biliary atresia in children (analytical literature review and review of own observation). WIADOMOSCI LEKARSKIE (WARSAW, POLAND : 1960) 2024; 77:577-584. [PMID: 38691803 DOI: 10.36740/wlek202403129] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/03/2024]
Abstract
OBJECTIVE Aim: to review information resources and analysis of the own experience on this problem for the provision of modern knowledge in the pathogenesis of the pathology, the latest diagnostic and treatment technologies, with consideration of the need to adhere to a single strategy in the management of patients with BA. PATIENTS AND METHODS Materials and Methods: The analysis of the data regarding the results of existing studies evaluating the clinical benefit and safety of diagnostic and treatment methods in Biliary atresia. CONCLUSION Conclusions: BA is the leading cause of neonatal cholestasis development. Early diagnostics of BA, based on the complex evaluation of clinical-laboratory, instrumental and morphological signs of the pathology, has a significant meaning. Surgical correction during the first 2 months of life - the Kasai procedure, as well as dynamic post-surgery follow-up significantly prolong the life of children and allow postponing liver transplantation. The highest patient survival both at the first stage of treatment - conduction of the Kasai procedure and the stage of liver transplantation may be achieved by joined work of surgeons and pediatricians, which allows considering the whole row of possible problems.
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Affiliation(s)
- Olga Gorbatyuk
- SHUPYK NATIONAL HEALTHCARE UNIVERSITY OF UKRAINE, KYIV, UKRAINE
| | - Halyna Kurylo
- DANYLO HALYTSKY LVIV NATIONAL MEDICAL UNIVERSITY, LVIV, UKRAINE
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Villani R, Serviddio G, Avolio C, Cassano T, D'Amico E. Autoimmune liver disease and multiple sclerosis: state of the art and future perspectives. Clin Exp Med 2023; 23:3321-3338. [PMID: 37421590 PMCID: PMC10618321 DOI: 10.1007/s10238-023-01128-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2022] [Accepted: 06/23/2023] [Indexed: 07/10/2023]
Abstract
Clinical observations suggest that the prevalence of autoimmune diseases is changing over time. Both autoimmune liver diseases and multiple sclerosis have shown a significant increase in the last decades. Although the coexistence of autoimmune diseases within individuals and families is a common phenomenon, the extent to which liver disease and multiple sclerosis co-occur is not clear. Case reports and few studies have reported the possible coexistence of multiple sclerosis with thyroid diseases, inflammatory bowel disease, psoriasis, and rheumatoid arthritis. It is unknown whether there is a definite association between multiple sclerosis and autoimmune liver diseases. We reviewed the literature to summarize the available studies on the association between different autoimmune liver diseases (autoimmune hepatitis, primary biliary cholangitis, and primary sclerosing cholangitis) and treated or untreated multiple sclerosis.
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Affiliation(s)
- Rosanna Villani
- Liver Unit, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy.
| | - Gaetano Serviddio
- Liver Unit, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | - Carlo Avolio
- Department of Medical and Surgical Sciences, Multiple Sclerosis Center, University of Foggia, Foggia, Italy
| | - Tommaso Cassano
- Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | - Emanuele D'Amico
- Department of Medical and Surgical Sciences, Multiple Sclerosis Center, University of Foggia, Foggia, Italy
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Zhang Y, Zhang D, Chen L, Zhou J, Ren B, Chen H. The progress of autoimmune hepatitis research and future challenges. Open Med (Wars) 2023; 18:20230823. [PMID: 38025543 PMCID: PMC10655690 DOI: 10.1515/med-2023-0823] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2023] [Revised: 09/24/2023] [Accepted: 09/28/2023] [Indexed: 12/01/2023] Open
Abstract
Autoimmune hepatitis (AIH) is a chronic liver inflammatory disease with various immune system manifestations, showing a global trend of increased prevalence. AIH is diagnosed through histological abnormalities, clinical manifestations, and biochemical indicators. The biochemical markers involve interfacial hepatitis, transaminase abnormalities, positive autoantibodies, etc. Although AIH pathogenesis is unclear, gene mutations and immunological factors could be the leading factors. AIH usually presents as a chronic liver disease and sometimes as acute hepatitis, making it challenging to distinguish it from drug-related hepatitis due to similar clinical symptoms. Normalizing transaminases and serum IgG levels is essential in assessing the remission status of AIH treatment. Glucocorticoids and azathioprine are the first-line AIH treatment, with lifelong maintenance therapy in some patients. The quality of life and survival can be improved after appropriate treatment. However, certain limitations jeopardize the quality of treatment, including long treatment cycles, side effects, poor patient compliance, and inability to inhibit liver fibrosis and cirrhosis. Accurate AIH animal models will help us understand the pathophysiology of the disease while providing fresh perspectives for avoiding and treating AIH. This review will help us understand AIH better, from the cellular and molecular causes to the clinical features, and will provide insight into new therapy techniques with fewer side effects.
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Affiliation(s)
- Yang Zhang
- Graduate Department of Zhejiang Chinese Medicine University, Hangzhou, Zhejiang, China
- Department of Infectious Diseases, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, China
| | - Dehe Zhang
- Department of Infectious Diseases, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, China
| | - Ling Chen
- Department of Infectious Diseases, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, China
| | - Jing Zhou
- Department of Infectious Diseases, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, China
| | - Binbin Ren
- Department of Infectious Diseases, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, China
| | - Haijun Chen
- Department of Infectious Diseases, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, China
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Buechter M, Dorn D, Möhlendick B, Siffert W, Baba HA, Gerken G, Kahraman A. Characteristics and Long-Term Outcome of 535 Patients with Autoimmune Hepatitis-The 20-Year Experience of a High-Volume Tertiary Center. J Clin Med 2023; 12:4192. [PMID: 37445225 DOI: 10.3390/jcm12134192] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2023] [Revised: 06/12/2023] [Accepted: 06/16/2023] [Indexed: 07/15/2023] Open
Abstract
Background and aims: Autoimmune hepatitis (AIH) is a complex and progressive inflammatory liver disease characterized by immune-mediated destruction of the liver parenchyma, hypergammaglobulinemia, the presence of circulating autoantibodies, and good response to immunosuppressive therapy. Since the prevalence of AIH is relatively rare, data on the clinical course and the long-term outcome are scarce. Patients and methods: We retrospectively analyzed the data of 535 well-documented AIH patients treated at the University Hospital Essen between 2000 and 2020. Results: The majority of patients were middle-aged females (75% women, mean age 45 years) with AIH type 1 (97%). Approximately 32% of patients were diagnosed with cirrhosis due to AIH, 29% had concomitant autoimmune (predominantly autoimmune thyroiditis), and 10% had psychiatric diseases, respectively. Skin tumors were the most common malignant diseases (47% of all tumors), while hepatocellular carcinoma rarely occurred (only six cases). Overall long-term mortality and liver-associated mortality were 9.16% and 4.67%, respectively. However, long-term survival was strongly associated with disease remission. Conclusions: Although AIH is a silent disease and cirrhosis is present in many cases, a favorable long-term prognosis can be achieved by consequent immunosuppressive therapy. The incidence of (liver-associated) complications seems to be lower in comparison to other etiologies, such as viral hepatitis or NASH, and mainly depends on the long-term side effects of immunosuppressive therapy.
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Affiliation(s)
- Matthias Buechter
- Department of Gastroenterology and Hepatology, University Clinic of Essen, University of Duisburg-Essen, 45122 Essen, Germany
- Department of Gastroenterology and Hepatology, Elisabeth Hospital, 58638 Iserlohn, Germany
| | - Dominik Dorn
- Department of Gastroenterology and Hepatology, University Clinic of Essen, University of Duisburg-Essen, 45122 Essen, Germany
| | - Birte Möhlendick
- Institute of Pharmacogenetics, University Clinic of Essen, University of Duisburg-Essen, 45122 Essen, Germany
| | - Winfried Siffert
- Institute of Pharmacogenetics, University Clinic of Essen, University of Duisburg-Essen, 45122 Essen, Germany
| | - Hideo A Baba
- Institute of Pathology, University Clinic of Essen, University of Duisburg-Essen, 45122 Essen, Germany
| | - Guido Gerken
- Department of Gastroenterology and Hepatology, University Clinic of Essen, University of Duisburg-Essen, 45122 Essen, Germany
- Department of Gastroenterology and Hepatology, Helios Clinic, 42549 Velbert, Germany
| | - Alisan Kahraman
- Department of Gastroenterology and Hepatology, University Clinic of Essen, University of Duisburg-Essen, 45122 Essen, Germany
- Department of Gastroenterology and Hepatology, Max Grundig Clinic, 77815 Bühl, Germany
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Yang H, Huang L, Xie Y, Bai M, Lu H, Zhao S, Gao Y, Hu J. A diagnostic model of autoimmune hepatitis in unknown liver injury based on noninvasive clinical data. Sci Rep 2023; 13:3996. [PMID: 36899037 PMCID: PMC10006218 DOI: 10.1038/s41598-023-31167-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2022] [Accepted: 03/07/2023] [Indexed: 03/12/2023] Open
Abstract
All the diagnostic criteria of autoimmune hepatitis (AIH) include histopathology. However, some patients may delay getting this examination due to concerns about the risks of liver biopsy. Therefore, we aimed to develop a predictive model of AIH diagnostic that does not require a liver biopsy. We collected demographic, blood, and liver histological data of unknown liver injury patients. First, we conducted a retrospective cohort study in two independent adult cohorts. In the training cohort (n = 127), we used logistic regression to develop a nomogram according to the Akaike information criterion. Second, we validated the model in a separate cohort (n = 125) using the receiver operating characteristic curve, decision curve analysis, and calibration plot to externally evaluate the performance of this model. We calculated the optimal cutoff value of diagnosis using Youden's index and presented the sensitivity, specificity, and accuracy to evaluate the model in the validation cohort compared with the 2008 International Autoimmune Hepatitis Group simplified scoring system. In the training cohort, we developed a model to predict the risk of AIH using four risk factors-The percentage of gamma globulin, fibrinogen, age, and AIH-related autoantibodies. In the validation cohort, the areas under the curve for the validation cohort were 0.796. The calibration plot suggested that the model had an acceptable accuracy (p > 0.05). The decision curve analysis suggested that the model had great clinical utility if the value of probability was 0.45. Based on the cutoff value, the model had a sensitivity of 68.75%, a specificity of 76.62%, and an accuracy of 73.60% in the validation cohort. While we diagnosed the validated population by using the 2008 diagnostic criteria, the sensitivity of prediction results was 77.77%, the specificity was 89.61% and the accuracy was 83.20%. Our new model can predict AIH without a liver biopsy. It is an objective, simple and reliable method that can effectively be applied in the clinic.
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Affiliation(s)
- Haiyan Yang
- General Medical Department, Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Lingying Huang
- Department of Hepatology, Shuguang Hospital, Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Ying Xie
- Department of Infectious Disease, Changzheng Hospital, Naval Medical University, Shanghai, China
| | - Mei Bai
- Department of Dermatology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University, Shanghai, China
| | - Huili Lu
- Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China
| | - Shiju Zhao
- Special medical department, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University, Shanghai, China
| | - Yueqiu Gao
- Department of Hepatology, Shuguang Hospital, Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Jianjun Hu
- Department of Infectious Disease, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, 1111 Xianxia Road, Shanghai, 200336, China.
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Zhai H, Zhang J, Shang D, Zhu C, Xiang X. The progress to establish optimal animal models for the study of acute-on-chronic liver failure. Front Med (Lausanne) 2023; 10:1087274. [PMID: 36844207 PMCID: PMC9947362 DOI: 10.3389/fmed.2023.1087274] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2022] [Accepted: 01/23/2023] [Indexed: 02/11/2023] Open
Abstract
Acute-on-chronic liver failure (ACLF) defines a complicated and multifaceted syndrome characterized by acute liver dysfunction following an acute insult on the basis of chronic liver diseases. It is usually concurrent with bacterial infection and multi-organ failure resulting in high short-term mortality. Based on the cohort studies in ACLF worldwide, the clinical course of ACLF was demonstrated to comprise three major stages including chronic liver injury, acute hepatic/extrahepatic insult, and systemic inflammatory response caused by over-reactive immune system especially bacterial infection. However, due to the lack of optimal experimental animal models for ACLF, the progress of basic study on ACLF is limping. Though several experimental ACLF models were established, none of them can recapitulate and simulate the whole pathological process of ACLF patients. Recently, we have developed a novel mouse model for ACLF combining chronic liver injury [injection of carbon tetrachloride (CCl4) for 8 weeks], acute hepatic insult (injection of a double dose CCl4), and bacterial infection (intraperitoneal injection of Klebsiella pneumoniae), which could recapitulate the major clinical features of patients with ACLF worsened by bacterial infection.
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Affiliation(s)
- Hengben Zhai
- Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China,Translational Lab of Liver Diseases, Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jinming Zhang
- Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China,Translational Lab of Liver Diseases, Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Dabao Shang
- Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China,Translational Lab of Liver Diseases, Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Chuanwu Zhu
- Department of Infectious Diseases, The Fifth People’s Hospital of Suzhou, Suzhou, China,Chuanwu Zhu,
| | - Xiaogang Xiang
- Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China,Translational Lab of Liver Diseases, Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China,*Correspondence: Xiaogang Xiang,
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9
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Harsini S, Rezaei N. Autoimmune diseases. Clin Immunol 2023. [DOI: 10.1016/b978-0-12-818006-8.00001-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
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Mack CL. HLA Associations in pediatric autoimmune liver diseases: Current state and future research initiatives. Front Immunol 2022; 13:1019339. [PMID: 36311765 PMCID: PMC9609783 DOI: 10.3389/fimmu.2022.1019339] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2022] [Accepted: 09/12/2022] [Indexed: 11/21/2024] Open
Abstract
The strongest genetic association with autoimmunity is within chromosome 6p21, where the human leukocyte antigen (HLA) complex resides. This review will focus on the HLA associations within pediatric autoimmune hepatitis, autoimmune sclerosing cholangitis and primary sclerosing cholangitis. In general, there is considerable overlap in HLA genotypes conferring susceptibility to pediatric autoimmune liver diseases, however unique HLA associations and protective HLA genotypes exist. There are numerous areas for future research initiatives in pediatric autoimmune liver diseases and HLA associations with clinical outcomes, autoantigen discovery and novel therapeutics targeting the HLA- autoantigen- T cell pathway will be highlighted.
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Affiliation(s)
- Cara L. Mack
- Department of Pediatrics, Division of Pediatric Gastroenterology, Hepatology & Nutrition Medical College of Wisconsin and Children’s Wisconsin, Milwaukee, WI, United States
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11
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Roy N, Nadda N, Kumar H, Prasad C, Kumar Jha J, Pandey HC, Vanamail P, Saraya A, Balhara YPS, Shalimar, Nayak B. Pattern recognition receptor CD14 gene polymorphisms in alcohol use disorder patients and its Influence on liver disease susceptibility. Front Immunol 2022; 13:975027. [PMID: 36238273 PMCID: PMC9551314 DOI: 10.3389/fimmu.2022.975027] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2022] [Accepted: 08/15/2022] [Indexed: 11/13/2022] Open
Abstract
Background Alcohol use disorders (AUDs) leading to liver disease is major concern over other spectrum of disorder. Excessive alcohol consumption resulting in leaky gut syndrome is attributed to alcohol-induced liver injury through portal translocation of bacterial endotoxin. Susceptibility to alcoholic liver disease (ALD) in AUD patients could be dependent upon genes responsible for inflammation and alcohol metabolism. The pattern recognition receptor CD14 gene is a major player in endotoxin-mediated inflammation and susceptibility to ALD. This study investigated the genetic association of CD14 polymorphisms and other mechanisms relevant to altered inflammatory responses leading to ALD. Methods Patients with alcohol use disorder with ALD (n = 128) and without liver disease (ALC, n = 184) and controls without alcohol use disorder (NALC, n = 152) from North India were enrolled. The CD4 gene polymorphisms in the North Indian population were evaluated by RFLP and sequencing. Secretory CD14 (sCD14), LBP, TLR4, MD2, TNFα, IL1b, IFNγ, IL6, IL10, and IL4 levels in serum were measured by ELISA among groups. The influence of polymorphisms on CD14 gene promoter activity and circulatory bacterial DNA level was determined. Results The CD14 gene promoter and exonic region SNPs were found to be monomorphic, except for SNP rs2569190 for the North Indian population. The genetic association of SNP rs2569190(C/T) with the risk of developing ALD was found significant for TT genotype [ORTT, 95% CI = 2.19, 1.16–4.13 for ALD vs. ALC and OR, 2.09, 1.18–3.72 for ALD vs. NALC]. An increased sCD14 level was observed in AUD patients compared to NALC control. Increased levels of LBP, TLR4, TNFα, IL1β, IFNγ, and IL6 and reduced levels of MD2, IL10, and IL4 were observed among the ALD patients compared to the other two control groups. Elevated levels of pro-inflammatory and reduced levels of anti-inflammatory cytokines were observed in the risk genotype TT groups of ALD patients and the ALC group compared to NALC. Promoter activity was observed in the intronic region flanking SNPs and risk genotype can influence reporter activity, indicating CD14 gene expression. Conclusion Enhanced CD14 expression associated with inflammatory responses increases susceptibility to ALD in the TT genotype of AUD patients.
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12
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Durazzo M, Ferro A. SARS-CoV-2 and autoimmune hepatitis onset: a new association. Minerva Gastroenterol (Torino) 2022; 68:259-260. [PMID: 36083103 DOI: 10.23736/s2724-5985.22.03167-9] [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: 11/08/2022]
Affiliation(s)
- Marilena Durazzo
- Department of Medical Sciences, University of Turin, Turin, Italy -
| | - Arianna Ferro
- Department of Medical Sciences, University of Turin, Turin, Italy
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13
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Centa M, Weinstein EG, Clemente JC, Faith JJ, Fiel MI, Lyallpuri R, Herbin O, Alexandropoulos K. Impaired central tolerance induces changes in the gut microbiota that exacerbate autoimmune hepatitis. J Autoimmun 2022; 128:102808. [PMID: 35276587 PMCID: PMC8963681 DOI: 10.1016/j.jaut.2022.102808] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2021] [Revised: 02/10/2022] [Accepted: 02/19/2022] [Indexed: 12/18/2022]
Abstract
Medullary thymic epithelial cells (mTECs) induce T cell tolerance in the thymus through the elimination of self-reactive thymocytes. Commensal bacteria are also critical for shaping T cell responses in the gut and distal organs. We previously showed that mice depleted of mTECs (Traf6ΔTEC) generated autoreactive T cells and developed autoimmune hepatitis (AIH). In this report, we found that Toll-like receptor (TLR)-mediated microbial sensing on liver hematopoietic cells and the gut microbiota contributed to AIH development in Traf6ΔTEC mice. While adoptive transfer of thymic Traf6ΔTEC T cells in immune-deficient mice was sufficient for AIH development, colonization of germ-free mice with Traf6ΔTEC microbiota failed to induce AIH, suggesting that the gut microbiota contributes to but is not sufficient for AIH development. Microbiota-mediated exacerbation of AIH associated with increased numbers of hepatic Foxp3+ T cells and their increase was proportional to the degree of inflammation. The contribution of the gut microbiota to AIH development associated with an altered microbial signature whose composition was influenced by the qualitative nature of the thymic T cell compartment. These results suggest that aberrant selection of T cells in the thymus can induce changes in the gut microbiota that lead to exacerbation of organ-specific autoimmunity and AIH. Our results add to our understanding of the mechanisms of AIH development and create a platform towards developing novel therapeutic approaches for treating this disease.
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Affiliation(s)
- Monica Centa
- Department of Medicine, Division of Clinical Immunology, Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | | | - Jose C Clemente
- Department of Medicine, Division of Clinical Immunology, Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Jeremiah J Faith
- Department of Medicine, Division of Clinical Immunology, Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - M Isabel Fiel
- Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Robby Lyallpuri
- Department of Medicine, Division of Clinical Immunology, Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | | | - Konstantina Alexandropoulos
- Department of Medicine, Division of Clinical Immunology, Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
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14
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Terziroli Beretta-Piccoli B, Mieli-Vergani G, Vergani D. Autoimmmune hepatitis. Cell Mol Immunol 2022; 19:158-176. [PMID: 34580437 PMCID: PMC8475398 DOI: 10.1038/s41423-021-00768-8] [Citation(s) in RCA: 83] [Impact Index Per Article: 27.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2021] [Accepted: 08/29/2021] [Indexed: 02/06/2023] Open
Abstract
Autoimmune hepatitis (AIH) is a T-cell mediated, inflammatory liver disease affecting all ages and characterized by female preponderance, elevated serum transaminase and immunoglobulin G levels, positive circulating autoantibodies, and presence of interface hepatitis at liver histology. AIH type 1, affecting both adults and children, is defined by positive anti-nuclear and/or anti-smooth muscle antibodies, while type 2 AIH, affecting mostly children, is defined by positive anti-liver-kidney microsomal type 1 and/or anti-liver cytosol type 1 antibody. While the autoantigens of type 2 AIH are well defined, being the cytochrome P4502D6 (CYP2D6) and the formiminotransferase cyclodeaminase (FTCD), in type 1 AIH they remain to be identified. AIH-1 predisposition is conferred by possession of the MHC class II HLA DRB1*03 at all ages, while DRB1*04 predisposes to late onset disease; AIH-2 is associated with possession of DRB1*07 and DRB1*03. The majority of patients responds well to standard immunosuppressive treatment, based on steroid and azathioprine; second- and third-line drugs should be considered in case of intolerance or insufficient response. This review offers a comprehensive overview of pathophysiological and clinical aspects of AIH.
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Affiliation(s)
- Benedetta Terziroli Beretta-Piccoli
- Epatocentro Ticino & Facoltà di Scienze Biomediche, Università della Svizzera Italiana, Lugano, Switzerland.
- Institute for Research in Biomedicine, Bellinzona, Switzerland.
- King's College London Faculty of Life Sciences & Medicine at King's College Hospital, London, UK.
| | - Giorgina Mieli-Vergani
- King's College London Faculty of Life Sciences & Medicine at King's College Hospital, London, UK
- Paediatric Liver, GI and Nutrition Centre, MowatLabs, King's College Hospital, London, UK
| | - Diego Vergani
- King's College London Faculty of Life Sciences & Medicine at King's College Hospital, London, UK
- Institute of Liver Studies, MowatLabs, King's College Hospital, London, UK
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15
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Armandi A, Actis GC, Ribaldone DG. Autoimmunity of the liver. TRANSLATIONAL AUTOIMMUNITY 2022:309-331. [DOI: 10.1016/b978-0-12-824466-1.00012-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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16
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Ma Y, Su H, Yuksel M, Longhi MS, McPhail M, Wang P, Bansal S, Wong GW, Graham J, Yang L, Thompson R, Doherty DG, Hadzic N, Zen Y, Quaglia A, Henghan M, Samyn M, Vergani D, Mieli-Vergani G. Human Leukocyte Antigen Profile Predicts Severity of Autoimmune Liver Disease in Children of European Ancestry. Hepatology 2021; 74:2032-2046. [PMID: 33971035 PMCID: PMC8463472 DOI: 10.1002/hep.31893] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2020] [Revised: 04/03/2021] [Accepted: 04/28/2021] [Indexed: 02/05/2023]
Abstract
BACKGROUND AND AIMS Genetic predisposition to autoimmune hepatitis (AIH) in adults is associated with possession of human leukocyte antigen (HLA) class I (A*01, B*08) and class II (DRB1*03, -04, -07, or -13) alleles, depending on geographic region. Juvenile autoimmune liver disease (AILD) comprises AIH-1, AIH-2, and autoimmune sclerosing cholangitis (ASC), which are phenotypically different from their adult counterparts. We aimed to define the relationship between HLA profile and disease course, severity, and outcome in juvenile AILD. APPROACH AND RESULTS We studied 236 children of European ancestry (152 female [64%], median age 11.15 years, range 0.8-17), including 100 with AIH-1, 59 with AIH-2, and 77 with ASC. The follow-up period was from 1977 to June 2019 (median 14.5 years). Class I and II HLA genotyping was performed using PCR/sequence-specific primers. HLA B*08, -DRB1*03, and the A1-B8-DR3 haplotype impart predisposition to all three forms of AILD. Homozygosity for DRB1*03 represented the strongest risk factor (8.8). HLA DRB1*04, which independently confers susceptibility to AIH in adults, was infrequent in AIH-1 and ASC, suggesting protection; and DRB1*15 (DR15) was protective against all forms of AILD. Distinct HLA class II alleles predispose to the different subgroups of juvenile AILD: DRB1*03 to AIH-1, DRB1*13 to ASC, and DRB1*07 to AIH-2. Possession of homozygous DRB1*03 or of DRB1*13 is associated with fibrosis at disease onset, and possession of these two genes in addition to DRB1*07 is associated with a more severe disease in all three subgroups. CONCLUSIONS Unique HLA profiles are seen in each subgroup of juvenile AILD. HLA genotype might be useful in predicting responsiveness to immunosuppressive treatment and course.
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Affiliation(s)
- Yun Ma
- Institute of Liver Studies, MowatLabs, Department of Inflammation Biology, School of Immunology & Microbial Sciences, Faculty of Liver Sciences and Medicine, King’s College London, London, UK
| | - Habin Su
- Institute of Liver Studies, MowatLabs, Department of Inflammation Biology, School of Immunology & Microbial Sciences, Faculty of Liver Sciences and Medicine, King’s College London, London, UK,Department of Liver Disease of Chinese PLA General Hospital, the Fifth Medical Center of PLA General Hospital, Beijing, China
| | - Muhammed Yuksel
- Institute of Liver Studies, MowatLabs, Department of Inflammation Biology, School of Immunology & Microbial Sciences, Faculty of Liver Sciences and Medicine, King’s College London, London, UK,Koc University Research Centre for Translational Medicine (KUTTAM), Istanbul, Turkey
| | - Maria Serena Longhi
- Institute of Liver Studies, MowatLabs, Department of Inflammation Biology, School of Immunology & Microbial Sciences, Faculty of Liver Sciences and Medicine, King’s College London, London, UK,Department of Anesthesia, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, MA 02215, USA
| | - Mark McPhail
- Institute of Liver Studies, MowatLabs, Department of Inflammation Biology, School of Immunology & Microbial Sciences, Faculty of Liver Sciences and Medicine, King’s College London, London, UK
| | - Pengyun Wang
- Institute of Liver Studies, MowatLabs, Department of Inflammation Biology, School of Immunology & Microbial Sciences, Faculty of Liver Sciences and Medicine, King’s College London, London, UK
| | - Sanjay Bansal
- Paediatric Liver, GI and Nutrition Centre, King’s College Hospital, Denmark Hill, London, UK
| | - Guan-Wee Wong
- Institute of Liver Studies, MowatLabs, Department of Inflammation Biology, School of Immunology & Microbial Sciences, Faculty of Liver Sciences and Medicine, King’s College London, London, UK,Department of Medicine, Ng Teng Fong General Hospital, 1 Jurong East Street, Singapore 609606
| | - Jonathon Graham
- Institute of Liver Studies, MowatLabs, Department of Inflammation Biology, School of Immunology & Microbial Sciences, Faculty of Liver Sciences and Medicine, King’s College London, London, UK
| | - Li Yang
- Department of Gastroenterology & Hepatology, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Richard Thompson
- Institute of Liver Studies, MowatLabs, Department of Inflammation Biology, School of Immunology & Microbial Sciences, Faculty of Liver Sciences and Medicine, King’s College London, London, UK,Paediatric Liver, GI and Nutrition Centre, King’s College Hospital, Denmark Hill, London, UK
| | - Derek G. Doherty
- Division of Immunology, School of Medicine, Trinity College Dublin, Dublin, Ireland
| | - Nedim Hadzic
- Paediatric Liver, GI and Nutrition Centre, King’s College Hospital, Denmark Hill, London, UK
| | - Yoh Zen
- Institute of Liver Studies, MowatLabs, Department of Inflammation Biology, School of Immunology & Microbial Sciences, Faculty of Liver Sciences and Medicine, King’s College London, London, UK
| | - Alberto Quaglia
- Institute of Liver Studies, MowatLabs, Department of Inflammation Biology, School of Immunology & Microbial Sciences, Faculty of Liver Sciences and Medicine, King’s College London, London, UK,Department of Cellular Pathology, Royal Free London NHS Foundation Trust, UCL Cancer Institute, Research Department of Pathology, London, UK
| | - Michael Henghan
- Institute of Liver Studies, MowatLabs, Department of Inflammation Biology, School of Immunology & Microbial Sciences, Faculty of Liver Sciences and Medicine, King’s College London, London, UK
| | - Marianne Samyn
- Paediatric Liver, GI and Nutrition Centre, King’s College Hospital, Denmark Hill, London, UK
| | - Diego Vergani
- Institute of Liver Studies, MowatLabs, Department of Inflammation Biology, School of Immunology & Microbial Sciences, Faculty of Liver Sciences and Medicine, King’s College London, London, UK
| | - Giorgina Mieli-Vergani
- Institute of Liver Studies, MowatLabs, Department of Inflammation Biology, School of Immunology & Microbial Sciences, Faculty of Liver Sciences and Medicine, King’s College London, London, UK,Paediatric Liver, GI and Nutrition Centre, King’s College Hospital, Denmark Hill, London, UK
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17
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Zachou K, Arvaniti P, Lyberopoulou A, Dalekos GN. Impact of genetic and environmental factors on autoimmune hepatitis. J Transl Autoimmun 2021; 4:100125. [PMID: 34622188 PMCID: PMC8479787 DOI: 10.1016/j.jtauto.2021.100125] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2021] [Accepted: 09/20/2021] [Indexed: 02/07/2023] Open
Abstract
Autoimmune hepatitis (AIH) is a chronic non-resolving liver disease characterized by diffuse hypergammaglobulinemia, the presence of autoantibodies and characteristic histological findings. The disease can have catastrophic outcome with the development of end-stage liver disease if misdiagnosed/undiagnosed and left untreated. AIH pathogenesis remains obscure and the main hypothesis supports its development in genetically predisposed individuals after being exposed to certain environmental triggers. Genetic predisposition is linked to the presence of certain HLA alleles, mainly HLA-DR3 and HLA-DR4. However, a wide number of non-HLA epitopes have also been associated with the disease although data vary significantly among different ethnic groups. Therefore, it is likely that epigenetic alterations may also play a crucial role in disease's pathogenesis, although not yet extensively studied. The aim of this review was to summarize the genetic and environmental factors that have been associated with AIH, but also to open new insights towards the role of epigenetic modifications in the etiology of the disease.
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Affiliation(s)
- Kalliopi Zachou
- Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center in Autoimmune Liver Diseases, University Hospital of Larissa, Larissa, Greece
| | - Pinelopi Arvaniti
- Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center in Autoimmune Liver Diseases, University Hospital of Larissa, Larissa, Greece
| | - Aggeliki Lyberopoulou
- Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center in Autoimmune Liver Diseases, University Hospital of Larissa, Larissa, Greece
| | - George N Dalekos
- Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center in Autoimmune Liver Diseases, University Hospital of Larissa, Larissa, Greece
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18
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Valencia-Rodríguez A, Vera-Barajas A, Chávez-Tapia NC, Uribe M, Méndez-Sánchez N. Looking into a new era for the approach of metabolic (dysfunction) associated fatty liver disease. Ann Hepatol 2020; 19:227-229. [PMID: 32359519 DOI: 10.1016/j.aohep.2020.04.001] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2020] [Revised: 04/06/2020] [Accepted: 04/09/2020] [Indexed: 02/04/2023]
Affiliation(s)
| | | | | | - Misael Uribe
- Liver Research Unit, Medica Sur Clinical Foundation, Mexico City, Mexico
| | - Nahum Méndez-Sánchez
- Liver Research Unit, Medica Sur Clinical Foundation, Mexico City, Mexico; Faculty of Medicine. National Autonomous University of Mexico, Mexico City, Mexico.
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19
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NUNES MEG, ROSA DV, FAGUNDES EDT, FERREIRA AR, MIRANDA DMD, FERRI LIU PM. HLA-DRB1 GENE POLYMORPHISMS IN PEDIATRIC PATIENTS WITH TYPE 1 AUTOIMMUNE HEPATITIS AND TYPE 1 AUTOIMMUNE HEPATITIS OVERLAP SYNDROME WITH AUTOIMMUNE CHOLANGITIS. ARQUIVOS DE GASTROENTEROLOGIA 2019; 56:146-150. [DOI: 10.1590/s0004-2803.201900000-29] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/08/2019] [Accepted: 03/19/2019] [Indexed: 12/25/2022]
Abstract
ABSTRACT BACKGROUND: Autoimmune hepatitis (AIH) is a rare chronic inflammatory liver disease associated with a loss of immunological tolerance to self-antigens. Susceptibility to AIH is partially determined by the presence of genes related to human leukocyte antigen (HLA), mainly allelic variants of DRB1. OBJECTIVE: The purpose of this study was to investigate the frequencies of the polymorphisms in HLA-DRB1 gene in children and adolescents with type 1 AIH and type 1 AIH overlap syndrome with autoimmune cholangitis (overlap syndrome, OS) in comparison to healthy sex and age-matched individuals (control group). METHODS: This is a cross-sectional study of 25 pediatric patients diagnosed with type 1 AIH and 18 with OS. Fifty-seven healthy individuals were included as controls. The polymorphisms of the HLA-DRB1 gene were evaluated by PCR and included HLA-DRB1*03, HLA-DRB1*04, HLA-DRB1*07, and HLA-DRB1*13. RESULTS: Our results showed that the presence of the allele HLA-DRB1*13 increased the chance of autoimmune cholangitis (OR=3.96, CI 1.07 to 14.61, P=0.04). The HLA-DRB1*04 and HLA- DRB1*07 have no association with the AIH and autoimmune cholangitis in a young sample. CONCLUSION: This work demonstrates an association of the main polymorphisms in the HLA-DRB1 gene to AIH with or without cholangitis in a Brazilian sample.
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20
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Zhao X, Ding S, Geng C, Man Z, Pan M, Sun L, Hu B, Wang H. Anti-CD200 attenuates concanavalin A induced hepatitis via modulating the imbalance of CD4 + T lymphocyte differentiation in mice. Am J Transl Res 2018; 10:4202-4209. [PMID: 30662663 PMCID: PMC6325521] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2018] [Accepted: 11/02/2018] [Indexed: 06/09/2023]
Abstract
Hepatitis occurs in critical ill patients with bad morbidity and mortality. It is known that imbalance of Th1 and Th2 lymphocytes differentiations plays a key role in its mechanisms. Recent studies indicated that type 1 membrane glycoprotein CD200 serves as co-inhibitory molecule, negatively regulating the immune response. In regard of this, we used Concanavalin A (Con A) induced liver injury model to research the effect of CD200 on the differentiation of CD4+ T lymphocyte and found that the expression of CD200 on CD4+ T was significantly higher in hepatitis mouse. The apoptosis of CD4+ T cell in Con A induced liver injury was significantly attenuated by anti-CD200. The concentration of solube IL-2 and IFN-γ was reduced by anti-CD200, in addition, the expression of T-bet, GATA3 and FoxP3 mRNA were all attenuated by anti-CD200. The phosphorylation of SH-2 containing inositol 5' polyphosphatase 1 (SHIP1) was significantly increased in Con A induced liver injury and reduced by anti-CD200. We hypothesized that, anti-CD200 inhibited the phosphorylation of SHIP1, the expression of T-bet, GATA3 and FoxP3 mRNA and CD4+ T differentiation to protect the liver from autoimmune hepatitis.
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Affiliation(s)
- Xiaohong Zhao
- Department of Anesthesiology, Shanghai Pudong Hospital, Fudan University Pudong Medical Center2800 Gongwei Road, Huinan Town, Pudong, Shanghai 201399, China
| | - Shuo Ding
- Department of Intensive Care, Fengxian People’s Hospital51 West Renmin Rd, Fenxian, Xuzhou 221700, China
| | - Chuan Geng
- Department of Anesthesiology, Fengxian People’s Hospital51 West Renmin Rd, Fenxian, Xuzhou 221700, China
| | - Zhong Man
- Department of Anesthesiology, Fengxian People’s Hospital51 West Renmin Rd, Fenxian, Xuzhou 221700, China
| | - Mengzhi Pan
- Department of Anesthesiology, Shanghai Pudong Hospital, Fudan University Pudong Medical Center2800 Gongwei Road, Huinan Town, Pudong, Shanghai 201399, China
| | - Leilei Sun
- Department of Anesthesiology, Shanghai Pudong Hospital, Fudan University Pudong Medical Center2800 Gongwei Road, Huinan Town, Pudong, Shanghai 201399, China
| | - Baoji Hu
- Department of Anesthesiology, Shanghai Pudong Hospital, Fudan University Pudong Medical Center2800 Gongwei Road, Huinan Town, Pudong, Shanghai 201399, China
| | - Hua Wang
- Department of Anesthesiology, Affiliated Hospital of Guilin Medical University15 Lequn Rd, Guilin 541001, China
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21
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Juvenile autoimmune hepatitis: A comprehensive review. J Autoimmun 2018; 95:69-76. [DOI: 10.1016/j.jaut.2018.10.007] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2018] [Accepted: 10/13/2018] [Indexed: 12/12/2022]
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22
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Christen U, Hintermann E. Pathogens and autoimmune hepatitis. Clin Exp Immunol 2018; 195:35-51. [PMID: 30113082 DOI: 10.1111/cei.13203] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2018] [Revised: 07/30/2018] [Accepted: 08/06/2018] [Indexed: 12/12/2022] Open
Abstract
Autoimmune hepatitis (AIH) is a severe form of hepatitis resulting in the autoimmune-mediated destruction of the liver parenchyma. Whereas many of the immunopathogenic events have been elucidated and some of the drivers of the disease have been identified, little is known about the aetiology of the disease. There are certain risk factors, such as particular human leucocyte antigen (HLA) haplotypes, that enhance the susceptibility for AIH or influence the severity of the disease. However, as for many other autoimmune diseases, the mere presence of such risk factors does not warrant the occurrence of the disease. Not all individuals carrying risk factors develop AIH, and not all patients with AIH are carriers of high-risk alleles. Thus, additional environmental factors need to be considered as triggers for AIH. Environmental factors include diet, sunlight exposure, stress, medication and hygiene, as well as pathogen infections and vaccinations. This review discusses if pathogens should be considered as triggers for the initiation and/or propagation of AIH.
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Affiliation(s)
- U Christen
- Pharmazentrum Frankfurt / ZAFES, Goethe University Hospital, Frankfurt am Main, Germany
| | - E Hintermann
- Pharmazentrum Frankfurt / ZAFES, Goethe University Hospital, Frankfurt am Main, Germany
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23
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Yamazaki T, Umemura T, Joshita S, Yoshizawa K, Tanaka E, Ota M. A cis-eQTL of HLA-DPB1 Affects Susceptibility to Type 1 Autoimmune Hepatitis. Sci Rep 2018; 8:11924. [PMID: 30093645 PMCID: PMC6085285 DOI: 10.1038/s41598-018-30406-9] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2018] [Accepted: 07/30/2018] [Indexed: 12/12/2022] Open
Abstract
Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease characterized by an autoimmune reaction to hepatocytes. A single nucleotide polymorphism in the 3′ untranslated region of HLA-DPB1, rs9277534, is associated with HLA-DPB1 expression. rs9277534 has been linked to hepatitis B virus recovery/persistence and the risk of graft-versus-host disease with HLA-DPB1 mismatching transplantation of hematopoietic cells, but its role along with that of HLA-DP expression in AIH have not been fully clarified. We genotyped rs9277534 in 146 Japanese patients with AIH and 326 healthy subjects. HLA-DPB1 expression was determined by quantitative PCR. HLA-DPB1 expression was significantly higher for rs9277534G than for rs9277534A (P < 0.05). rs9277534 genotype was in strong linkage disequilibrium with the HLA-DPB1 allele (pairwise D′ = 0.82–1.00). Although HLA-DP alleles were not significantly associated with AIH, the frequency of the rs9277534G allele was significantly higher in AIH patients compared with healthy subjects (P = 0.002, odds ratio [OR] = 1.56). Logistic regression analysis revealed that the HLA-DRB1*04:05 allele (P < 0.001, OR = 4.61) and rs9277534 (P = 0.004, OR = 1.67) were independently associated with AIH susceptibility. rs9277534G in the HLA-DP gene is an eQTL that affects gene expression and may contribute to AIH susceptibility.
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Affiliation(s)
- Tomoo Yamazaki
- Department of Medicine, Division of Hepatology and Gastroenterology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Takeji Umemura
- Department of Medicine, Division of Hepatology and Gastroenterology, Shinshu University School of Medicine, Matsumoto, Japan. .,Research Center for Next Generation Medicine, Shinshu University, Matsumoto, Japan.
| | - Satoru Joshita
- Department of Medicine, Division of Hepatology and Gastroenterology, Shinshu University School of Medicine, Matsumoto, Japan.,Research Center for Next Generation Medicine, Shinshu University, Matsumoto, Japan
| | - Kaname Yoshizawa
- Department of Gastroenterology, NHO Ueda Medical Center, Ueda, Japan
| | - Eiji Tanaka
- Department of Medicine, Division of Hepatology and Gastroenterology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Masao Ota
- Department of Medicine, Division of Hepatology and Gastroenterology, Shinshu University School of Medicine, Matsumoto, Japan
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24
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Zhernakova DV, Kliver S, Cherkasov N, Tamazian G, Rotkevich M, Krasheninnikova K, Evsyukov I, Sidorov S, Dobrynin P, Yurchenko AA, Shimansky V, Shcherbakova IV, Glotov AS, Valle DL, Tang M, Shin E, Schwarz KB, O'Brien SJ. Analytical "bake-off" of whole genome sequencing quality for the Genome Russia project using a small cohort for autoimmune hepatitis. PLoS One 2018; 13:e0200423. [PMID: 29995946 PMCID: PMC6040705 DOI: 10.1371/journal.pone.0200423] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2017] [Accepted: 06/26/2018] [Indexed: 12/23/2022] Open
Abstract
A comparative analysis of whole genome sequencing (WGS) and genotype calling was initiated for ten human genome samples sequenced by St. Petersburg State University Peterhof Sequencing Center and by three commercial sequencing centers outside of Russia. The sequence quality, efficiency of DNA variant and genotype calling were compared with each other and with DNA microarrays for each of ten study subjects. We assessed calling of SNPs, indels, copy number variation, and the speed of WGS throughput promised. Twenty separate QC analyses showed high similarities among the sequence quality and called genotypes. The ten genomes tested by the centers included eight American patients afflicted with autoimmune hepatitis (AIH), plus one case’s unaffected parents, in a prelude to discovering genetic influences in this rare disease of unknown etiology. The detailed internal replication and parallel analyses allowed the observation of two of eight AIH cases carrying a rare allele genotype for a previously described AIH-associated gene (FTCD), plus multiple occurrences of known HLA-DRB1 alleles associated with AIH (HLA-DRB1-03:01:01, 13:01:01 and 7:01:01). We also list putative SNVs in other genes as suggestive in AIH influence.
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Affiliation(s)
- Daria V. Zhernakova
- Theodosius Dobzhansky Center for Genome Bioinformatics, St. Petersburg State University, St. Petersburg, Russian Federation
- University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, the Netherlands
- * E-mail: (DVZ); (SJO)
| | - Sergei Kliver
- Theodosius Dobzhansky Center for Genome Bioinformatics, St. Petersburg State University, St. Petersburg, Russian Federation
| | - Nikolay Cherkasov
- Theodosius Dobzhansky Center for Genome Bioinformatics, St. Petersburg State University, St. Petersburg, Russian Federation
| | - Gaik Tamazian
- Theodosius Dobzhansky Center for Genome Bioinformatics, St. Petersburg State University, St. Petersburg, Russian Federation
| | - Mikhail Rotkevich
- Theodosius Dobzhansky Center for Genome Bioinformatics, St. Petersburg State University, St. Petersburg, Russian Federation
| | - Ksenia Krasheninnikova
- Theodosius Dobzhansky Center for Genome Bioinformatics, St. Petersburg State University, St. Petersburg, Russian Federation
| | - Igor Evsyukov
- Theodosius Dobzhansky Center for Genome Bioinformatics, St. Petersburg State University, St. Petersburg, Russian Federation
| | - Sviatoslav Sidorov
- Theodosius Dobzhansky Center for Genome Bioinformatics, St. Petersburg State University, St. Petersburg, Russian Federation
| | - Pavel Dobrynin
- Theodosius Dobzhansky Center for Genome Bioinformatics, St. Petersburg State University, St. Petersburg, Russian Federation
| | - Andrey A. Yurchenko
- Theodosius Dobzhansky Center for Genome Bioinformatics, St. Petersburg State University, St. Petersburg, Russian Federation
| | - Valentin Shimansky
- Theodosius Dobzhansky Center for Genome Bioinformatics, St. Petersburg State University, St. Petersburg, Russian Federation
| | - Irina V. Shcherbakova
- Research Resource Center for Molecular and Cell Technologies, Research Park, Saint-Petersburg State University, St. Petersburg, Russia
| | - Andrey S. Glotov
- Research Resource Center for Molecular and Cell Technologies, Research Park, Saint-Petersburg State University, St. Petersburg, Russia
| | - David L. Valle
- Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States of America
| | | | - Emilia Shin
- Pediatric Liver Center, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, United States of America
| | - Kathleen B. Schwarz
- Pediatric Liver Center, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, United States of America
| | - Stephen J. O'Brien
- Theodosius Dobzhansky Center for Genome Bioinformatics, St. Petersburg State University, St. Petersburg, Russian Federation
- Guy Harvey Oceanographic Center, Halmos College of Natural Sciences and Oceanography, Nova Southeastern University, Fort Lauderdale, Florida, United States of America
- * E-mail: (DVZ); (SJO)
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25
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Christen U. Animal models of autoimmune hepatitis. Biochim Biophys Acta Mol Basis Dis 2018; 1865:970-981. [PMID: 29857050 DOI: 10.1016/j.bbadis.2018.05.017] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2018] [Revised: 05/14/2018] [Accepted: 05/22/2018] [Indexed: 02/06/2023]
Abstract
Many animal models for autoimmune hepatitis (AIH) have been described in the past. Most models had to deal with the relative immunosuppressive environment of the liver. Therefore, some models used a combination of several triggering factors often on a susceptible background to generate an aggressive immune response that targets the liver. In addition, in order to be able to track the immune response the models used specific model autoantigens as targets that are either not present or have not been identified as a natural autoantigen in AIH patients. Thereby the feasibility of such models is somewhat questionable. Although many historic approaches included challenges of experimental animals with liver homogenates it was only in the last decade that natural occurring liver autoantigens have been used in animal models. This article reflects on the requirements for breaking liver tolerance and on how an ideal experimental model for AIH would look like. In addition, it discusses historic as well as recent animal models in the context of feasibility of induction, similarity of the clinical outcome to human AIH, and gain of knowledge for possible future therapies.
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Affiliation(s)
- Urs Christen
- Pharmazentrum Frankfurt/ZAFES, Goethe University Hospital, Frankfurt am Main, Germany.
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26
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Mieli-Vergani G, Vergani D, Czaja AJ, Manns MP, Krawitt EL, Vierling JM, Lohse AW, Montano-Loza AJ. Autoimmune hepatitis. Nat Rev Dis Primers 2018; 4:18017. [PMID: 29644994 DOI: 10.1038/nrdp.2018.17] [Citation(s) in RCA: 272] [Impact Index Per Article: 38.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Autoimmune hepatitis (AIH) is a severe liver disease that affects children and adults worldwide. The diagnosis of AIH relies on increased serum transaminase and immunoglobulin G levels, presence of autoantibodies and interface hepatitis on liver histology. AIH arises in genetically predisposed individuals when a trigger, such as exposure to a virus, leads to a T cell-mediated autoimmune response directed against liver autoantigens; this immune response is permitted by inadequate regulatory immune control leading to a loss of tolerance. AIH responds favourably to immunosuppressive treatment, which should be started as soon as the diagnosis is made. Standard regimens include fairly high initial doses of corticosteroids (prednisone or prednisolone), which are tapered gradually as azathioprine is introduced. For those patients who do not respond to standard treatment, second-line drugs should be considered, including mycophenolate mofetil, calcineurin inhibitors, mechanistic target of rapamycin (mTOR) inhibitors and biologic agents, which should be administered only in specialized hepatology centres. Liver transplantation is a life-saving option for those who progress to end-stage liver disease, although AIH can recur or develop de novo after transplantation. In-depth investigation of immune pathways and analysis of changes to the intestinal microbiota should advance our knowledge of the pathogenesis of AIH and lead to novel, tailored and better tolerated therapies.
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Affiliation(s)
- Giorgina Mieli-Vergani
- Paediatric Liver, GI and Nutrition Centre, MowatLabs, King's College Hospital, Denmark Hill, SE5 9RS London, UK
| | - Diego Vergani
- Institute of Liver Studies, MowatLabs, King's College Hospital, Denmark Hill, SE5 9RS London, UK
| | - Albert J Czaja
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN, USA
| | - Michael P Manns
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.,Helmholtz Centre for Infection Research (HZI), Braunschweig, Germany
| | - Edward L Krawitt
- Department of Medicine, University of Vermont, Burlington, VT, USA.,Department of Medicine, Geisel School of Medicine at Dartmouth College, Hanover, NH, USA
| | - John M Vierling
- Division of Abdominal Transplantation and Section of Gastroenterology and Hepatology, Departments of Medicine and Surgery, Baylor College of Medicine, Houston, TX, USA
| | - Ansgar W Lohse
- Department of Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
| | - Aldo J Montano-Loza
- Division of Gastroenterology and Liver Unit, University of Alberta, Edmonton, Alberta, Canada
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27
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Díaz-Ramírez GS, Marín-Zuluaga JI, Donado-Gómez JH, Muñoz-Maya O, Santos-Sánchez Ó, Restrepo-Gutiérrez JC. Characterization of patients with autoimmune hepatitis at an university hospital in Medellín-Colombia: cohort study. GASTROENTEROLOGIA Y HEPATOLOGIA 2017; 41:87-96. [PMID: 29126693 DOI: 10.1016/j.gastrohep.2017.09.003] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/06/2017] [Revised: 08/17/2017] [Accepted: 09/15/2017] [Indexed: 12/16/2022]
Abstract
INTRODUCTION Autoimmune hepatitis is a chronic liver disease that impacts on morbidity and mortality of patients. Few epidemiological data exist of this in Latin America and Colombia. OBJECTIVES The aim of this study is to describe the demographic, clinical and laboratory characteristics of the patients; the treatment and the response to it, the evolution and course of the disease, requirement of liver transplantation and mortality. METHODS Historical cohort study that include patients attended at an University Hospital in Medellin, Colombia between January 2010 and December 2016 with ≥16 years age at the time of diagnosis of autoimmune hepatitis. Data collection was done from the review of medical records. Statistical analysis was performed using SPSS version 20. RESULTS The study included 278 patients, 90% of the patients were women, the median age at diagnosis was 50 years. 37.8% were cirrhotic at the time of diagnosis. The biochemical remission was 85%. In patients who developed cirrhosis it was found a higher proportion of men (21.2 vs. 7.8%, p=.027), a greater frequency of overlap autoimmune-primary sclerosant cholangitis (6.0 vs. 0% p=.006) and a greater frequency of non-response to treatment (12.1 vs. 1.6%, p=.004). CONCLUSION Autoimmune hepatitis is not a rare disease in Colombian population; it predominates in women but has a less favourable course in men. An important number of patients are cirrhotic at the time of diagnosis, the response to treatment and complications in our population are similar to those described worldwide.
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Affiliation(s)
| | - Juan Ignacio Marín-Zuluaga
- Grupo de Gastrohepatología, Universidad de Antioquia, Medellín, Colombia; Unidad de Hepatología y Trasplante Hepático, Hospital Pablo Tobón Uribe, Medellín, Colombia
| | | | - Octavio Muñoz-Maya
- Grupo de Gastrohepatología, Universidad de Antioquia, Medellín, Colombia; Unidad de Hepatología y Trasplante Hepático, Hospital Pablo Tobón Uribe, Medellín, Colombia
| | - Óscar Santos-Sánchez
- Grupo de Gastrohepatología, Universidad de Antioquia, Medellín, Colombia; Unidad de Hepatología y Trasplante Hepático, Hospital Pablo Tobón Uribe, Medellín, Colombia
| | - Juan Carlos Restrepo-Gutiérrez
- Grupo de Gastrohepatología, Universidad de Antioquia, Medellín, Colombia; Unidad de Hepatología y Trasplante Hepático, Hospital Pablo Tobón Uribe, Medellín, Colombia
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Abstract
Primary sclerosing cholangitis (PSC) is a chronic disease leading to fibrotic scarring of the intrahepatic and extrahepatic bile ducts, causing considerable morbidity and mortality via the development of cholestatic liver cirrhosis, concurrent IBD and a high risk of bile duct cancer. Expectations have been high that genetic studies would determine key factors in PSC pathogenesis to support the development of effective medical therapies. Through the application of genome-wide association studies, a large number of disease susceptibility genes have been identified. The overall genetic architecture of PSC shares features with both autoimmune diseases and IBD. Strong human leukocyte antigen gene associations, along with several susceptibility genes that are critically involved in T-cell function, support the involvement of adaptive immune responses in disease pathogenesis, and position PSC as an autoimmune disease. In this Review, we survey the developments that have led to these gene discoveries. We also elaborate relevant interpretations of individual gene findings in the context of established disease models in PSC, and propose relevant translational research efforts to pursue novel insights.
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Gidwaney NG, Pawa S, Das KM. Pathogenesis and clinical spectrum of primary sclerosing cholangitis. World J Gastroenterol 2017; 23:2459-2469. [PMID: 28465630 PMCID: PMC5394509 DOI: 10.3748/wjg.v23.i14.2459] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2016] [Revised: 01/21/2017] [Accepted: 03/20/2017] [Indexed: 02/06/2023] Open
Abstract
Primary sclerosing cholangitis (PSC) is a disease of the biliary tract, which has been documented in the literature since 1867. This disease has a strong predilection for affecting men and can be seen in individuals as young as 2 years of age. PSC has a strong associated with inflammatory bowel disease, more commonly with ulcerative colitis, and is also part of the clinical spectrum of IgG4-related diseases. Small-duct PSC, a variant of PSC, also has an association with inflammatory bowel disease. The exact pathogenesis of PSC is not well understood at present, however, is likely a combination of a genetic predisposition with alteration of the molecular structure of the gut. Abnormal serum liver chemistry and presence of certain autoimmune markers are usually the first indicators leading to a diagnosis of PCS, however, these may often be normal in early stages of this disease. The diagnosis is made by cholangiography, which is now considered the gold standard. PSC is a known pre-malignant condition. Such patients have an increased risk of developing cholangiocarcinoma, gallbladder neoplasia, and colon cancer. Many new treatment modalities have emerged in the recent past, including anti-tumor necrosis factor- α and anti-integrins; however, liver transplantation is the only known cure for PSC. Despite past and present research, PSC remains an enigmatic biliary disease with few viable treatment options.
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30
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Chascsa D, Carey EJ, Lindor KD. Old and new treatments for primary biliary cholangitis. Liver Int 2017; 37:490-499. [PMID: 28371104 DOI: 10.1111/liv.13294] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2016] [Accepted: 10/27/2016] [Indexed: 02/13/2023]
Abstract
Primary biliary cholangitis (formerly primary biliary cirrhosis) is a rare progressive cholestatic liver disease, whose hallmark features include a persistently elevated alkaline phosphatase level, presence of anti-mitochondrial antibodies and characteristic histology. Since 1998, ursodeoxycholic acid (UDCA), a bile acid, has been the only available therapeutic agent. Primary biliary cholangitis is associated with the development of end-stage liver disease, increased morbidity and mortality. UDCA has been shown to improve serum biochemistries, histology and delay the need for liver transplantation. The clinical issue is that approximately 25%-40% of patients do not respond to this standard therapy. In recent years, many trials have investigated alternative and adjunctive treatments, leading to the recent approval of obeticholic acid, an analogue of chenodeoxycholic acid, which has shown significant and sustained reductions in alkaline phosphatase levels in combination with UDCA. Obeticholic acid has rapidly been embraced as a new agent to improve the biochemical profile in refractory patients, in addition to being approved for use as monotherapy in patients who cannot tolerate UDCA. There are several other studies and targets which are being investigated. This review is intended to highlight the benefits of UDCA, educate the reader on the newly available obeticholic acid, and to summarize the many ongoing trials and therapeutic targets being investigated in attempts to control and cure primary biliary cholangitis.
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Affiliation(s)
- David Chascsa
- Division of Gastroenterology and Hepatology, Mayo Clinic, Phoenix, AZ, USA
| | - Elizabeth J Carey
- Division of Gastroenterology and Hepatology, Mayo Clinic, Phoenix, AZ, USA
| | - Keith D Lindor
- Division of Gastroenterology and Hepatology, Mayo Clinic, Phoenix, AZ, USA.,College of Health Solutions, Arizona State University, Phoenix, AZ, USA
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31
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Ylinen E, Salmela L, Peräsaari J, Jaatinen T, Tenca A, Vapalahti O, Färkkilä M, Jalanko H, Kolho K. Human leucocyte antigens B*08, DRB1*03 and DRB1*13 are significantly associated with autoimmune liver and biliary diseases in Finnish children. Acta Paediatr 2017; 106:322-326. [PMID: 27759901 DOI: 10.1111/apa.13641] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2016] [Revised: 09/05/2016] [Accepted: 10/17/2016] [Indexed: 12/13/2022]
Abstract
AIM The human leucocyte antigen (HLA) allele and haplotype frequencies of the Finnish population are unique because of the restricted and homogenous gene population. There are no published data on HLA genotype associations in paediatric autoimmune liver diseases in Scandinavia. This study characterised the HLA genotypes of children with autoimmune liver or biliary disease in Finland. METHODS The study cohort comprised 19 paediatric patients (13 female) aged three years to 15 years treated for autoimmune liver or biliary disease at the Children's Hospital, Helsinki University Hospital, between 2000 and 2011, and followed up for four years and three months to 14.6 years. We genotyped HLA-B and HLA-DRB1 in the children, and the HLA antigen frequencies were compared with 19 807 records from the Finnish Bone Marrow Donor Registry. RESULTS All paediatric patients with autoimmune liver or biliary disease had either autoimmune HLA haplotype B*08;DRB1*03 or DRB1*13. These were significantly more common among patients with autoimmune hepatitis, primary sclerosing cholangitis and autoimmune hepatitis/primary sclerosing cholangitis overlap syndrome than the Finnish control population. HLA RB1*04 was not found in the study cohort. CONCLUSION Our study found that B*08, DRB1*03 and DRB1*13 were significantly associated with autoimmune liver and biliary diseases in Finnish paediatric patients.
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Affiliation(s)
- E Ylinen
- Department of Paediatric Nephrology and Transplantation Children's Hospital University of Helsinki Helsinki University Hospital Helsinki Finland
- Department of Gastroenterology Children's Hospital University of Helsinki Helsinki University Hospital Helsinki Finland
| | - L Salmela
- Medical School University of Helsinki Helsinki Finland
| | - J Peräsaari
- Clinical Laboratory Finnish Red Cross Blood Service Helsinki Finland
| | - T Jaatinen
- Clinical Laboratory Finnish Red Cross Blood Service Helsinki Finland
| | - A Tenca
- Clinic of Gastroenterology University of Helsinki Helsinki University Hospital Helsinki Finland
| | - O Vapalahti
- Department of Virology and Immunology HUSLAB Hospital District of Helsinki and Uusimaa Helsinki Finland
| | - M Färkkilä
- Clinic of Gastroenterology University of Helsinki Helsinki University Hospital Helsinki Finland
| | - H Jalanko
- Department of Paediatric Nephrology and Transplantation Children's Hospital University of Helsinki Helsinki University Hospital Helsinki Finland
| | - K‐L Kolho
- Department of Gastroenterology Children's Hospital University of Helsinki Helsinki University Hospital Helsinki Finland
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32
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Liver immunology: How to reconcile tolerance with autoimmunity. Clin Res Hepatol Gastroenterol 2017; 41:6-16. [PMID: 27526967 DOI: 10.1016/j.clinre.2016.06.003] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2016] [Accepted: 06/01/2016] [Indexed: 02/04/2023]
Abstract
There are several examples of liver tolerance: the relative ease by which liver allografts are accepted and the exploitation of the hepatic microenvironment by the malarial parasite and hepatotrophic viruses are notable examples. The vasculature of the liver supports a unique population of antigen presenting cells specialised to maintain immunological tolerance despite continuous exposure to gut-derived antigens. Liver sinusoidal endothelial cells and Kupffer cells appear to be key to the maintenance of immune tolerance, by promoting T cell anergy or deletion and the generation of regulatory cell subsets. Despite this, there are three liver diseases with likely autoimmune involvement: primary biliary cirrhosis, primary sclerosing cholangitis and autoimmune hepatitis. How can we reconcile this with the inherent tolerogenicity of the liver? Genetic studies have uncovered several associations with genes involved in the activation of the innate and adaptive immune systems. There is also evidence pointing to pathogenic and xenobiotic triggers of autoimmune liver disease. Coupled to this, impaired immunoregulatory mechanisms potentially play a permissive role, allowing the autoimmune response to proceed.
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33
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Christen U, Hintermann E. Immunopathogenic Mechanisms of Autoimmune Hepatitis: How Much Do We Know from Animal Models? Int J Mol Sci 2016; 17:ijms17122007. [PMID: 27916939 PMCID: PMC5187807 DOI: 10.3390/ijms17122007] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2016] [Revised: 11/22/2016] [Accepted: 11/23/2016] [Indexed: 12/14/2022] Open
Abstract
Autoimmune hepatitis (AIH) is characterized by a progressive destruction of the liver parenchyma and a chronic fibrosis. The current treatment of autoimmune hepatitis is still largely dependent on the administration of corticosteroids and cytostatic drugs. For a long time the development of novel therapeutic strategies has been hampered by a lack of understanding the basic immunopathogenic mechanisms of AIH and the absence of valid animal models. However, in the past decade, knowledge from clinical observations in AIH patients and the development of innovative animal models have led to a situation where critical factors driving the disease have been identified and alternative treatments are being evaluated. Here we will review the insight on the immunopathogenesis of AIH as gained from clinical observation and from animal models.
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Affiliation(s)
- Urs Christen
- Pharmazentrum Frankfurt/ZAFES, Goethe University Hospital, Theodor-Stern Kai 7, 60590 Frankfurt am Main, Germany.
| | - Edith Hintermann
- Pharmazentrum Frankfurt/ZAFES, Goethe University Hospital, Theodor-Stern Kai 7, 60590 Frankfurt am Main, Germany.
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34
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Liberal R, Mieli-Vergani G, Vergani D. Autoimmune hepatitis: From mechanisms to therapy. Rev Clin Esp 2016. [DOI: 10.1016/j.rceng.2016.04.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
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35
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Liberal R, Mieli-Vergani G, Vergani D. Autoimmune hepatitis: From mechanisms to therapy. Rev Clin Esp 2016; 216:372-383. [PMID: 27161382 DOI: 10.1016/j.rce.2016.04.003] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2016] [Accepted: 04/02/2016] [Indexed: 12/13/2022]
Abstract
Autoimmune hepatitis (AIH) is a progressive inflammatory hepatopathy and an important cause of end-stage liver disease. Its aetiology remains unknown, though both genetic and environmental factors are involved in its development. The major mechanism of autoimmune liver damage involves immune reactions against host liver antigens. Numerical and functional defects of regulatory T-cells play a permissive role enabling autoimmune liver injury to occur and persist. The most typical features of AIH are female preponderance, hypergammaglobulinaemia, seropositivity for circulating autoantibodies and a picture of interface hepatitis on histology. Two types of AIH are distinguished according to serological profile: AIH type 1 patients are positive for anti-nuclear and/or anti-smooth muscle antibodies, whereas AIH type 2 patients are defined by the positivity for anti-liver kidney microsomal type 1 antibody and/or for anti-liver cytosol type 1 antibody. Clinical manifestations are variable, and AIH onset is often ill-defined, frequently mimicking acute hepatitis; its course may be fluctuating. AIH responds to immunosuppressive treatment in the majority of cases. Steroids with or without azathioprine should be instituted promptly upon diagnosis. Remission is achieved in some 80% of patients. For the remaining 20% of patients, alternative immunosuppressive agents such as mycophenolate mofetil and calcineurin inhibitors are an option. Liver transplantation should be considered for those patients who progress to cirrhosis and develop complications of end-stage liver disease, as well as for those presenting with acute liver failure; outcomes are excellent, although the disease may recur in the allograft.
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Affiliation(s)
- R Liberal
- Institute of Liver Studies, King's College London, Faculty of Life Sciences & Medicine, London, UK; Department of Gastroenterology, Centro Hospitalar São João and Faculty of Medicine, University of Porto, Porto, Portugal
| | - G Mieli-Vergani
- Institute of Liver Studies, King's College London, Faculty of Life Sciences & Medicine, London, UK; Paediatric Liver, GI & Nutrition Centre, King's College Hospital, London, UK
| | - D Vergani
- Institute of Liver Studies, King's College London, Faculty of Life Sciences & Medicine, London, UK.
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36
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Webb GJ, Hirschfield GM. Using GWAS to identify genetic predisposition in hepatic autoimmunity. J Autoimmun 2016; 66:25-39. [PMID: 26347073 DOI: 10.1016/j.jaut.2015.08.016] [Citation(s) in RCA: 82] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2015] [Accepted: 08/23/2015] [Indexed: 12/20/2022]
Abstract
Primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC) and autoimmune hepatitis (AIH) represent the three major hepatic autoimmune conditions. Patient morbidity and mortality remain high across these three diseases, and an unmet need for rational therapy exists. Disease understanding has focused on combining clinical and laboratory based science to provide better insights into the joint host and environmental factors necessary for the initiation, and perpetuation, of hepato-biliary inflammation. Twin studies, family studies, population studies and an inter-relationship with other autoimmune phenomena suggest a genetic component to risk for each disease. Until recently, understanding of this genetic risk has been limited to HLA haplotypes. Associations with risk-conferring and protective HLA haplotypes are present in all three diseases. Over the last few years, genome-wide association studies (GWAS), and related genetic association studies, have greatly increased understanding of the genetic risk signature of these three diseases and autoimmunity in general. Here we consider the rationale for GWAS in general and with specific reference to hepatic autoimmunity. We consider the process of GWAS, and highlight major findings to date. Potential functional implications of key findings are discussed including the IL-12/STAT4 pathway in PBC and the CD28/IL-2 pathway in PSC. We describe the marked pleiotropy demonstrated by PBC and PSC, which is consistent with other autoimmune diseases. Further, we focus on specific gene associations including SH2B3, which is common to all three diseases, and FUT2 in PSC, which represents a link between environment and genetics. We review attempts to translate GWAS findings into basic laboratory models including in vivo systems and highlight where clinical observations relate to genetics. Finally we describe deficiencies in GWAS to date and consider future study of genetics in hepatic autoimmunity.
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Affiliation(s)
- G J Webb
- NIHR Birmingham Liver Biomedical Research Unit, University of Birmingham, Birmingham, UK
| | - G M Hirschfield
- NIHR Birmingham Liver Biomedical Research Unit, University of Birmingham, Birmingham, UK.
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37
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Genetic factors affect the etiology, clinical characteristics and outcome of autoimmune hepatitis. Clin J Gastroenterol 2015; 8:360-6. [DOI: 10.1007/s12328-015-0620-9] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2015] [Accepted: 11/19/2015] [Indexed: 02/06/2023]
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38
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Wu Z, Qin W, Zeng J, Huang C, Lu Y, Li S. Association Between IL-4 Polymorphisms and Risk of Liver Disease: An Updated Meta-Analysis. Medicine (Baltimore) 2015; 94:e1435. [PMID: 26334904 PMCID: PMC4616498 DOI: 10.1097/md.0000000000001435] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Interleukin-4 (IL-4) polymorphisms have been reported to influence an individual's susceptibility to liver disease as it is a central anti-inflammatory Th2 cytokine; however, these results remain controversial.A comprehensive meta-analysis of the relevant literature was thus performed to better estimate the relationship between IL-4 polymorphisms and liver disease.Systematic searches of various databases (PubMed, Embase, Cochrane Library, and China National Knowledge Infrastructure) for studies published before July 5, 2015 were performed. Odds ratios (ORs) with 95% confidence intervals (CIs) calculated in fixed or random-effects models were used to estimate the strength of the association. Subgroup analyses, meta-regression, Galbraith plots, and sensitivity analyses were also performed.A total of 16 case-control studies, of which 15 involved the -590C/T polymorphism and 3 involved the -33T/C polymorphism, were included in the study. With respect to the -590C/T polymorphism, a significantly increased risk of liver diseases was found in the overall population (TT + CT vs CC: OR = 1.25, 95% CI = 1.06-1.49, P = 0.009 and CT vs CC: OR = 1.22, 95% CI = 1.00-1.48, P = 0.048) and the Asian population (TT + CT vs CC: OR = 1.28, 95% CI = 1.04-1.57, P = 0.020). Further subgroup analyses also showed significant associations between the -590C > T polymorphism and the risk of hepatitis C infection and hepatocellular carcinoma. However, no association was found between the -33T/C polymorphism and risk of liver diseases in all comparison models.This meta-analysis suggested that the IL-4 -590C > T polymorphism is associated with an increased risk of hepatitis C infection and hepatocellular carcinoma, especially among the Asian population.
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Affiliation(s)
- Zhitong Wu
- From the Department of Clinical Laboratory, Guigang People's Hospital, Guigang, Guangxi, China (ZW, WQ); Department of Clinical Laboratory, Liuzhou City People's Hospital, Liuzhou, Guangxi, China (JZ); and Department of Clinical Laboratory, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China (CH, YL, SL)
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Abstract
Autoimmune hepatitis (AIH) is a complex multifactorial liver disease with unknown etiology. It may be induced by certain triggers that cause immune disorders and autoimmune attack in genetically susceptible individuals, which ultimately results in chronic persistent interface inflammation of the liver. The diagnosis of AIH is made based on comprehensive evaluation score system. All AIH patients should receive interventions and the mainstay therapy is prednisone alone or in combination with azathioprine. Further exploratory researches on refractory AIH have been developed. Liver transplantation is still the only effective option for patients with decompensated cirrhosis or hepatic failure.
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Affiliation(s)
- Jiang Yi Zhu
- Department of Gastroenterology, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi Province, China
| | - Ying Han
- Department of Gastroenterology, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi Province, China
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40
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Aguilar-Nájera O, Velasco-Zamora JA, Torre A. Overlap syndromes of autoimmune hepatitis: diagnosis and treatment. REVISTA DE GASTROENTEROLOGÍA DE MÉXICO 2015; 80:150-9. [PMID: 26091564 DOI: 10.1016/j.rgmx.2015.04.001] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/17/2015] [Revised: 04/21/2015] [Accepted: 04/23/2015] [Indexed: 12/17/2022]
Abstract
Some patients with autoimmune liver disease have characteristics of cholestasis, as well as of autoimmune hepatitis. Despite the fact that this is a relatively frequent clinical condition seen in referral centers for liver diseases, there is little evidence as regards the clinical management of these syndromes due to their low prevalence and the lack of standardized definitions and diagnostic criteria. This is relevant, given that published studies report that there is a lower therapeutic response and poorer outcome in patients with overlap syndrome than in those presenting solely with autoimmune hepatitis. Whether overlap syndromes are distinct entities or the presence of 2 concurrent diseases is still a subject of debate. They should be suspected in autoimmune hepatitis patients that present with signs of cholestasis, as it is known that overlap behavior tends to be more aggressive, with higher rates of cirrhosis and the need for liver transplantation. Treatment response is also poorer and should be directed at the predominant component. Standardized definitions are necessary so that these syndromes can be studied in controlled clinical trials.
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Affiliation(s)
- O Aguilar-Nájera
- Departamento de Gastroenterología, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, México, D.F., México
| | - J A Velasco-Zamora
- Departamento de Gastroenterología, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, México, D.F., México
| | - A Torre
- Departamento de Gastroenterología, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, México, D.F., México.
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Manns MP, Lohse AW, Vergani D. Autoimmune hepatitis--Update 2015. J Hepatol 2015; 62:S100-11. [PMID: 25920079 DOI: 10.1016/j.jhep.2015.03.005] [Citation(s) in RCA: 245] [Impact Index Per Article: 24.5] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2015] [Revised: 03/03/2015] [Accepted: 03/04/2015] [Indexed: 12/17/2022]
Affiliation(s)
| | | | - Diego Vergani
- Institute of Liver Studies, King's College Hospital, London, United Kingdom
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Overlap syndromes of autoimmune hepatitis: diagnosis and treatment. REVISTA DE GASTROENTEROLOGÍA DE MÉXICO (ENGLISH EDITION) 2015. [DOI: 10.1016/j.rgmxen.2015.07.001] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/23/2023] Open
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Alexandropoulos K, Bonito AJ, Weinstein EG, Herbin O. Medullary thymic epithelial cells and central tolerance in autoimmune hepatitis development: novel perspective from a new mouse model. Int J Mol Sci 2015; 16:1980-2000. [PMID: 25603179 PMCID: PMC4307344 DOI: 10.3390/ijms16011980] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2014] [Accepted: 01/07/2015] [Indexed: 02/07/2023] Open
Abstract
Autoimmune hepatitis (AIH) is an immune-mediated disorder that affects the liver parenchyma. Diagnosis usually occurs at the later stages of the disease, complicating efforts towards understanding the causes of disease development. While animal models are useful for studying the etiology of autoimmune disorders, most of the existing animal models of AIH do not recapitulate the chronic course of the human condition. In addition, approaches to mimic AIH-associated liver inflammation have instead led to liver tolerance, consistent with the high tolerogenic capacity of the liver. Recently, we described a new mouse model that exhibited spontaneous and chronic liver inflammation that recapitulated the known histopathological and immunological parameters of AIH. The approach involved liver-extrinsic genetic engineering that interfered with the induction of T-cell tolerance in the thymus, the very process thought to inhibit AIH induction by liver-specific expression of exogenous antigens. The mutation led to depletion of specialized thymic epithelial cells that present self-antigens and eliminate autoreactive T-cells before they exit the thymus. Based on our findings, which are summarized below, we believe that this mouse model represents a relevant experimental tool towards elucidating the cellular and molecular aspects of AIH development and developing novel therapeutic strategies for treating this disease.
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Affiliation(s)
- Konstantina Alexandropoulos
- Department of Medicine and Clinical Immunology, the Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1089, New York, NY 10029, USA.
| | - Anthony J Bonito
- Department of Medicine and Clinical Immunology, the Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1089, New York, NY 10029, USA.
| | - Erica G Weinstein
- Department of Medicine and Clinical Immunology, the Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1089, New York, NY 10029, USA
| | - Olivier Herbin
- Department of Medicine and Clinical Immunology, the Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1089, New York, NY 10029, USA.
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Mechanisms of tissue injury in autoimmune liver diseases. Semin Immunopathol 2014; 36:553-68. [PMID: 25082647 DOI: 10.1007/s00281-014-0439-3] [Citation(s) in RCA: 55] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2014] [Accepted: 06/24/2014] [Indexed: 02/06/2023]
Abstract
Autoimmune diseases affecting the liver are mainly represented by autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC). The characteristic morphologic patterns of injury are a chronic hepatitis pattern of damage in AIH, destruction of small intrahepatic bile ducts in PBC and periductal fibrosis and inflammation involving larger bile ducts in PSC. The factors responsible for initiation and perpetuation of the injury in all the three autoimmune liver diseases are not understood completely but are likely to be environmental triggers on the background of genetic variation in immune regulation. In this review, we summarise the current understanding of the mechanisms underlying the breakdown of self-tolerance in autoimmune liver diseases.
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The association between Cytotoxic T lymphocyte associated antigen-4, Fas, tumour necrosis factor-α gene polymorphisms and autoimmune hepatitis: a meta-analysis. Dig Liver Dis 2014; 46:541-8. [PMID: 24629822 DOI: 10.1016/j.dld.2014.02.003] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2013] [Revised: 01/27/2014] [Accepted: 02/06/2014] [Indexed: 12/11/2022]
Abstract
BACKGROUND Several previous studies have assessed the association of Cytotoxic T Lymphocyte Associated Antigen-4, Fas, and Tumour Necrosis Factor-α gene polymorphisms with autoimmune hepatitis risk, but the results were inconsistent and inconclusive. We performed a meta-analysis to better evaluate these associations. METHODS PubMed, EMBASE and MEDLINE were searched in all languages. Overall odd ratios with 95% confidence intervals were calculated to assess the strength of associations using a fixed-effects or random-effects models. RESULTS 15 relevant studies were identified. No significant association was found between CTLA-4+49A/G and AH. TNF-α-308A/G was significantly associated with autoimmune hepatitis risk. Individuals with the "A" allele had a 67% increased risk of autoimmune hepatitis (odds ratio=1.67, 95% confidence interval 1.11-2.52). The genotype "AA" was a potential predisposing factor for autoimmune hepatitis, when compared with the genotype "GG" and "AG+GG" (odds ratio=2.71, 95% confidence interval 1.12-6.57; odds ratio=2.14, 95% confidence interval 1.30-3.52). Besides, no significant association was found between the Fas-670G/A and TNF-α-238A/G polymorphisms and autoimmune hepatitis risk using any model. CONCLUSION The meta-analysis identified the TNF-α-308 "A" allele as a predisposing factor for autoimmune hepatitis, whereas the genotype "GG" was a protective factor. This study did not find a significant association between CTLA-4+49A/G, Fas-670G/A, TNF-α-238A/G and susceptibility to autoimmune hepatitis.
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Samuel B, Fioravanti G, Polimera H, Mayer A, Dorville F, Little E. Autoimmune hepatitis in a 20-year-old African American man. Lab Med 2014; 45:161-71. [PMID: 24868999 DOI: 10.1309/lmag0di6ee4nycyn] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022] Open
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Tsaitas C, Semertzidou A, Sinakos E. Update on inflammatory bowel disease in patients with primary sclerosing cholangitis. World J Hepatol 2014; 6:178-187. [PMID: 24799986 PMCID: PMC4009473 DOI: 10.4254/wjh.v6.i4.178] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2013] [Revised: 03/05/2014] [Accepted: 03/13/2014] [Indexed: 02/06/2023] Open
Abstract
Patients with primary sclerosing cholangitis (PSC) complicated by inflammatory bowel disease (IBD) represent a distinct subset of patients with unique characteristics, which have serious clinical implications. The aim of this literature review was to shed light to the obscure clinical and molecular aspects of the two diseases combined utilizing current data available and putting issues of diagnosis and treatment into perspective. The prevalence of IBD, mainly ulcerative colitis in PSC patients is estimated to be 21%-80%, dependent on screening programs and nationality. PSC-associated colitis is likely to be extensive, characterized by rectal sparing, backwash ileitis, and generally mild symptoms. It is also more likely to progress to colorectal malignancy, making it imperative for clinicians to maintain a high level of suspicion when tackling PSC patients. There is no optimal surveillance strategy but current guidelines advocate that colonoscopy is necessary at the time of PSC diagnosis with annual endoscopic follow-up. Random biopsies have been criticized and a shift towards targeted biopsies using chromoendoscopy, laser endomicroscopy and narrow-band imaging has been noted. Techniques directed towards genetic mutations instead of histological abnormalities hold promise for easier, more accurate diagnosis of dysplastic lesions. Chemopreventive measures against colorectal cancer have been sought in these patients. Ursodeoxycholic acid seemed promising at first but subsequent studies yielded conflicting results showing anticarcinogenic effects in low doses (8-15 mg/kg per day) and carcinogenic properties in high doses (15-30 mg/kg per day).
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Affiliation(s)
- Christos Tsaitas
- Christos Tsaitas, Anysia Semertzidou, Emmanouil Sinakos, 4 Internal Medicine Unit, University Hospital of Thessaloniki, Thessaloniki 54642, Greece
| | - Anysia Semertzidou
- Christos Tsaitas, Anysia Semertzidou, Emmanouil Sinakos, 4 Internal Medicine Unit, University Hospital of Thessaloniki, Thessaloniki 54642, Greece
| | - Emmanouil Sinakos
- Christos Tsaitas, Anysia Semertzidou, Emmanouil Sinakos, 4 Internal Medicine Unit, University Hospital of Thessaloniki, Thessaloniki 54642, Greece
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Zhao DT, Liao HY, Zhang X, Liu YM, Zhao Y, Zhang HP, Sun LM, Ma YX, Yan HP. Human leucocyte antigen alleles and haplotypes and their associations with antinuclear antibodies features in Chinese patients with primary biliary cirrhosis. Liver Int 2014; 34:220-6. [PMID: 23809616 DOI: 10.1111/liv.12236] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2012] [Accepted: 05/28/2013] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS Primary biliary cirrhosis (PBC) is an autoimmune liver disease. Genetic factors are critical in determining susceptibility to PBC. Among human leuocyte antigen (HLA) genes, an association between the DRB1*08 allele and PBC has been reported in many populations, but not in Chinese patients. METHODS We investigated HLA-A, B, DRB1, and DQB1 alleles and haplotypes in 145 PBC patients and 500 healthy subjects. Patients were also stratified according to autoantibody features, and associations between these and HLA alleles were analyzed. RESULTS Significant associations existed between HLA-DRB1*08:03 (22.1% vs. 9.0%, Pc < 0.0001, OR = 2.86), DQ2 (41.4% vs. 25.4%, Pc < 0.0001, OR = 2.07) and DQB1*06:01 (31.0% vs. 17.8%, Pc = 0.014, OR = 2.08) alleles and PBC. DRB1*08:03-DQB1*06:01 (22.1% vs. 8.2%, P < 0.0001, OR = 3.17) and DRB1*07:01-DQB1*02:02 haplotypes (28.3% vs. 17.6%, P = 0.005, OR = 1.85) were also associated with PBC susceptibility. In contrast, the DQB1*03:01 allele (21.4% vs. 39.2%, Pc < 0.0001, OR = 0.42) and DRB1*12:02-DQB1*03:01 haplotype (6.9% vs. 14.6%, P = 0.015, OR = 0.43) were significantly decreased in PBC patients compared with controls. DRB1*14:54 and DQ5(1) protected against antinuclear antibody (ANA) (OR = 0.25) and anti-gp210 antibody (OR = 0.39) production, respectively, while HLA-B*44:03 predisposed patients to anti-gp210 antibody (OR = 5.70) production. CONCLUSION These results suggest that Chinese patients with PBC have a distinct genetic background in eastern Asia, and we confirmed the role of HLA genes in determining PBC susceptibility and autoantibody features in the Chinese population.
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Affiliation(s)
- Dan-Tong Zhao
- Clinical Research Center for Autoimmune Liver Disease, Beijing You'an Hospital, Capital Medical University, Beijing, China
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Abstract
We recently introduced the concept of the infectome as a means of studying all infectious factors which contribute to the development of autoimmune disease. It forms the infectious part of the exposome, which collates all environmental factors contributing to the development of disease and studies the sum total of burden which leads to the loss of adaptive mechanisms in the body. These studies complement genome-wide association studies, which establish the genetic predisposition to disease. The infectome is a component which spans the whole life and may begin at the earliest stages right up to the time when the first symptoms manifest, and may thus contribute to the understanding of the pathogenesis of autoimmunity at the prodromal/asymptomatic stages. We provide practical examples and research tools as to how we can investigate disease-specific infectomes, using laboratory approaches employed from projects studying the “immunome” and “microbiome”. It is envisioned that an understanding of the infectome and the environmental factors that affect it will allow for earlier patient-specific intervention by clinicians, through the possible treatment of infectious agents as well as other compounding factors, and hence slowing or preventing disease development.
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Pár A, Pár G, Tornai I, Szalay F, Várszegi D, Fráter E, Papp M, Lengyel G, Fehér J, Varga M, Gervain J, Schuller J, Nemes Z, Péterfi Z, Tusnádi A, Hunyady B, Haragh A, Szinku Z, Vincze Á, Szereday L, Kisfali P, Melegh B. IL28B and IL10R -1087 polymorphisms are protective for chronic genotype 1 HCV infection and predictors of response to interferon-based therapy in an East-Central European cohort. BMC Res Notes 2014; 7:12. [PMID: 24398031 PMCID: PMC3896726 DOI: 10.1186/1756-0500-7-12] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2013] [Accepted: 01/03/2014] [Indexed: 01/23/2023] Open
Abstract
BACKGROUND Previous studies have shown that single nucleotide polymorphisms (SNP) in IL28B and IL10R are associated with sustained virological response (SVR) in chronic hepatitis C patients treated with pegilated interferon plus ribavirin (P/R). The present study extends our earlier investigations on a large East-Central European cohort. The allele frequencies of IL28B and IL10R in genotype 1 HCV infection were compared with that of healthy controls for the purpose of examining the relationship between the polymorphisms and the SVR to P/R treatment. METHODS A total of 748 chronic HCV1 infected patients (365 male, 383 female; 18-82 years) and 105 voluntary blood donors as controls were enrolled. Four hundred and twenty HCV patients were treated with P/R for 24-72 weeks, out of them 195 (46.4%) achieved SVR. The IL28 rs12979860 SNP was determined using Custom Taqman SNP Genotyping Assays. The IL10R -1087 (also known as IL10R -1082 (rs1800896) promoter region SNP was determined by RT-PCR and restriction fragment length polymorphism analysis. RESULTS The IL28B CC genotype occurred with lower frequency in HCV patients than in controls (26.1% vs 51.4%, p<0.001). P/R treated patients with the IL28B CC genotype achieved higher SVR rate, as compared to patients with CT (58.6% vs 40.8%, p=0.002). The prevalence of IL10R -1087 GG genotype was lower in patients than in controls (31.8 % vs 52.2%, p<0.001). Among patients achieving SVR, the IL10R -1087 GG genotype occurred with higher frequency than the AA (32.0% vs 17.4%, p=0.013). The IL28B T allele plus IL10R A allele combination was found with higher prevalence in patients than in controls (52% vs 20.7%, p<0.001). The IL28B CC plus IL10R A allele combination occurred with higher frequency among patients with SVR than in non-responders (21.3% vs 12.8%, p=0.026). Both the IL28B CC plus IL10R GG and the IL28B CC plus IL10R A allele combinations occurred with lower frequency in patients than in controls. CONCLUSIONS In our HCV1 patients, both the IL28B CC and IL10R GG genotypes are associated with clearance of HCV. Moreover, distinct IL28B and IL10R allele combinations appear to be protective against chronic HCV1 infection and predictors of response to P/R therapy.
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MESH Headings
- Adolescent
- Adult
- Aged
- Aged, 80 and over
- Antiviral Agents/therapeutic use
- Drug Resistance, Multiple, Viral
- Drug Therapy, Combination
- Female
- Gene Frequency
- Genotype
- Hepacivirus/drug effects
- Hepacivirus/genetics
- Hepatitis C, Chronic/drug therapy
- Hepatitis C, Chronic/epidemiology
- Hepatitis C, Chronic/genetics
- Hepatitis C, Chronic/prevention & control
- Humans
- Hungary
- Interferon alpha-2
- Interferon-alpha/therapeutic use
- Interferons
- Interleukins/genetics
- Male
- Middle Aged
- Patient Selection
- Polyethylene Glycols/therapeutic use
- Polymorphism, Single Nucleotide
- Promoter Regions, Genetic/genetics
- Receptors, Interleukin-10/genetics
- Recombinant Proteins/therapeutic use
- Ribavirin/therapeutic use
- Treatment Outcome
- Young Adult
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Affiliation(s)
- Alajos Pár
- First Department of Medicine, University of Pécs, Rákóczi u. 2, 7623 Pécs, Hungary
| | - Gabriella Pár
- First Department of Medicine, University of Pécs, Rákóczi u. 2, 7623 Pécs, Hungary
| | - István Tornai
- Second Department of Medicine, University of Debrecen, 4012 Debrecen, Hungary
| | - Ferenc Szalay
- First Department of Medicine, Semmelweis University, 1082 Budapest, Hungary
| | - Dalma Várszegi
- Department of Dermatology, University of Pécs, 7627 Pécs, Hungary
| | - Edit Fráter
- Second Department of Medicine, University of Debrecen, 4012 Debrecen, Hungary
| | - Mária Papp
- Second Department of Medicine, University of Debrecen, 4012 Debrecen, Hungary
| | - Gabriella Lengyel
- Second Department of Medicine, Semmelweis University, 1088 Budapest, Hungary
| | - János Fehér
- Second Department of Medicine, Semmelweis University, 1088 Budapest, Hungary
| | - Márta Varga
- Réthy Pál Hospital, 5600 Békéscsaba, Hungary
| | | | - János Schuller
- United Szent István and Szent László Hospital, 1097 Budapest, Hungary
| | - Zsuzsanna Nemes
- First Department of Medicine, University of Pécs, Rákóczi u. 2, 7623 Pécs, Hungary
| | - Zoltán Péterfi
- First Department of Medicine, University of Pécs, Rákóczi u. 2, 7623 Pécs, Hungary
| | | | - Béla Hunyady
- First Department of Medicine, University of Pécs, Rákóczi u. 2, 7623 Pécs, Hungary
| | - Attila Haragh
- Kaposi Mór Teaching Hospital, 7400 Kaposvár, Hungary
| | - Zsolt Szinku
- Kaposi Mór Teaching Hospital, 7400 Kaposvár, Hungary
| | - Áron Vincze
- First Department of Medicine, University of Pécs, Rákóczi u. 2, 7623 Pécs, Hungary
| | - László Szereday
- Department of Medical Microbiology and Immunology, University of Pécs, 7624 Pécs, Hungary
| | - Péter Kisfali
- Department of Medical Genetics, University of Pécs, 7624 Pécs, Hungary
| | - Béla Melegh
- Department of Medical Genetics, University of Pécs, 7624 Pécs, Hungary
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