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Lv H, Deng A, Chen Y, Su Z. Clinical Performance of the Line Immunoassay and Digital Liquid Chip Method for Detecting Autoimmune Liver Disease Autoantibodies. Arch Pathol Lab Med 2025; 149:271-275. [PMID: 38830630 DOI: 10.5858/arpa.2024-0057-oa] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/01/2024] [Indexed: 06/05/2024]
Abstract
CONTEXT.— The identification of autoantibodies associated with autoimmune liver disease (ALD) is crucial for diagnosis and management. Various laboratory methods have been introduced to detect autoantibody profiles. However, the variable performance of these assays may create challenges for clinicians and patients. OBJECTIVE.— To investigate the concordance rates and diagnostic performance of 2 commercially available assays, line immunoassay (LIA) and digital liquid chip method (DLCM), in patients with ALD. DESIGN.— A total of 291 serum samples were collected, consisting of 180 sera from patients with ALD and 111 sera from controls. The samples were detected through LIA and DLCM. The agreement and diagnostic performance of each assay were analyzed. RESULTS.— There was substantial to almost perfect agreement among prevalent autoantibodies (anti-mitochondrial antibody M2; antibodies against gp210, Sp100, and Ro52). Nevertheless, the Cohen κ coefficient of some uncommon autoantibodies (anti-LKM-1, anti-LC-1, and anti-SLA/LP) between the 2 methods was not ideal. LIA showed slightly better sensitivity, accuracy, and negative predictive value, while DLCM exhibited slightly higher specificity and positive predictive value. CONCLUSIONS.— LIA and DLCM demonstrated comparable performance for the detection of common ALD-related autoantibodies. LIA seemed to be more sensitive, while DLCM displayed more specificity. However, standardization of ALD autoantibody detection still faces challenges between these diverse detection systems. Comprehensive interlaboratory validation is essential to mitigate potential misunderstanding and confusion among patients and clinicians.
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Affiliation(s)
- Heye Lv
- From the Department of Laboratory Medicine, West China Hospital of Sichuan University, Chengdu, China (Lv, Su)
| | - Ao Deng
- the Department of Laboratory Medicine, West China Tianfu Hospital of Sichuan University, Chengdu, China (Deng, Chen)
| | - Yijun Chen
- the Department of Laboratory Medicine, West China Tianfu Hospital of Sichuan University, Chengdu, China (Deng, Chen)
| | - Zhenzhen Su
- From the Department of Laboratory Medicine, West China Hospital of Sichuan University, Chengdu, China (Lv, Su)
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Kamran TE, Faisal S, Khalid R, Haider Z, Inam R, Siddiqui Y, Iqbal M, Khan SA. A novel case report of benign recurrent intrahepatic cholestasis-associated USP53 genetic mutation in a Pakistani girl. SAGE Open Med Case Rep 2024; 12:2050313X241266813. [PMID: 39071191 PMCID: PMC11282528 DOI: 10.1177/2050313x241266813] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2024] [Accepted: 06/07/2024] [Indexed: 07/30/2024] Open
Abstract
Benign recurrent intrahepatic cholestasis is an autosomal recessive disorder presenting with intermittent episodes of cholestatic jaundice. The initial episode of benign recurrent intrahepatic cholestasis tends to occur within the first two decades of a patient's life. Episodes can occur unprompted but can often be precipitated by infections or pregnancy. We report an interesting case of a 13-year-old girl presented with recurrent intrahepatic cholestasis. The patient has a unique homozygous USP53 genetic mutation, the first patient to present with this mutation within the South Asian region. The patient was initially misdiagnosed as a case of autoimmune hepatitis, and when presenting to our set-up was diagnosed as a case of benign recurrent intrahepatic cholestasis. The patient has since been managed on medication and remains regular in follow-up, responding well to treatment.
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Affiliation(s)
- Tafiya Erum Kamran
- Shifa College of Medicine, Shifa Tameer-e-Millat University, Islamabad, Islamabad Capital Territory, Pakistan
| | - Seyreen Faisal
- Shifa College of Medicine, Shifa Tameer-e-Millat University, Islamabad, Islamabad Capital Territory, Pakistan
| | - Rimsha Khalid
- Shifa College of Medicine, Shifa Tameer-e-Millat University, Islamabad, Islamabad Capital Territory, Pakistan
| | - Zaira Haider
- Shifa College of Medicine, Shifa Tameer-e-Millat University, Islamabad, Islamabad Capital Territory, Pakistan
| | - Rida Inam
- Shifa College of Medicine, Shifa Tameer-e-Millat University, Islamabad, Islamabad Capital Territory, Pakistan
| | - Yusra Siddiqui
- Shifa College of Medicine, Shifa Tameer-e-Millat University, Islamabad, Islamabad Capital Territory, Pakistan
| | - Munir Iqbal
- Shifa College of Medicine, Shifa Tameer-e-Millat University, Islamabad, Islamabad Capital Territory, Pakistan
| | - Sabeen Abid Khan
- Shifa College of Medicine, Shifa Tameer-e-Millat University, Islamabad, Islamabad Capital Territory, Pakistan
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SORRENTINO MC, a nome del GdS-AI SIPMeL, CARBONE T, CINQUANTA L, ALESSIO MG, INFANTINO M, DELEONARDI G, TREVISAN MT, PORCELLI B, TERZUOLI L, PLATZGUMMER S, BRUSCA I, ANTICO A, TAMPOIA M, PESCE G, VILLALTA D, BIZZARO N. Linee guida SIPMeL per la determinazione degli autoanticorpi nella diagnosi delle malattie autoimmuni del fegato. LA RIVISTA ITALIANA DELLA MEDICINA DI LABORATORIO 2024; 20. [DOI: 10.23736/s1825-859x.24.00226-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Mercado LA, Gil-Lopez F, Chirila RM, Harnois DM. Autoimmune Hepatitis: A Diagnostic and Therapeutic Overview. Diagnostics (Basel) 2024; 14:382. [PMID: 38396421 PMCID: PMC10887775 DOI: 10.3390/diagnostics14040382] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2024] [Revised: 02/02/2024] [Accepted: 02/06/2024] [Indexed: 02/25/2024] Open
Abstract
Autoimmune hepatitis is an immune-mediated inflammatory condition of the liver of undetermined cause that affects both sexes, all ages, races, and ethnicities. Its clinical presentation can be very broad, from having an asymptomatic and silent course to presenting as acute hepatitis, cirrhosis, and acute liver failure potentially requiring liver transplantation. The diagnosis is based on histological abnormalities (interface hepatitis), characteristic clinical and laboratory findings (increased aspartate aminotransferase, alanine aminotransferase, and serum IgG concentration), and the presence of one or more characteristic autoantibodies. The large heterogeneity of these clinical, biochemical, and histological findings can sometimes make a timely and proper diagnosis a difficult task. Treatment seeks to achieve remission of the disease and prevent further progression of liver disease. First-line therapy includes high-dose corticosteroids, which are later tapered to decrease side effects, and azathioprine. In the presence of azathioprine intolerance or a poor response to the standard of care, second-line therapy needs to be considered, including mycophenolate mofetil. AIH remains a diagnostic and therapeutic challenge, and a further understanding of the pathophysiological pathways of the disease and the implementation of randomized controlled trials are needed.
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Affiliation(s)
- Lydia A. Mercado
- Department of Liver Transplant, Mayo Clinic Florida, Jacksonville, FL 32224, USA
| | - Fernando Gil-Lopez
- Department of Liver Transplant, Mayo Clinic Florida, Jacksonville, FL 32224, USA
| | - Razvan M. Chirila
- Department of General Internal Medicine, Mayo Clinic Florida, Jacksonville, FL 32224, USA;
| | - Denise M. Harnois
- Department of Liver Transplant, Mayo Clinic Florida, Jacksonville, FL 32224, USA
- Department of Gastroenterology and Hepatology, Mayo Clinic Florida, Jacksonville, FL 32224, USA
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Abstract
Autoimmune hepatitis (AIH) is a chronic immunologic disorder in which the immune system targets the liver. The disease has a genetic basis and this accounts for the epidemiologic variation observed in serologic testing and clinical presentation across different populations. The incidence of AIH increases with age into the 70s and seems to be increasing in prevalence. Most patients test positive for antinuclear antibody, ASMA, or anti-LKM but about 20% of patients do not have these serologic markers. At clinical presentation, patients may be asymptomatic, symptomatic, have acute liver failure, or decompensated cirrhosis.
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Affiliation(s)
- Mitchell L Shiffman
- Bon Secours Liver Institute of Richmond, Bon Secours Mercy Health, 5855 Bremo Road, Suite 509, Richmond, VA 23226, USA; Bon Secours Liver Institute of Hampton Roads, Bon Secours Mercy Health, 12720 Mc Manus Boulevard, Suite 313, Newport News, VA, 23602, USA.
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Yilmaz K, Haeberle S, Kim YO, Fritzler MJ, Weng SY, Goeppert B, Raker VK, Steinbrink K, Schuppan D, Enk A, Hadaschik EN. Regulatory T-cell deficiency leads to features of autoimmune liver disease overlap syndrome in scurfy mice. Front Immunol 2023; 14:1253649. [PMID: 37818371 PMCID: PMC10561387 DOI: 10.3389/fimmu.2023.1253649] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2023] [Accepted: 09/08/2023] [Indexed: 10/12/2023] Open
Abstract
Introduction Scurfy mice have a complete deficiency of functional regulatory T cells (Treg) due to a frameshift mutation in the Foxp3 gene. The impaired immune homeostasis results in a lethal lymphoproliferative disorder affecting multiple organs, including the liver. The autoimmune pathology in scurfy mice is in part accompanied by autoantibodies such as antinuclear antibodies (ANA). ANA are serological hallmarks of several autoimmune disorders including autoimmune liver diseases (AILD). However, the underlying pathogenesis and the role of Treg in AILD remain to be elucidated. The present study therefore aimed to characterize the liver disease in scurfy mice. Methods Sera from scurfy mice were screened for ANA by indirect immunofluorescence assay (IFA) and tested for a wide range of AILD-associated autoantibodies by enzyme-linked immunosorbent assay, line immunoassay, and addressable laser bead immunoassay. CD4+ T cells of scurfy mice were transferred into T cell-deficient B6/nude mice. Monoclonal autoantibodies from scurfy mice and recipient B6/nude mice were tested for ANA by IFA. Liver tissue of scurfy mice was analyzed by conventional histology. Collagen deposition in scurfy liver was quantified via hepatic hydroxyproline content. Real-time quantitative PCR was used to determine fibrosis-related hepatic gene expression. Hepatic immune cells were differentiated by flow cytometry. Results All scurfy mice produced ANA. AILD-associated autoantibodies, predominantly antimitochondrial antibodies, were detected at significantly higher levels in scurfy sera. CD4+ T cells from scurfy mice were sufficient to induce anti-dsDNA autoantibodies and ANA with an AILD-related nuclear envelope staining pattern. Liver histology revealed portal inflammation with bile duct damage and proliferation, as in primary biliary cholangitis (PBC), and interface hepatitis with portal-parenchymal necroinflammation, as found in autoimmune hepatitis (AIH). In scurfy liver, TNFα and fibrosis-related transcripts including Col1a1, Timp1, Acta2, Mmp2, and Mmp9 were upregulated. The level of proinflammatory monocytic macrophages (Ly-6Chi) was increased, while M2-type macrophages (CD206+) were downregulated compared to wildtype controls. Despite severe hepatic inflammation, fibrosis did not develop within 25 days, which is close to the lifespan of scurfy mice. Discussion Our findings suggest that Treg-deficient scurfy mice spontaneously develop clinical, serological, and immunopathological characteristics of AILD with overlapping features of PBC and AIH.
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Affiliation(s)
- Kaan Yilmaz
- Department of Dermatology, University of Heidelberg, Heidelberg, Germany
- Department of Dermatology, University Medical Center Mannheim, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
| | - Stefanie Haeberle
- Department of Dermatology, University of Heidelberg, Heidelberg, Germany
| | - Yong Ook Kim
- Institute of Translational Immunology, University Medical Center of Johannes Gutenberg University Mainz, Mainz, Germany
| | - Marvin J. Fritzler
- Department of Medicine, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Shih-Yen Weng
- Institute of Translational Immunology, University Medical Center of Johannes Gutenberg University Mainz, Mainz, Germany
- Smart Healthcare Interdisciplinary College, National Taipei University of Nursing and Health Sciences, Taipei, Taiwan
| | - Benjamin Goeppert
- Institute of Tissue Medicine and Pathology, University of Bern, Bern, Switzerland
- Institute of Pathology and Neuropathology, RKH Klinikum Ludwigsburg, Ludwigsburg, Germany
| | - Verena K. Raker
- Department of Dermatology, University Hospital Muenster, Muenster, Germany
| | - Kerstin Steinbrink
- Department of Dermatology, University Hospital Muenster, Muenster, Germany
| | - Detlef Schuppan
- Institute of Translational Immunology, University Medical Center of Johannes Gutenberg University Mainz, Mainz, Germany
- Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States
| | - Alexander Enk
- Department of Dermatology, University of Heidelberg, Heidelberg, Germany
| | - Eva N. Hadaschik
- Department of Dermatology, University of Heidelberg, Heidelberg, Germany
- Department of Dermatology, University Hospital of Essen, Essen, Germany
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Wang R, Jing K, Liu Y, Zhao H, Cai J. Viral hepatitis is associated with increased risk of decompensated cirrhosis or liver failure in patients positive for liver cytosol antibody type 1. Scand J Immunol 2023; 98:e13281. [PMID: 38441215 DOI: 10.1111/sji.13281] [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: 02/15/2023] [Accepted: 05/01/2023] [Indexed: 03/07/2024]
Abstract
Liver cytosol antibody type 1 (anti-LC1) is reported to be a marker of type 2 autoimmune hepatitis (AIH), a type of autoimmune liver disease (AILD). However, anti-LC1 is not entirely disease-specific, and its clinical value in other hepatic diseases has not been well elucidated. Our study aimed to explore the associations between the diagnoses and outcome of decompensated cirrhosis or liver failure (DC/LF) in patients positive for anti-LC1. A total of 157 patients positive for anti-LC1 were included in our final analysis. DC/LF was defined as the outcome of patients positive for anti-LC1. The risk of DC/LF according to diagnosis was estimated using multivariable Cox proportional hazards models, while stratified Cox regression models were used in the subgroup analyses. The diagnoses of patients positive for anti-LC1 were found to be comprised of various liver disorders. Versus other diagnoses, viral hepatitis was associated with a 2.25-fold increased risk of DC/LF in these patients, independent of sex, age, disease course, treatment and drinking history. Additionally, the associations were more significant by subgroup analysis in male patients, younger patients, non-newly diagnosed patients, patients without treatment and patients without drinking history. Anti-LC1 is not a disease-specific antibody, as it was found in multiple types of hepatic disease. Furthermore, viral hepatitis rather than AILD was associated with an increased risk of DC/LF in patients positive for anti-LC1. These findings emphasize the important role of viral hepatitis in the progression of DC/LF in patients positive for anti-LC1.
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Affiliation(s)
- Rong Wang
- Department of Clinical Laboratory, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, School of Clinical Medicine, Henan University, Zhengzhou, China
| | - Keying Jing
- Department of Clinical Laboratory, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, School of Clinical Medicine, Henan University, Zhengzhou, China
| | - Yang Liu
- Department of Clinical Laboratory, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, School of Clinical Medicine, Henan University, Zhengzhou, China
| | - Huijuan Zhao
- College of Basic Medicine and Forensic Medicine, Henan University of Science and Technology, Luoyang, China
| | - Jun Cai
- Department of Clinical Laboratory, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, School of Clinical Medicine, Henan University, Zhengzhou, China
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Dalekos GN, Gatselis NK. Autoimmune serology testing in clinical practice: An updated roadmap for the diagnosis of autoimmune hepatitis. Eur J Intern Med 2023; 108:9-17. [PMID: 36400668 DOI: 10.1016/j.ejim.2022.11.013] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2022] [Revised: 11/04/2022] [Accepted: 11/06/2022] [Indexed: 11/18/2022]
Abstract
Diagnosis of autoimmune hepatitis (AIH) is in most cases challenging for clinicians as there is not a single specific laboratory or histological marker to diagnose or exclude the presence of the disease. The clinical spectrum of AIH varies from completely asymptomatic to acute-severe or even rarely fulminant hepatic failure, while everybody can be affected irrespective of age, gender, and ethnicity. The old revised and the newer simplified diagnostic scores have been established by the International Autoimmune Hepatitis Group (IAIHG) in 1999 and 2008, respectively, which are based on several clinical, laboratory and histological parameters. Additionally, a thorough differential diagnosis from other diseases mimicking AIH is absolutely indicated. In this context, autoantibodies detection in patients with suspected AIH is mandatory -even though not pathognomonic- not only for AIH diagnosis but furthermore, for AIH classification (AIH-type 1 and AIH-type 2). Although autoimmune serology can be supportive of AIH diagnosis in ≥95% of cases if testing has been performed according to the IAIHG guidelines, this is not the case under real-life circumstances in routine clinical laboratories. Clinicians should be careful both for the importance of the required testing and how to interpret the results and therefore, they should communicate and discuss with the laboratory personnel to achieve the maximum benefit for the patient. Herein, a detailed and updated review of the diagnostic work-up for AIH diagnosis under real-life conditions is given to minimize the underestimation and misdiagnosis of AIH which can result in progression of the disease and unfavourable outcomes.
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Affiliation(s)
- George N Dalekos
- Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, Larissa, Greece; European Reference Network on Hepatological Diseases (ERN RARE-LIVER), General University Hospital of Larissa, Larissa, Greece.
| | - Nikolaos K Gatselis
- Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, Larissa, Greece; European Reference Network on Hepatological Diseases (ERN RARE-LIVER), General University Hospital of Larissa, Larissa, Greece
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9
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Kayser C, Dutra LA, Dos Reis-Neto ET, Castro CHDM, Fritzler MJ, Andrade LEC. The Role of Autoantibody Testing in Modern Personalized Medicine. Clin Rev Allergy Immunol 2022; 63:251-288. [PMID: 35244870 DOI: 10.1007/s12016-021-08918-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/22/2021] [Indexed: 02/08/2023]
Abstract
Personalized medicine (PM) aims individualized approach to prevention, diagnosis, and treatment. Precision Medicine applies the paradigm of PM by defining groups of individuals with akin characteristics. Often the two terms have been used interchangeably. The quest for PM has been advancing for centuries as traditional nosology classification defines groups of clinical conditions with relatively similar prognoses and treatment options. However, any individual is characterized by a unique set of multiple characteristics and therefore the achievement of PM implies the determination of myriad demographic, epidemiological, clinical, laboratory, and imaging parameters. The accelerated identification of numerous biological variables associated with diverse health conditions contributes to the fulfillment of one of the pre-requisites for PM. The advent of multiplex analytical platforms contributes to the determination of thousands of biological parameters using minute amounts of serum or other biological matrixes. Finally, big data analysis and machine learning contribute to the processing and integration of the multiplexed data at the individual level, allowing for the personalized definition of susceptibility, diagnosis, prognosis, prevention, and treatment. Autoantibodies are traditional biomarkers for autoimmune diseases and can contribute to PM in many aspects, including identification of individuals at risk, early diagnosis, disease sub-phenotyping, definition of prognosis, and treatment, as well as monitoring disease activity. Herein we address how autoantibodies can promote PM in autoimmune diseases using the examples of systemic lupus erythematosus, antiphospholipid syndrome, rheumatoid arthritis, Sjögren syndrome, systemic sclerosis, idiopathic inflammatory myopathies, autoimmune hepatitis, primary biliary cholangitis, and autoimmune neurologic diseases.
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Affiliation(s)
- Cristiane Kayser
- Rheumatology Division, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil
| | | | | | | | - Marvin J Fritzler
- Department of Medicine, Cumming School of Medicine, University of Calgary, Calgary, Canada
| | - Luis Eduardo C Andrade
- Rheumatology Division, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil. .,Immunology Division, Fleury Medicine and Health Laboratories, São Paulo, Brazil.
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B cells in autoimmune hepatitis: bystanders or central players? Semin Immunopathol 2022; 44:411-427. [PMID: 35488094 PMCID: PMC9256567 DOI: 10.1007/s00281-022-00937-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2022] [Accepted: 04/07/2022] [Indexed: 02/07/2023]
Abstract
B cells are central for the adaptive immune system to mount successful immune responses not only as antibody producers but also as regulators of cellular immunity. These multifaceted features are also reflected in autoimmunity where autoreactive B cells can fuel disease by production of cytotoxic autoantibodies, presentation of autoantigens to autoreactive T cells, and secretion of cytokines and chemokines that either promote detrimental immune activation or impair regulatory T and B cells. The role of B cells and autoantibodies in autoimmune hepatitis (AIH) have been controversially discussed, with typical autoantibodies and hypergammaglobulinemia indicating a key role, while strong HLA class II association suggests T cells as key players. In this review, we summarize current knowledge on B cells in AIH and how different B cell subpopulations may drive AIH progression beyond autoantibodies. We also discuss recent findings of B cell-directed therapies in AIH.
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Muñoz-Sánchez G, Pérez-Isidro A, Ortiz de Landazuri I, López-Gómez A, Bravo-Gallego LY, Garcia-Ormaechea M, Julià MR, Viñas O, Ruiz-Ortiz E, on behalf of the 2020 GEAI-SEI Workshop Participants. Working Algorithms and Detection Methods of Autoantibodies in Autoimmune Liver Disease: A Nationwide Study. Diagnostics (Basel) 2022; 12:diagnostics12030697. [PMID: 35328252 PMCID: PMC8947365 DOI: 10.3390/diagnostics12030697] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2022] [Revised: 03/09/2022] [Accepted: 03/10/2022] [Indexed: 02/06/2023] Open
Abstract
Autoantibody detection is the cornerstone of autoimmune liver diseases (AILD) diagnosis. Standardisation of working algorithms among autoimmunity laboratories, as well as being aware of the sensitivity and specificity of various commercial techniques in daily practice, are still necessary. The aim of this nationwide study is to report the results of the 2020 Autoimmunity Workshop organised by the Autoimmunity Group of the Spanish Society of Immunology and to provide useful information to clinicians and laboratory specialists to improve the management of autoantibody detection in AILD diagnoses. Serum samples from 17 patients with liver diseases were provided by the organisers of the 2020 Autoimmunity Workshop and were subsequently analysed by the 40 participating laboratories. Each laboratory used different techniques for the detection of autoantibodies in each patients’ serum sample, according to their working algorithm. Thus, almost 680 total complete patient reports were obtained, and the number of results from different autoantibody detection techniques was >3000. Up to eight different working algorithms were employed, including indirect immunofluorescence assays (IFA) and antigen-specific techniques (AgST). The IFA of HEp-2 cells was more sensitive than IFA of rat triple tissue for the study of anti-nuclear autoantibodies (ANA) associated with AILD. The IFA of a human neutrophil study for the analysis of anti-neutrophil cytoplasmic autoantibodies was not carried out systemically in all patients, or by all laboratories. AgSTs were the most sensitive methods for the detection of anti-smooth muscle/F-actin, soluble liver antigen, liver cytosol-1, M2-mitochondrial autoantibodies, and ANA associated with primary biliary cholangitis. The main differences in AMA detection were due to patients with autoantibodies against the non-dominant epitope of pyruvate dehydrogenase complex. Given that they are complementary, IFA and AgST should be performed in parallel. If there is high suspicion of AILD, AgST should always be performed.
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Affiliation(s)
- Guillermo Muñoz-Sánchez
- Department of Immunology, Centre de Diagnòstic Biomèdic, Hospital Clínic de Barcelona, Villarroel 170-Escala 4, Planta 0, 08036 Barcelona, Spain; (G.M.-S.); (A.P.-I.); (I.O.d.L.); (L.Y.B.-G.); (O.V.)
| | - Albert Pérez-Isidro
- Department of Immunology, Centre de Diagnòstic Biomèdic, Hospital Clínic de Barcelona, Villarroel 170-Escala 4, Planta 0, 08036 Barcelona, Spain; (G.M.-S.); (A.P.-I.); (I.O.d.L.); (L.Y.B.-G.); (O.V.)
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona, 08036 Barcelona, Spain
| | - Iñaki Ortiz de Landazuri
- Department of Immunology, Centre de Diagnòstic Biomèdic, Hospital Clínic de Barcelona, Villarroel 170-Escala 4, Planta 0, 08036 Barcelona, Spain; (G.M.-S.); (A.P.-I.); (I.O.d.L.); (L.Y.B.-G.); (O.V.)
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona, 08036 Barcelona, Spain
| | - Antonio López-Gómez
- Department of Immunology, Hospital Universitari Son Espases, 07120 Palma de Mallorca, Spain; (A.L.-G.); (M.R.J.)
- Institut d’Investigació Sanitària Illes Balears, 07120 Palma de Mallorca, Spain
| | - Luz Yadira Bravo-Gallego
- Department of Immunology, Centre de Diagnòstic Biomèdic, Hospital Clínic de Barcelona, Villarroel 170-Escala 4, Planta 0, 08036 Barcelona, Spain; (G.M.-S.); (A.P.-I.); (I.O.d.L.); (L.Y.B.-G.); (O.V.)
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona, 08036 Barcelona, Spain
| | | | - Maria Rosa Julià
- Department of Immunology, Hospital Universitari Son Espases, 07120 Palma de Mallorca, Spain; (A.L.-G.); (M.R.J.)
- Institut d’Investigació Sanitària Illes Balears, 07120 Palma de Mallorca, Spain
| | - Odette Viñas
- Department of Immunology, Centre de Diagnòstic Biomèdic, Hospital Clínic de Barcelona, Villarroel 170-Escala 4, Planta 0, 08036 Barcelona, Spain; (G.M.-S.); (A.P.-I.); (I.O.d.L.); (L.Y.B.-G.); (O.V.)
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona, 08036 Barcelona, Spain
| | - Estíbaliz Ruiz-Ortiz
- Department of Immunology, Centre de Diagnòstic Biomèdic, Hospital Clínic de Barcelona, Villarroel 170-Escala 4, Planta 0, 08036 Barcelona, Spain; (G.M.-S.); (A.P.-I.); (I.O.d.L.); (L.Y.B.-G.); (O.V.)
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona, 08036 Barcelona, Spain
- Correspondence:
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Khedr MA, Salem TA, Boghdadi GM, Elharoun AS, El-Shahaway AA, Atallah HR, Sira MM. Seronegative autoimmune hepatitis in children : A real diagnostic challenge. Wien Klin Wochenschr 2022; 134:195-201. [PMID: 34283299 DOI: 10.1007/s00508-021-01907-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2020] [Accepted: 06/11/2021] [Indexed: 02/07/2023]
Abstract
BACKGROUND AND AIM Classical autoimmune hepatitis (AIH) is characterized by the presence of conventional autoantibodies (anti-smooth muscle, antinuclear and anti-liver-kidney-microsomal antibodies). The absence of such autoantibodies in some patients does not preclude AIH diagnosis or the need for its treatment. This group of patients was termed seronegative AIH. Whether non-conventional autoantibodies can identify this group of patients is still elusive. We aimed to study the prevalence of seronegativity of conventional autoantibodies and the occurrence of non-conventional autoantibodies in children with AIH. METHODS In this study, 55 children with AIH were investigated for non-conventional autoantibodies (anti-neutrophil cytoplasmic antibodies, antibodies to soluble liver antigen, anti-tissue transglutaminase and antiplatelet antibodies). All the patients received immunosuppressive therapy and were assessed for treatment response. RESULTS Of the patients 44 had classical AIH (type 1, 70.09%, type 2, 9.09%) and 20% were seronegative. The four studied non-conventional autoantibodies occurred in four patients, one for each. All non-conventional autoantibodies were exclusively associated with type 1 AIH. The clinical profile, ultrasonographic findings, liver biochemistry and histopathological findings were comparable in the classical and seronegative AIH. The majority of patients with classical (72.7%) and seronegative (54.5%) AIH were treatment responders. CONCLUSION Seronegative AIH represents a substantial percentage of pediatric patients diagnosed with AIH. They were even negative for non-conventional autoantibodies. Furthermore, apart from autoantibodies, seronegative AIH is almost indistinguishable from the classical AIH and the majority of patients were treatment responders. This favorable response to immunosuppression deserves sustainable efforts for considering such a diagnosis and start therapy to halt disease progression is worthwhile.
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Affiliation(s)
- Mohammed A Khedr
- Department of Pediatric Hepatology, Gastroenterology and Nutrition, National Liver Institute, Menoufia University, 32511, Shebin El-koom, Menoufia, Egypt
| | - Tahany A Salem
- Department of Pediatric Hepatology, Gastroenterology and Nutrition, National Liver Institute, Menoufia University, 32511, Shebin El-koom, Menoufia, Egypt.
| | - Ghada M Boghdadi
- Department of Immunology Research Laboratories, Microbiology and Immunology, Faculty of Medicine, Zagazig University, 44519, El-Sharkiya, Egypt
| | - Ahmed S Elharoun
- Department of Microbiology and Immunology, Faculty of Medicine, Menoufia University, Shebin El-koom, Menoufia, Egypt
| | - Allia A El-Shahaway
- Department of Immunology Research Laboratories, Microbiology and Immunology, Faculty of Medicine, Zagazig University, 44519, El-Sharkiya, Egypt
| | - Hany R Atallah
- Department of Pediatrics, Ahmed Maher Teaching Hospital, Ministry of Health, Cairo, Egypt
| | - Mostafa M Sira
- Department of Pediatric Hepatology, Gastroenterology and Nutrition, National Liver Institute, Menoufia University, 32511, Shebin El-koom, Menoufia, Egypt
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13
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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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14
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Terziroli Beretta-Piccoli B, Mieli-Vergani G, Vergani D. Autoimmune Hepatitis: Serum Autoantibodies in Clinical Practice. Clin Rev Allergy Immunol 2022; 63:124-137. [PMID: 34491531 PMCID: PMC9464171 DOI: 10.1007/s12016-021-08888-9] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/24/2021] [Indexed: 01/13/2023]
Abstract
Circulating autoantibodies are a key diagnostic tool in autoimmune hepatitis (AIH), being positive in 95% of the cases if tested according to dedicated guidelines issued by the International Autoimmune Hepatitis Group. They also allow the distinction between type 1 AIH, characterized by positive anti-nuclear and/or anti-smooth muscle antibody, and type 2 AIH, characterized by positive anti-liver kidney microsomal type 1 and/or anti-liver cytosol type 1 antibody. Anti-soluble liver antigen is the only AIH-specific autoantibody, and is found in 20-30% of both type 1 and type 2 AIH. Anti-neutrophil cytoplasmic antibody is frequently positive in type 1 AIH, being associated also with inflammatory bowel disease and with primary/autoimmune sclerosing cholangitis. The reference method for autoantibody testing remains indirect immunofluorescence on triple tissue (rodent liver, kidney and stomach), allowing both the detection of the majority of liver-relevant reactivities, including those autoantibodies whose molecular target antigens are unknown. Of note, the current knowledge of the clinical significance of autoantibodies relies on studies based on this technique. However, immunofluorescence requires trained laboratory personnel, is observer-dependent, and lacks standardization, leading to ongoing attempts at replacing this method with automated assays, the sensitivity, and specificity of which, however, require further studies before they can be used as a reliable alternative to immunofluorescence; currently, they may be used as complementary to immunofluorescence.
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Affiliation(s)
- Benedetta Terziroli Beretta-Piccoli
- grid.29078.340000 0001 2203 2861Epatocentro Ticino & Facoltà Di Scienze Biomediche, Università Della Svizzera Italiana, Lugano, Switzerland ,grid.29078.340000 0001 2203 2861Institute for Research in Biomedicine, Bellinzona, Switzerland ,grid.46699.340000 0004 0391 9020King’s College London Faculty of Life Sciences &, Medicine At King’s College Hospital, London, UK
| | - Giorgina Mieli-Vergani
- grid.46699.340000 0004 0391 9020King’s College London Faculty of Life Sciences &, Medicine At King’s College Hospital, London, UK ,grid.46699.340000 0004 0391 9020Paediatric Liver, GI and Nutrition Centre, MowatLabs, King’s College Hospital, London, UK
| | - Diego Vergani
- grid.46699.340000 0004 0391 9020King’s College London Faculty of Life Sciences &, Medicine At King’s College Hospital, London, UK ,grid.46699.340000 0004 0391 9020Institute of Liver Studies, MowatLabs, King’s College Hospital, London, UK
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15
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Thomas-Dupont P, Grube-Pagola P, Izaguirre-Hernández IY, Hernández-Flores KG, Sánchez-Marce EE, Cano-Contreras AD, Remes-Troche JM, Vivanco-Cid H. Development of a New Murine Model of Type 2 Autoimmune Hepatitis Using a Human Liver Protein. THE AMERICAN JOURNAL OF PATHOLOGY 2022; 192:21-30. [PMID: 34717895 DOI: 10.1016/j.ajpath.2021.10.006] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/07/2021] [Revised: 09/13/2021] [Accepted: 10/04/2021] [Indexed: 11/17/2022]
Abstract
Autoimmune hepatitis (AIH) is a chronic inflammatory condition of the liver characterized by parenchymal destruction, hypergammaglobulinemia, specific autoantibody production, and hepatic fibrosis and necrosis. Murine models of AIH have been described; however, little is known about the immunologic mechanisms of tissue destruction. In this study, a new murine model of type 2 AIH was developed using recombinant human cytochrome P450 (CYP) 2D6 emulsified with complete Freund's adjuvant (CFA). BALB/c mice were immunized with 2 μg/mL i.p. of CYP2D6 in CFA. The control group received CFA or phosphate-buffered saline alone. Alanine aminotransferase activity, autoantibody production, IgG concentrations, histologic damage, and specific T-cell response were evaluated. Persistent AIH, characterized by cellular infiltration, hepatic fibrosis, elevated alanine aminotransferase, and the production of anti-liver kidney microsomal antibody type 1 developed in CFA/CYP2D6-immunized mice. These mice presented high levels of IgG and its subclasses IgG1, IgG2a, and IgG2b against liver self-proteins. Interestingly, IL-2+ and interferon γ-positive Cyp2d6-specific T cells were present in greater concentrations in mice immunized with CFA/CYP2D6 compared with control. Immunization with CFA, in combination with a natural human autoantigen like CYP2D6, was demonstrated to break tolerance, resulting in a chronic form of autoimmune-related liver damage. This murine model of type 2 AIH is expected to be instrumental in understanding the immunologic mechanisms of the pathogenesis of this autoimmune liver disease.
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Affiliation(s)
- Pablo Thomas-Dupont
- Instituto de Investigaciones Medico-Biológicas, Universidad Veracruzana, Veracruz, México
| | - Peter Grube-Pagola
- Instituto de Investigaciones Medico-Biológicas, Universidad Veracruzana, Veracruz, México
| | | | | | - Elvis E Sánchez-Marce
- Hospital Regional de Alta Especialidad de Veracruz, Servicios de Salud de Veracruz, Veracruz, México
| | - Ana D Cano-Contreras
- Instituto de Investigaciones Medico-Biológicas, Universidad Veracruzana, Veracruz, México
| | - José M Remes-Troche
- Instituto de Investigaciones Medico-Biológicas, Universidad Veracruzana, Veracruz, México
| | - Héctor Vivanco-Cid
- Instituto de Investigaciones Medico-Biológicas, Universidad Veracruzana, Veracruz, México.
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16
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Highton AJ, Schuster IS, Degli-Esposti MA, Altfeld M. The role of natural killer cells in liver inflammation. Semin Immunopathol 2021; 43:519-533. [PMID: 34230995 PMCID: PMC8260327 DOI: 10.1007/s00281-021-00877-6] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2021] [Accepted: 06/03/2021] [Indexed: 02/07/2023]
Abstract
The liver is an important immunological site that can promote immune tolerance or activation. Natural killer (NK) cells are a major immune subset within the liver, and therefore understanding their role in liver homeostasis and inflammation is crucial. Due to their cytotoxic function, NK cells are important in the immune response against hepatotropic viral infections but are also involved in the inflammatory processes of autoimmune liver diseases and fatty liver disease. Whether NK cells primarily promote pro-inflammatory or tolerogenic responses is not known for many liver diseases. Understanding the involvement of NK cells in liver inflammation will be crucial in effective treatment and future immunotherapeutic targeting of NK cells in these disease settings. Here, we explore the role that NK cells play in inflammation of the liver in the context of viral infection, autoimmunity and fatty liver disease.
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Affiliation(s)
- A J Highton
- Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany
| | - I S Schuster
- Experimental and Viral Immunology, Department of Microbiology and Infection and Immunity Program, Monash Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia.,Experimental Immunology, Lions Eye Institute, Perth, Western Australia, Australia
| | - M A Degli-Esposti
- Experimental and Viral Immunology, Department of Microbiology and Infection and Immunity Program, Monash Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia.,Experimental Immunology, Lions Eye Institute, Perth, Western Australia, Australia
| | - M Altfeld
- Institute for Immunology, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.
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17
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Mack CL, Adams D, Assis DN, Kerkar N, Manns MP, Mayo MJ, Vierling JM, Alsawas M, Murad MH, Czaja AJ. Diagnosis and Management of Autoimmune Hepatitis in Adults and Children: 2019 Practice Guidance and Guidelines From the American Association for the Study of Liver Diseases. Hepatology 2020; 72:671-722. [PMID: 31863477 DOI: 10.1002/hep.31065] [Citation(s) in RCA: 548] [Impact Index Per Article: 109.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2019] [Accepted: 11/25/2019] [Indexed: 02/06/2023]
Affiliation(s)
- Cara L Mack
- Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO
| | - David Adams
- Centre for Liver Research, University of Birmingham, Birmingham, UK
| | - David N Assis
- Department of Internal Medicine, Yale School of Medicine, New Haven, CT
| | - Nanda Kerkar
- Golisano Children's Hospital at Strong, University of Rochester Medical Center, New York, NY
| | - Michael P Manns
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Marlyn J Mayo
- Division of Digestive and Liver Diseases, University of Texas SW Medical Center, Dallas, TX
| | - John M Vierling
- Medicine and Surgery, Baylor College of Medicine, Houston, TX
| | | | - Mohammad H Murad
- Mayo Knowledge and Encounter Research Unit, Mayo Clinic College of Medicine, Rochester, MN
| | - Albert J Czaja
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN
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18
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Autoimmune Hepatitis-Immunologically Triggered Liver Pathogenesis-Diagnostic and Therapeutic Strategies. J Immunol Res 2019; 2019:9437043. [PMID: 31886312 PMCID: PMC6899271 DOI: 10.1155/2019/9437043] [Citation(s) in RCA: 82] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2019] [Revised: 09/15/2019] [Accepted: 09/21/2019] [Indexed: 12/20/2022] Open
Abstract
Autoimmune hepatitis (AIH) is a severe liver disease that arises in genetically predisposed male and female individuals worldwide. Diagnosis of AIH is made clinically applying diagnostic scores; however, the heterotopic disease phenotype often makes a rapid determination of disease challenging. AIH responds favorably to steroids and pharmacologic immunosuppression, and liver transplantation is only necessary in cases with acute liver failure or end-stage liver cirrhosis. Recurrence or development of de novo AIH after transplantation is possible, and treatment is similar to standard AIH therapy. Current experimental investigations of T cell-mediated autoimmune pathways and analysis of changes within the intestinal microbiome might advance our knowledge on the pathogenesis of AIH and trigger a spark of hope for novel therapeutic strategies.
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19
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Webb GJ, Hirschfield GM, Krawitt EL, Gershwin ME. Cellular and Molecular Mechanisms of Autoimmune Hepatitis. ANNUAL REVIEW OF PATHOLOGY-MECHANISMS OF DISEASE 2019; 13:247-292. [PMID: 29140756 DOI: 10.1146/annurev-pathol-020117-043534] [Citation(s) in RCA: 96] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Autoimmune hepatitis is an uncommon idiopathic syndrome of immune-mediated destruction of hepatocytes, typically associated with autoantibodies. The disease etiology is incompletely understood but includes a clear association with human leukocyte antigen (HLA) variants and other non-HLA gene variants, female sex, and the environment. Pathologically, there is a CD4+ T cell-rich lymphocytic inflammatory infiltrate with variable hepatocyte necrosis and subsequent hepatic fibrosis. Attempts to understand pathogenesis are informed by several monogenetic syndromes that may include autoimmune liver injury, by several drug and environmental agents that have been identified as triggers in a minority of cases, by human studies that point toward a central role for CD4+ effector and regulatory T cells, and by animal models of the disease. Nonspecific immunosuppression is the current standard therapy. Further understanding of the disease's cellular and molecular mechanisms may assist in the design of better-targeted therapies, aid the limitation of adverse effects from therapy, and inform individualized risk assessment and prognostication.
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Affiliation(s)
- G J Webb
- National Institute for Health Research Liver Biomedical Research Centre, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham B15 2TT, United Kingdom; ,
| | - G M Hirschfield
- National Institute for Health Research Liver Biomedical Research Centre, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham B15 2TT, United Kingdom; ,
| | - E L Krawitt
- Department of Medicine, University of Vermont, Burlington, Vermont 05405, USA; .,Department of Medicine, Dartmouth College, Hanover, New Hampshire 03755, USA
| | - M E Gershwin
- Division of Rheumatology, Allergy, and Clinical Immunology, School of Medicine, University of California, Davis, California 95817, USA;
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20
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Terziroli Beretta-Piccoli B, Mieli-Vergani G, Vergani D. The clinical usage and definition of autoantibodies in immune-mediated liver disease: A comprehensive overview. J Autoimmun 2018; 95:144-158. [DOI: 10.1016/j.jaut.2018.10.004] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2018] [Revised: 10/09/2018] [Accepted: 10/11/2018] [Indexed: 02/06/2023]
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21
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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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22
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Sebode M, Weiler-Normann C, Liwinski T, Schramm C. Autoantibodies in Autoimmune Liver Disease-Clinical and Diagnostic Relevance. Front Immunol 2018; 9:609. [PMID: 29636752 PMCID: PMC5880919 DOI: 10.3389/fimmu.2018.00609] [Citation(s) in RCA: 81] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2018] [Accepted: 03/12/2018] [Indexed: 12/12/2022] Open
Abstract
Testing for liver-related autoantibodies should be included in the workup of patients with hepatitis or cholestasis of unknown origin. Although most of these autoantibodies are not disease specific, their determination is a prerequisite to diagnose autoimmune hepatitis (AIH) and primary biliary cholangitis (PBC), and they are components of the diagnostic scoring system in these diseases. In primary sclerosing cholangitis (PSC), on the other hand, autoantibodies are frequently present but play a minor role in establishing the diagnosis. In PSC, however, data on antibodies suggest a link between disease pathogenesis and the intestinal microbiota. This review will focus on practical aspects of antibody testing in the three major autoimmune liver diseases AIH, PBC, and PSC.
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Affiliation(s)
- Marcial Sebode
- 1st Department of Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
| | - Christina Weiler-Normann
- 1st Department of Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.,Martin Zeitz Centre for Rare Diseases, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
| | - Timur Liwinski
- 1st Department of Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
| | - Christoph Schramm
- 1st Department of Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.,Martin Zeitz Centre for Rare Diseases, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
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23
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Terziroli Beretta-Piccoli B, Mieli-Vergani G, Vergani D. Serology in autoimmune hepatitis: A clinical-practice approach. Eur J Intern Med 2018; 48:35-43. [PMID: 29056396 DOI: 10.1016/j.ejim.2017.10.006] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/03/2017] [Accepted: 10/06/2017] [Indexed: 12/23/2022]
Abstract
Serology is key to the diagnosis of autoimmune hepatitis (AIH). Clinicians need to be aware of which tests to request, how to interpret the laboratory reports, and be familiar with the laboratory methodology. If correctly tested, >95% of AIH patients show some serological reactivity. Indirect immunofluorescence on triple rodent tissue is recommended as first screening step, since it allows the detection of all liver-relevant autoantibodies, except for anti-soluble liver antigen (SLA) antibody, which needs to be detected by molecular based assays. The threshold of immunofluorescence positivity is a titer equal or exceeding 1/40, but for patients younger than 18years even lower titers are clinically significant. Anti-nuclear antibody (ANA) and/or anti-smooth muscle (SMA) antibody characterize type 1 AIH. ANA in AIH typically shows a homogeneous staining pattern on HEp2 cells, without any specific target antigen. Anti-SMA displays different staining patterns on indirect immunofluorescence: the vascular/glomerular (VG) and the vascular/glomerular/tubular (VGT) patterns are considered specific for AIH, whilst the V pattern can be found in a variety of diseases. Type 2 AIH, which is rare and affects mostly children/adolescents, is characterized by anti-liver kidney microsomal 1 and/or anti-liver cytosol 1 antibodies. The presence of anti-neutrophil cytoplasmic antibody (ANCA), particularly atypical p-ANCA (pANNA), points to the diagnosis of AIH, especially in absence of other autoantibodies. Since it is associated with sclerosing cholangitis and inflammatory bowel disease, these conditions have to be ruled out. The only antibody specific for AIH is anti-SLA, which is associated with a more severe disease course.
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Affiliation(s)
| | - Giorgina Mieli-Vergani
- Paediatric Liver, GI and Nutrition Centre, MowatLabs, King's College Hospital, Denmark Hill, London SE5 9RS, UK
| | - Diego Vergani
- Institute of Liver Studies, MowatLabs, King's College Hospital, Denmark Hill, London SE5 9RS, UK.
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24
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Sebode M, Hartl J, Vergani D, Lohse AW. Autoimmune hepatitis: From current knowledge and clinical practice to future research agenda. Liver Int 2018; 38:15-22. [PMID: 28432836 DOI: 10.1111/liv.13458] [Citation(s) in RCA: 65] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2017] [Accepted: 04/12/2017] [Indexed: 12/12/2022]
Abstract
Autoimmune hepatitis is a chronic inflammatory liver disease. Unknown triggers lead to a mainly T cell-mediated immune response targeting the liver, the main auto-antigen of which has not been identified yet. The diagnosis of autoimmune hepatitis is based on the elevation of immunoglobulin G/hypergammaglobulinemia, detection of characteristic autoantibodies as well as a typical pattern on liver histology. Exclusion of other causes of hepatitis and response to immunosuppressive treatment support the diagnosis of autoimmune hepatitis. The mainstay of autoimmune hepatitis treatment has, from its first description to the current time, consisted of predniso(lo)ne to induce remission, in combination with azathioprine, which is used to maintain it. Nonetheless, side effects and non-response with ongoing inflammation despite standard therapy demand treatment alternatives. Only through a better understanding of the pathogenesis of autoimmune hepatitis can a more selective and effective treatment be offered to patients in the future. Until this goal is reached, improvement of diagnostic approaches and optimization of current therapy rank highest on the research agenda for autoimmune hepatitis.
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Affiliation(s)
- Marcial Sebode
- I. Department of Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
| | - Johannes Hartl
- I. Department of Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
| | - Diego Vergani
- Institute of Liver Studies, King's College Hospital, London, UK
| | - Ansgar W Lohse
- I. Department of Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
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25
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Sebode M, Schulz L, Lohse AW. "Autoimmune(-Like)" Drug and Herb Induced Liver Injury: New Insights into Molecular Pathogenesis. Int J Mol Sci 2017; 18:ijms18091954. [PMID: 28895915 PMCID: PMC5618603 DOI: 10.3390/ijms18091954] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2017] [Revised: 09/04/2017] [Accepted: 09/08/2017] [Indexed: 12/12/2022] Open
Abstract
Idiosyncratic drug-induced liver injury (DILI) and hepatic injury due to herbal and dietary supplements (HDS) can adapt clinical characteristics of autoimmune hepatitis (AIH), such as the appearance of autoantibodies and infiltration of the liver by immune competent cells. To describe these cases of DILI/HDS, the poorly-defined term "autoimmune(-like)" DILI/HDS came up. It is uncertain if these cases represent a subgroup of DILI/HDS with distinct pathomechanistic and prognostic features different from "classical" DILI/HDS. Besides, due to the overlap of clinical characteristics of "immune-mediated" DILI/HDS and AIH, both entities are not easy to differentiate. However, the demarcation is important, especially with regard to treatment: AIH requires long-term, mostly lifelong immunosuppression, whereas DILI/HDS does not. Only through exact diagnostic evaluation, exclusion of differential diagnoses and prolonged follow-up can the correct diagnosis reliably be made. Molecular mechanisms have not been analysed for the subgroup of "autoimmune(-like)" DILI/HDS yet. However, several pathogenetic checkpoints of DILI/HDS in general and AIH are shared. An analysis of these shared mechanisms might hint at relevant molecular processes of "autoimmune(-like)" DILI/HDS.
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Affiliation(s)
- Marcial Sebode
- Department of Medicine, University Medical Centre Hamburg-Eppendorf, 20246 Hamburg, Germany.
| | - Lisa Schulz
- Department of Medicine, University Medical Centre Hamburg-Eppendorf, 20246 Hamburg, Germany.
| | - Ansgar W Lohse
- Department of Medicine, University Medical Centre Hamburg-Eppendorf, 20246 Hamburg, Germany.
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26
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Muratori P, Lenzi M, Cassani F, Lalanne C, Muratori L. Diagnostic approach to autoimmune hepatitis. Expert Rev Clin Immunol 2017; 13:769-779. [PMID: 28480763 DOI: 10.1080/1744666x.2017.1327355] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease which, if left without treatment, can evolve into cirrhosis and possibly liver failure. The diagnosis of AIH is hampered by the lack of specific and reliable markers of the disease and a number of clinical, biochemical, immunological, histological and genetic factors should be considered to reach a confident diagnosis Areas covered: Clinical expression of AIH, histological features, serological and genetic profiles, differential diagnosis, overlap with other autoimmune liver diseases, assessed on the basis of personal experience and review of published literature in the last 10 years through a systematic Medline search (keywords: autoimmune hepatitis, diagnosis) Expert commentary: Notwithstanding numerous efforts to identify simple and reliable markers of the disease, the diagnosis of AIH is still based on the combination of histological, immunological and biochemical features and often can represent a real challenge for the hepatologist.
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Affiliation(s)
- Paolo Muratori
- a Center for the Study and Treatment of Autoimmune Diseases of the Liver and Biliary System , Policlinico di Sant'Orsola, University of Bologna , Bologna , Italy
| | - Marco Lenzi
- a Center for the Study and Treatment of Autoimmune Diseases of the Liver and Biliary System , Policlinico di Sant'Orsola, University of Bologna , Bologna , Italy
| | - Fabio Cassani
- a Center for the Study and Treatment of Autoimmune Diseases of the Liver and Biliary System , Policlinico di Sant'Orsola, University of Bologna , Bologna , Italy
| | - Claudine Lalanne
- a Center for the Study and Treatment of Autoimmune Diseases of the Liver and Biliary System , Policlinico di Sant'Orsola, University of Bologna , Bologna , Italy
| | - Luigi Muratori
- a Center for the Study and Treatment of Autoimmune Diseases of the Liver and Biliary System , Policlinico di Sant'Orsola, University of Bologna , Bologna , Italy
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Diagnostic autoantibodies for autoimmune liver diseases. Clin Transl Immunology 2017; 6:e139. [PMID: 28690845 PMCID: PMC5493583 DOI: 10.1038/cti.2017.14] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2016] [Revised: 03/22/2017] [Accepted: 03/22/2017] [Indexed: 12/17/2022] Open
Abstract
Autoimmune liver diseases are conditions of low prevalence that comprise the triad of autoimmune hepatitis, primary biliary cholangitis (cirrhosis) and primary sclerosing cholangitis and their poorly characterised overlapping syndromes. Diagnostic autoantibodies are associated with autoimmune hepatitis and primary biliary cholangitis but not with primary sclerosing cholangitis. Autoantibodies are useful disease markers that facilitate early diagnosis of autoimmune hepatitis and primary biliary cholangitis and allow for therapeutic intervention to prevent progression to liver cirrhosis and associated complications. Adult onset type 1 autoimmune hepatitis is associated with F-actin reactive smooth muscle autoantibody, antinuclear autoantibody in 60% of patients, and autoantibody to SLA/LP in 15–20%. Juvenile onset type 2 autoimmune hepatitis is associated with LKM-1 and LC-1 autoantibodies. Primary biliary cholangitis is associated with a mitochondria-associated autoantibody designated M2 in >90% of patients and with disease-specific antinuclear autoantibodies in 50% that bind to antigens in the nuclear core complex and in multiple nuclear dots. Autoantibodies to the nuclear core complex target gp210, nucleoporin p62 and nuclear lamin B receptor. Autoantibodies to multiple nuclear dots target Sp100 and PML antigens. Liver autoantibodies in asymptomatic patients with normal liver function may precede the subsequent development of overt autoimmune liver disease. For routine diagnostic immunology laboratories, initial screening for liver autoantibodies by immunofluorescence remains the method of choice with confirmation for reactivity with their target antigen by enzyme-linked immunosorbent assay (ELISA) or line blot when required.
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Joshi D, Gupta N, Samyn M, Deheragoda M, Dobbels F, Heneghan MA. The management of childhood liver diseases in adulthood. J Hepatol 2017; 66:631-644. [PMID: 27914924 DOI: 10.1016/j.jhep.2016.11.013] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2016] [Revised: 11/20/2016] [Accepted: 11/21/2016] [Indexed: 12/12/2022]
Abstract
An increasing number of patients with childhood liver disease survive into adulthood. These young adults are now entering adult services and require ongoing management. Aetiologies can be divided into liver diseases that develop in young adults which present to adult hepatologists i.e., biliary atresia and Alagille syndrome or liver diseases that occur in children/adolescents and adults i.e., autoimmune hepatitis or Wilson's disease. To successfully manage these young adults, a dynamic and responsive transition service is essential. In this review, we aim to describe the successful components of a transition service highlighting the importance of self-management support and a multi-disciplinary approach. We will also review some of the liver specific aetiologies which are unique to young adults, offering an update on pathogenesis, management and outcomes.
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Affiliation(s)
- Deepak Joshi
- Institute of Liver Studies, King's College Hospital, London, UK.
| | - Nitika Gupta
- Division of Paediatric Gastroenterology, Emory University School of Medicine, Atlanta, USA
| | - Marianne Samyn
- Institute of Liver Studies, King's College Hospital, London, UK
| | | | - Fabienne Dobbels
- Academic Centre for Nursing and Midwifery, Katholieke Universiteit Leuven, Belgium
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Cassim S, Bilodeau M, Vincent C, Lapierre P. Novel Immunotherapies for Autoimmune Hepatitis. Front Pediatr 2017; 5:8. [PMID: 28184367 PMCID: PMC5266689 DOI: 10.3389/fped.2017.00008] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2016] [Accepted: 01/10/2017] [Indexed: 12/23/2022] Open
Abstract
Autoimmune hepatitis (AIH) is a multifactorial autoimmune disease of unknown pathogenesis, characterized by a loss of immunological tolerance against liver autoantigens resulting in the progressive destruction of the hepatic parenchyma. Current treatments are based on non-specific immunosuppressive drugs. Although tremendous progress has been made using specific biological agents in other inflammatory diseases, progress has been slow to come for AIH patients. While current treatments are successful in the majority of patients, treatment discontinuation is difficult to achieve, and relapses are frequent. Lifelong immunosuppression is not without risks, especially in the pediatric population; 4% of patient with type 1 AIH will eventually develop hepatocellular carcinoma with a 2.9% probability after 10 years of treatment. Therefore, future treatments should aim to restore tolerance to hepatic autoantigens and induce long-term remission. Promising new immunotherapies have been tested in experimental models of AIH including T and B cell depletion and regulatory CD4+ T cells infusion. Clinical studies on limited numbers of patients have also shown encouraging results using B-cell-depleting (rituximab) and anti-TNF-α (infliximab) antibodies. A better understanding of key molecular targets in AIH combined with effective site-specific immunotherapies could lead to long-term remission without blanket immunosuppression and with minimal deleterious side effects.
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Affiliation(s)
- Shamir Cassim
- Laboratoire d'hépatologie cellulaire, Centre de recherche du Centre hospitalier de l'Université de Montréal (CRCHUM) , Montréal, QC , Canada
| | - Marc Bilodeau
- Laboratoire d'hépatologie cellulaire, Centre de recherche du Centre hospitalier de l'Université de Montréal (CRCHUM), Montréal, QC, Canada; Département de médecine, Université de Montréal, Montréal, QC, Canada
| | - Catherine Vincent
- Département de médecine, Université de Montréal , Montréal, QC , Canada
| | - Pascal Lapierre
- Laboratoire d'hépatologie cellulaire, Centre de recherche du Centre hospitalier de l'Université de Montréal (CRCHUM), Montréal, QC, Canada; Département de médecine, Université de Montréal, Montréal, QC, Canada
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Mitra S, Minz RW. Autoantibodies in Autoimmune Liver Diseases-Methods of Detection and Interpretation: An Update for the Reporting Pathologist. Int J Surg Pathol 2016; 24:576-85. [PMID: 27388199 DOI: 10.1177/1066896916657643] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
Autoimmune liver disease (AILD) is a type of chronic liver disease with autoimmune etiology. The diagnosis of the disease is multipronged and detection of autoantibodies in AILDs is an important diagnostic tool and it also helps in the classification of the disease. There are multiple autoantibodies that are detected in AILDs but none is diagnostic. Moreover, these autoantibodies are detected in many other pathological and nonpathological conditions. So the significance of seropositivity for these autoantibodies should be known by both the pathologists as well as the clinicians. In addition, there is prognostic significance associated with some of the antibodies and they also sometimes help in the disease monitoring. The whole array of antibodies detected in AILDs is discussed in detail in this review along with their clinical significance and interpretation.
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Affiliation(s)
- Suvradeep Mitra
- PGIMER (Post-Graduate Institute of Medical Education and Research), Chandigarh, India
| | - Ranjana Walker Minz
- PGIMER (Post-Graduate Institute of Medical Education and Research), Chandigarh, India
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31
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Czaja AJ. Diagnosis and Management of Autoimmune Hepatitis: Current Status and Future Directions. Gut Liver 2016; 10:177-203. [PMID: 26934884 PMCID: PMC4780448 DOI: 10.5009/gnl15352] [Citation(s) in RCA: 101] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2015] [Accepted: 11/04/2015] [Indexed: 02/06/2023] Open
Abstract
Autoimmune hepatitis is characterized by autoantibodies, hypergammaglobulinemia, and interface hepatitis on histological examination. The features lack diagnostic specificity, and other diseases that may resemble autoimmune hepatitis must be excluded. The clinical presentation may be acute, acute severe (fulminant), or asymptomatic; conventional autoantibodies may be absent; centrilobular necrosis and bile duct changes may be present; and the disease may occur after liver transplantation or with features that suggest overlapping disorders. The diagnostic criteria have been codified, and diagnostic scoring systems can support clinical judgment. Nonstandard autoantibodies, including antibodies to actin, α-actinin, soluble liver antigen, perinuclear antineutrophil antigen, asialoglycoprotein receptor, and liver cytosol type 1, are tools that can support the diagnosis, especially in patients with atypical features. Prednisone or prednisolone in combination with azathioprine is the preferred treatment, and strategies using these medications in various doses can ameliorate treatment failure, incomplete response, drug intolerance, and relapse after drug withdrawal. Budesonide, mycophenolate mofetil, and calcineurin inhibitors can be considered in selected patients as frontline or salvage therapies. Molecular (recombinant proteins and monoclonal antibodies), cellular (adoptive transfer and antigenic manipulation), and pharmacological (antioxidants, antifibrotics, and antiapoptotic agents) interventions constitute future directions in management. The evolving knowledge of the pathogenic pathways and the advances in technology promise new management algorithms.
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Affiliation(s)
- Albert J. Czaja
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN,
USA
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Bittencourt PL, Cançado ELR, Couto CA, Levy C, Porta G, Silva AEB, Terrabuio DRB, Carvalho Filho RJD, Chaves DM, Miura IK, Codes L, Faria LC, Evangelista AS, Farias AQ, Gonçalves LL, Harriz M, Lopes Neto EPA, Luz GO, Oliveira P, Oliveira EMGD, Schiavon JLN, Seva-Pereira T, Parise ER, Parise ER. Brazilian society of hepatology recommendations for the diagnosis and management of autoimmune diseases of the liver. ARQUIVOS DE GASTROENTEROLOGIA 2015; 52 Suppl 1:15-46. [DOI: 10.1590/s0004-28032015000500002] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
ABSTRACT In order to draw evidence-based recommendations concerning the management of autoimmune diseases of the liver, the Brazilian Society of Hepatology has sponsored a single-topic meeting in October 18th, 2014 at São Paulo. An organizing committee comprised of seven investigators was previously elected by the Governing Board to organize the scientific agenda as well as to select twenty panelists to make a systematic review of the literature and to present topics related to the diagnosis and treatment of autoimmune hepatitis, primary sclerosing cholangitis, primary biliary cirrhosis and their overlap syndromes. After the meeting, all panelists gathered together for the discussion of the topics and the elaboration of those recommendations. The text was subsequently submitted for suggestions and approval of all members of the Brazilian Society of Hepatology through its homepage. The present paper is the final version of the reviewed manuscript organized in topics, followed by the recommendations of the Brazilian Society of Hepatology.
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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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Muratori P, Lalanne C, Fabbri A, Cassani F, Lenzi M, Muratori L. Type 1 and type 2 autoimmune hepatitis in adults share the same clinical phenotype. Aliment Pharmacol Ther 2015; 41:1281-1287. [PMID: 25898847 DOI: 10.1111/apt.13210] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2015] [Revised: 02/24/2015] [Accepted: 03/31/2015] [Indexed: 12/12/2022]
Abstract
BACKGROUND Autoimmune hepatitis (AIH) is historically classified into type 1 and type 2 on the basis of the autoantibody profile, anti-nuclear and/or anti-smooth muscle antibodies being the serological markers of type 1 AIH, whereas anti-liver/kidney microsomal antibody type 1 and/or anti-liver cytosol antibody type 1 characterise type 2 AIH. AIM To evaluate whether such a distinction is justified on the basis of different expression of the disease in adults. METHODS Twenty-six adult patients with type 2 AIH and 52 age- and sex-matched patients with type 1 AIH, representative of the entire cohort of adults with type 1 AIH, were compared at onset and during follow-up. RESULTS At diagnosis, median age was 26 years (range 17-53), female sex 86%, acute presentation 43%, severe liver histology 54%, cirrhosis 14%, complete response to treatment 52%, progression of the disease 17%, and median disease duration 72 months (range 12-280). HLA-DRB1*0301 was present in 26%, HLA-DRB1*0401 in 23% and HLA-DRB1*0701 in 25%. Clinical presentation, biochemical parameters, severe liver histology, genetic profile, response rate and progression of the disease were identical between type 1 and type 2 AIH. CONCLUSION There is not enough clinical, biochemical, histological or genetic reason to subdivide adults with autoimmune hepatitis into type 1 and type 2 on the basis of the autoantibody profile, and the term 'autoimmune hepatitis' without qualification should be preferred.
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Affiliation(s)
- P Muratori
- Centro per lo Studio e la Cura delle Malattie Autoimmuni del Fegato e delle Vie Biliari, Bologna, Italy
- Dipartimento di Scienze Mediche e Chirurgiche (DIMEC), Alma Mater Studiorum - Università di Bologna, Bologna, Italy
| | - C Lalanne
- Centro per lo Studio e la Cura delle Malattie Autoimmuni del Fegato e delle Vie Biliari, Bologna, Italy
- Dipartimento di Scienze Mediche e Chirurgiche (DIMEC), Alma Mater Studiorum - Università di Bologna, Bologna, Italy
| | - A Fabbri
- Centro per lo Studio e la Cura delle Malattie Autoimmuni del Fegato e delle Vie Biliari, Bologna, Italy
- Dipartimento di Scienze Mediche e Chirurgiche (DIMEC), Alma Mater Studiorum - Università di Bologna, Bologna, Italy
| | - F Cassani
- Centro per lo Studio e la Cura delle Malattie Autoimmuni del Fegato e delle Vie Biliari, Bologna, Italy
- Azienda Ospedaliero-Universitaria di Bologna, Policlinico Sant'Orsola-Malpighi, via Massarenti 9, Bologna 40138, Bologna, Italy
| | - M Lenzi
- Centro per lo Studio e la Cura delle Malattie Autoimmuni del Fegato e delle Vie Biliari, Bologna, Italy
- Dipartimento di Scienze Mediche e Chirurgiche (DIMEC), Alma Mater Studiorum - Università di Bologna, Bologna, Italy
| | - L Muratori
- Centro per lo Studio e la Cura delle Malattie Autoimmuni del Fegato e delle Vie Biliari, Bologna, Italy
- Dipartimento di Scienze Mediche e Chirurgiche (DIMEC), Alma Mater Studiorum - Università di Bologna, Bologna, Italy
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Regulatory T Cells in Autoimmune and Viral Chronic Hepatitis. J Immunol Res 2015; 2015:479703. [PMID: 26106627 PMCID: PMC4464004 DOI: 10.1155/2015/479703] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2015] [Accepted: 05/21/2015] [Indexed: 12/26/2022] Open
Abstract
In both autoimmune liver disease and chronic viral hepatitis, the injury results from an immune-mediated cytotoxic T cell response to liver cells. As such, it is not surprising that CD4(+) regulatory T cells, a key regulatory population of T cells able to curb immune responses, could be involved in both autoimmune hepatitis and chronic viral hepatitis. The liver can induce the conversion of naïve CD4(+) T cells to CD4(+) regulatory T cells and induce tolerance to locally expressed antigens. This tolerance mechanism is carefully regulated in physiological conditions but any imbalance could be pathological. An overly tolerant immune response can lead to chronic infections while an overreactive and unbridled immune response can lead to autoimmune hepatitis. With the recent advent of monoclonal antibodies able to target regulatory T cells (daclizumab) and improve immune responses and several ongoing clinical trials analysing the impact of regulatory T cell infusion on autoimmune liver disease or liver transplant tolerance, modulation of immunological tolerance through CD4(+) regulatory T cells could be a key element of future immunotherapies for several liver diseases allowing restoring the balance between proper immune responses and tolerance. .
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Liberal R, Vergani D, Mieli-Vergani G. Update on Autoimmune Hepatitis. J Clin Transl Hepatol 2015; 3:42-52. [PMID: 26357634 PMCID: PMC4542083 DOI: 10.14218/jcth.2014.00032] [Citation(s) in RCA: 65] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2014] [Revised: 12/08/2014] [Accepted: 12/08/2014] [Indexed: 12/17/2022] Open
Abstract
Autoimmune hepatitis (AIH), a liver disorder affecting both children and adults, is characterized by inflammatory liver histology, elevated transaminase levels, circulating nonorganspecific autoantibodies, and increased levels of immunoglobulin G, in the absence of a known etiology. Two types of AIH are recognized according to seropositivity: smooth muscle antibody and/or antinuclear antibody define AIH type 1 and antibodies to liver-kidney microsome type 1 and/or liver cytosol type 1 define AIH type 2. AIH type 1 affects both adults and children, while AIH type 2 is mainly a paediatric disease, though it does occasionally affects young adults. AIH should be considered during the diagnostic workup of any patient with increased liver enzyme levels. AIH is exquisitely responsive to immunosuppressive treatment with prednisolone with or without azathioprine, with symptom free long-term survival for the majority of patients. For those who do not respond to standard treatment, or who are difficult-to-treat, mycophenolate mofetil and, in the absence of a response, calcineurin inhibitors should be tried in addition to steroids. The pathogenesis of AIH is not fully understood, although there is mounting evidence that genetic susceptibility, molecular mimicry and impaired immunoregulatory networks contribute to the initiation and perpetuation of the autoimmune attack. Liver damage is thought to be mediated primarily by CD4 T-cells, although recent studies support the involvement of diverse populations, including Th17 cells. A deeper understanding of the pathogenesis of AIH is likely to contribute to the development of novel treatments, such as the adoptive transfer of autologous expanded antigenspecific regulatory T-cells, which ultimately aim at restoring tolerance to liver-derived antigens.
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Affiliation(s)
- Rodrigo Liberal
- Paediatric Liver, GI & Nutrition Centre and Institute of Liver Studies, King's College London School of Medicine at King's College Hospital, London, UK
| | - Diego Vergani
- Paediatric Liver, GI & Nutrition Centre and Institute of Liver Studies, King's College London School of Medicine at King's College Hospital, London, UK
| | - Giorgina Mieli-Vergani
- Paediatric Liver, GI & Nutrition Centre and Institute of Liver Studies, King's College London School of Medicine at King's College Hospital, London, UK
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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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Gatselis NK, Zachou K, Koukoulis GK, Dalekos GN. Autoimmune hepatitis, one disease with many faces: Etiopathogenetic, clinico-laboratory and histological characteristics. World J Gastroenterol 2015; 21:60-83. [PMID: 25574080 PMCID: PMC4284362 DOI: 10.3748/wjg.v21.i1.60] [Citation(s) in RCA: 128] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2014] [Revised: 10/30/2014] [Accepted: 11/19/2014] [Indexed: 02/06/2023] Open
Abstract
Autoimmune hepatitis (AIH) is an unresolving progressive liver disease of unknown etiology characterized by hypergammaglobulinemia, autoantibodies detection and interface hepatitis. Due to the absence of specific diagnostic markers and the large heterogeneity of its clinical, laboratory and histological features, AIH diagnosis may be potentially difficult. Therefore, in this in-depth review we summarize the substantial progress on etiopathogenesis, clinical, serological and histological phenotypes of AIH. AIH has a global distribution affecting any age, both sexes and all ethnic groups. Clinical manifestations vary from asymptomatic to severe or rarely fulminant hepatitis. Hypergammaglobulinemia with selective elevation of IgG is found in most cases. Autoimmune attack is perpetuated, possibly via molecular mimicry, and favored by the impaired control of T-regulatory cells. Histology (interface hepatitis, emperipolesis and hepatic rosette formation) and autoantibodies detection although not pathognomonic, are still the hallmark for a timely diagnosis. AIH remains a major diagnostic challenge. AIH should be considered in every case in the absence of viral, metabolic, genetic and toxic etiology of chronic or acute hepatitis. Laboratory personnel, hepato-pathologists and clinicians need to become more familiar with disease expressions and the interpretation of liver histology and autoimmune serology to derive maximum benefit for the patient.
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Maggiore G, Nastasio S, Sciveres M. Juvenile autoimmune hepatitis: Spectrum of the disease. World J Hepatol 2014; 6:464-476. [PMID: 25067998 PMCID: PMC4110538 DOI: 10.4254/wjh.v6.i7.464] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2013] [Revised: 03/19/2014] [Accepted: 05/29/2014] [Indexed: 02/06/2023] Open
Abstract
Juvenile autoimmune hepatitis (JAIH) is a progressive inflammatory liver disease, affecting mainly young girls, from infancy to late adolescence, characterized by active liver damage, as shown by high serum activity of aminotransferases, by elevated immunoglobulin G levels, high titers of serum non organ-specific and organ-specific autoantibodies, and by interface hepatitis on liver biopsy. It is a multifactorial disease of unknown etiology in which environmental factors act as a trigger in genetically predisposed individuals. Two types of JAIH are identified according to the autoantibody panel detected at diagnosis: AIH-1, characterized by the presence of anti-smooth muscle antibody and/or antinuclear antibody and AIH-2, by anti-liver-kidney microsomal antibody type 1 and/or by the presence of anti-liver cytosol type 1 antibody. Epidemiological distribution, genetic markers, clinical presentation and pattern of serum cytokines differentiate the two types of AIH suggesting possible pathogenetic mechanisms. The most effective therapy for AIH is pharmacological suppression of the immune response. Treatment should be started as soon as the diagnosis is made to avoid severe liver damage and progression of fibrosis. The aim of this review is to outline the most significant and peculiar features of JAIH, based largely on our own personal database and on a review of current literature.
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Kapila N, Higa JT, Longhi MS, Robson SC. Autoimmune Hepatitis: Clinical Review with Insights into the Purinergic Mechanism of Disease. J Clin Transl Hepatol 2013; 1:79-86. [PMID: 26356124 PMCID: PMC4521285 DOI: 10.14218/jcth.2013.00015] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2013] [Revised: 10/04/2013] [Accepted: 10/15/2013] [Indexed: 12/11/2022] Open
Abstract
Autoimmune hepatitis (AIH) is an important disorder that predominantly results in inflammatory liver disease in genetically predisposed women. The clinicopathological picture is characterized by symptoms associated with both systemic inflammation and hepatic dysfunction, and with increased serum aminotransferases, elevated IgG, autoantibodies, and interface hepatitis on liver biopsy. AIH usually results in liver injury as a consequence of chronic hepatitis and cirrhosis. However, rarely, patients may present with fulminant liver failure. Early diagnosis is important in all instances because the disease can be highly responsive to immunosuppressive therapeutic options. Left untreated, the disease is associated with high morbidity and mortality. Here we provide an overview of the current state of knowledge on AIH and summarize the treatment options for this serious condition in adults. We also discuss the pathogenesis of the disease as a possible consequence of autoimmunity and the breakdown of hepatic tolerance. We focus on regulatory T cell impairments as a consequence of changes in CD39 ectonucleotidase expression and altered purinergic signaling. Further understanding of hepatic tolerance may aid in the development of specific and well-tolerated therapies for AIH.
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Affiliation(s)
- Nikhil Kapila
- Department of Medicine, University of Connecticut, Farmington, CT, USA
- These authors contributed equally to this work
| | - Jennifer T. Higa
- Gastroenterology Division and Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA
- These authors contributed equally to this work
| | - Maria Serena Longhi
- Gastroenterology Division and Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA
- Institute of Liver Studies, King's College London School of Medicine at King's College Hospital, Denmark Hill, London, UK
| | - Simon C. Robson
- Gastroenterology Division and Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA
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Zachou K, Muratori P, Koukoulis GK, Granito A, Gatselis N, Fabbri A, Dalekos GN, Muratori L. Review article: autoimmune hepatitis -- current management and challenges. Aliment Pharmacol Ther 2013; 38:887-913. [PMID: 24010812 DOI: 10.1111/apt.12470] [Citation(s) in RCA: 121] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2013] [Revised: 03/22/2013] [Accepted: 08/12/2013] [Indexed: 12/14/2022]
Abstract
BACKGROUND Autoimmune hepatitis (AIH) is a disease of unknown aetiology characterised by interface hepatitis, hypergammaglobulinaemia, circulating autoantibodies and a favourable response to immunosuppression. AIM To review recent advancements in understanding aetiopathogenesis, clinical, serological and histological features, diagnostic criteria and treatment strategies of AIH. METHODS Published studies on AIH extracted mainly from PubMed during the last 15 years. RESULTS Autoimmune hepatitis has a global distribution affecting any age, both sexes and all ethnic groups. Clinical manifestations are variable ranging from no symptoms to severe acute hepatitis and only seldom to fulminant hepatic failure. Autoimmune attack is perpetuated, possibly via molecular mimicry mechanisms, and favoured by the impaired control of regulatory T-cells. A typical laboratory finding is hypergammaglobulinaemia with selective elevation of IgG, although in 15-25% of patients - particularly children, elderly and acute cases - IgG levels are normal. Liver histology and autoantibodies, although not pathognomonic, still remain the hallmark for diagnosis. Immunosuppressive treatment is mandatory and life-saving; however, to meet strict response criteria, the conventional therapy with prednisolone with or without azathioprine is far from ideal. CONCLUSIONS Autoimmune hepatitis remains a major diagnostic and therapeutic challenge. The clinician, the hepato-pathologist and the laboratory personnel need to become more familiar with different expressions of the disease, interpretation of liver histology and autoimmune serology. According to the strict definition of treatment response issued by the 2010 AASLD guidelines, many patients are nonresponders to conventional treatment. Newer immunosuppressive agents targeting pathogenetic mechanisms can improve patient management, which needs to be tailored on a case-by-case basis.
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Affiliation(s)
- K Zachou
- Department of Medicine and Research Laboratory of Internal Medicine, Medical School, Thessaly University, Larissa, Greece
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42
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Liberal R, Mieli-Vergani G, Vergani D. Clinical significance of autoantibodies in autoimmune hepatitis. J Autoimmun 2013; 46:17-24. [DOI: 10.1016/j.jaut.2013.08.001] [Citation(s) in RCA: 68] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2013] [Accepted: 08/04/2013] [Indexed: 01/14/2023]
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Floreani A, Liberal R, Vergani D, Mieli-Vergani G. Autoimmune hepatitis: Contrasts and comparisons in children and adults - a comprehensive review. J Autoimmun 2013; 46:7-16. [PMID: 24035197 DOI: 10.1016/j.jaut.2013.08.004] [Citation(s) in RCA: 80] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2013] [Revised: 08/13/2013] [Accepted: 08/14/2013] [Indexed: 12/24/2022]
Abstract
This review concentrates on autoimmune hepatitis (AIH), a liver disorder affecting both children and adults, characterized by inflammatory liver histology, elevated transaminase levels, circulating non-organ-specific autoantibodies, and increased levels of immunoglobulin G, in the absence of a known aetiology. Two types of AIH are recognized according to seropositivity: smooth muscle antibody and/or antinuclear antibody define AIH type 1, while antibodies to liver-kidney microsome type 1 and/or liver cytosol type 1 define AIH type 2. AIH type 1 affects both adults and children, while AIH type 2 is mainly a paediatric disease, though it does occasionally affects young adults. There is a female predominance in both types. AIH is particularly aggressive in children/adolescents, progressing rapidly unless immunosuppressive treatment is started promptly. With appropriate treatment 80% of patients achieve remission and long-term survival. In childhood/adolescence, sclerosing cholangitis with strong autoimmune features, including interface hepatitis and serological features identical to AIH type 1, is as prevalent as AIH, but it affects boys and girls equally. The differential diagnosis relies on cholangiographic studies. In autoimmune sclerosing cholangitis, liver parenchymal damage responds satisfactorily to immunosuppressive treatment, whereas bile duct disease progresses in 50% of cases, leading to a worse prognosis and higher transplantation requirement; it has a higher recurrence rate after transplant than AIH. AIH can arise de novo in patients transplanted for non-autoimmune liver disease. Post transplant de novo AIH affects children and adults and responds well to the same treatment schedule used for classical AIH, but not to that used for acute rejection.
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Affiliation(s)
- Annarosa Floreani
- Dept. of Surgical, Oncological and Gastroenterological Sciences, University of Padova, Italy.
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44
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Ferri Liu PM, de Miranda DM, Fagundes EDT, Ferreira AR, Simões e Silva AC. Autoimmune hepatitis in childhood: the role of genetic and immune factors. World J Gastroenterol 2013; 19:4455-4463. [PMID: 23901220 PMCID: PMC3725369 DOI: 10.3748/wjg.v19.i28.4455] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2013] [Revised: 06/05/2013] [Accepted: 06/08/2013] [Indexed: 02/06/2023] Open
Abstract
Autoimmune hepatitis (AIH) is a rare chronic inflammatory disease of the liver, which affects a group of patients who lost their immunological tolerance to antigens of the liver. It is clinically characterized by hypergammaglobulinemia, elevated liver enzymes, presence of autoantibodies and histological changes. Although being rare in children, it represents a serious cause of chronic hepatic disease that can lead to cirrhosis and hepatic failure. Clinical findings, exclusion of more common liver disorders and the detection of antibodies antinuclear antibodies, smooth muscle antibodies and anti-LKM1 are usually enough for diagnosis on clinical practice. The pathogenic mechanisms that lead to AIH remain obscure, but some research findings suggest the participation of immunologic and genetic factors. It is not yet knew the triggering factor or factors that stimulate inflammatory response. Several mechanisms proposed partially explain the immunologic findings of AIH. The knowledge of immune factors evolved might result in better markers of prognosis and response to treatment. In this review, we aim to evaluate the findings of research about genetic and immune markers and their perspectives of application in clinical practice especially in pediatric population.
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45
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Bonito AJ, Aloman C, Fiel MI, Danzl NM, Cha S, Weinstein EG, Jeong S, Choi Y, Walsh MC, Alexandropoulos K. Medullary thymic epithelial cell depletion leads to autoimmune hepatitis. J Clin Invest 2013; 123:3510-24. [PMID: 23867620 DOI: 10.1172/jci65414] [Citation(s) in RCA: 57] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2012] [Accepted: 05/17/2013] [Indexed: 12/23/2022] Open
Abstract
TRAF6, an E3 ubiquitin protein ligase, plays a critical role in T cell tolerance by regulating medullary thymic epithelial cell (mTEC) development. mTECs regulate T cell tolerance by ectopically expressing self-antigens and eliminating autoreactive T cells in the thymus. Here we show that mice with mTEC depletion due to conditional deletion of Traf6 expression in murine thymic epithelial cells (Traf6ΔTEC mice) showed a surprisingly narrow spectrum of autoimmunity affecting the liver. The liver inflammation in Traf6ΔTEC mice exhibited all the histological and immunological characteristics of human autoimmune hepatitis (AIH). The role of T cells in AIH establishment was supported by intrahepatic T cell population changes and AIH development after transfer of liver T cells into immunodeficient mice. Despite a 50% reduction in natural Treg thymic output, peripheral tolerance in Traf6ΔTEC mice was normal, whereas compensatory T regulatory mechanisms were evident in the liver of these animals. These data indicate that mTECs exert a cell-autonomous role in central T cell tolerance and organ-specific autoimmunity, but play a redundant role in peripheral tolerance. These findings also demonstrate that Traf6ΔTEC mice are a relevant model with which to study the pathophysiology of AIH, as well as autoantigen-specific T cell responses and regulatory mechanisms underlying this disease.
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Affiliation(s)
- Anthony J Bonito
- Department of Medicine/Clinical Immunology, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA
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46
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Johanet C, Ballot E. Autoantibodies in autoimmune hepatitis: anti-liver kidney microsome type 1 (anti-LKM1) and anti-liver cytosol type 1 (anti-LC1) antibodies. Clin Res Hepatol Gastroenterol 2013; 37:216-8. [PMID: 23523312 DOI: 10.1016/j.clinre.2013.02.004] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2013] [Accepted: 02/07/2013] [Indexed: 02/06/2023]
Affiliation(s)
- Catherine Johanet
- Unité d'immunologie, CHU Saint-Antoine, AP-HP, 75571 Paris cedex 12, France.
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47
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Liberal R, Grant CR, Mieli-Vergani G, Vergani D. Autoimmune hepatitis: A comprehensive review. J Autoimmun 2013; 41:126-39. [DOI: 10.1016/j.jaut.2012.11.002] [Citation(s) in RCA: 147] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2012] [Accepted: 11/05/2012] [Indexed: 12/12/2022]
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48
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Fallatah HI, Akbar HO. Autoimmune hepatitis as a unique form of an autoimmune liver disease: immunological aspects and clinical overview. Autoimmune Dis 2012; 2012:312817. [PMID: 23304455 PMCID: PMC3530748 DOI: 10.1155/2012/312817] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2012] [Revised: 09/09/2012] [Accepted: 10/12/2012] [Indexed: 12/11/2022] Open
Abstract
Autoimmune hepatitis (AIH) is a unique form of immune-mediated disease that attacks the liver through a variety of immune mechanisms. The outcomes of AIH are either acute liver disease, which can be fatal, or, more commonly, chronic progressive liver disease, which can lead to decompensated liver cirrhosis if left untreated. AIH has characteristic immunological, and pathological, features that are important for the establishment of the diagnosis. More importantly, most patients with AIH have a favorable response to treatment with prednisolone and azathioprine, although some patients with refractory AIH or more aggressive disease require more potent immune-suppressant agents, such as cyclosporine or Mycophenolate Mofetil. In this paper, we discuss the immunological, pathological and clinical features of AIH, as well as the standard and alternative treatments for AIH.
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Affiliation(s)
- Hind I. Fallatah
- Medical Department, Arab Board and Saudi Board of Internal Medicine, MACP, King Abdul Aziz University Hospital, P.O. Box 9714, Jeddah 21423, Saudi Arabia
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49
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Achenza MIS, Meda F, Brunetta E, Selmi C. Serum autoantibodies for the diagnosis and management of autoimmune liver diseases. Expert Rev Gastroenterol Hepatol 2012; 6:717-29. [PMID: 23237257 DOI: 10.1586/egh.12.58] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The spectrum of autoimmune liver diseases (AILD) includes primary biliary cirrhosis, primary sclerosing cholangitis and autoimmune hepatitis. The immunological mechanisms triggering the initiation and perpetuation of AILD remains unknown, while autoantigens are now recognized in most cases, and are generally nontraditional in their widespread distribution. Sensitive and specific methods for the detection of serum autoantibodies in patients affected by AILD represent a challenge for researchers and clinicians who desire to obtain an early and certain diagnosis as well as markers of disease control. To this regard, the use and interpretation of serum autoantibodies in AILD may be seen as paradigmatic for the large gaps in our knowledge based on the lack of true population-based studies. The present review article will critically discuss the available evidence on the use of autoantibody findings in the diagnosis or management of autoimmune liver disease.
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Affiliation(s)
- Maria I S Achenza
- Rheumatology and Clinical Immunology, Humanitas Clinical and Research Center, Rozzano, Milan, Italy
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50
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Vergani D, Mieli-Vergani G. Cutting edge issues in autoimmune hepatitis. Clin Rev Allergy Immunol 2012; 42:309-21. [PMID: 21207191 DOI: 10.1007/s12016-010-8236-9] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Autoimmune hepatitis is an inflammatory liver disease affecting mainly females and characterised histologically by interface hepatitis, biochemically by elevated transaminase levels and serologically by circulating autoantibodies and increased levels of immunoglobulin G. Autoimmune hepatitis responds to immunosuppressive treatment, which should be instituted as soon as diagnosis is made. Seropositivity for smooth muscle and/or antinuclear antibody defines type 1 autoimmune hepatitis, while positivity for liver kidney microsomal type 1 antibody defines type 2 autoimmune hepatitis. The aetiology of autoimmune hepatitis is unknown, though both genetic and environmental factors are involved in its expression. The major mechanism of liver damage involves immune reactions against host liver antigens that are not adequately controlled by defective regulatory T cells. Current research aiming at potentiating regulatory T cell function in vitro to reconstitute tolerance in vivo has given promising results.
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Affiliation(s)
- Diego Vergani
- Institute of Liver Studies, King's College London School of Medicine at King's College Hospital, Denmark Hill, London, SE5 9RS, UK.
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