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Wang Z, Li Y, Ren L, Li Y, Xu T, Li W, Gao W, Sun G, Liu M. Clinical performance of AMA-M2, anti-gp210 and anti-sp100 antibody levels in primary biliary cholangitis: When detected by multiplex bead-based flow fluorescent immunoassay. Immun Inflamm Dis 2024; 12:e1161. [PMID: 38270327 PMCID: PMC10797653 DOI: 10.1002/iid3.1161] [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: 09/28/2023] [Revised: 12/14/2023] [Accepted: 01/10/2024] [Indexed: 01/26/2024] Open
Abstract
BACKGROUND AND AIM Primary biliary cholangitis (PBC) is a chronic autoimmune cholangiopathy, characterized by the presence of some autoantibodies in the serum. This study aimed to evaluate the clinical significance of AMA-M2, anti-gp210 and anti-sp100 antibody levels detected by multiplex bead-based flow fluorescent immunoassay (MBFFI) in PBC. METHODS This study cohort included 238 PBC patients, 81 autoimmune hepatitis (AIH) patients, 62 systemic lupus erythematosus (SLE) patients, and 118 healthy controls. Serum AMA-M2, anti-gp210 and anti-sp100 antibody were detected by MBFFI and immunoblotting assay (IBT). The relationship between three antibody levels and cirrhosis, liver function, cholestasis markers and therapeutic effect to ursodesoxycholic acid (UDCA) was evaluated in PBC. RESULTS MBFFI were presented good coincidence rate (87.39%-95.38%) with IBT. The level of AMA-M2, anti-gp210 and anti-sp100 antibodies in PBC patients were higher than other disease group and healthy controls (p ＜ .01). When compared with the healthy controls group, the AUC of AMA-M2, anti-gp210 and anti-sp100 antibodies were 0.9245, 0.7619, and 0.6789, respectively. In addition, gp210 antibody levels have diagnostic value in patients with liver cirrhosis (AUC: 0.7567). We found that when combine detect these three antibodies, the sensitivity was higher than individually detection. High level of serum anti-gp210 antibody could be related to worse liver function and more severe cholestasis in PBC patients. Moreover, serum antibody levels may decrease or remained flat in patients who responded well to UDCA. CONCLUSION The detection of AMA-M2, anti-gp210 and anti-sp100 antibody levels by MBFFI showed good performance in the diagnosis of PBC. Serum anti-gp210 antibody level is related to cirrhosis, poor liver function and severe cholestasis in PBC.
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Affiliation(s)
- Zhan Wang
- Department of Clinical Laboratory, Key Laboratory of Laboratory MedicineThe Affiliated Hospital of Qingdao UniversityQingdaoChina
| | - Yongxin Li
- Department of Clinical Laboratory, Key Laboratory of Laboratory MedicineThe Affiliated Hospital of Qingdao UniversityQingdaoChina
| | - Lisheng Ren
- Department of Clinical Laboratory, Key Laboratory of Laboratory MedicineThe Affiliated Hospital of Qingdao UniversityQingdaoChina
| | - Yujie Li
- Qingdao Women and Children's HospitalQingdao UniversityQingdaoChina
| | - Tiantian Xu
- Department of Clinical Laboratory, Key Laboratory of Laboratory MedicineThe Affiliated Hospital of Qingdao UniversityQingdaoChina
| | - Wenshuai Li
- Department of Clinical Laboratory, Key Laboratory of Laboratory MedicineThe Affiliated Hospital of Qingdao UniversityQingdaoChina
| | - Weize Gao
- Department of Clinical Laboratory, Key Laboratory of Laboratory MedicineThe Affiliated Hospital of Qingdao UniversityQingdaoChina
| | - Guirong Sun
- Department of Clinical Laboratory, Key Laboratory of Laboratory MedicineThe Affiliated Hospital of Qingdao UniversityQingdaoChina
| | - Mingjun Liu
- Department of Clinical Laboratory, Key Laboratory of Laboratory MedicineThe Affiliated Hospital of Qingdao UniversityQingdaoChina
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Rigopoulou EI, Bogdanos DP. Role of autoantibodies in the clinical management of primary biliary cholangitis. World J Gastroenterol 2023; 29:1795-1810. [PMID: 37032725 PMCID: PMC10080701 DOI: 10.3748/wjg.v29.i12.1795] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2022] [Revised: 01/04/2023] [Accepted: 03/14/2023] [Indexed: 03/28/2023] Open
Abstract
Primary biliary cholangitis (PBC) is a chronic cholestatic liver disease characterized by immune-driven destruction of small intrahepatic bile ducts leading a proportion of patients to hepatic failure over the years. Diagnosis at early stages in concert with ursodeoxycholic acid treatment has been linked with prevention of disease progression in the majority of cases. Diagnosis of PBC in a patient with cholestasis relies on the detection of disease-specific autoantibodies, including anti-mitochondrial antibodies, and disease-specific anti-nuclear antibodies targeting sp100 and gp210. These autoantibodies assist the diagnosis of the disease, and are amongst few autoantibodies the presence of which is included in the diagnostic criteria of the disease. They have also become important tools evaluating disease prognosis. Herein, we summarize existing data on detection of PBC-related autoantibodies and their clinical significance. Moreover, we provide insight on novel autoantibodies and their possible prognostic role in PBC patients.
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Affiliation(s)
- Eirini I Rigopoulou
- Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, Larissa 41110, Greece
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), General University Hospital of Larissa, Larissa 41110, Greece
| | - Dimitrios P Bogdanos
- Department of Rheumatology and Clinical Immunology, Faculty of Medicine, School of Health Sciences, University of Thessaly, Larissa 41110, Greece
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Leitch AC, Ibrahim I, Abdelghany TM, Charlton A, Roper C, Vidler D, Palmer JM, Wilson C, Jones DE, Blain PG, Wright MC. The methylimidazolium ionic liquid M8OI is detectable in human sera and is subject to biliary excretion in perfused human liver. Toxicology 2021; 459:152854. [PMID: 34271081 PMCID: PMC8366605 DOI: 10.1016/j.tox.2021.152854] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2021] [Revised: 06/28/2021] [Accepted: 07/07/2021] [Indexed: 12/14/2022]
Abstract
M8OI was recently found to be contaminating the environment. M8OI was detected in the sera from 5/20 PBC patients and 1/10 controls. M8OI is taken up by human liver hepatocytes. M8OI is sequentially metabolised by CYPs followed by oxidation by dehydrogenases. The final carboxylic acid metabolite COOH7IM is, in part, excreted into human bile. A methylimidizolium ionic liquid (M8OI) was recently found to be contaminating the environment and to be related to and/or potentially a component of an environmental trigger for the autoimmune liver disease primary biliary cholangitis (PBC). The aims of this study were to investigate human exposure to M8OI, hepatic metabolism and excretion. PBC patient and control sera were screened for the presence of M8OI. Human livers were perfused with 50μM M8OI in a closed circuit and its hepatic disposition examined. Metabolism was examined in cultured human hepatocytes and differentiated HepaRG cells by the addition of M8OI and metabolites in the range 10–100 μM. M8OI was detected in the sera from 5/20 PBC patients and 1/10 controls. In perfused livers, M8OI was cleared from the plasma with its appearance – primarily in the form of its hydroxylated (HO8IM) and carboxylated (COOH7IM) products – in the bile. Metabolism was reflected in cultured hepatocytes with HO8IM production inhibited by the cytochrome P450 inhibitor ketoconazole. Further oxidation of HO8IM to COOH7IM was sequentially inhibited by the alcohol and acetaldehyde dehydrogenase inhibitors 4-methyl pyrazole and disulfiram respectively. Hepatocytes from 1 donor failed to metabolise M8OI to COOH7IM over a 24 h period. These results demonstrate exposure to M8OI in the human population, monooxygenation by cytochromes P450 followed by alcohol and acetaldehyde dehydrogenase oxidation to a carboxylic acid that are excreted, in part, via the bile in human liver.
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Affiliation(s)
- Alistair C Leitch
- Institute of Translation and Clinical Research, Newcastle University, Newcastle Upon Tyne, NE2 4AA, United Kingdom
| | - Ibrahim Ibrahim
- Institute of Translation and Clinical Research, Newcastle University, Newcastle Upon Tyne, NE2 4AA, United Kingdom; Freeman Hospital, Newcastle upon Tyne, Tyne and Wear, NE7 7DN, United Kingdom
| | - Tarek M Abdelghany
- Institute of Translation and Clinical Research, Newcastle University, Newcastle Upon Tyne, NE2 4AA, United Kingdom; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Kasr El-Aini St., Cairo, 11562, Egypt
| | - Alex Charlton
- School of Natural and Environmental Sciences, Bedson Building, Newcastle University, NE1 8QB, United Kingdom
| | - Clair Roper
- Institute of Translation and Clinical Research, Newcastle University, Newcastle Upon Tyne, NE2 4AA, United Kingdom
| | - Dan Vidler
- Institute of Translation and Clinical Research, Newcastle University, Newcastle Upon Tyne, NE2 4AA, United Kingdom
| | - Jeremy M Palmer
- Institute of Translation and Clinical Research, Newcastle University, Newcastle Upon Tyne, NE2 4AA, United Kingdom
| | - Colin Wilson
- Institute of Translation and Clinical Research, Newcastle University, Newcastle Upon Tyne, NE2 4AA, United Kingdom; Freeman Hospital, Newcastle upon Tyne, Tyne and Wear, NE7 7DN, United Kingdom
| | - David E Jones
- Institute of Translation and Clinical Research, Newcastle University, Newcastle Upon Tyne, NE2 4AA, United Kingdom
| | - Peter G Blain
- Institute of Translation and Clinical Research, Newcastle University, Newcastle Upon Tyne, NE2 4AA, United Kingdom
| | - Matthew C Wright
- Institute of Translation and Clinical Research, Newcastle University, Newcastle Upon Tyne, NE2 4AA, United Kingdom.
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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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Tana MM, Shums Z, Milo J, Norman GL, Leung PS, Gershwin ME, Noureddin M, Kleiner DE, Zhao X, Heller T, Hoofnagle JH. The Significance of Autoantibody Changes Over Time in Primary Biliary Cirrhosis. Am J Clin Pathol 2015; 144:601-6. [PMID: 26386081 PMCID: PMC5092169 DOI: 10.1309/ajcpqv4a7qaeefev] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
OBJECTIVES In primary biliary cirrhosis (PBC), the antimitochondrial antibody is a cornerstone of diagnosis, but there have been conflicting reports about the correlation of autoantibodies with disease stage and prognosis. We studied whether autoantibody levels changed over time and sought correlations with clinical outcomes in a cohort of patients with PBC. METHODS We tested serial serum samples from patients with PBC at a research institution for several autoantibodies. Long-term clinical follow-up data were used to calculate the slopes (change over time) for autoantibodies, platelet count, Ishak fibrosis score, biopsy copper, and number of portal areas with bile ducts. An adverse clinical outcome was defined as hepatic decompensation, development of hepatocellular carcinoma, liver transplantation, or liver-related death. We performed linear or logistic regression or Fisher exact test as appropriate, adjusting for multiple comparisons. RESULTS Twenty-seven patients with PBC with 145 serum samples were studied. Of the cohort, 85% was white, 81% was female, and median follow-up time was 20 years. Of the autoantibodies tested, only sp100 changed significantly over time. The sp100 slope was inversely associated with the Ishak fibrosis slope (parameter estimate, -0.05; P = .0003). CONCLUSIONS While changes in most autoantibodies over time do not seem to correlate with clinical outcomes in PBC, a change in the sp100 autoantibody level may have prognostic utility with respect to the development of fibrosis on liver biopsy.
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Affiliation(s)
- Michele M Tana
- From the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD;
| | | | - Jay Milo
- Inova Diagnostics, San Diego, CA; and
| | | | - Patrick S Leung
- Division of Rheumatology, Allergy and Clinical Immunology, University of California, Davis, CA
| | - M Eric Gershwin
- Division of Rheumatology, Allergy and Clinical Immunology, University of California, Davis, CA
| | - Mazen Noureddin
- From the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD
| | - David E Kleiner
- From the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD
| | - Xiongce Zhao
- From the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD
| | - Theo Heller
- From the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD
| | - Jay H Hoofnagle
- From the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD
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Jopson L, Newton JL, Palmer J, Floudas A, Isaacs J, Qian J, Wilkinson J, Trenell M, Blamire A, Howel D, Jones DE. RITPBC: B-cell depleting therapy (rituximab) as a treatment for fatigue in primary biliary cirrhosis: study protocol for a randomised controlled trial. BMJ Open 2015; 5:e007985. [PMID: 26297361 PMCID: PMC4550715 DOI: 10.1136/bmjopen-2015-007985] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
INTRODUCTION Primary biliary cirrhosis (PBC) is an autoimmune liver disease with approximately 50% of patients experiencing fatigue. This can be a particularly debilitating symptom, affecting quality of life and resulting in social isolation. Fatigue is highlighted by patients as a priority for research and patient support groups were involved in designing this trial. This is the first randomised controlled trial to investigate a treatment for fatigue in PBC. The trial protocol is innovative as it utilises novel magnetic resonance spectroscopy (MRS) techniques as an outcome measure. The protocol will be valuable to research groups planning clinical trials targeting fatigue in PBC and also transferrable to other conditions associated with fatigue. METHODS AND ANALYSIS RITPBC is a Medical Research Council (MRC) and National Institute for Health Research (NIHR) Efficacy and Mechanism Evaluation Programme (EME)-funded project. It is a phase II, single-centre, randomised controlled, double-blinded trial comparing rituximab with placebo in fatigued PBC patients. 78 patients with PBC and moderate to severe fatigue will be randomised to receive two infusions of rituximab or placebo. The study aims to assess whether rituximab improves fatigue in patients with PBC, the safety, and tolerability of rituximab in PBC and the sustainability of any beneficial actions. The primary outcome will be an improvement in fatigue domain score of the PBC-40, a disease-specific quality of life measure, evaluated at 12-week assessment. Secondary outcome measures include novel MRS techniques assessing muscle bioenergetic function, physical activity, anaerobic threshold and symptom, and quality of life measures. The trial started recruiting in October 2012 and recruitment is ongoing. ETHICS AND DISSEMINATION The trial has ethical approval from the NRES Committee North East, has Clinical Trial Authorisation from MHRA and local R&D approval. Trial results will be communicated to participants, presented at national and international meetings and published in peer-reviewed journals. TRIAL REGISTRATION NUMBER ISRCTN03978701.
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Affiliation(s)
- Laura Jopson
- Institute of Cellular Medicine, Medical School, Newcastle upon Tyne, UK
| | - Julia L Newton
- Institute of Health and Ageing, Medical School, Newcastle upon Tyne, UK
| | - Jeremy Palmer
- Institute of Cellular Medicine, Medical School, Newcastle upon Tyne, UK
| | - Achilleas Floudas
- Institute of Cellular Medicine, Medical School, Newcastle upon Tyne, UK
| | - John Isaacs
- Institute of Cellular Medicine, Medical School, Newcastle upon Tyne, UK
| | - Jessica Qian
- Newcastle Clinical Trials Unit, Institute of Health and Society, Newcastle University, Newcastle upon Tyne, UK
| | - Jennifer Wilkinson
- Newcastle Clinical Trials Unit, Institute of Health and Society, Newcastle University, Newcastle upon Tyne, UK
| | - Mike Trenell
- Movelab @ Newcastle University, Medical School, Newcastle upon Tyne, UK
| | - Andrew Blamire
- Institute of Cellular Medicine, Newcastle Magnetic Resonance Centre, Newcastle University, Newcastle upon Tyne, UK
| | - Denise Howel
- Institute of Health and Society, Newcastle University, Newcastle upon Tyne, UK
| | - David E Jones
- Institute of Cellular Medicine, Medical School, Newcastle upon Tyne, UK
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Predictive scores in primary biliary cirrhosis: a retrospective single center analysis of 204 patients. J Clin Gastroenterol 2015; 49:438-47. [PMID: 25014239 DOI: 10.1097/mcg.0000000000000176] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
GOALS The aim of this study was to assess the long-term outcome of primary biliary cirrhosis (PBC) patients and to test the clinical value of various outcome models, such as the Mayo Risk Score (MRS), in a large single-center cohort in Germany. BACKGROUND PBC is a chronic autoimmune liver disease with a female gender predominance and a peak incidence in the fifth decade of life. PBC is characterized by portal inflammation and immune-mediated destruction of intrahepatic bile ducts in liver histology and the presence of antimitochondrial antibodies in the serum of nearly 95% of patients. In 5% to 20% of patients an overlap syndrome with autoimmune hepatitis (AIH) is diagnosed. Ursodeoxycholic acid is widely accepted as the standard medical treatment. STUDY A total of 204 patients with PBC or PBC/AIH were retrospectively analyzed with regard to their clinical, biochemical, serological, and histologic features. PBC was diagnosed on the basis of the American Association for the Study of Liver Diseases criteria. Specific PBC scores, such as the MRS, the European and the Yale model, as well as nonspecific scores such as the Child-Pugh, the Model for End-stage Liver Disease, and Aspartate Aminotransferase to Platelet Ratio Index score were analyzed for their utility to predict the clinical outcome of patients. RESULTS One hundred eighty-four patients with PBC alone and 20 with primary biliary cirrhosis/autoimmune hepatitis overlap were followed up for an average of 7.0 (range, 0.5 to 33.2) years. Importantly, baseline values of serum bilirubin, alkaline phosphatase, immunoglobulin M (IgM) and IgG, as well as antimitochondrial antibodies titers did not allow in properly predicting patient's outcome. The MRS proved clinical applicability. Patients with an R-value <6 did not develop liver-related complications. The Aspartate Aminotransferase to Platelet Ratio Index score had a significant correlation with the histologic degree of liver fibrosis, with limited value of scores between 1.0 and 1.5. Patients with a Model for End-stage Liver Disease score ≥8 (n=17) had a significantly higher risk to undergo liver transplantation or liver-related death. Outcome was less favorable than predicted by the European model. All scores showed low positive predictive values, limiting their applicability in clinical practice. CONCLUSIONS Herein, we demonstrate that clinical risk scores in PBC should be interpreted with care. The MRS proved to be helpful to predict a favorable outcome. Novel approaches to predict outcome are needed to identify patients who may benefit from alternative, intensified treatment regimens.
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A rare association of rheumatoid arthritis and primary biliary cirrhosis treated with rituximab: a case report. J Med Case Rep 2013; 7:99. [PMID: 23570499 PMCID: PMC3668294 DOI: 10.1186/1752-1947-7-99] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2012] [Accepted: 03/18/2013] [Indexed: 11/25/2022] Open
Abstract
Introduction Primary biliary cirrhosis is an autoimmune disease that tends to progress to fibrosis and cirrhosis with hepatic failure. Primary biliary cirrhosis is often associated with other non- hepatic autoimmune diseases. An association with rheumatoid arthritis has been suggested to coexist in 1.8% to 5.6% of patients with primary biliary cirrhosis, but data supporting this association are scarce. The etiologic and pathogenetic mechanisms are not yet fully understood and several factors have been implicated. The therapeutic management must consider the two pathologies. Case presentation We describe the case of a 60-year-old Moroccan woman with severe erosive rheumatoid arthritis and primary biliary cirrhosis treated with rituximab. During treatment, we observed a good clinical and biological response of her rheumatoid arthritis but persistent abnormal liver function tests. Conclusion B cells seem to play a major role in the pathogenesis of both rheumatoid arthritis and primary biliary cirrhosis. Additional studies are necessary to better determine the therapeutic role of rituximab in both diseases.
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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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10
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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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Affiliation(s)
- David E J Jones
- School of Clinical Medical Sciences, Medical School, University of Newcastle, Framlington Place, Newcastle-upon-Tyne, UK.
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Hollingsworth KG, Newton JL, Taylor R, McDonald C, Palmer JM, Blamire AM, Jones DEJ. Pilot study of peripheral muscle function in primary biliary cirrhosis: potential implications for fatigue pathogenesis. Clin Gastroenterol Hepatol 2008; 6:1041-8. [PMID: 18691944 DOI: 10.1016/j.cgh.2008.04.013] [Citation(s) in RCA: 56] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2008] [Revised: 03/28/2008] [Accepted: 04/13/2008] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Primary biliary cirrhosis (PBC) is characterized in 95% of patients by autoantibody responses directed against the mitochondrial antigen pyruvate dehydrogenase complex (PDC). Although anti-PDC inhibits PDC function in vitro, mitochondrial function in vivo in PBC has not been examined. METHODS (31)P magnetic resonance spectroscopy was performed in PBC patients (n = 15) and fatigued (chronic fatigue syndrome/myalgic encephalomyelitis, n = 8), cholestatic (primary sclerosing cholangitis [PSC], n = 4), and normal (n = 8) controls to define mitochondrial function and pH regulation in peripheral muscle during exercise at 25% and 35% of maximum voluntary contraction. RESULTS Normal, chronic fatigue syndrome/myalgic encephalomyelitis, and PSC subjects all showed close correlation between kinetics of adenosine diphosphate (ADP) and phosphocreatine (PCr) recovery after low-impact exercise, reflecting the normal tight regulation of PCr "response" by mitochondria to ADP "drive." This relationship was lost in PBC patients, indicating mitochondrial dysfunction (normal r(2) = 0.78, P < .005; PBC r(2) = 0.007, P = ns). Ratio between PCr and ADP recovery half-times (constant in controls, indicating normal mitochondrial responsivity) was significantly elevated in PBC patients (but not PSC) and was associated with anti-PDC levels. At higher levels of exercise PBC (but not PSC) patients showed excess muscle acidosis, with pH correlating with elevation of PCr/ADP recovery ratio, indicating a link to mitochondrial dysfunction. PBC patients alone also showed significant prolongation of muscle pH recovery time after exercise (unrelated to mitochondrial function), which correlated with clinical fatigue. CONCLUSIONS PBC patients exhibit a variable degree of muscle mitochondrial dysfunction that manifests as excess acidosis after exercise. The extent to which patients can recover rapidly from acidosis appears to determine whether they are clinically fatigued.
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Affiliation(s)
- Kieren G Hollingsworth
- Newcastle Magnetic Resonance Centre, Newcastle University, Newcastle-upon-Tyne, United Kingdom
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Antimitochondrial antibodies and other antibodies in primary biliary cirrhosis: diagnostic and prognostic value. Clin Liver Dis 2008; 12:261-76; vii. [PMID: 18456179 DOI: 10.1016/j.cld.2008.02.009] [Citation(s) in RCA: 49] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Antimitochondrial antibodies (AMA) are the serologic cornerstone in the diagnosis of primary biliary cirrhosis (PBC), even if they are not detectable in a proportion of patients, notwithstanding the most sensitive and sophisticated technologies used. To fill in the serologic gap in AMA-negative PBC, there is sound evidence to consider antinuclear antibody (ANA) patterns, such as anti-multiple nuclear dots and anti-membranous/rim-like, as PBC-specific surrogate hallmarks of the disease, and their detection can be considered virtually diagnostic. Furthermore, particular ANA specificities, such as anti-gp210, anti-p62, anticentromere antibodies, and anti-dsDNA, may provide additional diagnostic and prognostic information.
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14
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Abstract
BACKGROUND Autoantibody responses reactive with the E2 and E3BP components of pyruvate dehydrogenase complex (PDC), which characterise primary biliary cirrhosis (PBC) crossreact, precluding the identification, from serological studies, of the antigen to which the principal breakdown of tolerance occurs. Although autoreactive T-cell responses to PDC-E2 have been well characterised it is, at present, unclear whether T-cell tolerance breakdown also occurs to PDC-E3BP. The aims of this study were to characterise autoreactive T-cell responses to PDC-E3BP in PBC and potential factors regulating their expression. METHODS Peripheral blood T-cell proliferative responses to purified recombinant human PDC-E2 and PDC-E3BP at a range of concentrations were characterised in PBC patients and control subjects. RESULTS T-cell proliferative responses to both E2 and E3BP were absent from control subjects (median peak stimulation index (SI) to PDC-E2 1.2 [range 0.3-1.9], 0/10 positive (SI>2.32), median peak SI to PDC-E3BP 1.1 [0.7-2.1]], 0/10 positive). Significant responses to PDC-E2 were seen in the majority of patients (median peak SI 11.4 [0.4-24.4], 17/20 (85%) positive) but to PDC-E3BP in only a minority (median peak SI 1-9 [0.6-9.95], 8/20 (40%) positive). Where responses to PDC-E3BP were seen they were universally secondary to responses to PDC-E2. CONCLUSIONS Despite the presence of antibodies reactive with PDC-E3BP in the majority of PBC patients this self-protein is not a dominant T-cell autoantigen in PBC.
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Affiliation(s)
- Anna McHugh
- Liver Research Group, University of Newcastle, Newcastle-upon-Tyne, UK
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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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16
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Wong GLH, Hui AY, Wong VWS, Chan FKL, Sung JJY, Chan HLY. A retrospective study on clinical features and prognostic factors of biopsy-proven primary biliary cirrhosis in Chinese patients. Am J Gastroenterol 2005; 100:2205-11. [PMID: 16181370 DOI: 10.1111/j.1572-0241.2005.50007.x] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVES Though extensive research has been performed on primary biliary cirrhosis (PBC) in Caucasian patients, little is known about the disease in the Asian population. PATIENTS AND METHODS This was a retrospective study of Chinese patients with biopsy-proven PBC. Electronic records of results from all liver biopsies (n = 1,021) performed between January 1996 and April 2004, together with records of patients labeled as "biliary cirrhosis," were retrieved. Patients with biopsy-proven PBC were identified, and their medical notes were reviewed. The demographic, clinical, biochemical, and histological parameters of these patients were analyzed for mortality predictors. RESULTS Thirty-nine patients with biopsy-proven PBC and a median follow-up of 44 (range: 5-114) months were identified. Twelve patients (30.8%) were asymptomatic at diagnosis. The patients were approximately equally divided into one-thirds at stages I, II, and III of the histological disease. Hepatic decompensation or hepatocellular carcinoma developed in 14 (35.9%) patients during the follow-up period. The overall 5-yr survival probability was 81.4%. Hypoalbuminemia was found to be the only independent predictor of mortality on multivariate analysis (hazard ratio = 0.50 per 1 g/L increase, 95% CI 0.30-0.84, p= 0.008). Using the median serum albumin level as the cutoff, the 5-yr survival probability was significantly higher for patients with serum albumin levels >35 g/L than for those with serum albumin levels < or =35 g/L (100% vs 69%, p= 0.007). No significant difference was found when baseline serum albumin was compared with the Mayo Risk Score and the model for end-stage liver disease (MELD) score for prediction of patient survival (p= 0.68) and death (p= 0.12) at 5 yr. CONCLUSIONS In this longitudinal cohort study of biopsy-proven PBC with up to 9 yr of follow-up, we found that Chinese patients with PBC had significant morbidity and mortality. Hypoalbuminemia at presentation was an independent and strong predictor of mortality.
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Affiliation(s)
- Grace Lai-Hung Wong
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, China
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17
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Mandel L, Dehlinger N. Primary biliary cirrhosis and Sjögren's syndrome: case report. J Oral Maxillofac Surg 2003; 61:1358-61. [PMID: 14613096 DOI: 10.1016/s0278-2391(03)00741-9] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Affiliation(s)
- Louis Mandel
- School of Dental and Oral Surgery, Columbia University, 630 West 168th Street, New York, NY 10032, USA.
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18
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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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19
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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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20
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Affiliation(s)
- A J Czaja
- Division of Gastroenterology and Hepatology, Mayo Clinic and Mayo Foundation, Rochester, Minnesota 55905, USA.
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21
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Abstract
The automimmune liver disease primary biliary cirrhosis (PBC) is characterised by serum autoantibodies directed at mitochondrial and nuclear antigens (seen in most patients and a subset of patients, respectively). The antimitochondrial antibodies (AMA) characteristic of PBC are directed at members of the 2-oxoacid dehydrogenase components of multienzyme complexes; in particular, the E2 and E3 binding protein (E3BP) components of the pyruvate dehydrogenase complex (PDC). The presence of autoantibodies reactive with PDC-E2 and/or E3BP is strongly predictive of the presence of PBC. Therefore, the detection of these antibodies plays a very important role in the diagnosis of PBC. Originally demonstrated using immunofluorescence approaches, AMA can now be detected by the use of commercially available enzyme linked immunosorbent assays (ELISAs). Although the ELISA based approaches have advantages in terms of laboratory practicality, they are slightly less sensitive for the diagnosis of PBC than immunofluorescence (occasional patients with PBC show reactivity with PDC related antigens not present in the antigen preparations available for use with ELISA). Therefore, immunofluorescence should continue to be available as a complementary diagnostic test for use in occasional patients. In a subset of patients with PBC, autoantibodies are directed at increasingly well characterised nuclear antigens. Antinuclear antibody (ANA) positive patients are typically AMA negative. There are no significant differences in disease phenotype between AMA positive and AMA negative groups. At present, the clinical detection of ANA is mostly by Hep2 immunofluorescence, although ELISA kits for individual nuclear antigens are increasingly becoming available.
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Affiliation(s)
- D E Jones
- Centre for Liver Research, Medical School, Framlington Place, Newcastle upon Tyne NE2 4HH, UK.
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22
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Jensen WA, Jois JA, Murphy P, De Giorgio J, Brown B, Rowley MJ, Mackay IR. Automated enzymatic mitochondrial antibody assay for the diagnosis of primary biliary cirrhosis. Clin Chem Lab Med 2000; 38:753-8. [PMID: 11071069 DOI: 10.1515/cclm.2000.107] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Primary biliary cirrhosis is a progressive autoimmune disease that affects middle aged women, resulting in liver cirrhosis. We describe here an automated enzymatic mitochondrial antibody assay adapted for performance on laboratory analysers for the serological diagnosis of primary biliary cirrhosis. This assay detects the characteristic autoantibody directed against the 74kDa E2 subunit of the pyruvate dehydrogenase complex. Analysis of receiver operator characteristic curve data indicated that the automated enzymatic mitochondrial assay procedure discriminated clinically identified patients with primary biliary cirrhosis from normal subjects with a sensitivity of 83% and a specificity of 100%. This method compared favourably against a commercial ELISA method which had a sensitivity of 73% and a specificity of 100%. The automated enzymatic mitochondrial antibody assay is a high throughput assay of use for the routine diagnosis of patients with primary biliary cirrhosis with autoantibodies to the E2 subunit of the pyruvate dehydrogenase complex. The method is of potential value for economical and rapid screening to detect asymptomatic primary biliary cirrhosis in the at-risk segment of the population, namely middle aged women.
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Affiliation(s)
- W A Jensen
- TRACE Scientific Ltd., Noble Park, Victoria, Australia.
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23
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Schmit P, Gilson G, Humbel RL. Evaluation of an Automated Enzyme Inhibition Assay for the Detection of Anti-Mitochondrial M2 Autoantibodies. Clin Chem 1999. [DOI: 10.1093/clinchem/45.12.2287] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Affiliation(s)
| | | | - René L Humbel
- Laboratoire de Biochimie et d’Immunopathologie, Centre Hospitalier de Luxembourg, Rue Barblé 4, L-1210 Luxembourg, Luxembourg
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24
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Jones DE, Palmer JM, Yeaman SJ, Kirby JA, Bassendine MF. Breakdown of tolerance to pyruvate dehydrogenase complex in experimental autoimmune cholangitis: a mouse model of primary biliary cirrhosis. Hepatology 1999; 30:65-70. [PMID: 10385640 DOI: 10.1002/hep.510300123] [Citation(s) in RCA: 44] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/07/2022]
Abstract
The autoimmune liver disease primary biliary cirrhosis (PBC) is characterized by autoreactive responses to a highly conserved self-antigen, pyruvate dehydrogenase complex (PDC). We recently reported the development of PBC-like lesions in SJL mice sensitized with PDC and have named this model disease experimental autoimmune cholangitis (EAC). In the present study, the breakdown of tolerance to PDC has been investigated in animals sensitized for EAC. Splenic mononuclear cells from SJL mice sensitized with bovine heart PDC (bPDC) in adjuvant showed T-cell proliferative and mixed Th1/Th2 cytokine secretory responses following in vitro stimulation with bPDC. Despite the likelihood of extensive sequence homology with mouse PDC (there is a greater than 95% sequence identity between rat and human PDC-E2 subunits), bPDC was highly immunogenic inducing significant T- and B-cell responses in the absence of any form of adjuvant. The multi-subunit quaternary structure of intact PDC was critical for this immunostimulatory activity because no response was produced by sensitization with monomeric recombinant PDC-E2 inner lipoyl domain. Mice sensitized with bPDC and CFA developed, within 2 weeks of sensitization, high-titer antibody responses reactive with bPDC that were fully cross-reactive with the murine homologue. Breakdown of T-cell tolerance to self-PDC took significantly longer, not being seen until 20 weeks postsensitization; a similar length of time to that previously shown to be required for EAC lesion development. Conclusions drawn from these data may have important implications for our understanding, and therapeutic manipulation, of PBC in humans.
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Affiliation(s)
- D E Jones
- Centre for Liver Research, University of Newcastle, Framlington Place, Newcastle-upon-Tyne, UK.
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25
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Palmer JM, Jones DE, Quinn J, McHugh A, Yeaman SJ. Characterization of the autoantibody responses to recombinant E3 binding protein (protein X) of pyruvate dehydrogenase in primary biliary cirrhosis. Hepatology 1999; 30:21-6. [PMID: 10385634 DOI: 10.1002/hep.510300106] [Citation(s) in RCA: 35] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Autoantibodies to the pyruvate dehydrogenase complex (PDC) are present in the serum of more than 95% of patients with primary biliary cirrhosis (PBC), the major epitope being the inner lipoyl domain of the E2 component. Immunoblotting suggests a similar prevalence of antibodies to a tightly associated lipoic acid-containing protein, E3 binding protein (E3BP). Attempts to resolve E3BP from E2 have been unsuccessful, restricting study of the nature and significance of antibody responses to the individual proteins. In particular, it is unclear (1) whether there is true cross-reactivity between E3BP and E2 and, if so, which is the originating response and (2) whether autoantibodies preferentially bind a lipoylated epitope on E3BP as is the case with PDC-E2. In this study, complementary DNAs encoding rE2, full-length rE3BP, its single lipoyl domain (rLip), and core domain (rE3BPCore) were cloned, and the proteins were expressed in Escherichia coli. Sera from 47 PBC patients were studied by immunoblotting and enzyme-linked immunosorbent assay (ELISA) against rE2, rE3BP, rE3BPCore, and both unlipoylated (U) and lipoylated (L) rLip. All sera were reactive by ELISA to some degree with all recombinant proteins except rE3BPCore, to which only 6 of 47 showed any reactivity. Significant correlations (P <.0001) were observed when comparing absorbance values for rE3BP with both rLip (U) (r = 0.793) and (L) (r = 0.963). The mean absorbance for rLip (U, 0.26 +/- 0.05) was, however, significantly lower than the absorbance for rLip (L) (0.78 +/- 0.12; P <.0001). After probing by immunoblotting and elution of antibodies from rE2 and rE3BP, subsequent reprobing against the components in whole PDC revealed true cross-reactivity. In summary, the response to E3BP is primarily directed against the lipoylated domain of the protein. It still remains unclear, however, whether the initial breakdown of tolerance is to E2 or E3BP.
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Affiliation(s)
- J M Palmer
- School of Biochemistry and Genetics, University of Newcastle upon Tyne, UK
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26
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Palmer JM, Diamond AG, Yeaman SJ, Bassendine MF, Jones DE. T cell responses to the putative dominant autoepitope in primary biliary cirrhosis (PBC). Clin Exp Immunol 1999; 116:133-9. [PMID: 10209517 PMCID: PMC1905223 DOI: 10.1046/j.1365-2249.1999.00803.x] [Citation(s) in RCA: 19] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/22/1998] [Indexed: 11/20/2022] Open
Abstract
PBC is characterized by T cell-mediated destruction of the biliary epithelial cells lining the small intrahepatic bile ducts. The E2 and E3 binding protein (E3BP (protein X)) components of pyruvate dehydrogenase complex (PDC) are disease-specific autoantigens in PBC. Attempts to localize the T cell autoepitopes within PDC-E2 have, however, generated contradictory results. One study has suggested the presence of T cell epitopes throughout PDC-E2, whilst another has identified a single dominant 14 amino acid T cell epitope (p163) spanning the lipoic acid binding lysine residue in the inner lipoyl domain (ILD) of PDC-E2. The aim of the current study was to determine the prevalence of T cell responses to p163 and PDC-E2 ILD, and the role played by lipoylation of these antigens in their immunogenicity, in a UK PBC population. We found that the majority of the PBC patients showing a 6-day peripheral blood T cell proliferative response to native human PDC also responded, in a MHC class II-restricted fashion, to biochemically purified PDC-E2 and E3BP (which co-purify) (9/10 positive (SI > 2.76), mean SI 5.74 +/- 5.04 (PDC-E2/E3BP) versus 6.67 +/- 3.84 (PDC), P = NS), implying that the important PBC-specific T cell epitopes are contained within the PDC-E2 or E3BP components of PDC. Only a minority of patients responsive to PDC, however, responded to either lipoylated recombinant PDC-E2 ILD (4/10 positive, mean SI 1.98 +/- 1.24, P < 0.005 versus PDC response) or lipoylated p163 (4/12 positive, mean SI 1.90 +/- 1.58, P < 0.001). The lipoylation state did not affect the T cell response to either ILD or p163. Our findings suggest that in some UK patients with PBC there are immunodominant T cell autoepitopes within PDC-E2/E3BP which are outside the ILD of PDC-E2.
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Affiliation(s)
- J M Palmer
- Centre for Liver Research, Medical School, University of Newcastle, Newcastle-upon-Tyne, UK
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27
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Kisand KE, Kisand KV, Karvonen AL, Vuoristo M, Mattila J, Mäkinen J, Uibo R. Antibodies to pyruvate dehydrogenase in primary biliary cirrhosis: correlation with histology. APMIS 1998; 106:884-92. [PMID: 9808415 DOI: 10.1111/j.1699-0463.1998.tb00235.x] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Antimitochondrial antibodies to pyruvate dehydrogenase are the hallmark of primary biliary cirrhosis. Their pathogenic role has not been proven, although antibodies to pyruvate dehydrogenase are bound to biliary epithelium. The aim of this study was to characterize serum IgA antibodies to pyruvate dehydrogenase and to evaluate their response to different treatment regimens. We also compared the level of antibodies with severity of histological lesions and the data of biochemical liver tests. Serum samples were collected at baseline and after 24 months from 61 primary biliary cirrhosis patients, whereas 23 patients were treated with ursodeoxycholic acid, 20 with colchicine, and 18 with placebo. ELISA was used to detect antibodies to pyruvate dehydrogenase. IgA and IgG were separated with jacalin and protein-A, respectively. Capacity of immunoglobulins to inhibit enzymatic activity was detected by spectrophotometric observation of the rate of enzyme reaction. 49 (80.3%) of the 61 patients possessed IgA antibodies to pyruvate dehydrogenase. Significant decrease in IgA antibodies was observed only in the ursodeoxycholic acid group (p<0.05). 15 of 18 IgA preparations and all 24 IgG preparations of patients' sera were inhibitory towards pyruvate dehydrogenase (mean inhibitory percent +/-SD: 42+/-33.4% and 79+/-22.4%, respectively, at a protein concentration of 100 microg/ml). The level of serum antibodies to pyruvate dehydrogenase correlated with several histological parameters (fibrosis, inflammatory infiltrate), but not with biochemical parameters. Our data reveal that IgA antibodies to pyruvate dehydrogenase inhibit enzyme function. The correlation between antibodies to pyruvate dehydrogenase and histological parameters might suggest the pathogenic role of these antibodies.
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Affiliation(s)
- K E Kisand
- Institute of General and Molecular Pathology, Department of Immunology, University of Tartu, Estonia
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28
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Abstract
Primary biliary cirrhosis (PBC) is a liver disease of unknown etiology characterized by chronic nonsuppurative destructive cholangitis (CNSDC) of intrahepatic septal and interlobular bile ducts. It is generally defined as an autoimmune disease. Characteristically, patients with PBC have a cholestatic serum hepatic profile and circulating antimitochondrial antibodies (AMA). PBC is progressive and ultimately leads to biliary cirrhosis and liver failure. It occurs at least three times more often in women than in men and it is the most common indication for liver transplantation in women around the world. There is no known cure for PBC. Despite the remarkable progress elucidating the genetics of breast cancer, and the effort placed on breast cancer education and screening methods, the mortality of breast cancer remains unacceptably high. In this essay, we describe the similarities between breast cancer and PBC and how their pathogenesis may be related. The hypothesis stated herein has evolved from reports from the early 1980s that linked an increased risk for breast cancer with PBC, and from the author's clinical experience with patients who suffer from both diseases. The association between these two diseases in the USA merits further investigation. If it is confirmed, risk factors involved in their pathogenesis will be identified.
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Affiliation(s)
- N V Bergasa
- Division of Gastroenterology and Liver Disease, Beth Israel Medical Center, New York, NY 10003, USA
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29
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Jones DE, James OF, Bassendine MF. Primary biliary cirrhosis: clinical and associated autoimmune features and natural history. Clin Liver Dis 1998; 2:265-82, viii. [PMID: 15560032 DOI: 10.1016/s1089-3261(05)70007-6] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Primary biliary cirrhosis, a chronic liver disease, predominately affects middle-aged women. The diagnosis is established by the presence of disease-specific autoantibodies and compatible liver histology showing focal immune-mediated damage to the intrahepatic bile ducts. Patients now are detected prior to the onset of symptoms typical of cholestasis with abnormal liver function tests, or even prior to the onset of abnormal liver function tests, with positive antimitochondrial antibodies. Earlier diagnosis is changing not only our appreciation of the prevalence of this condition, but also of the natural history. The disease appears to be heterogeneous with some patients having a slow progression and a normal life-expectancy, although other patients have a more aggressive course developing symptoms and end-stage disease that leads to death or liver transplantation.
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Affiliation(s)
- D E Jones
- Centre for Liver Research, The Medical School, University of Newcastle upon Tyne, New Castle upon Tyne, United Kingdom
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Klein R, Pointner H, Zilly W, Glässner-Bittner B, Breuer N, Garbe W, Fintelmann V, Kalk JF, Müting D, Fischer R, Tittor W, Pausch J, Maier KP, Berg PA. Antimitochondrial antibody profiles in primary biliary cirrhosis distinguish at early stages between a benign and a progressive course: a prospective study on 200 patients followed for 10 years. LIVER 1997; 17:119-28. [PMID: 9249725 DOI: 10.1111/j.1600-0676.1997.tb00793.x] [Citation(s) in RCA: 23] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
In recent retrospective studies, it was shown that subtypes of antimitochondrial antibodies (AMA) can help to discriminate between a benign [only anti-M9 and/or anti-M2 positive by enzyme-linked immunosorbent assay (ELISA)] and a rather progressive course (anti-M2, -M4 and/or -M8 positive). According to different constellations of these AMA subspecificities in ELISA and complement fixation test (CFT), four AMA profiles (A-D) were defined. In 1984 we started a prospective study based on 200 PBC patients with known AMA profiles in order to correlate the antibody pattern with the clinical outcome. Progression was defined primarily as the necessity of liver transplantation and death due to hepatic failure or variceal bleeding. At entry, 18 (9%) of the 200 patients had AMA profile A (only anti-M9), 57 (29%) profile B (only anti-M2 with or without anti-M9), 74 (37%) profile C (anti-M2 in association with anti-M4/-M8 by ELISA), and 51 (26%) profile D (anti-M2/-M4/-M8 by ELISA and CFT). At the beginning of the study, 177 patients had PBC stage I/II. During the observation period of ten years, ten patients died and in 18 orthotopic liver transplantation (OLT) was performed; all these patients belonged to profile C/D. Furthermore, 44% of the patients with profile C and 31% of the patients with profile D progressed to late stages, as defined by histology and clinical manifestations such as portal hypertension and increase of bilirubin, while only one of the patients with profile B and none of the profile A-patients developed late stage PBC. A significant increase of bilirubin was observed only in C/D-patients. AMA profiles did not change during the follow-up. In conclusion, AMA profiles discriminate between a benign and a progressive course of PBC already at early stages.
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Affiliation(s)
- R Klein
- Medizinische Klinik, University of Tübingen, Germany
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Kuroda M, Morito T, Takagi T, Ohira H, Kokubun M, Kojima T, Ono K, Kochi H, Kasukawa R. Antibodies to E1 and E2/Protein X components of pyruvate dehydrogenase complex in sera of patients with primary biliary cirrhosis. J Hepatol 1996; 25:867-76. [PMID: 9007715 DOI: 10.1016/s0168-8278(96)80291-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
AIMS/METHODS Using purified E1 component of pyruvate dehydrogenase complex (PDC) from bovine heart, we measured the levels of anti-E1 antibodies in PBC sera using ELISA and determined the degree of inhibition that these antibodies exerted on E1 enzyme activity. We also estimated levels of anti-E2/Protein X (Pro-X) antibodies in PBC sera using purified E2 and Pro-X of PDC which were copurified with E1. RESULTS/CONCLUSIONS Anti-E1 antibodies were detected in 87.5% (35/40) of PBC sera. Some of these sera inhibited E1 enzyme activity but inhibition did not correlate with levels of anti-E1 antibodies. A high positive correlation (r = 0.918) was found between levels of anti-E1 and anti-E2/Pro-X antibodies, suggesting that anti-PDC antibody production was stimulated by PDC itself. Levels of IgG class anti-E2/Pro-X antibodies were significantly higher in sera of symptomatic PBC patients than in those of asymptomatic PBC patients. It was also found that patients who were positive for only IgM class anti-E2/Pro-X antibodies had early-stage PBC.
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Affiliation(s)
- M Kuroda
- Department of Internal Medicine II, Fukushima Medical College, Japan
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Abstract
BACKGROUND In 1986, we reported a group of 29 patients who were positive in serum for antimitochondrial antibody (AMA), the disease-specific marker for primary biliary cirrhosis (PBC), but who had normal liver function test results and no symptoms of liver disease. However, liver histology was diagnostic or compatible with PBC in 24 patients and normal in only two. The aims of this 10-year follow-up study were to establish whether patients with AMA have very early PBC, to assess the outlook for such patients, and to follow the progression of the disease. METHODS All patients were assessed every year at our PBC clinic: records were reviewed, cause of death verified when applicable, and current clinical and biochemical data collected, including repeat liver histology as indicated. Serum samples from the original study were located. Original and follow-up serum samples were tested by ELISA for E2 components of pyruvate dehydrogenase complex and 2-oxoglutarate dehydrogenase complex. FINDINGS Five patients died during follow-up; no deaths were attributable to liver disease. Median follow-up of patients who survived was 17.8 years (range 11.0-23.9) from first-detected AMA to the last follow-up review. Overall, 22 (76%) developed symptoms of PBC and 24 (83%) had liver function tests persistently showing cholestasis. Repeat liver biopsy samples were obtained from ten patients; among these patients PBC progressed from Scheuer grade 1 to grade 2 in two and from grade 1 to grade 3 in two. No patient developed clinically apparent cirrhosis. ELISA of baseline serum samples from 27 patients was positive in 21, all of whom had original liver histology compatible with or diagnostic of PBC. Of the six patients who tested negative, only one had an original liver biopsy sample that was compatible with PBC. INTERPRETATION This study confirms that before the advent of any clinical or biomedical indications, individuals positive for AMA do have PBC. This finding extends the natural history of PBC back in some cases for many years. What determines the eventual progression to biochemically and clinically apparent disease is not yet understood. During our study no patient developed clinically apparent portal hypertension or cirrhosis. Thus, although the finding of a solitary persistently raised AMA is confirmation of a diagnosis of PBC, patients with AMA but no other signs or symptoms of PBC seem to have slow progression of the disease.
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Affiliation(s)
- J V Metcalf
- School of Clinical Medical Sciences, University of Newcastle, Newcastle upon Tyne, UK
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33
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O'Donohue J, Williams R. Antimitochondrial antibody and primary biliary cirrhosis: can there be one without the other? J Hepatol 1996; 25:574-7. [PMID: 8912159 DOI: 10.1016/s0168-8278(96)80219-4] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
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34
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Omagari K, Rowley MJ, Whittingham S, Jois JA, Byron SL, Mackay IR. Autoantibodies to M2 mitochondrial autoantigens in normal human sera by immunofluorescence and novel assays. J Gastroenterol Hepatol 1996; 11:610-6. [PMID: 8840233 DOI: 10.1111/j.1440-1746.1996.tb00301.x] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
Primary biliary cirrhosis (PBC) is characterized by the presence of antimitochondrial antibodies (anti-M2), directed against the E2 subunits of the 2-oxo-acid dehydrogenase complexes (2-OADC), chiefly pyruvate dehydrogenase complex (PDC-E2). We present here a detailed study, based on a large panel of normal sera, of the specificity of tests for anti-M2 by immunofluorescence and for anti-PDC by other assays for the diagnosis of PBC. The assays for anti-PDC included immunoblotting with bovine heart mitochondria, ELISA using recombinant PDC-E2 and an enzyme inhibition assay using purified porcine PDC. The positivity rates for normal sera were 0 (0/170), 2 (4/201), 1.5 (3/198) and 0% (0/186) for immunofluorescence, immunoblotting, ELISA and the enzyme inhibition assay, respectively. The seven positive reactions detected either by immunoblotting (n = 4) or ELISA (n = 3) were negative by the other three assays and in no instance did biochemical indices give any indication of chronic liver disease. Thus, as judged by reactivity with normal sera, the specificity of a positive test for the antibody to the major M2 autoantigen (PDC-E2) is 100% for immunofluorescence and the enzyme inhibition assay, 98% for immunoblotting and 98.5% for ELISA.
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Affiliation(s)
- K Omagari
- Centre for Molecular Biology and Medicine, Monash University, Clayton, Victoria, Australia
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35
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Berg PA, Klein R. Mitochondrial antigen/antibody systems in primary biliary cirrhosis: revisited. LIVER 1995; 15:281-92. [PMID: 8609807 DOI: 10.1111/j.1600-0676.1995.tb00687.x] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Methods for the evaluation of the four antimitochondrial antibody subtypes in primary biliary cirrhosis - anti-M2, -M4, -M8, -M9 - are described. The importance of the application of different preparations for the demonstration of complement fixing antibodies and the detection of antibodies by ELISA or Western blotting is emphasized. Complement fixing antigens can be prepared by discontinuous isopynic sucrose density gradient centrifugation using mitochondrial subfractions derived with from beef heart (M2), rat liver (M4), or pig kidney (M8). Anti-M9 antibodies do not fix complement. For ELISA, the pyruvate dehydrogenase or the ATPase-associated antigen fraction (M2), the sulfite oxidase fraction (M4), and the chromatographically purified M8-fraction should be used. The same antigen fractions are suitable for Western blotting, but anti-M4 and anti-M8 by ELISA and Western blotting a purified fraction prepared from rat liver has to be applied. Correlating antimitochondrial antibody-subtypes with clinical condition and the natural course, there is convincing evidence that especially the presence of complement fixing antibodies against the subtypes M2, M4, and M8 is a reliable indicator for a more active course. Patients expressing only anti-M9 (without anti-M2) have biochemically all the typical features also found in classical anti-M2 positive primary biliary cirrhosis patients, but seem not to advance to late stages. Since these antimitochondrial antibody-subtypes are present even in very early stages stages without changing their pattern during the course, antimitochondrial antibody-profiles can also be taken as early prognostic parameters. The evaluation of the immunological activity by antimitochondrial antibody-subtype testing may further facilitate the decision whether therapy with ursodeoxycholic acid should be combined with steroids and/or immunosuppressive agents. The role of mitochondrial autoantigens in the induction of this chronic destructive bile duct process is also discussed. The concept is put forward that not bile ducts but naive(?) B-cells expose the different mitochondrial antigens, thereby stimulating autoreactive T-cells to provide a second signal for antibody production. The degree of breakage of tolerance to the different mitochondrial epitopes may be one crucial factor which determines the diversity of antimitochondrial antibody-subtypes in patients with primary biliary cirrhosis.
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Affiliation(s)
- P A Berg
- Department of Internal Medicine, University of Tübingen, Germany
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36
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Jones DE, Palmer JM, James OF, Yeaman SJ, Bassendine MF, Diamond AG. T-cell responses to the components of pyruvate dehydrogenase complex in primary biliary cirrhosis. Hepatology 1995. [PMID: 7705811 DOI: 10.1002/hep.1840210417] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Primary biliary cirrhosis (PBC) is an autoimmune condition that results in destruction of the intrahepatic biliary epithelial cells and is characterized by autoantibodies to pyruvate dehydrogenase complex (PDC). The portal tract T-cell infiltrate and up-regulation of HLA class I, HLA class II, and cell adhesion molecules such as intercellular adhesion molecule-1 on the biliary epithelial cells suggest that T cells play a significant role in mediating this damage. The authors have characterized the peripheral blood T-cell proliferative responses of 24 PBC patients and 48 controls (20 normal, 28 non-PBC chronic liver disease) to the dominant autoantigen PDC, and its constituent components E1, E2 and protein X (which co-purify), and E3. A significant proportion of both PBC patients and controls showed T-cell responses to whole PDC (12 of 24 vs. 24 of 48 SI > 2.5 P = NS) and E1 (15 of 24 vs. 25 of 48 P = NS). Responses to PDC and E1 are thus seen in normal individuals and are not limited to PBC patients. T-cell responses to E2/X were seen in most PBC patients (14 of 24), but in only a small number of controls (6 of 48, P < .0001), responses to E2/X being significantly more frequent in pre-cirrhotic PBC patients (stages I to III, 12 of 15) than cirrhotic (stage IV, 2 of 9 P < .05). Peripheral blood T-cell responses to E2/X are thus strongly associated with early PBC. Responses to E3 were low in both PBC patients and controls.(ABSTRACT TRUNCATED AT 250 WORDS)
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Affiliation(s)
- D E Jones
- Department of Medicine, University of Newcastle, England
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37
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Priestman DA, Mistry SC, Halsall A, Randle PJ. Role of protein synthesis and of fatty acid metabolism in the longer-term regulation of pyruvate dehydrogenase kinase. Biochem J 1994; 300 ( Pt 3):659-64. [PMID: 8010947 PMCID: PMC1138218 DOI: 10.1042/bj3000659] [Citation(s) in RCA: 27] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
Antibodies were raised in rabbits to free rat liver pyruvate dehydrogenase (PDH) kinase alpha-chain and shown to react with PDH kinase alpha-chain in rat heart and liver PDH complexes, in purified pig heart PDH complex and in bovine kidney dihydrolipoamide acetyltransferase-protein X-PDH kinase subcomplex. E.l.i.s.a for PDHE1 (pyruvate dehydrogenase) and PDH kinase have been developed and applied to assays of these proteins in extracts of rat liver and rat heart mitochondria; the measured immunoreactivities for PDHE1 (heart > liver) and for PDH kinase alpha-chain (liver > heart) paralleled known differences in PDH complex and PDH kinase activities respectively. The results of e.l.i.s.a of PDH kinase alpha-chain in extracts of rat liver mitochondria showed that the effects of starvation to increase PDH kinase activity in vivo, and the effects of dibutyryl cyclic AMP or palmitate to increase PDH kinase activity in hepatocytes cultured in vitro, are due largely (> 90%) to an increase in the specific activity of PDH kinase. The effect, in cultured hepatocytes, of dibutyryl cyclic AMP to increase PDH kinase activity was blocked by cycloheximide; the effect of palmitate was blocked by an inhibitor of carnitine palmitoyltransferase I (Etomoxir), but not by cycloheximide.
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Affiliation(s)
- D A Priestman
- Nuffield Department of Clinical Biochemistry, Radcliffe Infirmary, Oxford, U.K
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38
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Kisand K, Kisand K, Salupere V, Uibo R. Enzyme-linked immunosorbent assays for the determination of IgG, IgA, and IgM autoantibodies to pyruvate dehydrogenase in primary biliary cirrhosis. INTERNATIONAL JOURNAL OF CLINICAL & LABORATORY RESEARCH 1994; 24:98-101. [PMID: 7919436 DOI: 10.1007/bf02593908] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
Autoantibodies to the recently described mitochondrial autoantigen, pyruvate dehydrogenase, have been shown to be specific for primary biliary cirrhosis. In the present study we describe enzyme-linked immunosorbent assays to detect antibodies of IgG, IgA, and IgM classes reactive with pyruvate dehydrogenase. These assays showed high sensitivity (95%) and specificity (100%) for primary biliary cirrhosis when evaluated in 28 patients with primary biliary cirrhosis, 59 disease controls, and 214 healthy persons. Quantitation of these autoantibodies by calculating the areas under the sera titration curves of 10 primary biliary cirrhosis patients indicated that an increase in IgA antibodies to pyruvate dehydrogenase is related to more rapid disease progression.
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Affiliation(s)
- K Kisand
- Institute of General and Molecular Pathology, Tartu University Hospital, Tartu University, Estonia
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39
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Kimura T, Suzuki K, Inada S, Hayashi A, Saito H, Miyai T, Ohsugi Y, Matsuzaki Y, Tanaka N, Osuga T. Induction of autoimmune disease by graft-versus-host reaction across MHC class II difference: modification of the lesions in IL-6 transgenic mice. Clin Exp Immunol 1994; 95:525-9. [PMID: 8137550 PMCID: PMC1535069 DOI: 10.1111/j.1365-2249.1994.tb07030.x] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023] Open
Abstract
We examined the effect of IL-6 on the development of autoimmune diseases (primary biliary cirrhosis, Sjögren's syndrome) employing murine graft-versus-host reaction (GVHR) model with MHC class II disparity. For this purpose, we used IL-6 transgenic (B6.6) mice in which a high level of IL-6 was detected. C57Bl/6 (B6) spleen T cells were injected into B6.6 mated with B6.C-H-2bm12 (bm12) mutant mice ((bm12 x B6.6)F1) and GVHR with MHC class II disparity was induced. The transgenic hybrid mice with GVHR showed a larger spleen index and contained a higher serum level of IL-6 than those without GVHR. Autoimmune-like lesions in transgenic recipients became weakened compared with those in non-transgenic (bm12 x B6)F1 recipients. In contrast, levels of antimitochondrial antibodies in (bm12 x B6.6)F1 GVHR group were significantly higher than that of (bm12 x B6)F1 GVHR group. These results indicate that IL-6 excessively produced in vivo might regulate the progression of autoimmune diseases.
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Affiliation(s)
- T Kimura
- Animal Centre for Biomedical Research, Faculty of Medicine, University of Tokyo, Japan
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40
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Michieletti P, Wanless IR, Katz A, Scheuer PJ, Yeaman SJ, Bassendine MF, Palmer JM, Heathcote EJ. Antimitochondrial antibody negative primary biliary cirrhosis: a distinct syndrome of autoimmune cholangitis. Gut 1994; 35:260-5. [PMID: 8307480 PMCID: PMC1374505 DOI: 10.1136/gut.35.2.260] [Citation(s) in RCA: 172] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
This study reports on a group of 20 patients with an initial diagnosis of primary biliary cirrhosis (PBC) whose serum tested negative for antimitochondrial antibodies by immunofluorescence. All had a clinical history compatible with primary biliary cirrhosis, and results of biochemical, histological, and radiological investigations were consistent with this diagnosis despite the absence of antimitochondrial antibodies by immunofluorescence. For comparison, these patients were matched for sex and serum bilirubin with 20 antimitochondrial antibody positive (> 1:160) and histologically confirmed primary biliary cirrhosis patients who served as controls. Serum samples from both groups were retested blindly for antimitochondrial antibodies using immunoblotting and for antibodies to the major M2 mitochondrial autoantigens by enzyme linked immunosorbent assay (ELISA). Three antimitochondrial antibody immunofluorescence negative patients had antimitochondrial antibodies by immunoblotting and ELISA; the remaining 17 patients were confirmed negative by all methods. The antimitochondrial antibody immunofluorescence positive controls were verified by immunoblotting or ELISA, or both. All 17 patients negative for antimitochondrial antibodies had antinuclear antibodies, often in high titres, compared with 3/17 of the antimitochondrial antibody positive controls (p = 0.0001). Additionally, the antimitochondrial antibody negative group also had significantly higher smooth muscle antibody titres (p = 0.03) and lower serum IgM (p = 0.01) and aspartate aminotransferase (p = 0.03) activities than the antimitochondrial antibody positive controls. Analysis of clinical findings, histological tests, serum bilirubin, alkaline phosphatase, alanine aminotransferase, and IgG, disclosed no significant differences between the two groups. This paper describes a group of patients with the clinical and histological features of PBC but who do not fulfil the usual criteria necessary to make this diagnosis. Because they also have very high titres of antinuclear antibodies, smooth muscle antibodies, and comparatively low IgM and aspartate aminotransferase activities, we believe they are distinct from PBC and have a syndrome of autoimmune cholangitis.
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Affiliation(s)
- P Michieletti
- Department of Medicine, University of Newcastle upon Tyne
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41
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Perros P, Palmer JM, Yeaman SJ, Kendall-Taylor P. Anti-mitochondrial antibodies in patients with Graves' disease may not signify primary biliary cirrhosis. Postgrad Med J 1994; 70:17-8. [PMID: 8140011 PMCID: PMC2397584 DOI: 10.1136/pgmj.70.819.17] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
Two patients with Graves' disease were incidentally found to have anti-mitochondrial antibodies by immunofluorescence in the absence of symptoms, clinical signs or biochemical evidence of liver dysfunction. Anti-mitochondrial antibody titres became undetectable in both patients on follow-up. Screening of the patients' sera by immunoblotting against the purified antigens of the M2 complex was negative. We conclude that in these cases, anti-mitochondrial antibodies detected by immunofluorescence were directed against antigens other than the primary biliary cirrhosis-associated M2 complex and therefore did not signify subclinical primary biliary cirrhosis.
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Affiliation(s)
- P Perros
- Department of Medicine, Medical School, University of Newcastle upon Tyne, UK
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42
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Kitami N, Ishii H, Shimizu H, Adachi H, Komada T, Mikami H, Yokoi Y, Sato N. Immunoreactivity to M2 proteins in antimitochondrial antibody-negative patients with primary biliary cirrhosis. J Gastroenterol Hepatol 1994; 9:7-12. [PMID: 8155871 DOI: 10.1111/j.1440-1746.1994.tb01208.x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
Although antimitochondrial auto-antibodies are characteristically present in the serum of patients with primary biliary cirrhosis (PBC), there is a discrepancy between the positivity for antimitochondrial antibody (AMA) and that for anti-M2 auto-antibody. In an attempt to explain the discrepancy, this study investigates the relationship between the AMA titre, determined by indirect immunofluorescence, and immunoreactivity to four inner mitochondrial membrane proteins (M2 proteins) with molecular weights of 70, 50, 47, and 40 kDa in 129 patients with PBC. Antimitochondrial antibody positivity was identified in 114 (88%) of 129 patients with clinically and histologically confirmed PBC. There were no significant differences between the AMA-negative and AMA-positive groups in clinical characteristics or histologically determined disease stage. Immunoblot analysis showed that all patients had anti-M2 auto-antibodies to one or more of the four M2 proteins. Nine (60%) of the 15 AMA-negative patients had antibodies to only one M2 protein (either 70 or 47 kDa). In contrast, 34 (53%) of the 64 patients with high AMA titres (> or = 1:320) had antibodies to all four M2 proteins. There was a significant rank correlation between the AMA titre and the number of antibodies to M2 proteins (P < 0.01). These findings indicate that the AMA titre is not influenced by the immunogenicity of M2 proteins but by the number of M2 proteins that elicit an antibody response and that decreased immunoreactivity to M2 proteins may induce AMA negativity in PBC serum samples.
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Affiliation(s)
- N Kitami
- Department of Gastroenterology, Juntendo University School of Medicine, Tokyo, Japan
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43
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Czaja AJ, Carpenter HA, Manns MP. Antibodies to soluble liver antigen, P450IID6, and mitochondrial complexes in chronic hepatitis. Gastroenterology 1993; 105:1522-8. [PMID: 8224657 DOI: 10.1016/0016-5085(93)90160-e] [Citation(s) in RCA: 96] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
BACKGROUND Antibodies to soluble liver antigen, P450IID6, and the E2 subunits of mitochondrial dehydrogenase complexes occur in autoimmune liver diseases, but their specificities and implications are uncertain. The aims of the present study were to assess the importance of these autoantibodies in different types of chronic hepatitis. METHODS Sera from 62 patients with autoimmune hepatitis, 37 patients with cryptogenic hepatitis, and 19 patients with chronic hepatitis C were assessed under code by enzyme immunoassay. RESULTS Antibodies to soluble liver antigen were found in 7 patients with autoimmune hepatitis (11%) and 5 patients with cryptogenic disease (14%). Patients with antibodies to soluble liver antigen were indistinguishable from seronegative counterparts with autoimmune hepatitis. Seropositive patients with cryptogenic hepatitis had autoimmune features, and they responded to corticosteroid therapy. Five patients (8%) with autoimmune hepatitis were seropositive for antibodies to mitochondrial complexes. Three lacked antimitochondrial antibodies. None of the patients had antibodies to P450IID6, and patients with chronic hepatitis C were seronegative for all markers. CONCLUSIONS Antibodies to soluble liver antigen do not define a distinct subgroup of patients with autoimmune hepatitis. They may be found in some patients with corticosteroid-responsive cryptogenic hepatitis. Antibodies to E2 subunits and P450IID6 are uncommon in adults with chronic hepatitis.
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Affiliation(s)
- A J Czaja
- Division of Gastroenterology and Internal Medicine, Mayo Clinic, Rochester, Minnesota
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44
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Affiliation(s)
- H C Mitchison
- Department of Medicine, University of Newcastle upon Tyne, UK
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45
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Caldwell SH, Leung PS, Spivey JR, Prindiville T, de Medina M, Saicheur T, Rowley M, Reddy KR, Coppel R, Jeffers LJ. Antimitochondrial antibodies in kindreds of patients with primary biliary cirrhosis: antimitochondrial antibodies are unique to clinical disease and are absent in asymptomatic family members. Hepatology 1992; 16:899-905. [PMID: 1398496 DOI: 10.1002/hep.1840160408] [Citation(s) in RCA: 27] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
The 2-oxo-acid dehydrogenase family of enzymes have been identified as the major mitochondrial autoantigens of primary biliary cirrhosis. Using immunoblotting, enzyme-linked immunosorbent assay and enzyme inhibition with both purified mitochondrial proteins and recombinant autoantigens, we have studied family members and spouses of patients with primary biliary cirrhosis for the presence of antimitochondrial antibodies. Antimitochondrial antibodies and other common autoantigens were also tested for by indirect immunofluorescence. This study included 27 index patients with primary biliary cirrhosis, 15 spouses and 48 first- and second-degree relatives. Overall, 7 relatives (11%) were positive for autoantibodies to nuclear and cytoplasmic antigens by indirect immunofluorescence against mouse liver and stomach sections. However, with immunofluorescence, the reactivity strictly paralleled that of antimitochondrial antibodies in only one of these (1:640)--a sibling with mild pruritus and a liver biopsy specimen diagnostic of primary biliary cirrhosis despite normal levels of serum alkaline phosphatase. In addition, one of the mothers, who had a history of sarcoidosis, was positive by immunoblotting for antibodies to the E2 subunit of the pyruvate dehydrogenase complex and protein X. All other relatives were negative for all of the assays. Antibodies to neither the 2-oxo-acid dehydrogenase enzymes nor the recently proposed family of naturally occurring mitochondrial antibodies were found in spouses or healthy relatives. Three other first-degree relatives suffered from liver disease: two died (one from primary biliary cirrhosis and the other from an unknown type of liver disease) and one (a sibling with primary biliary cirrhosis) was unavailable for testing. Our results are consistent with a familial predisposition to primary biliary cirrhosis.(ABSTRACT TRUNCATED AT 250 WORDS)
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Affiliation(s)
- S H Caldwell
- Center for Liver Disease, University of Miami, Florida
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46
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Mitchison HC, Palmer JM, Bassendine MF, Watson AJ, Record CO, James OF. A controlled trial of prednisolone treatment in primary biliary cirrhosis. Three-year results. J Hepatol 1992; 15:336-44. [PMID: 1447500 DOI: 10.1016/0168-8278(92)90065-w] [Citation(s) in RCA: 128] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
The results of a 3-year, placebo-controlled trial of prednisolone treatment in primary biliary cirrhosis (PBC) are presented. The active (n = 19) and placebo (n = 17) arms were initially well matched for age, menopausal status and disease severity. At 3 years hepatic symptoms were relatively improved in the prednisolone group. Hepatic mortality was 3/19 (prednisolone), 5/17 (placebo) (p = n.s.). For all liver blood tests the trend favoured prednisolone treatment, though the differences were only significant for alkaline phosphatase and protein. All immunoglobulins fell significantly. Quantitative ELISA determination of antimitochondrial antibody showed a significant fall in the prednisolone group compared with placebo (p less than 0.001 at 1 year, p less than 0.05 at 3 years). Deterioration in histology (appearance of cirrhosis) was more common in the placebo group. Overall hepatic function (hepatic mortality, doubling in bilirubin, 6 milligrams fall in albumin, de novo appearance of cirrhosis or symptoms of portal hypertension) was significantly worse in the placebo group (p less than 0.01). After 3 years no significant differences could be detected in bone mineral content (single photon absorptiometry of radius and femur) between the two groups or in comparison with other PBC patients. Thus, after 3 years, prednisolone treatment was associated with a better overall hepatic outcome and little evidence of increased bone loss.
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Affiliation(s)
- H C Mitchison
- Department of Medicine, University of Newcastle upon Tyne, United Kingdom
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47
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Leung PS, Iwayama T, Prindiville T, Chuang DT, Ansari AA, Wynn RM, Dickson R, Coppel R, Gershwin ME. Use of designer recombinant mitochondrial antigens in the diagnosis of primary biliary cirrhosis. Hepatology 1992; 15:367-72. [PMID: 1371979 DOI: 10.1002/hep.1840150302] [Citation(s) in RCA: 37] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
The appearance of autoantibodies against mitochondria in patients with primary biliary cirrhosis has been known for more than 25 yr. In the past, based on the biochemical complexity of the mitochondrion and the use of crude extracts for immunodiagnosis, a degree of nonspecificity in assaying for antibodies to mitochondria has been present. This problem has been largely circumvented by the cloning of the mitochondrial antigens and the identification of the E2 subunits of the pyruvate dehydrogenase complex and the branched chain 2-oxo-acid dehydrogenase complex as the major and immunodominant autoantigens of primary biliary cirrhosis. More than 90% of patients with primary biliary cirrhosis have been shown to react with one or both of these enzymes using either recombinant antigen or purified native protein. Approximately 10% of patients recognize only E2 subunits of branched chain 2-oxo-acid dehydrogenase complex and not pyruvate dehydrogenase complex. Such patients would be missed by diagnostic assay that has a low sensitivity to antibodies against E2 subunits of branched chain 2-oxo-acid dehydrogenase complex. The use of recombinant and biochemically pure antigens has permitted structural and conformational analysis of epitope mapping. We have taken advantage of the antigenic mapping studies of both primary biliary cirrhosis and branched chain 2-oxo-acid dehydrogenase complex E2 subunits and designed a molecule that expresses the immunodominant epitopes of both. Using this dual-headed molecule that coexpresses the epitope of two different antigens, we report herein a sensitive and reproducible assay for antibodies to mitochondria in patients with primary biliary cirrhosis.(ABSTRACT TRUNCATED AT 250 WORDS)
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Affiliation(s)
- P S Leung
- Department of Internal Medicine, University of California, Davis
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48
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Bassendine MF, Yeaman SJ. Serological markers of primary biliary cirrhosis: diagnosis, prognosis and subsets. Hepatology 1992; 15:545-8. [PMID: 1544636 DOI: 10.1002/hep.1840150329] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
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49
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Butler P, Valle F, Burroughs AK. Mitochondrial antigens and antibodies in primary biliary cirrhosis. Postgrad Med J 1991; 67:790-7. [PMID: 1946125 PMCID: PMC2399104 DOI: 10.1136/pgmj.67.791.790] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Affiliation(s)
- P Butler
- University Department of Medicine, Royal Free Hospital and School of Medicine, Hampstead, London, UK
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