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Rahim MN, Miquel R, Heneghan MA. Approach to the patient with acute severe autoimmune hepatitis. JHEP Rep 2020; 2:100149. [PMID: 32995712 PMCID: PMC7509236 DOI: 10.1016/j.jhepr.2020.100149] [Citation(s) in RCA: 49] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2020] [Revised: 07/09/2020] [Accepted: 07/15/2020] [Indexed: 12/11/2022] Open
Abstract
Autoimmune hepatitis is associated with varied clinical presentations and natural history, as well as somewhat unpredictable treatment responses. Understanding how to stratify patients who require further escalation of therapy will help clinicians manage these patients. The presentation of acute severe autoimmune hepatitis (AS-AIH) is relatively uncommon, although its prevalence is potentially greater than currently perceived. Previous studies consist of small retrospective single-centre series and are not directly comparable due to the diversity of presentations, disease definitions and non-standardised treatment regimens. We define AS-AIH as those who present acutely with AIH and are icteric with an international normalised ratio ≥1.5 and no evidence of hepatic encephalopathy. Those with hepatic encephalopathy should be defined as having AS-AIH with acute liver failure. In this review, we provide a structured practical approach for diagnosing and managing this unique group of patients.
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Key Words
- ACLF, acute-on-chronic liver failure
- AIH, autoimmune hepatitis
- ALF, acute liver failure
- ALI, acute liver injury
- ALT, alanine aminotransferase
- ANA, anti-nuclear antibody
- AS-AIH, acute severe autoimmune hepatitis
- ASMA, anti-smooth muscle antibody
- AST, aspartate aminotransferase
- AUROC, analysis of area under the receiver operator characteristic curve
- Acute liver failure
- Acute severe presentation
- Autoimmune hepatitis
- CT, computed tomography
- Corticosteroids
- DILI, drug-induced liver injury
- EBV, Epstein-Barr virus
- HE, hepatic encephalopathy
- HLA, human leukocyte antigen
- IAIHG, International Autoimmune Hepatitis Group
- INR, international normalised ratio
- LT, liver transplantation
- Liver transplantation
- MELD, model for end-stage liver disease
- MELD-Na, model for end-stage liver disease-sodium
- MHN, massive hepatic necrosis
- NAC, N-acetylcysteine
- PT, prothrombin time
- UKELD, United Kingdom end-stage liver disease
- USALF, United States Acute Liver Failure
- anti-LC-1, anti-liver cytosol-1
- anti-LKM, anti-liver kidney microsomal
- anti-SLA/LP, anti-soluble liver antigen/liver pancreas
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Affiliation(s)
- Mussarat N. Rahim
- Institute of Liver Studies, King's College Hospital, London, SE5 9RS, UK
| | - Rosa Miquel
- Liver Histopathology Laboratory, King's College Hospital, London, SE5 9RS, UK
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Czaja AJ. Examining pathogenic concepts of autoimmune hepatitis for cues to future investigations and interventions. World J Gastroenterol 2019; 25:6579-6606. [PMID: 31832000 PMCID: PMC6906207 DOI: 10.3748/wjg.v25.i45.6579] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2019] [Revised: 11/25/2019] [Accepted: 11/29/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Multiple pathogenic mechanisms have been implicated in autoimmune hepatitis, but they have not fully explained susceptibility, triggering events, and maintenance or escalation of the disease. Furthermore, they have not identified a critical defect that can be targeted. The goals of this review are to examine the diverse pathogenic mechanisms that have been considered in autoimmune hepatitis, indicate investigational opportunities to validate their contribution, and suggest interventions that might evolve to modify their impact. English abstracts were identified in PubMed by multiple search terms. Full length articles were selected for review, and secondary and tertiary bibliographies were developed. Genetic and epigenetic factors can affect susceptibility by influencing the expression of immune regulatory genes. Thymic dysfunction, possibly related to deficient production of programmed cell death protein-1, can allow autoreactive T cells to escape deletion, and alterations in the intestinal microbiome may help overcome immune tolerance and affect gender bias. Environmental factors may trigger the disease or induce epigenetic changes in gene function. Molecular mimicry, epitope spread, bystander activation, neo-antigen production, lymphocytic polyspecificity, and disturbances in immune inhibitory mechanisms may maintain or escalate the disease. Interventions that modify epigenetic effects on gene expression, alter intestinal dysbiosis, eliminate deleterious environmental factors, and target critical pathogenic mechanisms are therapeutic possibilities that might reduce risk, individualize management, and improve outcome. In conclusion, diverse pathogenic mechanisms have been implicated in autoimmune hepatitis, and they may identify a critical factor or sequence that can be validated and used to direct future management and preventive strategies.
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Affiliation(s)
- Albert J Czaja
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, MN 55905, United States
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3
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Eder M, Strassl R, Beinhardt S, Stättermayer AF, Kozbial K, Lagler H, Holzmann H, Trauner M, Hofer H. High seroprevalence of anti-Hepatitis E antibodies in Austrian patients with autoimmune hepatitis. Liver Int 2019; 39:640-645. [PMID: 30431228 DOI: 10.1111/liv.14005] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2018] [Revised: 10/29/2018] [Accepted: 11/01/2018] [Indexed: 12/17/2022]
Abstract
BACKGROUND & AIMS Increasing numbers of autochthonous hepatitis E virus infections have been reported in Europe. Chronic infections have been shown in immune-compromised patients after solid organ transplantation. Hepatitis E virus might be a possible trigger for autoimmune hepatitis and might cause disease flares or relapses in the further course of disease. Aim of this study was to investigate the presence of hepatitis E virus antibodies and hepatitis E virus RNA, and to analyse their impact on immunosuppressive treatment in patients with autoimmune hepatitis. METHODS Sera from 92 autoimmune hepatitis patients (73/79.3% female, age: 42.2 ± 16.3 years [mean ± SD]) were tested. Patients were scored according to the simplified and revised scoring systems of the International Autoimmune Hepatitis Group. The prevalence of anti- hepatitis E virus antibodies (Beijing Wantai Biological Pharmacy Enterprises Co., Ltd, Beijing, China) and hepatitis E virus RNA was determined. RESULTS 19/20.7% autoimmune hepatitis patients tested positive for hepatitis E virus-IgG, which was higher than in previous reports of healthy Austrian individuals (12.4%, P = 0.031); hepatitis E virus RNA was not detectable in any patient. Anti-hepatitis E virus positive patients were older (49.5 ± 9.5 vs 40.4 ± 17.2 years [mean ± SD], P = 0.033) but did not differ in laboratory findings at diagnosis (AST: 14.6 [1.3-70.6] vs 9.5 [0.7-62.7] × ULN [median/range]; P = 0.387, alanine aminotransferase: 18.3 [1.6-62.7] vs. 12.9 [0.8-62.6] × ULN; P = 0.511; IgG: 1.4 [1.0-2.5] vs 1.3 [0.6-3.8] g/dL × ULN; P = 0.278) nor in alanine aminotransferase levels after six months (0.7 [0.5-2.4] vs 1.0 U/L × ULN [0.1-22.4]; P = 0.077). CONCLUSIONS No chronic hepatitis E virus infection was observed in our cohort of autoimmune hepatitis patients. Anti- hepatitis E virus-IgG positive patients were older and the seroprevalence was nearly twice as high as reported previously in healthy Austrian individuals, suggesting that hepatitis E virus-infection might act as trigger for the development of autoimmune hepatitis.
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Affiliation(s)
- Michael Eder
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria.,Division of Nephrology and Dialysis, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Robert Strassl
- Division of Nephrology and Dialysis, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria.,Division of Clinical Virology, Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria
| | - Sandra Beinhardt
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria.,Medizinische Abteilung - Gastroenterologie und Hepatologie, Universitätsklinikum St. Pölten, St. Pölten, Austria
| | - Albert Friedrich Stättermayer
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Karin Kozbial
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Heimo Lagler
- Division of Infectious Diseases and Tropical Medicine, Department of Medicine I, Medical University of Vienna, Vienna, Austria
| | | | - Michael Trauner
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Harald Hofer
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria.,Department of Internal Medicine I, Klinikum Wels-Grieskirchen, Wels, Austria
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4
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Brankin B, Osman M, Herlihy L, Hawkins S, Cosby S. Failure to Detect Measles Virus Rna, by Reverse Transcription-Polymerase Chain Reaction, in Peripheral Blood Leucocytes of Patients with Multiple Sclerosis. Mult Scler 2018. [DOI: 10.1177/135245859600100403] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
We have examined peripheral blood leucocytes (PBLs) from 17 multiple sclerosis patients, two patients with rheumatoid arthritis, one case of acute childhood measles and one case of subacute sclerosing panencephalitis, as well as 19 healthy adult controls for measles virus (MV) RNA, by the technique of reverse transcription-polymerase chain reaction. MV nucleocapsid gene specific primers were used to amplify all PBL-derived cDNA samples. These proved to be negative with the exception of the sample derived from the acute measles case. Selected cases were examined further, using fusion gene and matrix gene specific primers. MV RNA could not be detected.
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Affiliation(s)
- B. Brankin
- Division of Molecular Biology, School of Biology and Biochemistry, Medical Biology Centre, The Queen's University of Belfast, 97 Lisburn Road, Belfast BT9 7BL
| | - M. Osman
- Division of Molecular Biology, School of Biology and Biochemistry, Medical Biology Centre, The Queen's University of Belfast, 97 Lisburn Road, Belfast BT9 7BL
| | - L. Herlihy
- Division of Molecular Biology, School of Biology and Biochemistry, Medical Biology Centre, The Queen's University of Belfast, 97 Lisburn Road, Belfast BT9 7BL
| | - S.A. Hawkins
- Department of Neurology, Royal Victoria Hospital, Grosvenor Road, Belfast BT12 6BL, UK
| | - S.L. Cosby
- Division of Molecular Biology, School of Biology and Biochemistry, Medical Biology Centre, The Queen's University of Belfast, 97 Lisburn Road, Belfast BT9 7BL
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5
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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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6
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Liver Disease Associated With Systemic Viral Infection. ZAKIM AND BOYER'S HEPATOLOGY 2018. [PMCID: PMC7099665 DOI: 10.1016/b978-0-323-37591-7.00038-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
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Sahebjam F, Hajdu CH, Nortey E, Sigal SH. Direct acting antiviral therapy is curative for chronic hepatitis C/autoimmune hepatitis overlap syndrome. World J Hepatol 2016; 8:632-636. [PMID: 27190580 PMCID: PMC4867421 DOI: 10.4254/wjh.v8.i14.632] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2015] [Revised: 02/18/2016] [Accepted: 03/14/2016] [Indexed: 02/06/2023] Open
Abstract
Autoimmune phenomena are common in patients with chronic hepatitis C. Management of chronic hepatitis C/autoimmune hepatitis syndrome has until recently been problematic due to the adverse effects of interferon on autoimmune processes and immunosuppression on viral replication. In this report we describe 3 patients with chronic hepatitis C/autoimmune hepatitis overlap syndrome who responded rapidly to direct acting anti-viral therapy. The resolution of the autoimmune process supports a direct viral role in its pathophysiology.
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8
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Czaja AJ. Transitioning from Idiopathic to Explainable Autoimmune Hepatitis. Dig Dis Sci 2015; 60:2881-900. [PMID: 25999246 DOI: 10.1007/s10620-015-3708-7] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2015] [Accepted: 05/06/2015] [Indexed: 02/08/2023]
Abstract
Autoimmune hepatitis lacks an identifiable cause, and its diagnosis requires the exclusion of etiologically defined diseases that resemble it. Insights into its pathogenesis are moving autoimmune hepatitis from an idiopathic to explainable disease, and the goal of this review is to describe the insights that are hastening this transition. Two types of autoimmune hepatitis are justified by serological markers, but they also have distinctive genetic associations (DRB1 and DQB1 genes) and autoantigens. DRB1 alleles are the principal susceptibility factors in white adults, and a six amino acid sequence encoded in the antigen-binding groove of class II molecules of the major histocompatibility complex can influence the selection of autoantigens. Polymorphisms, including variants of SH2B3 and CARD10 genes, may affect immune reactivity and disease severity. The cytochrome mono-oxygenase, CYP2D6, is the autoantigen associated with type 2 autoimmune hepatitis, and it shares homologies with multiple viruses that might promote self-intolerance by molecular mimicry. Chemokines, especially CXCL9 and CXCL10, orchestrate the migration of effector cells to sites of injury and are associated with disease severity. Cells of the innate and adaptive immune responses promote tissue damage, and possible deficiencies in the number and function of regulatory T cells may facilitate the injurious process. Receptor-mediated apoptosis is the principal mechanism of hepatocyte loss, and cell-mediated and antibody-dependent mechanisms of cytotoxicity also contribute. Insights that explain autoimmune hepatitis will allow triggering exogenous antigens to be characterized, risk management to be improved, prognostic indices to be refined, and site-specific therapeutic interventions to emerge.
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Affiliation(s)
- Albert J Czaja
- Professor Emeritus of Medicine, Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, 200 First Street S.W., Rochester, MN, 55905, USA.
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9
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Abstract
Autoimmune disorders afflicting the liver comprise the bona fide autoimmune diseases, primary biliary cirrhosis, primary sclerosing cholangitis, and autoimmune hepatitis as well as drug-induced autoimmune-like diseases, such as halothane hepatitis. Whereas drug-induced forms of acute or chronic hepatitis often have a clear triggering factor, the etiology of classical autoimmune liver diseases is only poorly understood. Besides a genetic component present in disease susceptible individuals, environmental triggering factors are likely to play a role in the initiation and/or propagation of the disease. In this article, we will review on current evidence obtained from epidemiological associations, case studies, and findings in animal models for pathogens, to be involved in the etiology of autoimmune liver disease with a special focus on autoimmune hepatitis.
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Affiliation(s)
- Urs Christen
- Pharmazentrum Frankfurt/ZAFES, Goethe University Hospital , Frankfurt am Main , Germany
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10
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Czaja AJ. Review article: permanent drug withdrawal is desirable and achievable for autoimmune hepatitis. Aliment Pharmacol Ther 2014; 39:1043-58. [PMID: 24628539 DOI: 10.1111/apt.12701] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2014] [Revised: 02/09/2014] [Accepted: 02/23/2014] [Indexed: 12/12/2022]
Abstract
BACKGROUND Autoimmune hepatitis can be rendered treatment-free, but the difficulty, frequency and risks associated with the pursuit of this outcome are unclear. AIM To describe the frequency that autoimmune hepatitis can be rendered treatment-free, identify the features that characterise these patients, examine the pathogenic pathways that may sustain or terminate the disease and indicate management protocols that can obtain this result. METHODS Studies cited in Pub Med from 1972-2014 for autoimmune hepatitis, treatment, relapse, remission and outcome were selected. RESULTS The frequency of a treatment-free state varies from 19% to 40% in patients observed for ≥3 years after drug withdrawal. Complete laboratory resolution and reversion to normal liver tissue prior to drug withdrawal favours this response. The development of cirrhosis during therapy may increase treatment-dependence. Persistent liver damage and the generation of neo-antigens during the apoptosis of hepatocytes may perpetuate the disease. Genetic and age-related effects on the vigour of the immune response may also contribute. Reversion to normal liver tissue is achieved in only 22% of patients during conventional corticosteroid therapy, and the emerging pharmacological and biological interventions may improve this frequency. A management strategy designed to achieve a treatment-free state accommodates all candidates for this outcome, and it can be modified to a long-term maintenance strategy as warranted by the clinical response. CONCLUSIONS Permanent drug withdrawal is a treatment outcome that is desirable and achievable in patients with autoimmune hepatitis. Normalisation of liver tests and liver tissue during treatment enhances this occurrence.
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Affiliation(s)
- A J Czaja
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN, USA
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11
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Hardtke-Wolenski M, Fischer K, Noyan F, Schlue J, Falk CS, Stahlhut M, Woller N, Kuehnel F, Taubert R, Manns MP, Jaeckel E. Genetic predisposition and environmental danger signals initiate chronic autoimmune hepatitis driven by CD4+ T cells. Hepatology 2013; 58:718-28. [PMID: 23475565 DOI: 10.1002/hep.26380] [Citation(s) in RCA: 69] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2012] [Accepted: 03/01/2013] [Indexed: 12/31/2022]
Abstract
UNLABELLED Autoimmune hepatitis (AIH) is defined as a chronic liver disease with loss of tolerance against liver tissue eventually leading to cirrhosis if left untreated. 80%-90% of patients can be treated with a life-long immunosuppression. Unfortunately, there are strong drug-related side effects and steroid-refractory patients. Therefore, there is a need for a model system to investigate the complex immunopathogenesis of this chronic disease and subsequently to develop new therapeutic interventions. We developed a new model of experimental murine AIH (emAIH) by a self-limited adenoviral infection with the hepatic autoantigen formiminotransferase cyclodeaminase (FTCD). After an initial transient hepatitis there was a chronic evolving AIH, finally leading to portal and lobular fibrosis. We could show that the genetic predisposition provided by the NOD background was essential for creating a fertile field for the development of liver-specific autoimmunity. However, a strong environmental trigger was additionally necessary to initiate the disease. Besides the break of humoral tolerance, T-cell tolerance against hepatic self-antigens was also broken and CD4(+) T cells were identified as essential drivers of the disease. As the disease was successfully treated with prednisolone and budesonide, the model will be helpful to develop and test new therapeutic interventions. CONCLUSION We developed a new murine AIH model closely resembling AIH in patients that explains the mechanisms of AIH pathophysiology. In addition, emAIH provides options to test therapeutic alternatives for patients not achieving remission, with reduced side effects of chronic nonspecific immunosuppression.
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Affiliation(s)
- Matthias Hardtke-Wolenski
- Department of Gastroenterology, Hepatology & Endocrinology, Hannover Medical School, Hannover, Germany
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Abstract
Autoimmune hepatitis frequently has an abrupt onset of symptoms, and it can present with acute liver failure. The abrupt presentation can indicate spontaneous exacerbation of a pre-existent chronic disease, newly created disease, a superimposed infectious or toxic injury, or new disease after viral infection, drug therapy, or liver transplantation. Deficiencies in the classical phenotype may include a low serum immunoglobulin G level and low or absent titers of the conventional autoantibodies. The original revised diagnostic scoring system of the International Autoimmune Hepatitis Group can guide the diagnostic evaluation, but low scores do not preclude the diagnosis. Liver tissue examination is valuable to exclude viral-related or drug-induced liver injury and support the diagnosis by demonstrating centrilobular necrosis (usually with interface hepatitis), lymphoplasmacytic infiltration, hepatocyte rosettes, and fibrosis. Conventional therapy with prednisone and azathioprine induces clinical and laboratory improvement in 68-75 % of patients with acute presentations, and high dose prednisone or prednisolone (preferred drug) is effective in 20-100 % of patients with acute severe (fulminant) presentations. Failure to improve or worsening of any clinical or laboratory feature within 2 weeks of treatment or worsening of a mathematical model of end-stage liver disease within 7 days justifies liver transplantation in acute liver failure. Liver transplantation for acute severe (fulminant) autoimmune hepatitis is as successful as liver transplantation for autoimmune hepatitis with a chronic presentation and other types of acute liver failure (patient survival >1 year, 80-94 %). Liver transplantation should not be delayed or superseded by protracted corticosteroid therapy or the empiric institution of nonstandard medications.
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Spengler U, Fischer HP, Caselmann WH. Liver Disease Associated with Viral Infections. ZAKIM AND BOYER'S HEPATOLOGY 2012. [PMCID: PMC7152320 DOI: 10.1016/b978-1-4377-0881-3.00034-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/03/2022]
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Abstract
Autoimmune hepatitis (AIH) is a chronic disease of unknown etiology that is characterized by the presence of circulatory autoantibodies and inflammatory histological changes in the liver. Although the pathogenesis of AIH is not known, it is thought that, in a genetically predisposed individual, environmental factors such as viruses can trigger the autoimmune process. Herpes simplex virus, Epstein-Barr virus, measles virus, and hepatitis viruses are thought to play a role in the etiology of AIH. Proteins belonging to these viruses may be similar to the amino acid chains of different autoantigens in the liver, this causes immune cross reactions and liver tissue damage. We report a case of severe AIH following varicella zoster infection in a 23-year-old man, and speculate that, based on the molecular mimicry hypothesis, the liver damage was caused by an immune cross reaction to the viral proteins. Varicella-zoster-induced AIH has not been reported previously.
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Kuwahara R, Saitsu H, Abe M, Takata A, Tanaka K, Hino T, Ide T, Kuromatsu R, Tanikawa K, Kage M, Kumashiro R, Sata M. Successful treatment with corticosteroid and lamivudine for autoimmune hepatitis in a patient with asymptomatic HBV infection. Dig Dis Sci 2007; 52:908-13. [PMID: 17342404 DOI: 10.1007/s10620-006-9113-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/13/2005] [Accepted: 11/01/2005] [Indexed: 12/09/2022]
Affiliation(s)
- Reiichiro Kuwahara
- The Second Department of Medicine, Kurume University School of Medicine and the Center of the 21st Century Center of Excellence Program for Medical Science, 67 Asahi-Machi, Kurume, Fukuoka 830-0011, Japan.
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Abstract
Morbilliviruses are a group of viruses that belong to the family Paramyxoviridae. The most instantly recognizable member is measles virus (MV) and individuals acutely infected with the virus exhibit a wide range of clinical symptoms ranging from a characteristic mild self-limiting infection to death. Canine distemper virus (CDV) and rinderpest virus (RPV) cause a similar but distinctive pathology in dogs and cattle, respectively, and these, alongside experimental MV infection of primates, have been useful models for MV pathogenesis. Traditionally, viruses were identified because a distinctive disease was observed in man or animals; an infectious agent was subsequently isolated, cultured, and this could be used to recapitulate the disease in an experimentally infected host. Thus, satisfying Koch's postulates has been the norm. More recently, particularly due to the advent of exceedingly sensitive molecular biological assays, many researchers have looked for infectious agents in disease conditions for which a viral aetiology has not been previously established. For these cases, the modified Koch's postulates of Bradford Hill have been developed as criteria to link a virus to a specific disease. Only in a few cases have these conditions been fulfilled. Therefore, many viruses have over the years been definitely and tentatively linked to human diseases and in this respect the morbilliviruses are no different. In this review, human diseases associated with morbillivirus infection have been grouped into three broad categories: (1) those which are definitely caused by the infection; (2) those which may be exacerbated or facilitated by an infection; and (3) those which currently have limited, weak, unsubstantiated or no credible scientific evidence to support any link to a morbillivirus. Thus, an attempt has been made to clarify the published data and separate human diseases actually linked to morbilliviruses from those that are merely anecdotally associated.
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Affiliation(s)
- Bertus K Rima
- School of Biomedical Sciences and Centre for Cancer Research and Cell Biology, The Queen's University of Belfast, UK.
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17
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Schattner A. Consequence or coincidence? The occurrence, pathogenesis and significance of autoimmune manifestations after viral vaccines. Vaccine 2005; 23:3876-86. [PMID: 15917108 DOI: 10.1016/j.vaccine.2005.03.005] [Citation(s) in RCA: 162] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2004] [Revised: 02/02/2005] [Accepted: 03/04/2005] [Indexed: 12/27/2022]
Abstract
BACKGROUND Viruses and virus-induced lymphokines may have an important role in the pathogenesis of autoimmunity (Schattner A. Clin Immunol Immunopathol; 1994). The occurrence and significance of autoimmune manifestations after the administration of viral vaccines remain controversial. METHODS Medline search of all relevant publications from 1966 through June 2004 with special emphasis on search of each individual autoimmune manifestation and vaccination, as well as specifically searching each viral vaccine for all potential autoimmune syndromes reported. All relevant publications were retrieved and critically analyzed. RESULTS The most frequently reported autoimmune manifestations for the various vaccinations, were: hepatitis A virus (HAV)--none; hepatitis B virus (HBV)--rheumatoid arthritis, reactive arthritis, vasculitis, encephalitis, neuropathy, thrombocytopenia; measles, mumps and rubella vaccine (MMR)--acute arthritis or arthralgia, chronic arthritis, thrombocytopenia; influenza--Guillain-Barre syndrome (GBS), vasculitis; polio--GBS; varicella--mainly neurological syndromes. Even these 'frequent' associations relate to a relatively small number of patients. Whenever controlled studies of autoimmunity following viral vaccines were undertaken, no evidence of an association was found. CONCLUSIONS Very few patients may develop some autoimmune diseases following viral vaccination (in particular - arthropathy, vasculitis, neurological dysfunction and thrombocytopenia). For the overwhelming majority of people, vaccines are safe and no evidence linking viral vaccines with type 1 diabetes, multiple sclerosis (MS) or inflammatory bowel disease can be found.
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Affiliation(s)
- Ami Schattner
- Department of Medicine, University of Cambridge, School of Clinical Medicine, Level 5, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2QQ, UK.
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Nozić D, Dimitrijević J, Knezević-Usaj S. Occurrence of autoimmune chronic hepatitis in siblings. VOJNOSANIT PREGL 2005; 62:591-4. [PMID: 16171025 DOI: 10.2298/vsp0508591n] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022] Open
Abstract
Background. Autoimmune hepatitis is a chronic inflammatory disease of the liver of unknown etiology, characterized by the loss of tolerance against hepatic tissue, leading to the destruction of hepatic parenchyma. It predominantly affects females, and rarely occurs in the same family. Case report. In this paper we presented brother and sister with autoimmune hepatitis according to the criteria of the International Autoimmune Hepatitis Group. Conclusion. Because of a possible genetic predisposition to autoimmune hepatitis, the occurrence of the disease in a family member suggested the need to examine other family members.
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Affiliation(s)
- Darko Nozić
- Vojnomedicinska akademija, Klinika za infektivne i tropske bolesti, Beograd, Srbija i Crna Gora
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Vento S, Cainelli F. Is there a role for viruses in triggering autoimmune hepatitis? Autoimmun Rev 2004; 3:61-69. [PMID: 14871651 DOI: 10.1016/s1568-9972(03)00053-3] [Citation(s) in RCA: 56] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2003] [Accepted: 03/26/2003] [Indexed: 11/29/2022]
Abstract
A role for viruses in autoimmune hepatitis (AH) has been repeatedly proposed but convincing evidence links only two viruses, hepatitis A and Epstein-Barr virus, to the type 1 form of the disease, and only in those rare cases where a genetic predisposition exists and the viral infection occurs at the right time, i.e. when other unknown factors are cooperating. In spite of an impressive amount of information conclusively showing molecular mimicry between cytochrome P450IID6 (the target autoantigen of autoantibodies characteristic of AH type 2) sequences and viral (hepatitis C virus, herpes simplex virus 1, cytomegalovirus, human T lymphotropic viruses 1 and 2) or bacterial (Salmonella typhimurium) antigens, no infectious agent is clearly able to induce this second form of the disease. In conclusion, the molecular mimicry theory has so far found little clinical evidence in its support and many more clinical observations are needed in order to unreveal possible links between viruses and AH.
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Affiliation(s)
- Sandro Vento
- Section of Infectious Diseases, Department of Pathology, University of Verona, 37138 Verona, Italy.
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20
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Medina J, García-Buey L, Moreno-Otero R. Review article: immunopathogenetic and therapeutic aspects of autoimmune hepatitis. Aliment Pharmacol Ther 2003; 17:1-16. [PMID: 12492728 DOI: 10.1046/j.1365-2036.2003.01389.x] [Citation(s) in RCA: 42] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Autoimmune hepatitis is a chronic, progressive liver disease that responds well to immunosuppressive therapy, but has a poor prognosis if untreated. Possible triggering factors include viruses, other autoimmune disorders and drugs. The molecular mechanisms contributing to the pathogenesis include: reactions of autoantibodies against their corresponding autoantigens; aberrant expression of histocompatibility antigen class I and II molecules, cell adhesion molecules and cytokines; increased oxidative stress; and the occurrence of angiogenesis. The prevalence of the disease is highest in Caucasians, Europeans and women. The natural history of autoimmune hepatitis shows a poor prognosis, with frequent progression to cirrhosis and hepatic insufficiency in untreated patients. The occurrence of hepatocellular carcinoma is rare and is found only in long-standing cirrhosis. Corticosteroids as monotherapy or in combination with azathioprine are the treatments of choice; different therapeutic schedules and particularities of treatment for pregnant women and children have been established. To avoid treatment-associated adverse effects, alternative therapies have been proposed, including ciclosporin, budesonide, tacrolimus, mycophenolate mofetil, ursodeoxycholic acid, methotrexate, cyclophosphamide, mercaptopurine and free radical scavengers. Liver transplantation is indicated for patients refractory to or intolerant of immunosuppressive therapy.
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Affiliation(s)
- J Medina
- Liver Unit, Hospital de la Princesa, Autonomous University of Madrid, Diego de León 62, E-28006 Madrid, Spain
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21
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Sacher T, Knolle P, Nichterlein T, Arnold B, Hämmerling GJ, Limmer A. CpG-ODN-induced inflammation is sufficient to cause T-cell-mediated autoaggression against hepatocytes. Eur J Immunol 2002; 32:3628-37. [PMID: 12516551 DOI: 10.1002/1521-4141(200212)32:12<3628::aid-immu3628>3.0.co;2-e] [Citation(s) in RCA: 43] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
Autoimmune diseases are often associated with microbial infections. Molecular mimicry between microbial antigens and self-epitopes has been suggested as a mechanism for breaking self-tolerance and induction of autoimmunity. Since infections also cause inflammatory responses we explored the role of local inflammation in organ-specific autoimmunity. For this purpose, transgenic mice were used expressing the MHC class I molecule Kb exclusively on hepatocytes. These mice exhibit Kb-specific tolerance as exemplified by the acceptance of Kb+ grafts. Inflammatory reactions were induced by injection of immunostimulatory cytosine-phosphorothioate-guanine (CpG)-rich oligodeoxynucleotides (ODN). Application of CpG-ODN is sufficient to break tolerance in vivo, and to cause activation of Kb-specific CD8+ T cells and subsequent autoaggression against hepatocytes. The CpG-ODN-induced inflammation appears to have two major effects. First, it causes infiltration of T cells into the liver parenchyma. Second, adhesion and costimulatory molecules are up-regulated on hepatocytes so that the infiltrating CD8+ T cells encounter Kb on hepatocytes, which display an APC-like phenotype, resulting in activation and tissue damage. Autoimmune hepatitis can be maintained for at least eight weeks by repeated application of CpG-ODN but subsides after termination of the inflammatory stimulus, suggesting the requirement of additional factors for a self-perpetuation of autoimmunity. These observations describe an additional pathway for the induction of autoimmunity, i.e. in the absence of microbial antigens inflammatory reactions alone can lead to infiltration of T cells into organs, resulting in breaking of tolerance and autoaggression. Moreover, the results provide evidence that T cell activation can take place not only in draining lymph nodes but also directly on parenchymal cells.
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22
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Abstract
Although viruses are commonly cited as triggers for autoimmune disease, the actual mechanisms by which they initiate autoimmunity are unknown. Molecular mimicry is the most popular hypothesis, and it proposes that viral antigens that share homologies with host antigens generate an immune response that damages host tissue. The viral antigen may not be needed for perpetuation of the disease, and cross-reacting immune responses can involve humoral, cellular, or both types of reactivity. Linear and conformational epitopes may be involved, and foreign antigens do not need to share exact amino acid sequences with self-proteins to activate autoreactive T cells. Bystander effects can enhance the autoimmune process if previously sequestered or cryptic antigens are exposed to the immune system, and superantigens that are produced by the pathogen and are not MHC restricted can result in marked polyclonal activation of CD4 and CD8 T cells. Future studies must differentiate the targets of pathologic immunity and distinguish self-antigens from infectious nonself-antigens. Transgenic animal models of AIH are needed to assess the pathogenicity of the antigenic targets.
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Affiliation(s)
- Arndt Vogel
- Department of Gastroenterology, Hepatology and Endocrinology, Medizinische Hochschule Hannover, Carl-Neuberg-Str. 1, D-30623, Hannover, Germany
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23
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Willis MS, Latimer MJ. Autoimmune Hepatitis Type 2. Lab Med 2002. [DOI: 10.1309/pwc8-5x4f-cfwf-ypex] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022] Open
Affiliation(s)
- Monte S. Willis
- Department of Pathology, University of Texas Southwestern Medical School, Dallas, TX
| | - M. Jane Latimer
- Department of Pathology, University of Texas Southwestern Medical School, Dallas, TX
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24
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Abstract
The diagnosis and management of autoimmune hepatitis continues to evolve as new diagnostic tests and new therapies are added to the armamentarium. Also encouraging are the advances in the understanding of the human immune system and its involvement in the origin and course of auto immune diseases in general and in the variants of autoimmune liver disease. Promising changes are expected in the next few years as new medications become available to the practicing hepatologist. New immune tests may allow therapies to be customized to patients, and antiviral therapies may also eventually be used in the management of this autoimmune liver diseases.
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Affiliation(s)
- R G Gish
- Departments of Medicine and Transplantation, California Pacific Medical Center, San Francisco, California, USA.
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25
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Abstract
OBJECTIVES The aim of this study was to review the pathogenic mechanisms of autoimmune hepatitis, identify gaps in knowledge, and focus future investigative efforts. METHODS The study was based on a review of all relevant articles on the mechanisms of autoimmunity in autoimmune liver disease from 1980 to 2000, extraction of pertinent concepts from the medical literature; and integration of evolving paradigms of pathogenesis with personal experiences and investigations. RESULTS Autoimmune hepatitis is a consequence of autoantigen exposure, genetic predisposition, and defective immunoregulatory mechanisms. Autoantigen is optimally presented by class II molecules of the major histocompatibility complex that have lysine residues at position DRbeta71 of the antigen-binding groove. Cytokines and non-disease-specific autoimmune promoters modulate immune reactivity. Cell-mediated and antibody-dependent mechanisms contribute to hepatocyte injury. CONCLUSIONS Multiple disturbances in the homeostatic mechanisms that preserve self-tolerance are likely in autoimmune hepatitis. Future investigations must focus on individual determinants of autoantigen presentation, immunocyte activation, and liver cell destruction. Findings can then be integrated into a comprehensive knowledge base that may be applicable to other autoimmune diseases.
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Affiliation(s)
- A J Czaja
- Division of Gastroenterology and Hepatology, Mayo Clinic and Mayo Foundation, Rochester, Minnesota, 55905, USA
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26
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Abstract
Several lines of evidence suggest that autoimmune hepatitis and primary biliary cirrhosis are autoimmune diseases. This article discusses both the immunologic mechanisms of liver injury and the mechanisms of cell injury mediated by lymphocytes. This article also reviews the proposed immunopathogenesis of autoimmune hepatitis and primary biliary cirrhosis.
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Affiliation(s)
- C L Mabee
- Division of Digestive Diseases, Department of Internal Medicine, Ohio State University Health Science Center, Columbus, Ohio
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27
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Abstract
Prednisone alone or in combination with azathioprine is the treatment of choice for severe type 1 autoimmune hepatitis. The combination regimen is preferred, especially in the elderly, because of a lower incidence of corticosteroid-related complications. Only patients with sustained severe laboratory abnormalities, bridging necrosis or multilobular necrosis on histological assessment, and/or incapacitating symptoms, have absolute indications for treatment based on controlled clinical trials. The institution of therapy must be individualised in other patients, based mainly on symptoms and disease behaviour. Serum aspartate aminotransferase and gamma-globulin levels are the most useful indices to monitor during therapy. Liver tissue examination is the best method of evaluating completeness of response. Most patients enter remission, but relapse occurs in 50 to 86% after drug withdrawal. Maintenance therapy with low dosages of prednisone or azathioprine can be used long term in patients who have relapsed repeatedly. Inability to achieve remission after 3 years (incomplete response), deterioration during therapy (treatment failure) and drug toxicity are unsatisfactory responses that warrant alternative strategies. Liver transplantation is effective in managing decompensated disease, but recurrence of autoimmune hepatitis after transplantation is possible. Tacrolimus and budesonide are promising new drugs.
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Affiliation(s)
- A J Czaja
- Division of Gastroenterology and Hepatology, Mayo Clinic and Mayo Foundation, Rochester, Minnesota 55905, USA
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28
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Limmer A, Sacher T, Alferink J, Kretschmar M, Schönrich G, Nichterlein T, Arnold B, Hämmerling GJ. Failure to induce organ-specific autoimmunity by breaking of tolerance: importance of the microenvironment. Eur J Immunol 1998; 28:2395-406. [PMID: 9710217 DOI: 10.1002/(sici)1521-4141(199808)28:08<2395::aid-immu2395>3.0.co;2-d] [Citation(s) in RCA: 97] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
Peripheral tolerance is considered to be a safeguard against autoimmunity. Using a TCR-transgenic mouse system displaying peripheral tolerance against a liver-specific MHC class I Kb antigen, we investigated whether the breaking of tolerance would result in autoimmunity. Reversal of tolerance was achieved by simultaneous challenge with cells expressing the Kb autoantigen and IL-2. Tolerance could not be broken with IL-2 alone or when Kb- and IL-2-expressing cells were applied to different sites of the mice. However, despite the presence of activated autoreactive T cells that were able to reject Kb-positive grafts no autoaggression against the Kb-positive liver was observed. These results indicate that breaking of tolerance per se is not sufficient to cause liver-specific autoimmunity. However, when in addition to breaking tolerance the mice were infected with a liver-specific pathogen, autoaggression occurred. Thus, in this system at least two independent steps seem to be required for organ-specific autoimmunity: reversal of peripheral tolerance resulting in functional activation of autoreactive T cells and conditioning of the liver microenvironment which enables the activated T cells to cause tissue damage.
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Affiliation(s)
- A Limmer
- Division of Molecular Immunology, German Cancer Research Center, Heidelberg
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29
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Abstract
Several diseases are regarded as autoimmune liver diseases. Apart from the cholestatic liver diseases, primary biliary cirrhosis, primary sclerosing cholangitis, these include autoimmune hepatitis, hepatitis as part of the autoimmune polyendocrine syndrome type 1 (APS-1) and particular overlap syndromes such as autoimmune cholangitis (also called antimitochondrial antibody negative primary biliary cirrhosis [PBC]), overlap syndrome chronic active hepatitis (CAH)/PBC and the overlap syndrome primary sclerosing hepatitis (PSC)/CAH. In addition, auto-antibodies may be observed during the course of chronic viral hepatitis, in particular chronic hepatitis C and D. Finally, a small number of drug-induced liver diseases is immune mediated. The following article will review our recent progress in the field of autoimmune hepatitis including APS-1 and autoimmunity in viral hepatitis and immune-mediated drug-induced liver disease.
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Affiliation(s)
- M P Manns
- Department of Gastroenterology and Hepatology, Hannover Medical School, Germany
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30
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Poitout F, Weiss DJ, Armstrong PJ. Cell-mediated immune responses to liver membrane protein in canine chronic hepatitis. Vet Immunol Immunopathol 1997; 57:169-78. [PMID: 9261956 DOI: 10.1016/s0165-2427(96)05614-0] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Peripheral blood mononuclear cells from dogs with chronic inflammatory liver disease and dogs with noninflammatory liver diseases were evaluated for proliferative responses to pokeweed mitogen and canine liver membrane protein. Dogs with chronic hepatitis were selected based on histopathological evidence of periportal lymphocytic infiltrates with or without neutrophilic infiltrates, fibrosis and necrosis. Incorporation of tritiated thymidine was assessed 72 hours after addition of liver membrane protein or pokeweed mitogen. Peripheral blood mononuclear cell proliferation in response to liver membrane protein was significantly higher in chronic hepatitis dogs compared to control dogs. Eight of 12 dogs with chronic hepatitis and 2 of 7 dogs with noninflammatory liver disease had proliferative responses to liver membrane protein greater than 2 standard deviations above the mean of the control group. These data support the hypothesis that immune-mediated processes are involved in canine chronic hepatitis, but did not determine whether this is a primary disorder or occurred secondary to liver destruction.
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Affiliation(s)
- F Poitout
- Department of Veterinary PathoBiology College of Veterinary Medicine, University of Minnesota, St. Paul 55108, USA
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31
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Schmitt K, Deutsch J, Tulzer G, Meindi R, Aberle S. Autoimmune hepatitis and adrenal insufficiency in an infant with human herpesvirus-6 infection. Lancet 1996; 348:966. [PMID: 8843841 DOI: 10.1016/s0140-6736(05)65385-8] [Citation(s) in RCA: 19] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
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32
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Meyer zum Büschenfelde KH, Dienes HP. Autoimmune hepatitis. Definition--classification--histopathology--immunopathogenesis. Virchows Arch 1996; 429:1-12. [PMID: 8865847 DOI: 10.1007/bf00196814] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
Autoimmune hepatitis (AIH) is a distinct form of acute and chronic inflammatory liver disease in which immune reactions against host antigens are found to be the major pathological mechanism. If left untreated it carries an unfavourable prognosis, and the diagnosis should be made as soon as possible. The diagnostic approach has been greatly facilitated by the establishment of a panel of marker autoantibodies, which do not define distinct therapeutic groups of AIH, but do allow a subgrouping based on differences in patient populations, some clinical features and prognosis. The characterization of organ-specific components of the liver cell surface as targets of cellular and humoral autoimmune reactions give new insights into the pathogenesis of the disease, even though the primary event triggering the disease remains to be defined. The most important disease-promoting factor seems to be a genetically determined background for autoimmunity. Without this different environmental factors, including viruses, toxins, cytokines and drugs, are only able to induce transient autoimmune phenomena and not autoimmune disease. The histopathology of AIH is in keeping with the present pathogenetic concept. Although there is no pathognomonic feature distinguishing this type of hepatitis from virus-induced forms, some distinct morphological lesions are regarded as characteristic. Clinical research on AIH has benefited greatly from observations of experimental AIH in mice. Recognition of the critical role of autoreactive T-lymphocytes in the pathogenesis and the observation of spontaneous recovery from AIH in the animal model associated with antigen-specific and antigen-non-specific T-cell suppression have made basic contributions to our improved understanding of the natural course of AIH in humans.
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33
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Mason AL, Perrillo RP. The A to Z of new hepatotropic agents: human hepatitis viruses and monkey business. LIVER TRANSPLANTATION AND SURGERY : OFFICIAL PUBLICATION OF THE AMERICAN ASSOCIATION FOR THE STUDY OF LIVER DISEASES AND THE INTERNATIONAL LIVER TRANSPLANTATION SOCIETY 1996; 2:395-405. [PMID: 9346683 DOI: 10.1002/lt.500020512] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Affiliation(s)
- A L Mason
- Section of Gastroenterology and Hepatology, Ochsner Clinic, New Orleans, LA 70121, USA
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34
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Noda K, Enomoto N, Arai K, Masuda E, Yamada Y, Suzuki K, Tanaka M, Yoshihara H. Induction of antinuclear antibody after interferon therapy in patients with type-C chronic hepatitis: its relation to the efficacy of therapy. Scand J Gastroenterol 1996; 31:716-22. [PMID: 8819224 DOI: 10.3109/00365529609009156] [Citation(s) in RCA: 22] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
BACKGROUND The prevalence of antinuclear antibody (ANA) and interferon (IFN)-induced ANA has been documented in patients with chronic hepatitis C. In the present study we evaluated whether the induction pattern of ANA after IFN therapy is related to the efficacy of IFN therapy. METHODS Forty-four patients with chronic hepatitis C were enrolled. Autoimmune hepatitis was excluded in all. ANA was measured every month before, during, and for 6 months after IFN therapy (total dose, 336-480 M units). RESULTS Eight of the 44 (18%) patients were positive for ANA before IFN therapy (group I). In group I six of the eight ANA-positive patients showed an increase in ANA titers during the therapy. Twenty-two of 36 (61%) ANA-negative patients turned positive for ANA, with titers of 1:80 or less during IFN therapy (group II). In 14 of the 36 (39%) ANA-negative patients ANA remained negative throughout the therapy (group III). The rates of sustained responders with a negativity of serum hepatitis C virus RNA and with normal alanine aminotransferase levels for at least 6 months after the cessation of therapy in groups I, II, and III were 25%, 23%, and 21%, respectively, giving no significant difference in the efficacy of therapy. No serious side effect was observed during the therapy. CONCLUSIONS Administration of IFN frequently produced an induction of ANA or an increase in its titer, which did not affect the efficacy of IFN therapy.
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Affiliation(s)
- K Noda
- Dept. of Gastroenterology, Osaka Rosai Hospital, Japan
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35
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Kawashima H, Mori T, Takekuma K, Hoshika A, Hata M, Nakayama T. Polymerase chain reaction detection of the hemagglutinin gene from an attenuated measles vaccine strain in the peripheral mononuclear cells of children with autoimmune hepatitis. Arch Virol 1996; 141:877-84. [PMID: 8678833 DOI: 10.1007/bf01718162] [Citation(s) in RCA: 19] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
We examined the measles H gene using reverse transcriptase-polymerase chain reaction in peripheral mononuclear cells obtained from 4 pediatric and 2 adult patients with autoimmune hepatitis and 12 healthy children who had been infected with measles or vaccinated with an attenuated measles vaccine in the past. All patients were positive for the presence of the gene. Only one healthy control, who had been vaccinated two weeks before the study, was positive, while the other 11 controls were negative for the presence of the gene. The restriction enzyme patterns of the products in the pediatric patients were different from those observed in adults. The sequences of amplified products from pediatric patients coincided with the vaccine strain, whereas those from adults were different from the vaccine strain. The sequence of those from one of two adult patients was similar to those of the isolates in 1990 and later. Our results demonstrated that children with autoimmune hepatitis can have persistence of the vaccine strain in vivo for many years after vaccination.
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Affiliation(s)
- H Kawashima
- Department of Pediatrics, Tokyo Medical College, Japan
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36
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Affiliation(s)
- E L Krawitt
- Gastroenterology Unit, University of Vermont College of Medicine, Burlington 05405-0068, USA
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37
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Kalvenes MB, Kalland KH, Haukenes G. Immunoglobulin G subclass antibodies to rubella virus in chronic liver disease, acute rubella and healthy controls. FEMS IMMUNOLOGY AND MEDICAL MICROBIOLOGY 1996; 13:43-50. [PMID: 8821397 DOI: 10.1111/j.1574-695x.1996.tb00214.x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
Ten patients with chronic liver disease, seven healthy seropositive individuals with a remote history of rubella, and three patients with acute rubella were examined for serum levels of IgG subclasses and subclass antibodies against rubella virus structural proteins. One patient with AICAH had no detectable total or rubella specific IgG3 or IgG4. The liver disease patients were hypergammaglobulinemic and had greatly raised IgG1 levels. Patients with acute rubella lacked antibodies to the rubella virus E2 protein and showed no IgG4 antibody response. The liver disease patients showed a somewhat weaker IgG4 antibody response against the core (C) protein than healthy controls. However, differences are suggested within the subclasses in antibody reactivity against the individual rubella virus antigens. It is concluded that test systems that discriminate reactivities against individual antigens have to be used for characterization of viral antibody subclass profiles.
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Affiliation(s)
- M B Kalvenes
- Department of Microbiology and Immunology, University of Bergen, Norway
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38
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Kalvenes MB, Haukenes G, Nysaeter G, Kalland KH, Myrmel H. Raised levels of antibodies to human viruses at the clinical onset of autoimmune chronic active hepatitis. J Viral Hepat 1995; 2:159-64. [PMID: 7493312 DOI: 10.1111/j.1365-2893.1995.tb00023.x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
Patients with autoimmune chronic active hepatitis (AICAH) often have very high titres of antibodies to rubella and/or measles virus. In the present study a young girl at the clinical onset of AICAH exhibited very high titres of antibodies against influenza viruses A and B, parainfluenza viruses, rubella virus and varicella-zoster virus. The titres normalized over 2 months except for rubella and varicella-zoster antibodies. Strong reactivities were seen against the rubella structural proteins E1, E2 and C in Western blot but IgM antibodies were not demonstrated. Total IgG was increased with normal ratios of subclasses. The IgG1 was the dominant antibody to E1 and E2, while IgG4 dominated the anti-C response. There was no significant shift in subclass reactivities over one year from onset. The polymerase chain reaction (PCR), using a nested primer set, was negative for rubella virus RNA in a liver biopsy obtained at the clinical onset and in peripheral blood mononuclear cells (PBMC) 1 year later. Co-cultivation experiments using PBMC and permissive cell lines were also negative for rubella virus. Hence, in the very early phase of AICAH there may be a transiently enhanced antibody response to various unrelated viruses.
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Affiliation(s)
- M B Kalvenes
- National Institute for Research in Virology, Department of Microbiology and Immunology, Gade Instituté, University of Bergen, Norway
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39
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Affiliation(s)
- A J Czaja
- Division of Gastroenterology and Internal Medicine, Mayo Clinic, Rochester, Minnesota 55905
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40
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Affiliation(s)
- M Katz
- March of Dimes Birth Defects Foundation, White Plains, NY 10605, USA
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41
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Kalvenes MB, Flø R, Kalland KH, Haukenes G. Elevated rubella antibodies in patients with chronic liver disease. J Med Virol 1994; 44:30-6. [PMID: 7798882 DOI: 10.1002/jmv.1890440107] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
Patients with autoimmune chronic active hepatitis (AICAH) and certain other chronic liver disorders often have very high titres of haemagglutination-inhibition (HI) antibodies to rubella virus. In this study it is shown, using floatation centrifugation, that the high rubella HI reactivity is not caused by nonspecific lipoprotein inhibitors but rather by antibodies specific for the rubella haemagglutinin (E1 glycoprotein). After sucrose density gradient ultracentrifugation of sera the major HI reactivity was recovered in the IgG containing fractions. The IgG antibody fraction was strongly reactive by an indirect enzyme-linked immunosorbent assay (ELISA). Higher prevalence and titres of rubella antibodies were also demonstrated by the complement fixation (CF) test using a haemagglutinin-free antigen, and by an indirect haemagglutination (IHA) test (Rubacell) using a cell-associated antigen which is distinct from the antigens used in the HI and CF tests. This high rubella antibody response is therefore demonstrated using three distinct antigen-antibody systems. By means of absorption experiments and radioimmunoprecipitation assays the coating antigen used in the IHA test was shown to reside in the E2 glycoprotein. The cause of this enhanced antibody response to rubella virus structural proteins remains elusive.
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Affiliation(s)
- M B Kalvenes
- Gade Institute, Department of Microbiology and Immunology, University of Bergen, Norway
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42
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Zeniya M, Aizawa Y, Watanabe F, Kawabe T, Hara M, Sakaguchi M, Toda G. HCV-marker-positive autoimmune-type chronic active hepatitis: a possible relation between HCV infection and liver autoreaction. LIVER 1994; 14:206-212. [PMID: 7526109 DOI: 10.1111/j.1600-0676.1994.tb00075.x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
This study focused on 32 patients who were diagnosed as having autoimmune hepatitis based upon clinical and histological factors. Fifteen of these patients were positive for HCV-RNA and for one of the HCV-related markers tested, including anti-C100, ELISA II, and RIBA 2 (Group 2). The remaining 17 patients were negative for all HCV-related markers (Group 1). Clinical factors in the two groups, including the frequency of autoantibodies, serum levels of aminotransferase and gammaglobulin, HLA phenotypes, and the response to corticosteroid treatments, were compared. The titer of serum anti-nuclear antibodies and the level of serum aminotransferase at initial diagnosis were significantly higher in Group 1 than in Group 2. Furthermore, the genetic background of the two groups, as indicated by HLA phenotypes, differed. All cases in Group 1 were HLA-DR4-positive, whereas only 60% of those in Group 2 cases had HLA-DR4. Also, all cases in Group 1 but only 66.7% of the cases in Group 2 showed good clinical responses to corticosteroid treatment. Finally, no cases of HCV-related-marker-positive autoimmune hepatitis (Group 2) had antibodies for LKM, suggesting that these cases were clinically different from type II autoimmune hepatitis. These data indicated that immunosuppressive treatment might be the preferred initial treatment in patients who either satisfy the criteria for AIH or who are sero-positive for an HCV-marker.
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Affiliation(s)
- M Zeniya
- Department of Internal Medicine (I), Jikei University School of Medicine, Tokyo, Japan
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44
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Dohmen K, Ohtsuka S, Nakamura H, Arase K, Yokogawa Y, Asayama R, Kuroiwa S, Ishibashi H. Post-infantile giant cell hepatitis in an elderly female patient with systemic lupus erythematosus. J Gastroenterol 1994; 29:362-8. [PMID: 8061807 DOI: 10.1007/bf02358378] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
A 69-year-old Japanese female was admitted because of general fatigue. Laboratory data showed elevation of serum total bilirubin, transaminase, gamma-glutamyl transpeptidase, and creatinine levels. An immunological study revealed hypergammaglobulinemia, low titer of complement, and high titers of antinuclear antibody, anti-DNA antibody, and circulating immune complexes. Antibodies to parainfluenza virus 3 were positive. Histology of the liver disclosed numerous giant cell hepatocyte transformations with the lobular architecture being slightly distorted by portal inflammation and fibrosis. These findings led us to make a diagnosis of giant cell hepatitis associated with systemic lupus erythematosus. Prednisolone was effective in improving the anemia and the serum immunoglobulin, immune complex, and antinuclear antibody levels. The addition of cyclosporine to the initial corticosteroid therapy was also beneficial in decreasing the transaminase level and in improving liver histology. The patient died of acute pneumonitis and renal failure on the 166th day after admission. Parainfluenza virus 3 and autoimmune mechanisms were thus considered to be the causes of the giant cell hepatitis.
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Affiliation(s)
- K Dohmen
- Department of Internal Medicine, Hamanomachi General Hospital, Fukuoka, Japan
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45
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Kalvenes MB, Kalland KH, Haukenes G. Radioimmunoprecipitation and immunoblot studies of antibodies to rubella virus in patients with chronic liver disease. Arch Virol 1994; 136:73-85. [PMID: 8002792 DOI: 10.1007/bf01538818] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
Patients with autoimmune chronic active hepatitis (AICAH) and some other chronic liver disorders often have very high titres of rubella HI antibodies. In the present study sera from 46 patients with chronic liver disease and controls were examined for rubella antibodies using radioimmunoprecipitation assay (RIPA) and Western blot. RIPA appeared to be more suitable than Western blot for the study of the individual antibody specificities provided that proteins (possibly actin) interfering with the resolution of the E2 glycoprotein band are identified. It was shown that patients with high rubella HI titres reacted strongly against the E1 glycoprotein and in general also against the core protein (C). Reactivity to the E2 glycoprotein was detected with all sera from patients with chronic liver disease but varied more in strength. Three patients with post-acute rubella showed very faint E2 reactivity, but strong E1 and C reactivities. Patients with primary biliary cirrhosis had normal HI titres and showed no increase in reactivity in RIPA. The present findings show that patients with chronic liver disease and high rubella HI antibody titres exhibit an enhanced specific antibody response to rubella virus structural proteins.
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Affiliation(s)
- M B Kalvenes
- Gade Institute, Department of Microbiology and Immunology, University of Bergen, Norway
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46
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Doherty DG, Underhill JA, Donaldson PT, Manabe K, Mieli-Vergani G, Eddleston AL, Vergani D, Demaine AG, Williams R. Polymorphism in the human complement C4 genes and genetic susceptibility to autoimmune hepatitis. Autoimmunity 1994; 18:243-9. [PMID: 7858109 DOI: 10.3109/08916939409009525] [Citation(s) in RCA: 37] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
Susceptibility to autoimmune hepatitis is associated with the HLA-DR3 and DR4 haplotypes, but which genes are directly involved in the pathogenesis, has not been established. Low levels of complement component C4 and elevated frequencies of C4 null allotypes have been described in patients, suggesting that the C4 genes, which are closely linked with the HLA loci, may play a role. We therefore examined restriction fragment length polymorphisms in the C4 and 21-hydroxylase genes, and determined HLA-A and B phenotypes, and HLA-DR, DQ and DP genotypes in a large series of Caucasoid patients with autoimmune hepatitis and matched controls. A DNA deletion of the C4A gene and the 21-hydroxylase A pseudogene was found to be present in 50% of patients compared to 23% of controls (Pc < 0.005, relative risk = 3.3). This increase, however, appears to be due to linkage disequilibrium with HLA-DR52a which was most strongly associated with the disease. Complete C4A deficiency, determined by homozygosity for the deletion increased the risk to 18.1 (16% versus 1%, Pc < 0.005), suggesting an additional role for C4 in disease susceptibility. C4 deletions were associated with an increased mortality and tendency to relapse whilst on treatment but did not correlate with age of onset of disease. Our data suggest that MHC-encoded susceptibility to autoimmune hepatitis is polygenic, involving the HLA-DR genes plus other loci, and C4 deficiency may be a marker of disease susceptibility and/or severity.
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Affiliation(s)
- D G Doherty
- Department of Child Health, King's College School of Medicine and Dentistry, London, UK
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47
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Tanaka E, Kiyosawa K, Seki T, Matsumoto A, Sodeyama T, Furuta S, Kumagai T, Kohara M. Low prevalence of hepatitis C virus infection in patients with auto-immune hepatitis type 1. J Gastroenterol Hepatol 1993; 8:442-7. [PMID: 7693009 DOI: 10.1111/j.1440-1746.1993.tb01545.x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
Hepatitis C virus (HCV) antibodies were measured in 28 patients with auto-immune hepatitis type 1 using six different assay kits, three for C100-3 antibody and three for second generation HCV antibody, and two confirmatory tests to determine the prevalence of HCV infection in auto-immune hepatitis. These patients were confirmed to have human leucocyte antigen DR 4 or 2 which is susceptible to auto-immune hepatitis in Japanese. Of the 28 patients, four (14.3%) were positive for HCV antibody in all assays and reacted positively in at least one of the two confirmatory tests, indicating a true positive finding. Eight were positive for HCV antibody only by the Ortho ELISA kit and were negative in both confirmatory tests. The cut-off level for these results was low and became negative soon after the patients received corticosteroid treatment. Thus, these eight patients are presumed to be false-positive reactors. Hepatitis C virus RNA was detected in the serum of two of the four patients with HCV antibody and in none of 24 patients without HCV antibody. No significant difference was observed between the patients with and without HCV antibody in terms of clinical background, liver function tests and auto-antibodies. Our results showed that the prevalence of a past or present HCV infection in patients with auto-immune hepatitis in Japan is low; thus, auto-immune hepatitis is thought to be distinct from hepatitis type C. However, it is also suggested that HCV infection can potentially trigger auto-immune hepatitis.
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Affiliation(s)
- E Tanaka
- Second Department of Internal Medicine, Shinshu University School of Medicine, Matsumoto, Japan
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48
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Schnorr JJ, Schneider-Schaulies S, Simon-Jödicke A, Pavlovic J, Horisberger MA, ter Meulen V. MxA-dependent inhibition of measles virus glycoprotein synthesis in a stably transfected human monocytic cell line. J Virol 1993; 67:4760-8. [PMID: 8392613 PMCID: PMC237862 DOI: 10.1128/jvi.67.8.4760-4768.1993] [Citation(s) in RCA: 102] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023] Open
Abstract
The alpha/beta (type I) interferon-inducible human MxA protein confers resistance to vesicular stomatitis virus (VSV) and influenza A virus in MxA-transfected mouse 3T3 cells (3T3/MxA). We investigated the inhibitory effects of the MxA protein on measles virus (MV) and VSV in the human monocytic cell line U937. In transfected U937 clones which constitutively express MxA (U937/MxA), the release of infectious MV and VSV was reduced approximately 100-fold in comparison with control titers. Transcription of VSV was inhibited similar to that observed for 3T3/MxA cells, whereas no difference was detected for MV in the rates of transcription or the levels of MV-specific mRNAs. In contrast, analysis of MV protein expression by immunofluorescence and immunoprecipitation revealed a significant reduction in the synthesis of MV glycoproteins F and H in U937/MxA cells. These data demonstrate a virus-specific effect of MxA which may, in the case of MV, contribute to the establishment of a persistent infection in human monocytic cells.
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Affiliation(s)
- J J Schnorr
- Institute for Virology and Immunobiology, Würzburg, Germany
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49
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Czaja AJ, Carpenter HA, Santrach PJ, Moore SB, Taswell HF, Homburger HA. Evidence against hepatitis viruses as important causes of severe autoimmune hepatitis in the United States. J Hepatol 1993; 18:342-52. [PMID: 8228128 DOI: 10.1016/s0168-8278(05)80279-x] [Citation(s) in RCA: 90] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
To determine if the hepatitis viruses are important etiologic factors in autoimmune hepatitis, the clinical, immunoserologic, virologic and HLA phenotypes of 105 of the latter patients were assessed prospectively and compared to 45 patients with chronic viral hepatitis. Patients with autoimmune hepatitis were more often women with higher serum aspartate aminotransferase and immunoglobulin levels than patients with viral disease. Only eight patients (8%) were seropositive for anti-HBc and anti-HBs (four patients) or anti-HCV (four patients) and none with anti-HCV were reactive by second generation immunoassay or recombinant immunoblot assay. Smooth muscle (90 vs. 22%, P < 0.001) and antinuclear (70 vs. 22%, P < 0.001) antibodies were more common in patients with autoimmune hepatitis and the titers more frequently exceeded 1:80 (84 vs. 11%, P < 0.0001). Patients with autoimmune hepatitis were more often positive for HLA B8 (48 vs. 20%, P < 0.01) and DR3 (49 vs. 20%, P < 0.003) and they more frequently had the HLA A1-B8-DR3 phenotype (38 vs. 10%, P < 0.003). Only one of the 120 patients tested for anti-LKM1 was seropositive. We conclude that in an American referral population autoimmune hepatitis usually lacks virologic markers and has a distinctive clinical, immunoserologic and HLA phenotype. Hepatitis viruses are not important immunogenic stimuli for non-organ specific antibodies and they are unlikely to be important causes of this form of autoimmune hepatitis.
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Affiliation(s)
- A J Czaja
- Division of Gastroenterology and Internal Medicine, Mayo Clinic, Rochester, Minnesota 55905
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50
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Scully LJ, Toze C, Sengar DP, Goldstein R. Early-onset autoimmune hepatitis is associated with a C4A gene deletion. Gastroenterology 1993; 104:1478-84. [PMID: 8482459 DOI: 10.1016/0016-5085(93)90359-k] [Citation(s) in RCA: 52] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
BACKGROUND Autoimmune hepatitis is an immunologically mediated disorder with some similarities to systemic lupus erythematosus, including an association with HLA-A1, B8, DR3. This haplotype includes a C4A, 21-OHA gene deletion. Low serum levels of complement and C4 null alleles have been reported in autoimmune hepatitis, but studies have been at the protein level only. METHODS Twenty-four white patients with autoimmune hepatitis were studied by Southern blots using a C4A gene complementary DNA probe. HLA A, B, and C typing was determined using standard microcytotoxicity assays, and DR and DQ specificities were determined by restriction fragment length polymorphism analysis. RESULTS Thirteen of 24 patients had the C4A gene deletion compared with 12 of 90 controls. HLA-A1 and B8 were increased in patients with autoimmune hepatitis, as were HLA-DR3 (DR17), Dw24, DQ2. Patients with a C4A gene deletion presented at a younger age than those without the deletion and had significantly lower serum C3 and C4 levels. The C4A gene deletion was associated with HLA-A1, B8, DR3 in all but 1 patient who was HLA-DR3 negative. CONCLUSIONS A C4A gene deletion is found in patients with autoimmune hepatitis, especially those presenting at a young age. This complement gene deletion may be an important factor in the development of this disease.
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Affiliation(s)
- L J Scully
- Department of Medicine, Ottawa Civic Hospital, Ontario, Canada
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