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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: 12] [Impact Index Per Article: 6.0] [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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John BV, Dahman B, Deng Y, Khakoo NS, Taddei TH, Kaplan DE, Levy C. Rates of decompensation, hepatocellular carcinoma and mortality in AMA-negative primary biliary cholangitis cirrhosis. Liver Int 2022; 42:384-393. [PMID: 34614294 PMCID: PMC8810619 DOI: 10.1111/liv.15079] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Revised: 09/21/2021] [Accepted: 09/30/2021] [Indexed: 02/03/2023]
Abstract
BACKGROUND The natural history of patients with anti-mitochondrial antibody (AMA)-negative Primary Biliary Cholangitis (PBC) cirrhosis has not been well defined, with prior studies showing discordant results. Furthermore, most studies of AMA-negative PBC have limited numbers of patients with cirrhosis and liver-related outcomes. METHODS We investigated the association of AMA-negative PBC and the development of death, liver-related death, decompensation and hepatocellular carcinoma (HCC), in a large cohort of predominantly male patients with PBC cirrhosis assembled from the Veterans Health Administration. RESULTS In a cohort of 521 patients with PBC cirrhosis (65 AMA-negative) with a total follow-up of 2504.3 person-years (PY) from cirrhosis diagnosis, patients with AMA-negative PBC were younger and more likely to be black but had similar rates of UDCA response. AMA-negative PBC cirrhosis was associated with similar unadjusted rates of liver-related death (4.6 vs 5.9 per 100 PY, P = .44), overall death (7.7 vs 9.6 per 100 PY, P = .31), decompensation (7.3 vs 5.1 per 100 PY, P = .12) and HCC (0.6 vs 1.0 per 100 PY, P = .63) to AMA-positive PBC. After adjusting for confounders, AMA-negative PBC cirrhosis was associated with similar rates of liver-related death (sub-Hazard Ratio [sHR] 1.27, 95% CI 0.71-2.28, P = .42, death [sHR] 1.24, 95% CI 0.81-1.90, P = .32), decompensation (sHR 1.05, 95% CI 0.56-1.98, P = .87) and HCC (sHR 0.48, 95% CI 0.11-2.10, P = .33) to AMA-positive patients. CONCLUSION In a cohort of predominantly male patients, AMA-negative PBC cirrhosis was associated with similar rates of overall or liver-related death, HCC or decompensation compared with AMA-positive disease.
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Affiliation(s)
- Binu V John
- Division of Hepatology, Bruce W Carter VA Medical Center, Miami, Florida, USA
- Division of Digestive Health and Liver Diseases, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - Bassam Dahman
- Department of Health Behavior and Policy, Virginia Commonwealth University, Richmond, Virginia, USA
| | - Yangyang Deng
- Department of Health Behavior and Policy, Virginia Commonwealth University, Richmond, Virginia, USA
| | - Nidah S Khakoo
- Department of Medicine, Jackson Memorial Hospital, Miami, Florida, USA
| | - Tamar H Taddei
- Section of Digestive Diseases, Yale School of Medicine, New Haven, Connecticut, USA
- VA Connecticut Healthcare System, West Haven, Connecticut, USA
| | - David E Kaplan
- Division of Gastroenterology and Hepatology, University of Pennsylvania, Philadelphia, Pennsylvania, USA
- Division of Gastroenterology and Hepatology, Corporal Michael J. Crescenz VA Medical Center, Philadelphia, Pennsylvania, USA
| | - Cynthia Levy
- Division of Digestive Health and Liver Diseases, University of Miami Miller School of Medicine, Miami, Florida, USA
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Zandanell S, Strasser M, Feldman A, Strebinger G, Aigner G, Niederseer D, Laimer M, Mussnig B, Paulweber B, Datz C, Aigner E. Similar clinical outcome of AMA immunoblot-M2-negative compared to immunoblot-positive subjects over six years of follow-up. Postgrad Med 2021; 133:291-298. [PMID: 33538618 DOI: 10.1080/00325481.2021.1885945] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Background: The detection of anti-mitochondrial antibodies (AMA) is considered a hallmark in diagnosing primary biliary cholangitis (PBC). The most important AMA-subtype is AMA-M2 directed against the E2-subunit of pyruvate dehydrogenase. It is common clinical interpretation that lack of M2 due to immunoblotting (IB) indicates absence of specific auto-reactivity. We aimed to define whether M2-IB confirmation is linked to clinical outcomes.Methods: Our cohort comprised 302 patients who tested positive for AMA with indirect immunofluorescence between 2006 and 2015. One hundred and eighty-four subjects (60.9%; male n = 29 [15.8%]) were tested M2-positive by confirmatory IB, whereas 118 subjects were IB-M2-negative (39.1%; male n = 25 [21.2%]). The natural history of 236 patients (78.1%) was evaluated by clinical follow-up (FU) assessing causes of death, leading health condition and response to PBC standard therapy if applicable.Results: Mean time to FU was 6.8 years. Twenty-eight M2-positive patients (15.2% of 184) and 28 M2-negative patients (23.7% of 118) had died (p = 0.0958). Thirty-four M2-positives (18.5%) and 32 M2-negatives (27.1%) were not available for FU. According to the clinical course by the time of FU, subjects were allocated to one of four groups: a) 34 patients had known PBC with n = 16 having an adequate and 18 an inadequate treatment response, b) 1 de novo PBC was detected, c) 13 were AMA-positive without biochemical evidence of PBC and d) 9 subjects were tested AMA-negative at FU. These numbers were comparable to M2-positive subjects with similar long-term clinical outcome.Conclusion: Our data suggest that the clinical value of confirmatory M2 immunoblotting in the diagnostic routine of PBC is overestimated as the clinical course appears not to be related to the test result.
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Affiliation(s)
- Stephan Zandanell
- First Department of Medicine, Paracelsus Medical University, Salzburg, Austria
| | - Michael Strasser
- First Department of Medicine, Paracelsus Medical University, Salzburg, Austria
| | - Alexandra Feldman
- First Department of Medicine, Paracelsus Medical University, Salzburg, Austria
| | - Georg Strebinger
- First Department of Medicine, Paracelsus Medical University, Salzburg, Austria
| | - Gerhild Aigner
- First Department of Medicine, Paracelsus Medical University, Salzburg, Austria
| | - David Niederseer
- Department of Internal Medicine, Oberndorf Hospital, Teaching Hospital of the Paracelsus Medical University, Salzburg, Austria.,Department of Cardiology, University Heart Center Zurich, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Martin Laimer
- Laboratory for Immunology, Allergology & Molecular Diagnostics, Department of Dermatology, Paracelsus Medical University, Salzburg, Austria
| | - Birgit Mussnig
- Laboratory for Immunology, Allergology & Molecular Diagnostics, Department of Dermatology, Paracelsus Medical University, Salzburg, Austria
| | - Bernhard Paulweber
- First Department of Medicine, Paracelsus Medical University, Salzburg, Austria
| | - Christian Datz
- Department of Internal Medicine, Oberndorf Hospital, Teaching Hospital of the Paracelsus Medical University, Salzburg, Austria
| | - Elmar Aigner
- First Department of Medicine, Paracelsus Medical University, Salzburg, Austria
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Clinical significance of IgG antimitochondrial M2 antibody levels in primary biliary cholangitis: A single center study from China. PLoS One 2020; 15:e0242164. [PMID: 33180817 PMCID: PMC7661052 DOI: 10.1371/journal.pone.0242164] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2020] [Accepted: 10/27/2020] [Indexed: 11/25/2022] Open
Abstract
Background and objective The relationship between antimitochondrial antibody (AMA) levels and the severity or prognosis of primary biliary cholangitis (PBC) is unclear. This study explored the clinical significance of serum IgG antimitochondrial M2 antibody (IgG-M2) levels. Methods From 2008 to 2017, a retrospective analysis was conducted with PBC patients who had available quantitative values of serum IgG-M2 levels obtained with ELISA based on triple expression hybrid clones. The patients were divided into two groups based on high and low concentrations of IgG-M2. Baseline parameters, the incidence of adverse events, and prognosis were compared. Results Among the 530 PBC patients, the levels of albumin, cholinesterase, hemoglobin, fibrinogen and triglycerides and the red blood cell count were significantly lower in the high-concentration group than in the low-concentration group (n = 263, 49.6%). The red cell distribution width (RDW) and levels of serum immunoglobulin (Ig) G, IgM and IgA were significantly higher in the high-concentration group than in the low-concentration group. Spearman’s correlation analysis suggested that the correlation between the above baseline indicators and IgG-M2 levels was statistically significant but weak (r < 0.2, P < 0.05). In total, 203 patients were followed up, of whom 87 (42.9%) were in the high-concentration group. During the median follow-up period of 52 months (range: 28–75), 121 (59.6%) experienced hepatic decompensation, and 37 (18.2%) died or underwent liver transplantation. There was no significant difference in the incidence of complications or survival (log-rank test: P = 0.079) between the two groups. One year after ursodeoxycholic acid (UDCA) treatment, the two groups had similar responses. In addition, the levels of IgG-M2 did not fluctuate significantly during treatment. Conclusion IgG-M2 levels were not related to the disease severity, prognosis or efficacy of UDCA. The levels of IgG-M2 did not change significantly during treatment.
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Liu H, Norman GL, Shums Z, Worman HJ, Krawitt EL, Bizzaro N, Vergani D, Bogdanos DP, Dalekos GN, Milkiewicz P, Czaja AJ, Heathcote EJ, Hirschfield GM, Tan EM, Miyachi K, Bignotto M, Battezzati PM, Lleo A, Leung PS, Podda M, Gershwin ME, Invernizzi P. PBC screen: an IgG/IgA dual isotype ELISA detecting multiple mitochondrial and nuclear autoantibodies specific for primary biliary cirrhosis. J Autoimmun 2010; 35:436-42. [PMID: 20932720 DOI: 10.1016/j.jaut.2010.09.005] [Citation(s) in RCA: 106] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2010] [Revised: 09/14/2010] [Accepted: 09/14/2010] [Indexed: 01/14/2023]
Abstract
A dual isotype (IgG, IgA) enzyme-linked immunosorbent assay (ELISA) designed to provide enhanced detection of primary biliary cirrhosis (PBC)-specific autoantibodies against both major mitochondrial and nuclear antigens has been developed and recently become commercially available. The assay (PBC Screen) simultaneously detects IgG and IgA autoantibodies to the immunodominant portions of the 3 major mitochondrial (MIT3) and nuclear (gp210, and sp100) antigens. The aim of this study was to compare the performance of the PBC Screen to the combined performance obtained with individual IgG ELISAs to MIT3, gp210, and sp100 on a large group of selected patients from multiple centers. A total of 1175 patients with PBC and 1232 subjects without PBC were evaluated. Non-PBC groups included healthy controls (624) as well as individuals with autoimmune hepatitis (281), primary sclerosing cholangitis (77), viral hepatitis (91 hepatitis B and 98 hepatitis C), other liver diseases (31), and other infectious or autoimmune diseases (30). The PBC Screen at the receiver operator characteristic optimized cutoff of 27.8 units, had an overall sensitivity of 83.8%, specificity of 94.7% and area under curve of 0.9212. This was similar to the specificity of 96.1% obtained by the combined results of individual MIT3, sp100, and gp210 IgG ELISAs (kappa index at 0.898). Of the 253 PBC patients without AMA detectable by immunofluorescence, 113 (44.7%) were interpreted as positive for PBC-specific autoantibodies. In conclusion, the PBC Screen is an appropriate first-line test for the diagnosis of PBC, including for patients negative for markers assessed using conventional methods.
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Affiliation(s)
- Haiying Liu
- Division of Internal Medicine and Center for Autoimmune Liver Diseases, IRCCS Istituto Clinico Humanitas, Rozzano, Italy
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Mendes F, Lindor KD. Antimitochondrial antibody-negative primary biliary cirrhosis. Gastroenterol Clin North Am 2008; 37:479-84, viii. [PMID: 18499032 DOI: 10.1016/j.gtc.2008.02.006] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
There is a subset of patients who have biochemical and histologic features consistent with primary biliary cirrhosis (PBC) who lack antimitochondrial antibodies (AMA). This entity is usually referred to as AMA-negative PBC or alternatively autoimmune cholangitis. Patients who have AMA-negative PBC are believed to have a similar clinical course, response to treatment, and prognosis as their AMA-positive counterparts. As more sensitive and specific serologic tests are developed to detect serum AMA, it is possible we may find that these patients initially believed to be AMA-negative are indeed AMA-positive, suggesting a single disease process.
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Affiliation(s)
- Flavia Mendes
- Division of Hepatology, University of Miami Miller School of Medicine, Miami, FL 33136, USA
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Sakauchi F, Oura A, Ohnishi H, Mori M. Comparison of the clinical features of Japanese patients with primary biliary cirrhosis in 1999 and 2004: utilization of clinical data when patients applied to receive public financial aid. J Epidemiol 2008; 17:210-4. [PMID: 18094520 PMCID: PMC7058463 DOI: 10.2188/jea.17.210] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
BACKGROUND In Asia there are few reports considering time intervals in the examination of clinical features of primary biliary cirrhosis (PBC). Therefore, we tried to compare the characteristics of patients with PBC in two different years. METHODS In two fiscal years (1999 and 2004), 9,761 and 13,142 patients with symptomatic PBC were registered to receive public financial aid from the Ministry of Health, Labour and Welfare of Japan, respectively. For the present study, clinical data from 2,127 patients in 1999 and 6,423 ones in 2004 were available. We compared the data in the two different years, including sex, age, major symptoms, and laboratory data. RESULTS Male/female ratios were the same figure (0.13 for 1999 and 2004). The median age was significantly older in 2004 than in 1999 (59 years for 1999, 63 years for 2004, respectively, p<0.01). Jaundice and esophageal varices were found significantly less frequent in 2004 than in 1999 (p<0.01 for each item). Levels of total bilirubin, γ-glutamyl transpeptidase (γ-GTP), total cholesterol, and immunoglobulin M were significantly lower in 2004 than in 1999 (p< 0.02 for total bilirubin, and p<0.01 for other each item). The positive rate of antimitochondrial antibodies was significantly higher in 1999 than in 2004 (87.0% for 1999, 83.5% for 2004, respectively, p<0.01)). Complicated autoimmune diseases such as Sjögren's syndrome, rheumatoid arthritis, and chronic thyroiditis were found significantly more frequent in 2004 than in 1999 (p<0.01 for each item). CONCLUSIONS Among the patients with PBC in 2004, an increase in median age, and lower levels of laboratory data such as γ-GTP have been found compared to 1999. These results may show an accumulation of patients with better prognosis and the recent medical progress in controlling patients with PBC.
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Affiliation(s)
- Fumio Sakauchi
- Department of Public Health, Sapporo Medical University School of Medicine, Sapporo, Japan.
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Nezu S, Tanaka A, Yasui H, Imamura M, Nakajima H, Ishida H, Takahashi SI. Presence of antimitochondrial autoantibodies in patients with autoimmune hepatitis. J Gastroenterol Hepatol 2006; 21:1448-54. [PMID: 16911691 DOI: 10.1111/j.1440-1746.2006.04434.x] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND AND AIM Antimitochondrial autoantibodies (AMA) are known to be a hallmark of primary biliary cirrhosis, and it has been suggested that AMA play a crucial role in generating biliary changes. Biliary tract lesions are not uncommon in patients with autoimmune hepatitis (AIH) and previous works have demonstrated that AMA are occasionally detectable in sera of patients with AIH. Therefore, the role of AMA as a cause of bile duct lesions in AIH livers should be addressed. The aim of the present study was to determine whether the presence of AMA is associated with clinical features, especially the occurrence of bile duct lesions, in patients with AIH. METHODS Forty-one patients diagnosed as having AIH according to the revised scoring system of the International Autoimmune Hepatitis Group were enrolled in this study. Clinical data were retrospectively reviewed, and histological findings of the liver were investigated. AMA reactivity was determined by immunoblotting using beef heart mitochondria as antigens. RESULTS Although not found in any enrolled patient by conventional indirect immunofluorescence, AMA were detectable in 14 out of 41 patients (34%). Clinical parameters including biochemistry, autoantibody profile, and responses to treatment were similar irrespective of AMA status. Bile duct lesions were noted in 14/14 (100%) and 23/27 (85%) of AMA-positive and -negative patients with AIH, respectively (P = 0.134). There was no statistically significant difference in the grade of inflammation or stage of fibrosis between the two groups. CONCLUSION Antimitochondrial autoantibodies were found to be present in sera of patients with AIH more frequently than expected, even at very low titer. However, clinical features and histological findings of AIH were not influenced by the AMA status.
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Affiliation(s)
- Saeko Nezu
- Third Department of Internal Medicine, School of Medicine, Kyorin University, Tokyo, Japan.
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Sakauchi F, Mori M, Zeniya M, Toda G. Antimitochondrial antibody negative primary biliary cirrhosis in Japan: utilization of clinical data when patients applied to receive public financial aid. J Epidemiol 2006; 16:30-4. [PMID: 16369106 PMCID: PMC7560548 DOI: 10.2188/jea.16.30] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND We examined patients who showed laboratory and histological evidence of primary biliary cirrhosis (PBC) in the absence of antimitochondrial antibody (AMA) to elucidate the characteristics of AMA negative PBC. METHODS From a total of 5,805 patients with symptomatic PBC, 2,419 cases (41.7%) were selected in the present study, who were diagnosed using the following criterion; chronic non-suppurative destructive cholangitis was histologically observed and laboratory data did not contradict PBC. The information collected from records included sex, age, symptoms, physical findings, and complicated autoimmune diseases. We then evaluated these data according to the positivity of AMA. RESULTS Of the total subjects, 470 cases (19.4%) were found to be negative for AMA. The proportion of female patients was higher among the AMA negative group than among the AMA positive one. Pruritus was found less frequently among patients with AMA negative PBC than among those with AMA positive PBC. Levels of alkaline phosphatase, γ-glutamyl transpeptidase, and IgM were significantly lower among patients with AMA negative PBC than among those with AMA positive PBC. Complications such as Sjögren’s syndrome, rheumatoid arthritis, and scleroderma, including CREST syndrome, were found with significantly higher frequency among patients with AMA negative PBC than among those with AMA positive PBC. CONCLUSION Considering serum level of IgM and frequencies of complicated autoimmune diseases, it is possible that Japanese patients with AMA negative PBC are consistent with the disease entity of autoimmune cholangitis reported in western countries.
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Affiliation(s)
- Fumio Sakauchi
- Department of Public Health, Sapporo Medical University School of Medicine, Japan.
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Omagari K, Hazama H, Kohno S. Enzyme inhibition assay for pyruvate dehydrogenase complex: Clinical utility for the diagnosis of primary biliary cirrhosis. World J Gastroenterol 2005; 11:6735-9. [PMID: 16425376 PMCID: PMC4725032 DOI: 10.3748/wjg.v11.i43.6735] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Primary biliary cirrhosis (PBC) is usually diagnosed by the presence of characteristic histopathological features of the liver and/or antimitochondrial antibodies (AMA) in the serum traditionally detected by immunofluorescence. Recently, new and more accurate serological assays for the detection of AMA, such as enzyme-linked immunosorbent assay (ELISA), immunoblotting, and enzyme inhibition assay, have been developed. Of these, the enzyme inhibition assay for the detection of anti- pyruvate dehydrogenase complex (PDC) antibodies offers certain advantages such as objectivity, rapidity, simplicity, and low cost. Since this assay has almost 100% specificity, it may have particular applicability in screening the at-risk segment of the population in developing countries. Moreover, this assay could be also used for monitoring the disease course in PBC. Almost all sera of PBC-suspected patients can be confirmed for PBC or non-PBC by the combination results of immunoblotting and enzyme inhibition assay without histopathological examination. For the development of a “complete” or "gold standard" diagnostic assay for PBC, similar assays of the enzyme inhibition for anti-2-oxoglutarate dehydrogenase complex (OGDC) and anti-branched chain oxo-acid dehydrogenase complex (BCOADC) antibodies will be needed in future.
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Affiliation(s)
- Katsuhisa Omagari
- Second Department of Internal Medicine, Nagasaki University School of Medicine, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan.
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Kim JH, Kim BH, Kim YW, Park JC, Jung YH, Lee BO, Han YS, Dong SH, Kim HJ, Chang YW, Lee JI, Chang R. Autoimmune cholangitis in a patient with thymoma. J Gastroenterol Hepatol 2004; 19:1324-7. [PMID: 15482546 DOI: 10.1111/j.1440-1746.2002.03239.x] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
Abstract
Autoimmune cholangitis is characterized biochemically by chronic cholestasis and histopathologically by chronic non-suppurative destructive cholangitis. It is associated with positive antinuclear antibody test and negative antimitochondrial antibody test results. Recently, we experienced a case of a 35-year-old woman with autoimmune cholangitis associated with thymoma who presented with pruritus, jaundice, chronic fatigue and anterior chest discomfort. Her laboratory examinations revealed marked increases in levels of serum alkaline phosphatase and gamma-glutamyl transpeptidase. In serological tests, antinuclear antibody was found, but antimitochondrial antibody was not. Liver biopsy findings were compatible with chronic non-suppurative destructive cholangitis. On computed tomography (CT) of the chest, a large anterior mediastinal mass was found. The mass was totally resected and the patient was treated with ursodeoxy cholic acid. Thereafter, her clinical symptoms improved and liver functions completely returned to the normal range. We describe here an uncommon association of autoimmune cholangitis with thymoma, which has not been reported previously in the English-written literature.
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Affiliation(s)
- Jang-Ha Kim
- Department of Internal Medicine, Kyung Hee University College of Medicine, Seoul, Korea
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Abstract
AMA are detected in the serum of 92% to 95% of patients with PBC using indirect immunofluorescent methods. AIC is the term used to describe the 5% to 8% of AMA-negative PBC patients who uniformly have ANA and SMA. Recent applications of more sensitive and specific tests to detect serum AMA have shown that most, if not all, patients with AIC actually do have AMA. Emerging evidence that AMA and mitochondrial autoantigens play important roles in the immunopathogenesis of NSDC also suggests that AIC and PBC are likely to be a single disease, exhibiting variation in the types of autoantibodies and in both the concentrations and immunoglobulin isotypes of AMA.
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Affiliation(s)
- John M Vierling
- Center for Liver Diseases and Transplantation, Los Angeles, CA 90048, USA.
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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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Jiang XH, Zhong RQ, Fan XY, Hu Y, An F, Sun JW, Kong XT. Characterization of M2 antibodies in asymptomatic Chinese population. World J Gastroenterol 2003; 9:2128-31. [PMID: 12970922 PMCID: PMC4656690 DOI: 10.3748/wjg.v9.i9.2128] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the presence of M2 antibodies specific for primary biliary cirrhosis (PBC) in asymptomatic Chinese and identify patients with early PBC.
METHODS: Enzyme-linked immunosorbent assay (ELISA) tests for M2 antibodies to recombinant protein were performed in 5011 subjects (age range, 26-85 years; mean age: 45.81 ± 15.02 years) who took an annual physical examination. M2-positive subjects were further analyzed for immunoglobulin (Ig) classes and subclasses of M2 antibodies. Clinical, biochemical and immunological data were obtained for M2-positive subjects. In addition, ultrasonography (US) or endoscopic retrograde cholangio-pancreatography (ERCP) was performed to exclude any disorders other than PBC.
RESULTS: M2 antibodies were detected in 8 (0.16%) of the 5011 subjects studied. Of the 8 subjects, 7 were female and 1 was male (age range: 40-74 years). An unexplained increase of serum alkaline phosphatase (ALP) and gamma glutamyl transpeptidase (γ-GT) values, often to striking levels, was detected in 4 M2-positive subjects, 3 of them accorded with the diagnostic criteria recommended by the American Association for the Study of Liver Diseases, even though they had no symptoms of PBC (such as fatigue, pruritus or jaundice). Liver biopsy was performed in two M2-positive subjects and the histology was compatible with PBC in both cases.
CONCLUSION: Our data, while not assessing the true prevalence of asymptomatic PBC in the general population, suggest that asymptomatic PBC is much more common in China than has been supposed.
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Affiliation(s)
- Xiao-Hua Jiang
- Department of Laboratory Medicine, 85 Hospital of Chinese PLA, Huashan Road, Shanghai 200052, China.
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Jiang XH, Zhong RQ, Yu SQ, Hu Y, Li WW, Kong XT. Construction and expression of a humanized M 2 autoantigen trimer and its application in the diagnosis of primary biliary cirrhosis. World J Gastroenterol 2003; 9:1352-5. [PMID: 12800255 PMCID: PMC4611815 DOI: 10.3748/wjg.v9.i6.1352] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To construct and express a humanized M2 autoantigen trimer designated as BPO and to apply it in the diagnosis of primary biliary cirrhosis (PBC).
METHODS: cDNA fragments encoding M2-reactive epitopes of pyruvate dehydrogenase complex E2 (PDC-E2), branched chain 2-oxo-acid dehydrogenase complex E2 (BCOADC-E2) and 2-oxo-glutarate dehydrogenase complex E2 (OGDC-E2) were amplified with PCR using total RNA extracted from human peripheral mononuclear blood cells. The fragments were cloned into the plasmid vector pQE-30 and then transferred into E. coli M15 (pREP4) for expression, which was induced by isopropylthio-β-D-galactoside. The expressed recombinant BPO protein was demonstrated by SDS-PAGE, Western-blotting and Immunoabsorption test, its antigenic reactivity and specificity were identified with seven M---positive sera confirmed at Euroimmun Research Center (Germany). Using the purified BPO, M2 antibodies in sera from patients with PBC and other liver related diseases were detected with ELISA.
RESULTS: The expressed BPO was observed with both antigenic reactivity and specificity of M2 autoantigens. The determination of M2 antibodies by BPO with ELISA was more sensitive than using the Euroimmun's kit with the coefficients of variation less than 10% in both interassay and intraassay. With the newly established method, M2 antibodies were found in 100% (20/20) of patients with PBC. Six cases of liver disease with unknown etiology and 1 patient with drug induced liver injury had detectable levels of serum M2 antibodies. There were also 2 patients with autoimmune cholangitis and 1 with autoimmune hepatitis showing M2-antibody positive.
CONCLUSION: Compared with the routine immunofluorescence assay and commercially available assay kit using porcine heart mitochondrial protein as the antigen, the detection system established in the present study shows higher sensitivity and specificity and may be used as a powerful tool for the diagnosis of PBC.
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Affiliation(s)
- Xiao-Hua Jiang
- Department of Laboratory Medicine, 85 Hospital of the Chinese PLA, Huashan Road, Shanghai 200052, China.
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Kadokawa Y, Omagari K, Hazama H, Ohba K, Masuda JI, Kinoshita H, Hayashida K, Isomoto H, Mizuta Y, Murase K, Murata I, Kohno S. Evaluation of newly developed ELISA using "MESACUP-2 test mitochondrial M2" kit for the diagnosis of primary biliary cirrhosis. Clin Biochem 2003; 36:203-10. [PMID: 12726929 DOI: 10.1016/s0009-9120(02)00439-3] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Abstract
OBJECTIVES An enzyme-linked immunosorbent assay (ELISA) using MESACUP-2 Test Mitochondria M2 kit (new-M2 ELISA) has recently become commercially available. The aim of this study was to evaluate the clinical utility of this newly developed ELISA for the diagnosis of primary biliary cirrhosis (PBC). DESIGN AND METHODS We tested the immunoreactivity of sera from 82 Japanese PBC patients to the 2-oxo-acid dehydrogenase complex (2-OADC) enzymes by indirect immunofluorescence, enzyme inhibition assay using commercially available TRACE Enzymatic Mitochondrial Antibody (M2) Assay (EMA) kit, commercial ELISAs using MESACUP Mitochondria M2 kit (old-M2 ELISA) and new-M2 ELISA, and immunoblotting on bovine heart mitochondria. RESULTS Each test gave the following positive results; antimitochondrial antibodies (AMA) by immunofluorescence in 71 (87%) out of the 82 sera, enzymatic inhibitory antibody to pyruvate dehydrogenase complex (PDC) by EMA in 61 (74%), immunoglobulin (Ig) G class anti-PDC antibody by old-M2 ELISA in 55 (67%), IgG/M/A class anti-E2 subunit of PDC (PDC-E2)/anti-E2 subunit of branched chain oxo-acid dehydrogenase complex (BCOADC-E2)/anti-E2 subunit of 2-oxoglutarate dehydrogenase complex (OGDC-E2) antibodies by new-M2 ELISA in 73 (89%), and IgG, IgM, or IgA class antibodies against at least one of the 2-OADC enzymes by immunoblotting in 82 (100%). Fifty-three of the 82 sera (65%) were all positive by these five assays. Of the 18 sera that were positive by new-M2 ELISA but negative by old-M2 ELISA, 12 were theoretically interpretable. Of the 11 sera that were negative for AMA by immunofluorescence but positive for at least one of anti-2-OADC enzymes by immunoblotting, four (36%) were positive by new-M2 ELISA, whereas only two and one sera were positive by EMA and old-M2 ELISA, respectively. CONCLUSIONS Our results indicated that the sensitivity of the newly developed new-M2 ELISA was higher than that of EMA and old-M2 ELISA, and comparable with that of immunofluorescence. However, it is still unclear whether the new-M2 ELISA could replace the conventional immunofluorescence testing for routine assay requests because six (7%) sera showed discrepant results between these two assays.
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Affiliation(s)
- Yoshiko Kadokawa
- Second Department of Internal Medicine, Nagasaki University School of Medicine, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan
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18
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Abstract
The diagnostic criteria for each of the three major autoimmune liver diseases must be codified and the boundaries between diseases established. There will always be syndromes with mixed or atypical features because classically defined disorders represent only the outer ends of the diagnostic spectrum. It is only after boundaries have been decided by consensus that the true variants of autoimmune liver disease can be appreciated. Until then, both the diagnosis and treatment of these syndromes will be arbitrary and unclear.
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Affiliation(s)
- Jenny Heathcote
- University Health Network, Toronto Western Hospital, 399 Bathurst Street, 6B #170 Fell Pavilion, Toronto, Ontario M5T 2S8, Canada.
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19
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Abstract
The diagnosis of primary biliary cirrhosis (PBC) is made via a composite of clinical, laboratory, serologic, and histologic assessments, but within each parameter there exists a wide spectrum, so that the features of PBC are not always uniform. PBC is just one of several liver diseases thought to have an autoimmune basis. Therefore, it is not surprising, given the complexity of the immune response, that some patients thought to have PBC may have features of autoimmune hepatitis (AIH). Whether such patients have PBC with features of AIH, or antimitochondrial antibody-negative PBC, or another disease altogether, remains unclear.
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Affiliation(s)
- J Heathcote
- University of Toronto, Toronto Hospital Western Division, Suite 1070, 6B Fell, 399 Bathurst Street, Toronto, Ontario M5T 2S8, Canada.
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20
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Heathcote EJ. Management of primary biliary cirrhosis. The American Association for the Study of Liver Diseases practice guidelines. Hepatology 2000; 31:1005-13. [PMID: 10733559 DOI: 10.1053/he.2000.5984] [Citation(s) in RCA: 320] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Primary biliary cirrhosis (PBC) is a presumed autoimmune disease of the liver, which predominantly affects women once over the age of 20 years. Most cases are diagnosed when asymptomatic (60%). The antimitochondrial antibody is present in serum in most, but not in all, patients with PBC. The disease generally progresses slowly but survival is less than an age- and gender-matched general population. The symptomatic patient may have fatigue, generalized pruritus, portal hypertension, osteoporosis, skin xanthomata, fat soluble vitamin deficiencies, and/or recurrent asymptomatic urinary tract infections. Many nonhepatic autoimmune diseases are found in association with PBC and may prompt initial presentation. To date, immunosuppressive therapy has not been shown to prolong survival in PBC. The hydrophilic bile acid, ursodeoxycholic acid (UDCA), has been shown when given in a dose of 13 to 15 mg/kg daily for up to 4 years to delay the time to liver transplantation or death. This therapy also causes a significant improvement of all the biochemical markers of cholestasis but has no beneficial effects on any of the symptoms or associated disorders. Treatment with UDCA does not obviate the need for liver transplantation. Therapies to prevent complications arising from malabsorption, portal hypertension, and/or osteoporosis are required as well. Good control of pruritus can be achieved in most patients. PBC is diagnosed with increasing frequency, but the agent(s) responsible for this slowly progressive destruction of the interlobular bile ducts remains elusive and hence a specific therapy remains unavailable.
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Affiliation(s)
- E J Heathcote
- Division of Gastroenterology, University of Toronto, The Toronto Hospital, Toronto, Ontario, Canada.
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21
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Miyakawa H, Abe K, Kitazawa E, Kikuchi K, Fujikawa H, Matsushita M, Kawaguchi N, Kako M. Detection of anti-branched chain 2-oxo acid dehydrogenase complex (BCOADC)-E2 antibody in primary biliary cirrhosis by ELISA using recombinant fusion protein. Autoimmunity 1999; 30:11-20. [PMID: 10433090 DOI: 10.3109/08916939908994755] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
Anti-M2 of anti-mitochondrial antibody (AMA) is a serological marker of primary biliary cirrhosis (PBC). Anti-pyruvate dehydrogenase complex-E2 (anti-PDC-E2) is recognized as the most frequently occurring anti-M2, and a routine laboratory test for this antibody has already been established. However, it is also known that there are patients with PBC who are negative for anti-PDC-E2. For the serological diagnosis of these patients, immunoblotting for anti-M2s is indicated. However, the technique currently utilized is too laborious to allow testing of a large number of samples. In this study, we have developed an enzyme-linked immunosorbent assay (ELISA) using a recombinant fusion protein in order to evaluate anti-branched chain 2-oxo-acid dehydrogenase complex-E2 (anti-BCOADC-E2), another frequently occurring anti-M2 in PBC patients. KB cell lines (CCL 17) were utilized as source material, and BCOADC-E2 cDNA (971 bp) including the lipoic acid binding domain was amplified by polymerase chain reaction. The amplified region was subcloned into pEX-3 vectors and expressed, and the resulting fusion protein (beta-galactosidase/BCOADC-E2) was utilized as antigen for an ELISA. We ascertained the specificity of this antigen by inhibition tests with ELISA and immunoblotting. We defined the cut-off optical density (OD) value as the mean + 3 SD (0.146) of sera from 60 normal controls. Anti-BCOADC-E2 could not be detected with this assay in sera from normal controls and from patients with autoimmune hepatitis and chronic viral hepatitis. Anti-BCOADC-E2 was detected in 119 of 210 sera (56.7%) from patients with PBC. In addition, anti-BCOADC-E2 was detected in 48 of 99 (48.5%) sera from PBC patients who were negative for anti-PDC-E2. Here, we have succeeded in developing a new ELISA for detecting anti-BCOADC-E2. This system is antigen-specific and easily performed. This assay should allow routine testing of a large number of serum samples, and should become especially useful for the serodiagnosis of anti-PDC-E2-negative PBC patients.
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Affiliation(s)
- H Miyakawa
- Fourth Department of Internal Medicine, Teikyo University School of Medicine, Kanagawa, Japan
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22
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Abstract
Currently available evidence is insufficient to classify PBC and AIC as separate diseases. The ultimate answer to the question of whether AIC, defined as AMA-negative PBC with ANA or SMA, is a disease distinct from AMA-positive PBC with or without ANA will require a detailed comparison of etiologic factors and pathogenetic mechanisms, once they are elucidated. It is intriguing to consider the suggestion of Heathcote that the term autoimmune cholangitis be adopted to describe PBC with or without detectable AMA. However, it is improbable that the venerable term PBC will be supplanted. Hepatologists will probably continue to use the terms AIC and AMA-negative PBC interchangeably, with little risk of being misunderstood.
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Affiliation(s)
- J M Vierling
- Center for Liver Diseases and Transplantation, Los Angeles, California, USA.
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23
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Affiliation(s)
- J Neuberger
- Liver Unit, Queen Elizabeth Hospital, Birmingham, UK.
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24
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Abstract
Several drugs have been evaluated in the treatment of primary biliary cirrhosis over a number of years. These drugs have immunosuppressive, antiinflammatory, cupruretic, antifibrotic and bile acid properties. Ursodeoxycholic acid has been shown to improve survival free of transplantation in a conclusive fashion. This drug is the single agent that can be recommended for the treatment of primary biliary cirrhosis. Corticosteroid therapy and ursodeoxycholic acid have been evaluated in a few patients with autoimmune cholangitis. This article reviews a large number of studies that have been published assessing different drugs in the treatment of these two entities, particularly in the treatment of primary biliary cirrhosis.
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Affiliation(s)
- P Angulo
- Division of Gastroenterology and Hepatology, Mayo Clinic and Mayo Foundation, Rochester, Minnesota 55905, USA
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