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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) presents a diagnostic challenge because it is relatively rare and heterogenous in presentation. This article presents the currently adopted approach to AIH diagnosis and explores the challenges with accurately identifying this disease entity. AIH offers no pathognomonic findings, instead relies on clinical presentation, serology, and histology to make the diagnosis. Diagnostic scoring systems support clinical judgment and serve as valuable tools in diagnosis and research. Histological analysis remains the cornerstone of diagnosis and to this day biopsy is essential to make the diagnosis.
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Affiliation(s)
- Ben Flikshteyn
- Rutgers New Jersey School of Medicine, 185 South Orange Avenue, MSB H-538, Newark, NJ 07103, USA.
| | - Kamal Amer
- Rutgers New Jersey School of Medicine, 185 South Orange Avenue, MSB H-538, Newark, NJ 07103, USA
| | - Zaid Tafesh
- Rutgers New Jersey School of Medicine, 185 South Orange Avenue, MSB H-538, Newark, NJ 07103, USA
| | - Nikolaos T Pyrsopoulos
- Rutgers New Jersey School of Medicine, 185 South Orange Avenue, MSB H-538, Newark, NJ 07103, USA
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3
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Villani R, Serviddio G, Avolio C, Cassano T, D'Amico E. Autoimmune liver disease and multiple sclerosis: state of the art and future perspectives. Clin Exp Med 2023; 23:3321-3338. [PMID: 37421590 PMCID: PMC10618321 DOI: 10.1007/s10238-023-01128-8] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2022] [Accepted: 06/23/2023] [Indexed: 07/10/2023]
Abstract
Clinical observations suggest that the prevalence of autoimmune diseases is changing over time. Both autoimmune liver diseases and multiple sclerosis have shown a significant increase in the last decades. Although the coexistence of autoimmune diseases within individuals and families is a common phenomenon, the extent to which liver disease and multiple sclerosis co-occur is not clear. Case reports and few studies have reported the possible coexistence of multiple sclerosis with thyroid diseases, inflammatory bowel disease, psoriasis, and rheumatoid arthritis. It is unknown whether there is a definite association between multiple sclerosis and autoimmune liver diseases. We reviewed the literature to summarize the available studies on the association between different autoimmune liver diseases (autoimmune hepatitis, primary biliary cholangitis, and primary sclerosing cholangitis) and treated or untreated multiple sclerosis.
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Affiliation(s)
- Rosanna Villani
- Liver Unit, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy.
| | - Gaetano Serviddio
- Liver Unit, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | - Carlo Avolio
- Department of Medical and Surgical Sciences, Multiple Sclerosis Center, University of Foggia, Foggia, Italy
| | - Tommaso Cassano
- Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | - Emanuele D'Amico
- Department of Medical and Surgical Sciences, Multiple Sclerosis Center, University of Foggia, Foggia, Italy
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Czaja AJ. Incorporating the Molecular Mimicry of Environmental Antigens into the Causality of Autoimmune Hepatitis. Dig Dis Sci 2023:10.1007/s10620-023-07967-5. [PMID: 37160542 PMCID: PMC10169207 DOI: 10.1007/s10620-023-07967-5] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2023] [Accepted: 05/01/2023] [Indexed: 05/11/2023]
Abstract
Molecular mimicry between foreign and self-antigens has been implicated as a cause of autoimmune hepatitis in experimental models and cross-reacting antibodies in patients. This review describes the experimental and clinical evidence for molecular mimicry as a cause of autoimmune hepatitis, indicates the limitations and uncertainties of this premise, and encourages investigations that assess diverse environmental antigens as sources of disease-relevant molecular mimics. Pertinent articles were identified in PubMed using multiple search phrases. Several pathogens have linear or conformational epitopes that mimic the self-antigens of autoimmune hepatitis. The occurrence of an acute immune-mediated hepatitis after vaccination for severe acute respiratory syndrome (SARS)-associated coronavirus 2 (SARS-CoV-2) has suggested that vaccine-induced peptides may mimic disease-relevant tissue antigens. The intestinal microbiome is an under-evaluated source of gut-derived antigens that could also engage in molecular mimicry. Chaperone molecules may enhance the pathogenicity of molecular mimics, and they warrant investigation. Molecular mimics of immune dominant epitopes within cytochrome P450 IID6, the autoantigen most closely associated with autoimmune hepatitis, should be sought in diverse environmental antigens and assessed for pathogenicity. Avoidance strategies, dietary adjustments, vaccine improvement, and targeted manipulation of the intestinal microbiota may emerge as therapeutic possibilities. In conclusion, molecular mimicry may be a missing causality of autoimmune hepatitis. Molecular mimics of key immune dominant epitopes of disease-specific antigens must be sought in diverse environmental antigens. The ubiquity of molecular mimicry compels rigorous assessments of peptide mimics for immunogenicity and pathogenicity in experimental models. Molecular mimicry may complement epigenetic modifications as causative mechanisms of autoimmune hepatitis.
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Affiliation(s)
- Albert J Czaja
- Professor Emeritus of Medicine, Mayo Clinic College of Medicine and Science, 200 First Street SW, Rochester, MN, 55905, USA.
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Hunyady P, Herrmann E, Bojunga J, Friedrich-Rust M, Pathil A, Zeuzem S, Mihm U. Diagnostic value of a liver biopsy in patients with an acute liver failure or acute liver injury. Eur J Gastroenterol Hepatol 2022; 34:801-806. [PMID: 35482907 DOI: 10.1097/meg.0000000000002382] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
OBJECTIVES The diagnostic value of liver biopsy in patients with acute liver injury or acute liver failure (ALI/ALF) was investigated. METHODS Data from the initial event and follow-up visits were retrospectively analyzed in all patients with a liver biopsy during ALI/ALF from January 2010 to May 2020 at the University Hospital Frankfurt, Germany. RESULTS The cohort comprised 66 patients. Post-biopsy hemorrhage occurred in 2 of 66 but was self-limited. In five patients suspected liver involvement by a systemic extrahepatic disease was confirmed and excluded in eight patients. In 4 of 66 patients, the etiology of ALI/ALF remained unknown. Liver biopsy hinted at the etiology of ALI/ALF in 2 of 6 patients with rare diagnoses (hemophagocytic lymphohistiocytosis: 2 of 66; ischemic liver injury: 1 of 66, ALI/ALF due to a systemic infection: 3 of 66). In 31 of 34 patients with drug-induced liver injury (DILI), histopathology suggested DILI; in further 2 patients, DILI was among the differential diagnoses. However, DILI was also the histopathologically preferred diagnosis in 12 of 15 patients with autoimmune hepatitis (AIH). Only in 3 of 15 patients, histopathology was considered compatible with AIH. Serum immunoglobulin G (IgG) and autoantibodies during ALI/ALF were higher in patients with AIH than with DILI. Patients with AIH did not show a more pronounced biochemical response to corticosteroids in the first 10 days of treatment than patients with DILI. CONCLUSIONS Liver biopsy is indispensable when liver involvement by an extrahepatic disease is suspected. To distinguish AIH from DILI in ALI/ALF, serum IgG, and autoantibodies seem more helpful than liver biopsy; long-term follow-up is needed in these patients.
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Affiliation(s)
- Peter Hunyady
- Department of Internal Medicine I, Goethe University Hospital Frankfurt
| | - Eva Herrmann
- Department of Medicine, Institute of Biostatistics and Mathematical Modelling, Goethe University, Frankfurt, Germany
| | - Joerg Bojunga
- Department of Internal Medicine I, Goethe University Hospital Frankfurt
| | | | - Anita Pathil
- Department of Internal Medicine I, Goethe University Hospital Frankfurt
| | - Stefan Zeuzem
- Department of Internal Medicine I, Goethe University Hospital Frankfurt
| | - Ulrike Mihm
- Department of Internal Medicine I, Goethe University Hospital Frankfurt
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6
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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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Rizvi S, Gawrieh S. Autoimmune Hepatitis in the Elderly: Diagnosis and Pharmacologic Management. Drugs Aging 2018; 35:589-602. [PMID: 29971609 DOI: 10.1007/s40266-018-0556-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Autoimmune hepatitis (AIH) may present as acute or chronic hepatitis in the elderly. Advanced hepatic fibrosis and cirrhosis are common on first presentation in this population. In this review, we discuss the presentation, approach to diagnosis and management of AIH in the elderly. As polypharmacy is common in the elderly, careful medication use history is essential for detecting drug-induced AIH-like hepatitis. Steroid-sparing or minimizing therapeutic regimens are preferred to treat AIH in the elderly. For the purpose of induction, budesonide or lower dose prednisone in combination with azathioprine (AZA) regimens are preferred over high-dose prednisone monotherapy due to the higher risk of side effects of the later in the elderly. The goal of maintenance therapy should be to achieve full biochemical and histologic remission. Bone density monitoring and interventions to prevent steroid-related bone disease should be implemented throughout the course of the disease. Liver transplantation should be considered in the elderly patient with liver failure or early hepatocellular carcinoma if there are no significant comorbidities or compromise in functional status.
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Affiliation(s)
- Syed Rizvi
- Gastroenterology and Hepatology Division, Medical College of Wisconsin, 9200 West Wisconsin Avenue, Milwaukee, WI, 53226, USA.
| | - Samer Gawrieh
- Gastroenterology and Hepatology Division, Indiana University School of Medicine, 702 Rotary Cir, Indianapolis, IN, 46202-5175, USA.
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8
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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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9
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Abstract
Overlapping features between autoimmune hepatitis (AIH) and cholestatic disorders (primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), or indeterminate cholestasis), so-called overlap syndromes, usually have a progressive course toward cirrhosis and liver failure without adequate treatment. The diagnosis of overlap syndrome requires the prominent features of classic AIH and secondary objective findings of PBC or PSC. Empiric treatment for patients with AIH-PBC overlap is immunosuppressive therapy plus ursodeoxycholic acid. Empiric treatment for patients with AIH-PSC and AIH-cholestatic overlap is immunosuppressive therapy with or without ursodeoxycholic acid. Liver transplantation is indicated for patients who have end-stage liver disease.
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Affiliation(s)
- Chalermrat Bunchorntavakul
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Pennsylvania, 2 Dulles, 3400 Spruce Street, Philadelphia, PA 19104, USA; Division of Gastroenterology and Hepatology, Department of Medicine, Rajavithi Hospital, College of Medicine, Rangsit University, Rajavithi Road, Ratchathewi, Bangkok 10400, Thailand
| | - K Rajender Reddy
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Pennsylvania, 2 Dulles, 3400 Spruce Street, Philadelphia, PA 19104, USA.
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10
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Schotte H, Willeke P, Schmalhorst J, Schlüter B. Diagnostic Performance of an Anti-Actin Autoantibody Binding Enzyme Immunodot Blot in Autoimmune Hepatitis Type 1. J Clin Lab Anal 2014; 30:123-9. [PMID: 25425293 DOI: 10.1002/jcla.21825] [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] [Received: 06/01/2014] [Accepted: 10/22/2014] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND A serologic hallmark of autoimmune hepatitis (AIH) type 1 are anti-smooth muscle autoantibodies (ASMA) with specificity for filamentous actin (F-actin; AAA (anti-actin antibodies)), traditionally detected by indirect immunofluorescence (IFT) using rat liver, kidney, and stomach tissue sections as substrates. However, IFT is a subjective method requiring an experienced investigator. Therefore, a more objective technique for the detection of AAA may be a helpful diagnostic tool. METHODS In a retrospective study with cross-sectional design, we evaluated AAA detected by an enzyme immunodot blot (IDB; Liver5 IgG BlueDot, D-tek, Mons, Belgium). Serum samples of patients with AIH type 1 (n = 47) and specified controls (n = 142) were included. For comparison, standard IFT was applied to rat LKS (liver, kidney, stomach) triple tissue sections. RESULTS IDB readings were done by two independent investigators (92% concordance). The diagnostic sensitivity of the AAA-IDB was 70%, compared to 51% of AAA-IFT (n.s.). The diagnostic specificity of AAA-IDB was significantly lower compared to AAA-IFT (76% vs. 94%; P < 0.0005). Correspondingly, the positive predictive value (49% vs. 75%; P < 0.05) and positive likelihood ratio (2.9 vs. 8.5) differed significantly. Neither prescreening for ANA or ASMA, nor the exclusion of infectious hepatopathies resulted in a significantly better diagnostic performance of the IDB. CONCLUSION Compared to standard IFT, testing for AAA via IDB did not result in a significantly better diagnostic performance for AIH type 1. A blot with higher antigen binding specificity may be more functional.
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Affiliation(s)
| | - Peter Willeke
- Medizinische Klinik und Poliklinik D, Universitätsklinikum Münster, Germany
| | | | - Bernhard Schlüter
- Centrum für Laboratoriumsmedizin, Universitätsklinikum Münster, Germany
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11
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Cholestatic phenotypes of autoimmune hepatitis. Clin Gastroenterol Hepatol 2014; 12:1430-8. [PMID: 24013108 DOI: 10.1016/j.cgh.2013.08.039] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2013] [Revised: 08/21/2013] [Accepted: 08/21/2013] [Indexed: 02/07/2023]
Abstract
Autoimmune hepatitis can have cholestatic features that are outside the codified diagnostic criteria. These features have uncertain effects on the clinical presentation and progression of disease. Patients with autoimmune hepatitis can have antimitochondrial antibodies and coincidental bile duct injury or loss (2%-13% of patients), focal biliary strictures and dilations based on cholangiography (2%-11%), or histologic changes of bile duct injury or loss in the absence of other features (5%-11%). These findings probably represent atypical manifestations of autoimmune hepatitis or variants of primary biliary cirrhosis or primary sclerosing cholangitis, depending on the predominant findings. Serum levels of alkaline phosphatase and γ-glutamyl transferase, histologic features of bile duct injury, and findings from cholangiography are associated with responsiveness to corticosteroid therapy and individualized alternative treatments. Corticosteroid therapy, in combination with low-dose ursodeoxycholic acid, has been promulgated by international societies, but these recommendations are not based on strong evidence. The frequency, variable outcomes, and uncertainties in diagnosis and management of the cholestatic phenotypes must be addressed by a collaborative investigational network. This network should define the genetic and pathologic features of these disorders, standardize their nomenclature, and establish a treatment algorithm. In this review, the different cholestatic phenotypes of autoimmune hepatitis, mechanisms of pathogenesis, current management strategies and outcomes, and opportunities for improving understanding and therapy are presented.
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Zhang WC, Zhao FR, Chen J, Chen WX. Meta-analysis: diagnostic accuracy of antinuclear antibodies, smooth muscle antibodies and antibodies to a soluble liver antigen/liver pancreas in autoimmune hepatitis. PLoS One 2014; 9:e92267. [PMID: 24651126 PMCID: PMC3961308 DOI: 10.1371/journal.pone.0092267] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2013] [Accepted: 02/20/2014] [Indexed: 12/15/2022] Open
Abstract
Background Antinuclear antibodies (ANA), smooth muscle antibodies (SMA) and antibodies to a soluble liver antigen/liver pancreas (anti-SLA/LP) are useful markers that can help clinicians to diagnose and classify autoimmune hepatitis (AIH). Objectives To determine whether ANA, SMA and anti-SLA/LP help to accurately diagnose patients with AIH. Search strategy The PubMed, CNKI, WANFANG, and SinoMed databases were accessed to retrieve studies published in English and Chinese. Studies published up to October 2013 were reviewed. Selection criteria Studies on the diagnostic value of ANA, SMA or anti-SLA/LP in the diagnosis of known or suspected AIH were included. Data collection and analysis Two authors evaluated studies independently and rated their methodological quality using quality assessment of diagnostic accuracy studies (QUADAS) tools; relevant data were abstracted. The random-effects method was used to summarize sensitivities, specificities, positive and negative likelihood ratios, and diagnostic odds ratios (DORs) from all 29 studies. Results The pooled sensitivity, specificity, positive and negative likelihood ratios, and DOR for ANA were 0.650 (95% confidence interval [CI], 0.619 to 0.680), 0.751 (95%CI, 0.737 to 0.764), 3.030 (95%CI, 2.349 to 3.910), 0.464 (95%CI, 0.356 to 0.604), and 7.380 (95%CI, 4.344 to 12.539), respectively. For SMA, the values were 0.593 (95%CI, 0.564 to 0.621), 0.926 (95%CI, 0.917 to 0.934), 11.740 (95%CI, 7.379 to 18.678), 0.449 (95%CI, 0.367 to 0.549), and 31.553 (95%CI, 17.147 to 58.060), respectively. Finally, for anti-SLA/LP, the values were 0.194 (95%CI, 0.168 to 0.222), 0.989 (95%CI, 0.985 to 0.993), 11.089 (95%CI, 7.601 to 16.177), 0.839 (95%CI, 0.777 to 0.905), and 16.867 (95%CI, 10.956 to 25.967), respectively. Authors’ conclusions ANA provided moderate sensitivity and specificity, while SMA gave moderate sensitivity and high specificity, and anti-SLA/LP exhibited low sensitivity and high specificity. All three antibodies were limited by their unsatisfactory sensitivities and lack of consistency.
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Affiliation(s)
- Wen-Chao Zhang
- The Department of Laboratory Medicine, the Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Feng-Rong Zhao
- The Department of Gynaecology and Obstetrics, Youyang People’s Hospital, Chongqing, China
| | - Juan Chen
- Institute of Viral Hepatitis, the Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Wei-Xian Chen
- The Department of Laboratory Medicine, the Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
- * E-mail:
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13
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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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Abstract
Autoimmune hepatitis has two major variant phenotypes in which the features of classical disease are co-mingled with those of primary biliary cirrhosis or primary sclerosing cholangitis. These overlap syndromes lack codified diagnostic criteria, established pathogenic mechanisms, and confident management strategies. Their clinical importance relates mainly to the identification of patients who respond poorly to conventional corticosteroid treatment. Scoring systems that lack discriminative power have been used in their definition, and a clinical phenotype based on pre-defined laboratory and histological findings has not been promulgated. The frequency of overlap with primary biliary cirrhosis is 7-13 %, and the frequency of overlap with primary sclerosing cholangitis is 8-17 %. Patients with autoimmune hepatitis and features of cholestatic disease must be distinguished from patients with cholestatic disease and features of autoimmune hepatitis. Variants of the overlap syndromes include patients with small duct primary sclerosing cholangitis, antimitochondrial antibody-negative primary biliary cirrhosis, autoimmune sclerosing cholangitis, and immunoglobulin G4-associated disease. Conventional corticosteroid therapy alone or in conjunction with ursodeoxycholic acid (13-15 mg/kg daily) has been variably effective, and cyclosporine, mycophenolate mofetil, and budesonide have been beneficial in selected patients. The key cholestatic features that influence the prognosis of autoimmune hepatitis must be defined and incorporated into the definition of the syndrome rather than rely on designations that imply the co-mingling of different diseases with manifestations of variable clinical relevance. The overlap syndromes in autoimmune hepatitis are imprecise, heterogeneous, and unfounded, but they constitute a clinical reality that must be accepted, diagnosed, refined, treated, and studied.
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Affiliation(s)
- Albert J Czaja
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, 200 First Street S.W., Rochester, MN 55905, USA.
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15
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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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17
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Auto-antibodies in autoimmune hepatitis: anti-soluble liver antigen (SLA). Clin Res Hepatol Gastroenterol 2012; 36:244-6. [PMID: 22306052 DOI: 10.1016/j.clinre.2011.10.013] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2011] [Accepted: 10/14/2011] [Indexed: 02/04/2023]
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Abstract
Autoimmune hepatitis has a variable clinical phenotype, and the absence of conventional autoantibodies does not preclude its diagnosis or need for treatment. The goals of this review are to describe the frequency and nature of autoantibody-negative autoimmune hepatitis, indicate its outcome after corticosteroid treatment, and increase awareness of the diagnosis in patients with unexplained acute and chronic hepatitis. The frequency of presumed autoantibody-negative autoimmune hepatitis in patients with acute and acute severe presentations is ≤7%, and its frequency in patients with chronic presentations is 1-34%. Patients with acute presentations can have normal serum γ-globulin levels, centrilobular zone 3 necrosis, and low pre-treatment international diagnostic scores. Liver tissue examination is essential for the diagnosis, and hepatic steatosis can be a co-morbid feature. The comprehensive international scoring system can support but never override the clinical diagnosis pre-treatment, and non-standard serological markers should be sought if the clinical diagnosis is uncertain or the diagnostic score is low. A 3-month treatment trial with corticosteroids should be considered in all patients, regardless of the serological findings, and improvements have occurred in 67-87% of cases. Autoantibody-negative autoimmune hepatitis may be associated with an autoantibody outside the conventional battery; it may have a signature autoantibody that is still undiscovered, or its characteristic autoantibodies may have been suppressed or have a delayed expression. The pathogenic mechanisms are presumed to be identical to those of classical disease. Autoantibody-negative autoimmune hepatitis is an infrequent but treatable disease that must be considered in unexplained acute and chronic hepatitis.
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Affiliation(s)
- Albert J Czaja
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, 200 First Street S.W., Rochester, MN 55905, USA.
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Performance parameters of the conventional serological markers for autoimmune hepatitis. Dig Dis Sci 2011; 56:545-54. [PMID: 21127976 DOI: 10.1007/s10620-010-1501-1] [Citation(s) in RCA: 52] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/23/2010] [Accepted: 11/15/2010] [Indexed: 12/15/2022]
Abstract
BACKGROUND Autoimmune hepatitis is defined by a conventional battery of autoantibodies that may also be present in other liver diseases. AIMS To define the performance parameters of the conventional autoantibodies for autoimmune hepatitis, determine the diagnostic implications of simultaneous autoantibody production, and assess the performances of serological assays based on indirect immunofluorescence and enzyme immunoassay. METHODS In this study, 265 adults satisfying codified criteria for autoimmune hepatitis and 342 adults who satisfied conventional diagnostic criteria for another chronic liver disease were each assessed for the conventional autoantibodies. RESULTS Antinuclear antibodies, smooth muscle antibodies, and antibodies to liver kidney type 1 had sensitivities of only 32, 16, and 1%, respectively, for the diagnosis of autoimmune hepatitis, and their diagnostic accuracy ranged from 56 to 61%. The combination of antinuclear antibodies and smooth muscle antibodies at presentation had superior sensitivity (43%), specificity (99%), positive (97%) and negative (69%) predictabilities, and diagnostic accuracy (74%) than each marker alone. The occurrence of multiple autoantibodies was lower in other chronic liver diseases than in autoimmune hepatitis (8% versus 51%, p < 0.000001). The enzyme immunoassay for antinuclear antibodies had an accuracy that was not discriminative for autoimmune hepatitis (p = 0.06). CONCLUSIONS Isolated autoantibodies have a low diagnostic accuracy for autoimmune hepatitis. Concurrent antinuclear antibodies and smooth muscle antibodies have superior performance parameters. The enzyme immunoassay for antinuclear antibodies performs less well than the assay based on indirect immunofluorescence.
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Overlap syndromes: the International Autoimmune Hepatitis Group (IAIHG) position statement on a controversial issue. J Hepatol 2011; 54:374-85. [PMID: 21067838 DOI: 10.1016/j.jhep.2010.09.002] [Citation(s) in RCA: 324] [Impact Index Per Article: 23.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2010] [Revised: 08/30/2010] [Accepted: 09/02/2010] [Indexed: 12/12/2022]
Abstract
Some patients present with overlapping features between disorders within the spectrum of autoimmune liver diseases (i.e. autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC), and primary sclerosing cholangitis (PSC)) and are commonly classified as having an "overlap syndrome". Standardized definitions of "overlap syndromes" are lacking. The aim of this report by the International Autoimmune Hepatitis Group (IAIHG) is to evaluate if there are important reasons to classify conditions with overlapping features between autoimmune liver diseases as separate diagnostic entities. Definition of diagnostic criteria for overlap conditions can only be arbitrary. The IAIHG scoring system for diagnosis of AIH has been widely used to diagnose "overlap syndromes", but was not intended for such use and has not proven to be an efficient tool for this purpose. Some patients with overlapping features between a cholestatic and hepatitic disorder appear to benefit from treatment with a combination of ursodeoxycholic acid and immunosuppressants, but this strategy is not evidence-based, and it seems unjustified to define new diagnostic groups in this regard. The IAIHG suggests that patients with autoimmune liver disease should be categorized according to the predominating feature(s) as AIH, PBC, and PSC/small duct PSC, respectively, and that those with overlapping features are not considered as being distinct diagnostic entities. The IAIHG scoring system should not be used to establish subgroups of patients. Patients with PBC and PSC with features of AIH should be considered for immunosuppressive treatment. Due to the low prevalence of such "overlap syndromes", prospective interventional therapeutic trials cannot be expected in the foreseeable future.
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Czaja AJ. Autoantibodies as prognostic markers in autoimmune liver disease. Dig Dis Sci 2010; 55:2144-61. [PMID: 20464491 DOI: 10.1007/s10620-010-1268-4] [Citation(s) in RCA: 55] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2010] [Accepted: 04/23/2010] [Indexed: 01/25/2023]
Abstract
Certain autoantibodies in autoimmune liver disease have prognostic implications that are under-utilized and under-developed. The goals of this review are to indicate progress in characterizing the autoantibodies with prognostic connotations and to indicate the feasibility and importance of discovering other markers. Prime source and review articles in English were selected by a Medline search through 2010. Antibodies to soluble liver antigen, actin, liver cytosol type 1, asialoglycoprotein receptor, chromatin, cyclic citrullinated peptide, and uridine glucuronosyltransferases have been associated with the occurrence, severity, and progression of autoimmune hepatitis, and antibodies to Sp100, gp210, and centromere have had similar implications in primary biliary cirrhosis. Antibodies to soluble liver antigen have shown the most promise in autoimmune hepatitis as they have been associated with severe histological changes, long durations of treatment, relapse after drug withdrawal, and high frequency of liver failure. Antibodies to the nuclear rim pore protein, gp210, have shown the most promise in primary biliary cirrhosis as they have been associated with severe interface hepatitis, lobular inflammation, and progression to liver failure. The major limitations of the autoantibodies have been their lack of standardized assays, low negative predictabilities, and fluctuating levels. Performance parameters will improve as critical pathogenic pathways, comprehensive testing batteries, and standardized assays through international exchange workshops are developed. Progress has been made in identifying the serological markers of prognosis in autoimmune liver disease, and they promise to reflect critical disease mechanisms and enhance patient management.
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Affiliation(s)
- Albert J Czaja
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
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22
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Czaja AJ. The role of autoantibodies as diagnostic markers of autoimmune hepatitis. Expert Rev Clin Immunol 2010; 2:33-48. [PMID: 20477086 DOI: 10.1586/1744666x.2.1.33] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Autoantibody testing is the first step towards the diagnosis of autoimmune hepatitis, and it is essential in the evaluation of acute and chronic hepatitis of undetermined cause and allograft dysfunction following liver transplantation. A standard diagnostic repertoire has been promulgated, and other autoantibodies are emerging that may have prognostic value. Supplemental autoantibodies may prove useful in assessing patients who lack the standard markers or who are distinctive among those with conventional markers. Serologic testing will improve as assays are standardized by serum exchange workshops, core diagnostic batteries are codified and promulgated, and markers emerge that are tightly associated with pathogenic mechanisms, and closely reflect disease activity and outcome.
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Affiliation(s)
- Albert J Czaja
- Mayo Clinic, Mayo Clinic, 200 First Street S.W., Rochester, MN 55905, USA.
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23
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Poupon R. Primary biliary cirrhosis: a 2010 update. J Hepatol 2010; 52:745-58. [PMID: 20347176 DOI: 10.1016/j.jhep.2009.11.027] [Citation(s) in RCA: 200] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2009] [Revised: 11/27/2009] [Accepted: 11/30/2009] [Indexed: 12/14/2022]
Abstract
Primary biliary cirrhosis (PBC) is a chronic inflammatory autoimmune disease that mainly targets the cholangiocytes of the interlobular bile ducts in the liver. The condition primarily affects middle-aged women. Without treatment, PBC generally progresses to cirrhosis and eventually liver failure over a period of 10-20 years. PBC is a rare disease with prevalence of less than 1/2000. PBC is thought to result from a combination of multiple genetic factors and superimposed environmental triggers. The contribution of the genetic predisposition is evidenced by the familial clustering. Several risk factors, including exposure to infectious agents and chemical xenobiotics, have been suggested. Ursodeoxycholic acid (UDCA) is currently the only FDA-approved medical treatment for PBC. When administered at doses of 13-15 mg/kg/day, a majority of patients with PBC have a normal life expectancy without additional therapeutic measures. One out of three patients does not adequately respond to UDCA therapy and may need additional medical therapy and/or liver transplantation. This review summarises current knowledge on the epidemiology, ethiopathogenesis, clinical, and therapeutic aspects of PBC.
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Affiliation(s)
- Raoul Poupon
- UPMC Univ Paris 06, France; INSERM, UMR_S 938, Paris, France.
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Abstract
Treatment decisions in autoimmune hepatitis are complicated by the diversity of its clinical presentations, uncertainties about its natural history, evolving opinions regarding treatment end points, varied nature of refractory disease, and plethora of alternative immunosuppressive agents. The goals of this article are to review the difficult treatment decisions and to provide the bases for making sound therapeutic judgments. The English literature on the treatment problems in autoimmune hepatitis were identified by Medline search up to October 2009 and 32 years of personal experience. Autoimmune hepatitis may have an acute severe presentation, mild inflammatory activity, lack autoantibodies, exhibit atypical histological changes (centrilobular zone 3 necrosis or bile duct injury), or have variant features reminiscent of another disease (overlap syndrome). Corticosteroid therapy must be instituted early, applied despite the absence of symptoms, or modified in an individualized fashion. Pursuit of normal liver tests and tissue is the ideal treatment end point, but this objective must be tempered against the risk of side effects. Relapse after treatment withdrawal requires long-term maintenance therapy, preferably with azathioprine. Treatment failure or an incomplete response warrants salvage therapy that can include conventional medications in modified dose or empirical therapies with calcineurin inhibitors or mycophenolate mofetil. Liver transplantation supersedes empirical drug therapy in decompensated patients. Elderly and pregnant patients warrant treatment modifications. Difficult treatment decisions in autoimmune hepatitis can be simplified by recognizing its diverse manifestations and individualizing treatment, pursuing realistic goals, applying appropriate salvage regimens, and identifying problematic patients early.
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Abstract
BACKGROUND Antibodies to actin, chromatin, soluble liver antigen/liver pancreas and liver cytosol type 1 have been ascribed prognostic value in autoimmune hepatitis. AIM Evaluate the performance parameters of these nonstandard autoantibodies and determine the critical battery for clinical application. METHODS All antibodies were tested concurrently by enzyme immunoassay in 106 patients who had reached a treatment outcome. Tests were repeated in 149 serum samples obtained later to assess durability of the findings. RESULTS Antibodies to chromatin and soluble liver antigen/liver pancreas were superior to the other markers in predicting relapse. Patients with antibodies to chromatin and/or soluble liver antigen/liver pancreas relapsed more frequently than patients without these markers (100 versus 79%, p < 0.0003). Maximum sensitivity and predictability for relapse required combined testing, and they were 54 and 60%, respectively. Antibody status remained stable in 60% of patients during 127 +/- 9 months of follow-up, and antibodies to soluble liver antigen/liver pancreas were less labile than antibodies to chromatin (frequency of status change, 4 versus 22%). None of the antibodies were associated with treatment failure, death from hepatic failure or requirement for liver transplantation. CONCLUSIONS Antibodies to chromatin and soluble liver antigen/liver pancreas are associated with relapse after corticosteroid withdrawal, and they may be useful prognostic markers. Combined testing improves but does not eliminate deficiencies in sensitivity, predictability and durability.
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Affiliation(s)
- Albert J Czaja
- Division of Gastroenterology and Hepatology, Mayo Clinic and Mayo Foundation, 200 First Street S.W., Rochester, MN 55905, USA. czaja.albert@edu
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Eyraud V, Chazouilleres O, Ballot E, Corpechot C, Poupon R, Johanet C. Significance of antibodies to soluble liver antigen/liver pancreas: a large French study. Liver Int 2009; 29:857-64. [PMID: 19302185 DOI: 10.1111/j.1478-3231.2009.01986.x] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND Antibodies to soluble liver antigen (SLA)/liver pancreas (LP) are generally considered as highly specific diagnostic markers of type 1 auto-immune hepatitis (AIH-1), and are particularly useful in patients without conventional antibodies. However, the presence of anti-SLA/LP in type 2 auto-immune hepatitis (AIH-2), primary sclerosing cholangitis (PSC) and hepatitis C has recently been reported. The aim was thus to describe the characteristics of anti-SLA/LP-positive patients in the largest series reported to date. METHODS Sera were selected from the period between 1998 and 2005, based on the presence of antibodies to SLA/LP detected by two methods. The clinical status of patients was determined from their medical records. RESULTS Eighty-one anti-SLA/LP-positive patients with available clinical data were included: 89% (72/81) had a diagnosis of AIH-1, including 10 (12%) associated with cholestatic diseases (primary biliary cirrhosis in seven cases and PSC in three cases). Six patients (7%) suffered from another liver disease: hepatitis C (n=3) and drug-induced hepatitis (n=3). No specific diagnosis was made in three patients. CONCLUSIONS Antibodies to SLA/LP are of a major diagnostic value for AIH-1, including paediatric forms and overlap syndromes with cholestatic diseases, but are not found in association with anti-liver/kidney/microsome type 1 or antibodies to liver cytosol type 1. They are rarely present in other liver diseases such as hepatitis C and drug-induced hepatitis.
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Affiliation(s)
- Violaine Eyraud
- AP-HP Hôpital Saint-Antoine, Unité d'Immunologie, Paris, France
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27
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Abstract
The management of autoimmune and cholestatic liver disorders is a challenging area of hepatology. Autoimmune and cholestatic liver diseases represent a comparatively small proportion of hepatobiliary disorders, yet their appropriate management is of critical importance for patient survival. In this article, management strategies are discussed, including the indications and expectations of pharmacologic therapy, endoscopic approaches, and the role of liver transplantation.
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Affiliation(s)
- Karen L Krok
- Division of Gastroenterology and Hepatology, University of Pennsylvania School of Medicine, 3400 Spruce Street, 3 Ravdin, Philadelphia, PA 19104, USA
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28
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Abstract
UNLABELLED The diagnostic criteria for autoimmune hepatitis (AIH) have been codified by an international panel, and a revision of the original scoring system based on 12 clinical components has been promulgated. A simplified scoring system has been proposed recently that is based on four clinical components. The goals of this study were to compare the performance parameters of the revised original and the simplified scoring systems and to determine the prowess of each as a diagnostic instrument. Diagnostic scores were determined using each scoring system in 435 patients with diverse chronic liver diseases, including 153 individuals with AIH by codified clinical criteria. The sensitivity, specificity, and predictability of each scoring system for the pretreatment diagnosis of AIH were determined. The revised original scoring system had greater sensitivity for the diagnosis than the simplified scoring system (100% versus 95%), and seven patients diagnosed as AIH using the revised original system were nondiagnostic by the simplified system (5%). The revised original scoring system also ascribed a diagnosis of AIH to 20 of 21 patients with cryptogenic chronic hepatitis, whereas only five patients were similarly classified by the simplified system (95% versus 24%). The simplified system had greater specificity (90% versus 73%) and predictability (92% versus 82%) for AIH than the revised original system, and it more commonly excluded the diagnosis in other diseases with concurrent immune features (83% versus 64%). CONCLUSION The revised original scoring system performs better in patients with few or atypical features of AIH, and the simplified system is better at excluding the diagnosis in diseases with concurrent immune manifestations. Each system has attributes that can be exploited.
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Affiliation(s)
- Albert J Czaja
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
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Montano-Loza AJ, Carpenter HA, Czaja AJ. Frequency, behavior, and prognostic implications of antimitochondrial antibodies in type 1 autoimmune hepatitis. J Clin Gastroenterol 2008; 42:1047-53. [PMID: 18719506 DOI: 10.1097/mcg.0b013e3181587d18] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND Antimitochondrial antibodies (AMA) can occur in autoimmune hepatitis, but their durability and prognostic significance are uncertain. OBJECTIVES Determine the frequency, behavior, and prognostic implications of AMA in type 1 autoimmune hepatitis. METHODS One hundred thirty patients were tested for AMA by the same enzyme-linked immunosorbent assay at accession and during 123+/-9 months of observation (mean, 6+/-0.2 determinations/patient). Findings were correlated with clinical and histologic features and treatment outcomes. RESULTS Twenty-four patients (18%) had AMA, including 17 who had the antibodies at accession (71%) and 7 who developed them during follow-up (29%). AMA persisted in 13 patients (54%) who were tested on 5+/-1 occasions during 141+/-33 months. Cholestatic histologic features occurred as commonly in patients with and without AMA at presentation (18% vs. 10%, P=0.4). AMA disappeared in 4 patients, and they developed in 7 patients after 34+/-7 months. Late expression of antibodies was not associated with a higher frequency of cholestatic histologic changes than continued seronegativity (14% vs. 9%, P=0.5). Remission (83% vs. 76%, P=0.4) and treatment failure (8% vs. 11%, P>0.9) occurred as commonly in both groups. CONCLUSIONS AMA can appear and disappear. They do not identify a subgroup that requires different treatment or that evolves quickly into a cholestatic syndrome.
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Affiliation(s)
- Aldo J Montano-Loza
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN, USA
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30
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Seo S, Toutounjian R, Conrad A, Blatt L, Tong MJ. Favorable outcomes of autoimmune hepatitis in a community clinic setting. J Gastroenterol Hepatol 2008; 23:1410-4. [PMID: 18373564 DOI: 10.1111/j.1440-1746.2008.05365.x] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
BACKGROUND AND AIM Autoimmune hepatitis (AIH) is an idiopathic disease with diverse clinical manifestations. The aims of the present study were: (i) to describe the clinical characteristics of AIH patients in a community clinic setting; and (ii) to determine factors which were associated with poor clinical outcomes. METHODS A retrospective review was performed on 72 AIH patients who: (i) had pretreatment sera: (ii) were treatment-naïve at presentation; and (iii) had a minimum of 24 months of follow up. RESULTS On initial presentation, 22 (30%) had an acute onset of symptoms simulating acute viral hepatitis, 34 (47%) had chronic symptoms of greater than 6 months duration, and the remaining 16 (22%) were asymptomatic. Twenty-six (36%) had coexisting autoimmune diseases. Anti-nuclear antibody (ANA) was positive in 73% of the patients, and antismooth muscle antibody was positive in 15% of ANA-negative patients. Those few patients who tested positive for soluble liver antigen, anti-liver-kidney, microsomal antibody type-1, and anti-mitochondrial antibody were all also ANA positive. The median (range) duration of follow up was 98 (24-331) months. After immunosuppressive therapy, 26 of 72 (36%) remained in remission without further treatment. However, 46 (64%) required maintenance immunosuppression. Three patients who presented under the age of 20 years progressed to liver failure while on therapy and died while waiting for liver transplantation. Two other patients developed hepatocellular carcinoma (HCC) while on therapy and died. CONCLUSIONS A majority of AIH patients have an excellent prognosis. However, presentation at a younger age is a predictor of poor disease outcome and, although uncommon, HCC may develop during the late stages of cirrhosis.
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Affiliation(s)
- Suk Seo
- Medicine and Surgery, David Geffen School of Medicine at UCLA, The Pfleger Liver Institute, Los Angeles, California 90095-7302, USA.
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31
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O'Brien C, Joshi S, Feld JJ, Guindi M, Dienes HP, Heathcote EJ. Long-term follow-up of antimitochondrial antibody-positive autoimmune hepatitis. Hepatology 2008; 48:550-6. [PMID: 18666262 DOI: 10.1002/hep.22380] [Citation(s) in RCA: 91] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
UNLABELLED Antimitochondrial antibodies (AMAs) are the serological hallmark for primary biliary cirrhosis (PBC). When AMAs are detected in patients with chronic hepatitis, they negatively impact on the autoimmune hepatitis (AIH) scoring system. The purpose of this study was to determine if AMAs detected in the sera of patients with overt AIH have clinical or pathological significance. All patients with a clinicopathologic diagnosis of AIH from one center were reviewed. Only those meeting the criteria for probable or definite AIH according to the International Autoimmune Hepatitis Group were included. Patients found to be consistently AMA-positive via enzyme-linked immunosorbent assay (ELISA) for pyruvate dehydrogenase complex E2 subunit were reviewed in detail. Fifteen of 126 patients with typical features of AIH (pretreatment AIH score >10) had detectable AMAs in serum. None had any histologic features suggestive of PBC. None had detectable anti-liver-kidney-microsomal antibodies. Of these 15 patients, all have remained persistently AMA-positive via ELISA. All 15 patients have been followed long-term, and their clinical course remained typical for AIH. No bile duct damage typical of PBC was seen on initial or follow-up liver biopsies. CONCLUSION Patients with overt AIH who test positive for AMAs at initial presentation and are treated with corticosteroid therapy have shown no clinical or histologic evidence of PBC despite the continued detection of AMAs over a follow-up of up to 27 years.
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Affiliation(s)
- Conor O'Brien
- Department of Medicine, University Health Network, Toronto Western Hospital, University of Toronto, Toronto, Canada
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32
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Czaja AJ. Clinical Features, Differential Diagnosis and Treatment of Autoimmune Hepatitis in the Elderly. Drugs Aging 2008; 25:219-39. [DOI: 10.2165/00002512-200825030-00005] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
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Silveira MG, Lindor KD. Overlap syndromes with autoimmune hepatitis in chronic cholestatic liver diseases. Expert Rev Gastroenterol Hepatol 2007; 1:329-40. [PMID: 19072425 DOI: 10.1586/17474124.1.2.329] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Conditions exhibiting features of two different autoimmune liver diseases are commonly designated overlap syndromes, although there is no current agreement on what constitutes an overlap syndrome or specific diagnostic criteria. As in the classic autoimmune liver diseases, such as autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC), the etiology is unknown but presumed to be related to alterations of immune regulation. Distinction of these clinical entities is important for management as outcomes may differ from outcomes of patients with diagnosis of classic autoimmune liver diseases. Due to their presumed rarity, no large therapeutic trials are available and treatment of overlap conditions is empirical and based upon extrapolation of data from the primary autoimmune liver diseases. PBC-AIH overlap is the most frequently described overlap syndrome and may be associated with a poor prognosis. This may represent an important and unrecognized cause of resistance to ursodeoxycholic acid in patients with PBC. PSC-AIH overlap is less commonly reported. Prognosis may be better than in patients with PSC alone; however, worse than in patients with AIH alone. Further studies are needed for determining diagnosis, natural history and optimal therapeutic strategies of overlap syndromes of autoimmune liver disease.
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Affiliation(s)
- Marina G Silveira
- Division of Gastroenterology and Hepatology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.
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34
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Abstract
Diagnostic criteria have been codified by the International Autoimmune Hepatitis Group, and a scoring system can quantify the strength of the diagnosis and over-ride the impact of absent or inconsistent features. The absence of a definable etiologic agent and precise diagnostic test, implies that the diagnosis may be missed or misapplied. Centrilobular (zone 3) necrosis may be an early form of autoimmune hepatitis and this pattern can transform to the classical pattern of interface hepatitis. An acute severe or fulminant presentation is possible, and different ethnic groups may have different manifestations and outcomes. Asymptomatic patients at presentation commonly become symptomatic, and treatment decisions must be based on objective features of disease severity and not the presence or absence of symptoms. Concurrent autoimmune diseases are frequent, and they may constitute an autoimmune polyglandular syndrome associated with a single gene mutation. Emerging autoantibodies of possible prognostic value are antibodies to soluble liver antigen/liver pancreas, asialoglycoprotein receptor, actin, and liver cytosol type 1. HLA DRB1*03, *04, *03-*04, *07, *13 and DQB1*02 are associated with the occurrence, clinical phenotype and outcome of autoimmune hepatitis. Variant syndromes should be suspected if cholestatic features are prominent and conventional treatment is ineffective.
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Affiliation(s)
- Albert J Czaja
- Mayo Clinic, 200 First Street S.W, Rochester, Minnesota 55905, USA.
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35
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Nezu S, Tanaka A, Yasui H, Imamura M, Nakajima H, Ishida H, Takahashi SI. Presence of antimitochondrial autoantibodies in patients with autoimmune hepatitis. J Gastroenterol Hepatol 2006; 21:1448-54. [PMID: 16911691 DOI: 10.1111/j.1440-1746.2006.04434.x] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND AND AIM Antimitochondrial autoantibodies (AMA) are known to be a hallmark of primary biliary cirrhosis, and it has been suggested that AMA play a crucial role in generating biliary changes. Biliary tract lesions are not uncommon in patients with autoimmune hepatitis (AIH) and previous works have demonstrated that AMA are occasionally detectable in sera of patients with AIH. Therefore, the role of AMA as a cause of bile duct lesions in AIH livers should be addressed. The aim of the present study was to determine whether the presence of AMA is associated with clinical features, especially the occurrence of bile duct lesions, in patients with AIH. METHODS Forty-one patients diagnosed as having AIH according to the revised scoring system of the International Autoimmune Hepatitis Group were enrolled in this study. Clinical data were retrospectively reviewed, and histological findings of the liver were investigated. AMA reactivity was determined by immunoblotting using beef heart mitochondria as antigens. RESULTS Although not found in any enrolled patient by conventional indirect immunofluorescence, AMA were detectable in 14 out of 41 patients (34%). Clinical parameters including biochemistry, autoantibody profile, and responses to treatment were similar irrespective of AMA status. Bile duct lesions were noted in 14/14 (100%) and 23/27 (85%) of AMA-positive and -negative patients with AIH, respectively (P = 0.134). There was no statistically significant difference in the grade of inflammation or stage of fibrosis between the two groups. CONCLUSION Antimitochondrial autoantibodies were found to be present in sera of patients with AIH more frequently than expected, even at very low titer. However, clinical features and histological findings of AIH were not influenced by the AMA status.
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Affiliation(s)
- Saeko Nezu
- Third Department of Internal Medicine, School of Medicine, Kyorin University, Tokyo, Japan.
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36
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Farias AQ, Gonçalves LL, Bittencourt PL, De Melo ES, Abrantes-Lemos CP, Porta G, Nakhle MC, Carrilho FJ, Cancado ELR. Applicability of the IAIHG scoring system to the diagnosis of antimitochondrial/anti-M2 seropositive variant form of autoimmune hepatitis. J Gastroenterol Hepatol 2006; 21:887-93. [PMID: 16704541 DOI: 10.1111/j.1440-1746.2006.04130.x] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
Abstract
BACKGROUND AND AIMS According to the International Autoimmune Hepatitis Group (IAIHG) criteria, circulating antimitochondrial antibodies (AMA) do not support the diagnosis of autoimmune hepatitis (AIH). The aims of this study were to characterize a subset of patients with AIH who have AMA and antiM2 seropositivity, and to assess the applicability of the revised scoring system of the IAIHG in the diagnosis of this variant form of AIH. METHODS Eighteen patients with AMA-AIH were enrolled and compared with 206 classical AIH and 85 primary biliary cirrhosis (PBC) controls. Human leukocyte antigen (HLA) class II alleles were determined by polymerase chain reaction (PCR) amplification with sequence-specific primers, and biopsies were blindly reevaluated. RESULTS The patients with AMA-AIH were, on average, older than patients with classical AIH and had an hepatocellular pattern of elevated liver enzymes, hypergammaglobulinemia and lower levels of cholesterol, when compared with PBC controls. There were no histological signs of PBC or overlapping forms in any AMA-AIH biopsies. The majority of patients with AMA-AIH carried HLA antigens associated with classical AIH (DRB1*03, n = 5; DRB1*04, n = 7, and DRB1*13, n = 6). Pretreatment scores classified all AMA-AIH patients with probable (n = 17) or improbable (n = 1) AIH. After treatment, only 28% of AMA-AIH patients reached scores for definite diagnosis, compared with 90.1% of AIH-1 and 96.4 AIH-2. In the AMA-AIH group, only patients who relapsed after immunosuppressive drug withdrawal could be classified with definite AIH. CONCLUSIONS AMA-AIH shares common features with classical AIH. The diagnosis of AMA-AIH may be swayed by the IAIHG criteria, rendering questionable the applicability of the revised scoring system to this variant form of AIH.
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Affiliation(s)
- Alberto Queiroz Farias
- Department of Gastroenterology, Institute of Tropical Medicine, Division of Pathology, University of Sao Paulo School of Medicine, Sao Paulo, Brazil.
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Schramm C, Lohse AW. Overlap syndromes of cholestatic liver diseases and auto-immune hepatitis. Clin Rev Allergy Immunol 2006; 28:105-14. [PMID: 15879617 DOI: 10.1385/criai:28:2:105] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Approximately 18% of patients with auto-immune liver disease present with features characteristic of a second auto-immune liver disease. These cases have been termed "overlap syndromes."The pathogenesis of overlap syndromes is poorly understood, and few data are available regarding the clinical characteristics and outcome of this disease. Therefore, a consensus on the definition of overlap syndromes has not been reached. A common genetic background between auto-immune hepatitis (AIH) and its overlap with primary biliary cirrhosis(PBC) or primary sclerosing cholangitis (PSC) might confer susceptibility to a more inflammatory phenotype, probably requiring combined immunosuppressive treatment. This article focuses on the prevalence, diagnosis, and treatment of the overlap syndrome of AIH and PBC or PSC.
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MESH Headings
- Autoantibodies/immunology
- Cholagogues and Choleretics/therapeutic use
- Cholangitis, Sclerosing/diagnosis
- Cholangitis, Sclerosing/drug therapy
- Cholangitis, Sclerosing/epidemiology
- Cholangitis, Sclerosing/immunology
- Diagnosis, Differential
- Hepatitis, Autoimmune/diagnosis
- Hepatitis, Autoimmune/drug therapy
- Hepatitis, Autoimmune/epidemiology
- Hepatitis, Autoimmune/immunology
- Humans
- Liver Cirrhosis, Biliary/diagnosis
- Liver Cirrhosis, Biliary/drug therapy
- Liver Cirrhosis, Biliary/epidemiology
- Liver Cirrhosis, Biliary/immunology
- Prevalence
- Ursodeoxycholic Acid/therapeutic use
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Affiliation(s)
- Christoph Schramm
- Medizinische Klinik I, Universitätsulinikum Hamburg-Eppendorf, Hamburg, Germany.
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Abstract
Autoantibodies indicate an immune reactive state, but in liver disease they lack pathogenicity and disease specificity. Antinuclear antibodies, smooth muscle antibodies, antibodies to liver/kidney microsome type 1, antimitochondrial antibodies, and perinuclear antineutrophil cytoplasmic antibodies constitute the standard serological repertoire that should be assessed in all liver diseases of undetermined cause. Antibodies to soluble liver antigen/liver pancreas, asialoglycoprotein receptor, actin, liver cytosol type 1, nuclear antigens specific to primary biliary cirrhosis, and pore complex antigens constitute an investigational repertoire that promises to have prognostic and diagnostic value. These autoantibodies may emerge as predictors of treatment response and outcome. Antibodies to histones, doubled-stranded DNA, chromatin, and lactoferrin constitute a supplemental repertoire, and they support the immune nature of the liver disease. Final diagnoses and treatment strategies do not depend solely on serological markers. Autoantibodies are floating variables, and their behavior does not correlate closely with disease activity. There are no minimum levels of significant seropositivity, especially in children. Over-interpretation is the major pitfall in the clinical application of the serological results. New autoantibodies will emerge as the search for target antigens and key pathogenic pathways continues.
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Affiliation(s)
- Albert J Czaja
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, Minnesota, USA
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Vergani D, Alvarez F, Bianchi FB, Cançado ELR, Mackay IR, Manns MP, Nishioka M, Penner E. Liver autoimmune serology: a consensus statement from the committee for autoimmune serology of the International Autoimmune Hepatitis Group. J Hepatol 2004; 41:677-83. [PMID: 15464251 DOI: 10.1016/j.jhep.2004.08.002] [Citation(s) in RCA: 272] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Affiliation(s)
- Diego Vergani
- Institute of Liver Studies, King's College Hospital, Denmark Hill, London SE5 9RS, UK.
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Paraná R, Codes L, Andrade Z, Freitas LARD, Santos-Jesus R, Reis M, Cotrim H, Cunha S, Trepo C. Clinical, histologic and serologic evaluation of patients with acute non-A-E hepatitis in north-eastern Brazil: is it an infectious disease? Int J Infect Dis 2004; 7:222-30. [PMID: 14563227 DOI: 10.1016/s1201-9712(03)90056-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Non-A-E hepatitis and acute cryptogenic hepatitis are the names given to the disease of patients with clinical hepatitis, but in whom serologic evidence of A-E hepatitis has not been found. Over a period of 8 years, we evaluated in Brazil 32 patients who fulfilled the criteria for this diagnosis in order to determine patterns of the clinical illness, laboratory parameters, or histologic features. Each patient was subjected to virologic tests to exclude A-E hepatitis and cytomegalovirus/Epstein-Barr virus infection. Drug-induced hepatitis and autoimmune disease were also excluded. Wilson's disease was excluded in young patients. The course of the disease was clinical/biochemical recovery in 3 months in 25 patients and persistent alanine aminotransferase (ALT) elevation in 7 patients. Three of these had chronic hepatitis, and one had severe fibrosis on liver biopsy. During the acute illness, mean peak ALT was 1267 IU/L, bilirubin was 4.0 mg/dL, and ferritin was 1393 IU/mL. GB virus type C (GBV-C) was found in six patients, and TT virus (TTV) in five patients. We conclude that, in Brazil, non-A-E hepatitis probably originates from still unidentified viruses. The course of the disease and the histologic patterns are similar to those recorded for known viruses. Continuous survey for the specific etiologic agents is needed.
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Affiliation(s)
- Raymundo Paraná
- Gastro-Hepatology Unit, University Hospital of Bahia, Bahia, Brazil,CPgMS-UFBA, Bahia-Salvador, Brazil.
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Abstract
The answers to these questions are key to understanding the pathogenesis of PBC. Although the study of PBC is significantly retarded by the lack of an adequate animal model, the molecular technology to address these issues is advancing rapidly. In addition, the ability to isolate and culture human biliary epithelial cells greatly facilitates in vitro studies. With the advent of these tools, investigators are well poised to address the important issues of PBC in the future.
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Affiliation(s)
- Marlyn J Mayo
- Division of Digestive and Liver Diseases, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Room F.4.120, Dallas, TX 75390, USA.
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Abstract
The overlap syndrome raises several questions. First could these patients have two coincident autoimmune diseases? Such possibility cannot be discarded in particular in the setting of consecutive occurrence of the two conditions (eg, PBC followed by AIH) and this is consistent with the fact that autoimmune diseases are associated with one another in about 5% to 10% of cases. Furthermore, it is presumed that they share similar genetic susceptibility. A second possibility could be that overlap syndrome represents the middle of a continuous spectrum of two autoimmune liver diseases. The systematic study of the relationships between elementary histologic lesions and biochemistries in "pure" PBC patients pleads strongly for such a hypothesis. Pure PBC is characterized by 2 different groups of elementary lesions that are not interrelated: first, florid bile duct lesions and bile duct paucity and second, lymphocytic piecemeal necrosis and lobular necro-inflammatory changes. Furthermore, the first set of lesions is selectively associated with biochemical cholestasis and IgM levels, whereas the second set of lesions is selectively associated with serum transaminase activities and IgG levels. These observations are consistent with the assumption that two main mechanisms are involved in the progression of liver injury in PBC. The first is bile duct destruction leading to chronic cholestasis and fibrosis of biliary pattern. The second is lymphocytic piecemeal necrosis of hepatocytes, which tends to lead to cirrhosis, the pattern of which resembles cirrhosis following various forms of chronic active hepatitis. The author has therefore speculated that the picture of pure PBC results always forms the clinical and biochemical expression of the two main histologic lesions, and combination of these processes might explain why the spectrum of PBC varies from typical PBC to AIH or PBC overlap. A third hypothesis is that an exaggerated hepatitic response in PBC is associated with the HLA haplotype commonly seen in AIH, eg, B8, DR3, DR4. Further studies are obviously needed to confirm such an attractive hypothesis. Other possible explanation for the concurrent occurrence of features of both conditions in the same individual includes the selective modulation of HLA class 1, class 2 expression and Rantes by cholestasis itself and in particular bile acids. It is conceivable that the degree of interface and lobular inflammation in PBC and PSC may be modulated by chemokines, their receptors, and the parenchymal concentrations of individual bile acids that are all, at least in part, genetically determined.
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Affiliation(s)
- Raoul Poupon
- Department of Hepatogastroenterology, Saint-Antoine Hospital, AP-Hôpitaux de Paris, France.
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Abstract
Primary biliary cirrhosis (PBC) is characterized by the presence of high-titer disease specific autoantibodies directed against mitochondrial antigens (AMA) of the inner mitochondrial membrane, that are members of the 2-oxo acid complex. Among numerous other autoantibodies found in PBC the focus of ongoing studies is on the PBC-specific anti-nuclear antibodies, that are of diagnostic and clinical relevance since they can be used as a 'positive tool' in the diagnosis of AMA-negative PBC while at the same time identifying a subgroup of patients with more advanced liver disease.
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Abstract
Autoantibodies are nonpathogenic manifestations of immune reactivity, and they may occur in acute and chronic liver diseases. Autoantibodies may be consequences rather than causes of the liver injury, and they should be regarded as diagnostic clues rather than etiologic markers. Conventional autoantibodies used in the categorization of autoimmune liver disease are antinuclear antibodies, smooth muscle antibodies, antibodies to liver/kidney microsome type 1, antimitochondrial antibodies, and atypical perinuclear anti-neutrophil cytoplasmic antibodies. Ancillary autoantibodies that enhance diagnostic specificity, have prognostic connotation, or direct treatment are antibodies to endomysium, tissue transglutaminase, histones, doubled-stranded DNA, and actin. Autoantibodies that have an emerging diagnostic and prognostic significance are antibodies to soluble liver antigen/liver pancreas, asialoglycoprotein receptor, liver cytosol type 1, and nuclear pore complex antigens. Autoantibodies of uncertain clinical value that remain under investigation are antibodies to chromatin, lactoferrin, and Saccharomyces cervisiae. Continued recognition and characterization of autoantibodies should improve diagnostic precision, provide prognostic indices, and elucidate target autoantigens. These advances may in turn clarify pathogenic mechanisms, facilitate the development of animal models, and generate novel site-specific therapies.
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Affiliation(s)
- Albert J Czaja
- Division of Gastroenterology and Hepatology, Mayo Clinic and Mayo Foundation, Rochester, Minnesota 55905, USA.
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Ballot E, Bruneel A, Labas V, Johanet C. Identification of rat targets of anti-soluble liver antigen autoantibodies by serologic proteome analysis. Clin Chem 2003; 49:634-43. [PMID: 12651817 DOI: 10.1373/49.4.634] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
BACKGROUND Anti-soluble liver antigen (SLA) autoantibodies are specific for autoimmune hepatitis type 1 and are the only immunologic marker found in 15-20% of hepatitis cases previously considered cryptogenic. Anti-SLA antibodies react with the 100 000g supernatant from rat liver homogenate, but the molecular targets remain controversial. METHODS We characterized anti-SLA targets by one- and two-dimensional immunoblotting analysis. The recognized proteins were identified by peptide mass fingerprint analysis after matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry. RESULTS Three proteins of 35 kDa and pI 6.0, 50 kDa and pI between 6.0 and 6.5, and 58 kDa and pI between 6.5 and 7.0 were stained more intensely by anti-SLA positive-sera than by control sera. After in-gel tryptic digestion, MALDI-TOF analysis of the generated peptides enabled the clear identification of N-hydroxyarylamine sulfotransferase, isoforms of alpha-enolase, and isoforms of catalase. CONCLUSIONS Possible antigens for anti-SLA antibodies include a sulfotransferase, alpha-enolase(s), and catalase(s). Two-dimensional electrophoresis combined with mass spectrometry offers a versatile tool to identify molecular targets of autoantibodies and thus to improve diagnostic tools and the understanding of the immune process.
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Affiliation(s)
- Eric Ballot
- Service d'Immunologie et Hématologie Biologiques, Hôpital Saint-Antoine, AP-HP, 75012 Paris, France
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Buchel E, Van Steenbergen W, Nevens F, Fevery J. Improvement of autoimmune hepatitis during pregnancy followed by flare-up after delivery. Am J Gastroenterol 2002; 97:3160-5. [PMID: 12492204 DOI: 10.1111/j.1572-0241.2002.07124.x] [Citation(s) in RCA: 108] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVES Pregnancy in autoimmune hepatitis has been a rare event, but it has become more frequent with improved therapy. The present study aimed to analyze the consequences for mother and child in patients with autoimmune hepatitis. METHODS Fourteen pregnancies have been followed in five patients with autoimmune chronic hepatitis (AIH) and in one with autoimmune sclerosing cholangitis (overlap AIH-PSC). RESULTS Features of AIH improved markedly from the second trimester of pregnancy onward, allowing a decrease in immunosuppressive therapy. After delivery (or stillbirth in one patient), the activity of the autoimmune disease flared up rapidly in 12 of 14 events. CONCLUSIONS Pregnancy induces a state of immune tolerance with improvement of the liver tests in AIH. This could result from a transition of TH1 to TH2 predominance during pregnancy. A flare-up often occurs after delivery. Preemptive increase of the immunosuppressive therapy is therefore advocated consecutive to delivery. Azathioprine use seems to be safe during pregnancy.
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Affiliation(s)
- Elwin Buchel
- Divison of Hepatobiliary and Pancreas Diseases, University Hospital Gasthuisberg, Leuven, Belgium
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Ballot E, Bruneel A, Johanet C, Yamamoto AM. Prevalence and clinical relevance of anti-soluble liver antigen (SLA) antibodies in autoimmune hepatitis. Hepatology 2002; 36:765-6; author reply 766-7. [PMID: 12198675 DOI: 10.1053/jhep.2002.34440] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/07/2022]
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Abstract
The diagnostic criteria for each of the three major autoimmune liver diseases must be codified and the boundaries between diseases established. There will always be syndromes with mixed or atypical features because classically defined disorders represent only the outer ends of the diagnostic spectrum. It is only after boundaries have been decided by consensus that the true variants of autoimmune liver disease can be appreciated. Until then, both the diagnosis and treatment of these syndromes will be arbitrary and unclear.
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Affiliation(s)
- Jenny Heathcote
- University Health Network, Toronto Western Hospital, 399 Bathurst Street, 6B #170 Fell Pavilion, Toronto, Ontario M5T 2S8, Canada.
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Czaja AJ, Donaldson PT. Gender effects and synergisms with histocompatibility leukocyte antigens in type 1 autoimmune hepatitis. Am J Gastroenterol 2002; 97:2051-7. [PMID: 12190176 DOI: 10.1111/j.1572-0241.2002.05921.x] [Citation(s) in RCA: 95] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVES Our goals were to determine the effect of gender on the clinical features and treatment outcome of type 1 autoimmune hepatitis, and to assess synergisms with the known genetic risk factors. METHODS Clinical findings and treatment outcomes were compared in 144 women and 41 men who were also assessed for HLA DR3, HLA DR4, HLA DR3 and DR4 alleles, and the DRB1*1501-DQA1*102 haplotype by polymerase chain reaction. A total of 102 healthy men and women were similarly typed. RESULTS Women were distinguished from men by higher frequencies of concurrent immune diseases (34% vs 17%, p = 0.05) and HLA DR4 (49% vs 24%, p = 0.007), as had been previously reported. Women, however, had a higher occurrence of non-DRB1*0401 DR4 alleles than men (15% vs 0%, p = 0.02), and men had a lower frequency of these alleles than did normal male subjects (0% vs 16%, p = 0.04). Men and women responded similarly to therapy. Treatment failure occurred more frequently in men only if they had HLA DR3 and women had HLA DR4 (25% vs 4%, p = 0.01). The DRB1*1501-DQA1*102 haplotype did not affect outcome. CONCLUSIONS Gender influences susceptibility and clinical manifestations, but not outcome. Women have HLA DR4 more commonly than men, but this difference relates to their higher frequency of non-DRB1*0401 DR4 alleles. Female gender may promote risk associated with different HLA DR4 alleles.
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Affiliation(s)
- Albert J Czaja
- Division of Gastroenterology and Hepatology, Mayo Clinic and Mayo Foundation, Rochester, Minnesota 55905, USA
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Affiliation(s)
- Albert J Czaja
- Division of Gastroenterology and Hepatology, Mayo Clinic and Mayo Foundation, Rochester, MN 55905, USA.
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