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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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Saffioti F, Gurusamy KS, Eusebi LH, Tsochatzis E, Davidson BR, Thorburn D, Cochrane Hepato‐Biliary Group. Pharmacological interventions for primary biliary cholangitis: an attempted network meta-analysis. Cochrane Database Syst Rev 2017; 3:CD011648. [PMID: 28350426 PMCID: PMC6464661 DOI: 10.1002/14651858.cd011648.pub2] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
BACKGROUND Primary biliary cholangitis (previously primary biliary cirrhosis) is a chronic liver disease caused by the destruction of small intra-hepatic bile ducts resulting in stasis of bile (cholestasis), liver fibrosis, and liver cirrhosis. The optimal pharmacological treatment of primary biliary cholangitis remains uncertain. OBJECTIVES To assess the comparative benefits and harms of different pharmacological interventions in the treatment of primary biliary cholangitis through a network meta-analysis and to generate rankings of the available pharmacological interventions according to their safety and efficacy. However, it was not possible to assess whether the potential effect modifiers were similar across different comparisons. Therefore, we did not perform the network meta-analysis, and instead, assessed the comparative benefits and harms of different interventions using standard Cochrane methodology. SEARCH METHODS We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2017, Issue 2), MEDLINE, Embase, Science Citation Index Expanded, World Health Organization International Clinical Trials Registry Platform, and randomised controlled trials registers to February 2017 to identify randomised clinical trials on pharmacological interventions for primary biliary cholangitis. SELECTION CRITERIA We included only randomised clinical trials (irrespective of language, blinding, or publication status) in participants with primary biliary cholangitis. We excluded trials which included participants who had previously undergone liver transplantation. We considered any of the various pharmacological interventions compared with each other or with placebo or no intervention. DATA COLLECTION AND ANALYSIS We used standard methodological procedures expected by Cochrane. We calculated the odds ratio (OR) and rate ratio with 95% confidence intervals (CI) using both fixed-effect and random-effects models based on available-participant analysis with Review Manager 5. We assessed risk of bias according to Cochrane, controlled risk of random errors with Trial Sequential Analysis, and assessed the quality of the evidence using GRADE. MAIN RESULTS We identified 74 trials including 5902 participants that met the inclusion criteria of this review. A total of 46 trials (4274 participants) provided information for one or more outcomes. All the trials were at high risk of bias in one or more domains. Overall, all the evidence was low or very low quality. The proportion of participants with symptoms varied from 19.9% to 100% in the trials that reported this information. The proportion of participants who were antimitochondrial antibody (AMA) positive ranged from 80.8% to 100% in the trials that reported this information. It appeared that most trials included participants who had not received previous treatments or included participants regardless of the previous treatments received. The follow-up in the trials ranged from 1 to 96 months.The proportion of people with mortality (maximal follow-up) was higher in the methotrexate group versus the no intervention group (OR 8.83, 95% CI 1.01 to 76.96; 60 participants; 1 trial; low quality evidence). The proportion of people with mortality (maximal follow-up) was lower in the azathioprine group versus the no intervention group (OR 0.56, 95% CI 0.32 to 0.98; 224 participants; 2 trials; I2 = 0%; low quality evidence). However, it has to be noted that a large proportion of participants (25%) was excluded from the trial that contributed most participants to this analysis and the results were not reliable. There was no evidence of a difference in any of the remaining comparisons. The proportion of people with serious adverse events was higher in the D-penicillamine versus no intervention group (OR 28.77, 95% CI 1.57 to 526.67; 52 participants; 1 trial; low quality evidence). The proportion of people with serious adverse events was higher in the obeticholic acid plus ursodeoxycholic acid (UDCA) group versus the UDCA group (OR 3.58, 95% CI 1.02 to 12.51; 216 participants; 1 trial; low quality evidence). There was no evidence of a difference in any of the remaining comparisons for serious adverse events (proportion) or serious adverse events (number of events). None of the trials reported health-related quality of life at any time point. FUNDING nine trials had no special funding or were funded by hospital or charities; 31 trials were funded by pharmaceutical companies; and 34 trials provided no information on source of funding. AUTHORS' CONCLUSIONS Based on very low quality evidence, there is currently no evidence that any intervention is beneficial for primary biliary cholangitis. However, the follow-up periods in the trials were short and there is significant uncertainty in this issue. Further well-designed randomised clinical trials are necessary. Future randomised clinical trials ought to be adequately powered; performed in people who are generally seen in the clinic rather than in highly selected participants; employ blinding; avoid post-randomisation dropouts or planned cross-overs; should have sufficient follow-up period (e.g. five or 10 years or more); and use clinically important outcomes such as mortality, health-related quality of life, cirrhosis, decompensated cirrhosis, and liver transplantation. Alternatively, very large groups of participants should be randomised to facilitate shorter trial duration.
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Affiliation(s)
- Francesca Saffioti
- Royal Free Hospital and the UCL Institute of Liver and Digestive HealthSheila Sherlock Liver CentrePond StreetHampsteadLondonUKNW3 2QG
- University of MessinaDepartment of Clinical and Experimental Medicine, Division of Clinical and Molecular HepatologyVia Consolare Valeria, 1MessinaMessinaItaly98125
| | - Kurinchi Selvan Gurusamy
- Royal Free Campus, UCL Medical SchoolDepartment of SurgeryRoyal Free HospitalRowland Hill StreetLondonUKNW3 2PF
| | - Leonardo Henry Eusebi
- Royal Free Hampstead NHS Foundation Trust and UCL Institute of Liver and Digestive HealthThe Royal Free Sheila Sherlock Liver CentreLondonUK
- University of BolognaDepartment of Medical and Surgical Sciences (DIMEC)BolognaItaly
| | - Emmanuel Tsochatzis
- Royal Free Hospital and the UCL Institute of Liver and Digestive HealthSheila Sherlock Liver CentrePond StreetHampsteadLondonUKNW3 2QG
| | - Brian R Davidson
- Royal Free Campus, UCL Medical SchoolDepartment of SurgeryRoyal Free HospitalRowland Hill StreetLondonUKNW3 2PF
| | - Douglas Thorburn
- Royal Free Hospital and the UCL Institute of Liver and Digestive HealthSheila Sherlock Liver CentrePond StreetHampsteadLondonUKNW3 2QG
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SP140L, an Evolutionarily Recent Member of the SP100 Family, Is an Autoantigen in Primary Biliary Cirrhosis. J Immunol Res 2015; 2015:526518. [PMID: 26347895 PMCID: PMC4548144 DOI: 10.1155/2015/526518] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2015] [Accepted: 07/07/2015] [Indexed: 12/21/2022] Open
Abstract
The SP100 family members comprise a set of closely related genes on chromosome 2q37.1. The widely expressed SP100 and the leukocyte-specific proteins SP110 and SP140 have been associated with transcriptional regulation and various human diseases. Here, we have characterized the SP100 family member SP140L. The genome sequence analysis showed the formation of SP140L gene through rearrangements of the two neighboring genes, SP100 and SP140, during the evolution of higher primates. The SP140L expression is interferon-inducible with high transcript levels in B cells and other peripheral blood mononuclear cells. Subcellularly, SP140L colocalizes with SP100 and SP140 in nuclear structures that are devoid of SP110, PML, or p300 proteins. Similarly to SP100 and SP140 protein, we detected serum autoantibodies to SP140L in patients with primary biliary cirrhosis using luciferase immunoprecipitation system and immunoblotting assays. In conclusion, our results show that SP140L is phylogenetically recent member of SP100 proteins and acts as an autoantigen in primary biliary cirrhosis patients.
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Chantran Y, Ballot É, Johanet C. Autoantibodies in primary biliary cirrhosis: antimitochondrial autoantibodies. Clin Res Hepatol Gastroenterol 2013; 37:431-3. [PMID: 23773485 DOI: 10.1016/j.clinre.2013.05.002] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2013] [Accepted: 05/06/2013] [Indexed: 02/04/2023]
Affiliation(s)
- Yannick Chantran
- Unité d'Immunologie, CHU Saint-Antoine, AP-HP, 75571 Paris cedex 12, France
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Kärner J, Meager A, Laan M, Maslovskaja J, Pihlap M, Remm A, Juronen E, Wolff ASB, Husebye ES, Podkrajšek KT, Bratanic N, Battelino T, Willcox N, Peterson P, Kisand K. Anti-cytokine autoantibodies suggest pathogenetic links with autoimmune regulator deficiency in humans and mice. Clin Exp Immunol 2013; 171:263-72. [PMID: 23379432 PMCID: PMC3569533 DOI: 10.1111/cei.12024] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/29/2012] [Indexed: 12/13/2022] Open
Abstract
Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED) is a recessive disorder resulting from mutations in the autoimmune regulator (AIRE). The patients' autoantibodies recognize not only multiple organ-specific targets, but also many type I interferons (IFNs) and most T helper type 17 (Th17) cell-associated cytokines, whose biological actions they neutralize in vitro. These anti-cytokine autoantibodies are highly disease-specific: otherwise, they have been found only in patients with thymomas, tumours of thymic epithelial cells that fail to express AIRE. Moreover, autoantibodies against Th17 cell-associated cytokines correlate with chronic mucocutaneous candidiasis in both syndromes. Here, we demonstrate that the immunoglobulin (Ig)Gs but not the IgAs in APECED sera are responsible for neutralizing IFN-ω, IFN-α2a, interleukin (IL)-17A and IL-22. Their dominant subclasses proved to be IgG1 and, surprisingly, IgG4 without IgE, possibly implicating regulatory T cell responses and/or epithelia in their initiation in these AIRE-deficiency states. The epitopes on IL-22 and IFN-α2a appeared mainly conformational. We also found mainly IgG1 neutralizing autoantibodies to IL-17A in aged AIRE-deficient BALB/c mice - the first report of any target shared by these human and murine AIRE-deficiency states. We conclude that autoimmunization against cytokines in AIRE deficiency is not simply a mere side effect of chronic mucosal Candida infection, but appears to be related more closely to disease initiation.
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Affiliation(s)
- J. Kärner
- Molecular Pathology Group, Institute of Biomedicine, University of TartuTartu, Estonia
| | - A. Meager
- Biotherapeutics, National Institute for Biological Standards and ControlSouth Mimms, UK
| | - M. Laan
- Molecular Pathology Group, Institute of Biomedicine, University of TartuTartu, Estonia
| | - J. Maslovskaja
- Molecular Pathology Group, Institute of Biomedicine, University of TartuTartu, Estonia
| | - M. Pihlap
- Molecular Pathology Group, Institute of Biomedicine, University of TartuTartu, Estonia
| | - A. Remm
- Molecular Pathology Group, Institute of Biomedicine, University of TartuTartu, Estonia
| | - E. Juronen
- Immune Analyze Group, Institute of Biomedicine, University of TartuTartu, Estonia
| | - A. S. B. Wolff
- Institute of Medicine, University of BergenBergen, Norway
| | - E. S. Husebye
- Institute of Medicine, University of BergenBergen, Norway
| | - K. T. Podkrajšek
- Centre for Medical Genetics, University Children's HospitalLjubljana, Slovenia
| | - N. Bratanic
- Centre for Medical Genetics, University Children's HospitalLjubljana, Slovenia
| | - T. Battelino
- Centre for Medical Genetics, University Children's HospitalLjubljana, Slovenia
| | - N. Willcox
- Neurosciences Group, Weatherall Institute of Molecular Medicine, University of OxfordOxford, UK
| | - P. Peterson
- Molecular Pathology Group, Institute of Biomedicine, University of TartuTartu, Estonia
| | - K. Kisand
- Molecular Pathology Group, Institute of Biomedicine, University of TartuTartu, Estonia
- Immunology Group, Institute of Biomedicine, University of TartuTartu, Estonia
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6
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Sex differences associated with primary biliary cirrhosis. Clin Dev Immunol 2012; 2012:610504. [PMID: 22693524 PMCID: PMC3369468 DOI: 10.1155/2012/610504] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2012] [Accepted: 02/27/2012] [Indexed: 12/14/2022]
Abstract
Primary biliary cirrhosis (PBC) is a cholestatic liver disease of autoimmune origin, characterised by the destruction of small intrahepatic bile ducts. The disease has an unpredictable clinical course but may progress to fibrosis and cirrhosis. The diagnostic hallmark of PBC is the presence of disease-specific antimitochondrial antibodies (AMA), which are pathognomonic for the development of PBC. The disease overwhelmingly affects females, with some cases of male PBC being reported. The reasons underlying the low incidence of males with PBC are largely unknown. Epidemiological studies estimate that approximately 7–11% of PBC patients are males. There does not appear to be any histological, serological, or biochemical differences between male and female PBC, although the symptomatology may differ, with males being at higher risk of life-threatening complications such as gastrointestinal bleeding and hepatoma. Studies on X chromosome and sex hormones are of interest when studying the low preponderance of PBC in males; however, these studies are far from conclusive. This paper will critically analyze the literature surrounding PBC in males.
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Uibo R, Kisand K, Yang CY, Gershwin ME. Primary biliary cirrhosis: a multi-faced interactive disease involving genetics, environment and the immune response. APMIS 2012; 120:857-71. [PMID: 23009110 DOI: 10.1111/j.1600-0463.2012.02914.x] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2012] [Accepted: 04/10/2012] [Indexed: 12/12/2022]
Abstract
Primary biliary cirrhosis (PBC) is considered a model autoimmune disease based on several features, including the presence of a highly directed and very specific immune response to mitochondrial autoantigens, a female predominance, a targeted destruction of the biliary epithelium, and homogeneity between patients. It is essentially a chronic progressive cholestatic liver disease characterized by immune-mediated destruction of small- and medium-sized intrahepatic bile ducts. There is considerable variation in the incidence and prevalence of the disease between regions of the world, although such differences likely reflect not only a true disparity in disease but also differences in awareness; for example, in the United States, PBC is often detected in an asymptomatic stage based on multi-phasic clinical testing. There has been considerable progress at defining the immune response in this disease, including quantitation of autoreactive T cells against PDC-E2, the major mitochondrial autoantigen. The overwhelming data suggests that patients develop PBC based on a genetic predisposition and loss of tolerance to one or more environmental agents. In this review, we will present an updated overview of PBC and place it in the context of autoimmunity.
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Affiliation(s)
- Raivo Uibo
- Institute of General and Molecular Pathology, Centre of Excellence for Translational Medicine, University of Tartu, Tartu, Estonia.
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Smyk D, Cholongitas E, Kriese S, Rigopoulou EI, Bogdanos DP. Primary biliary cirrhosis: family stories. Autoimmune Dis 2011; 2011:189585. [PMID: 21687641 PMCID: PMC3112499 DOI: 10.4061/2011/189585] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2010] [Revised: 02/09/2011] [Accepted: 03/07/2011] [Indexed: 01/03/2023] Open
Abstract
Primary biliary cirrhosis (PBC) is a chronic immune-mediated cholestatic liver disease of unknown aetiology which affects mostly women in middle age. Familial PBC is when PBC affects more than one member of the same family, and data suggest that first-degree relatives of PBC patients have an increased risk of developing the disease. Most often, these familial clusters involve mother-daughter pairs, which is consistent with the female preponderance of the disease. These clusters provide evidence towards a genetic basis underlying PBC. However, clusters of nonrelated individuals have also been reported, giving strength to an environmental component. Twin studies have demonstrated a high concordance for PBC in monozygotic twins and a low concordance among dizygotic twins. In conclusion, studies of PBC in families clearly demonstrate that genetic, epigenetic, and environmental factors play a role in the development of the disease.
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Affiliation(s)
- Daniel Smyk
- Institute of Liver Studies, King's College London School of Medicine at King's College Hospital, Denmark Hill Campus, London SE5 9RS, UK
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Omagari K, Kadokawa Y, Nakamura M, Akazawa S, Ohba K, Ohnita K, Mizuta Y, Daikoku M, Yatsuhashi H, Ishibashi H, Kohno S. IgA class antibodies to 2-oxo-acid dehydrogenase complex are not predictive markers of histopathological progression in primary biliary cirrhosis. Autoimmunity 2009; 39:107-12. [PMID: 16698666 DOI: 10.1080/08916930600633006] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
Abstract
Although antimitochondrial antibody (AMA) is the characteristic serological feature of primary biliary cirrhosis (PBC), its pathogenic role remains unclear. In our previous study, we reported a positive correlation between immunoglobulin (Ig) A class anti-2-oxo-acid dehydrogenase complex (2-OADC) and histopathological stage. To determine whether the appearance of IgA class anti-2-OADC by immunoblotting represents an early marker of more aggressive disease or whether it is late finding during the disease course of PBC, we tested not only the entire IgA class but also IgA1, IgA2 and secretory IgA class anti-2-OADC in serial serum samples from 15 patients with PBC. During the median observation period of 51 months, four cases showed histopathological progression (from stage 1 to 2, stage 1 to 3, stage 1 to 4 and stage 2 to 4). There was no statistically significant correlation between the above IgA class anti-2-OADCs and histopathological progression. There was no significant correlation between histopathological stages and IgA2 class anti-2-OADC or secretory IgA class anti-2-OADC by immunoblotting. IgA class anti-2-OADC was more frequent in stages 3-4 than in stages 1-2 (p = 0.0049), but IgA1 class anti-2-OADC was more frequent in stages 1-2 than in stages 3-4 (p = 0.0232). Our present study demonstrated that serum IgA class 2-OADC was not a predictive marker of histopathological progression but was associated with the histopathological stage of PBC. Although the IgA class AMA may have a specific pathogenic role for PBC, the discrepant results between IgA and IgA1 class anti-2-OADC should be further assessed to investigate different functional activities depending on their molecular form.
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Affiliation(s)
- Katsuhisa Omagari
- Nagasaki University School of Medicine, Second Department of Internal Medicine, Nagasaki, Japan.
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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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Gabeta S, Norman GL, Liaskos C, Papamichalis PA, Zografos T, Garagounis A, Rigopoulou EI, Dalekos GN. Diagnostic relevance and clinical significance of the new enhanced performance M2 (MIT3) ELISA for the detection of IgA and IgG antimitochondrial antibodies in primary biliary cirrhosis. J Clin Immunol 2007; 27:378-387. [PMID: 17514501 DOI: 10.1007/s10875-007-9092-0] [Citation(s) in RCA: 49] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2007] [Accepted: 03/08/2007] [Indexed: 12/12/2022]
Abstract
BACKGROUND/AIMS Antimitochondrial antibodies (AMAs) are the serological hallmark of primary biliary cirrhosis (PBC). We evaluated the sensitivity and specificity of a new M2 enhanced performance enzyme-linked immunosorbent assay (ELISA) (MIT3) for the detection of IgG- and IgA-specific isotypes of AMA in PBC patients including a number of PBC patients negative for AMA by indirect immunofluorescence (IIF) as well as in patients with diverse, non-PBC disorders. We also investigated the clinical significance of IgG and IgA AMA in PBC. METHODS One hundred and three Greek PBC patients including 27 with AMA IIF-negative at the time of the investigation, 29 with autoimmune hepatitis-1 (AIH-1), 12 with primary sclerosing cholangitis (PSC), 26 with hepatitis C virus (HCV), 15 with hepatitis B virus (HBV), and 29 healthy were investigated for AMA (IgG and IgA) using the MIT3-based ELISAs (INOVA Diagnostics, San Diego, CA). The samples were also tested by conventional anti-M2 ELISA (INOVA Diagnostics, Inc.). RESULTS The IgG MIT3-based ELISA significantly increased AMA detection in the cohort of PBC patients, over 26% of whom were AMA IIF-negative, from 63.1% by the conventional anti-M2, and 73.7% by IIF to 79.6% by MIT3-based ELISA (p<0.001). IgA AMAs were detected in 47.6% patients. Overall, IgG/IgA AMAs were detected in 84/103 (81.6%). IgG MIT3-based ELISA detected 12/27 IIF AMA-negative samples (44.4%), while IgG/IgA MIT3-based ELISAs detected 13/27 IIF AMA-negative patients (48.1%). The specificities of MIT3-based ELISAs (IgG and IgA) were 82.8% and 89.7%, respectively, in AIH-1, 100% and 93.3%, respectively, in HBV, 100% in PSC, and 96% and 93.3%, respectively, in HCV. Patients positive for IgG AMA had significantly more severe disease as shown by worse histology and elevated biochemical markers; IgG and IgA AMA titers were associated positively with the Mayo risk score but none of the isotypes were able to predict disease outcome. CONCLUSIONS The new IgG and IgA MIT3-based ELISAs seem to have higher specificity and sensitivity for AMA detection than IIF and the conventional anti-M2. Interestingly, these assays were able to unmask AMA presence in almost half of the AMA-negative samples by IIF. These findings may suggest the use of MIT3-based ELISAs as first-line investigation for AMA detection, particularly, when the laboratories are unfamiliar with the use and interpretation of the IIF patterns of AMA. The presence of IgG AMA seems to characterize PBC patients with more severe disease, but both IgG and IgA isotypes of AMAs were not predictive markers of disease outcome.
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Affiliation(s)
- Stella Gabeta
- Department of Medicine, Research Laboratory of Internal Medicine, Larissa Medical School, University of Thessaly, Larissa, Greece
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Kadaja L, Kisand KE, Peet N, Braun U, Metsküla K, Teesalu K, Vibo R, Kisand KV, Uibo R, Jockusch H, Seppet EK. IgG from patients with liver diseases inhibit mitochondrial respiration in permeabilized oxidative muscle cells: impaired function of intracellular energetic units? Mol Cell Biochem 2004; 256-257:291-303. [PMID: 14977189 DOI: 10.1023/b:mcbi.0000009876.23921.e6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
The effect of IgG purified from the sera of healthy persons and patients with primary biliary cirrhosis (PBC) and chronic hepatitis (CH) on ADP dependent respiration (oxidative phosphorylation) in skinned muscle fibers from rat oxidative muscles (heart and M. soleus) and glycolytic skeletal muscle (M. gastrocnemius) was studied. The results show that IgG from three different sources inhibited the rate of respiration by 13, 44 and 42%, respectively, these effects being equally expressed in both types of oxidative muscles, whereas no inhibition was observed in glycolytic muscle. The following washout of unbound IgG did not abolish the inhibition of respiration suggesting that the specific interaction of IgG with antigens had taken place. Laser confocal analysis revealed binding of IgG predominantly to the sarcomeric structures such as Z-disk and M-lines in the cardiomyocytes. The staining of IgG within Z-disks and intermitochondrial space coincided throughout the muscle cells so that transversally serial spaces, each containing mitochondria and adjacent sarcomere, became clearly visible. When the IgG from a CH patient was incubated with the skinned myocardial fibers of the desmin knockout mice, its binding to Z-disks and the sarcomeric area was found to be similar to that in normal cardiac muscle. However, the transversal staining pattern was disintegrated, because of the slippage of the myofibrils in relation to each other and accumulation of mitochondria between them. These observations support the recent hypothesis that in oxidative muscles the mitochondria and adjacent sarcomeres form complexes, termed as the intracellular energetic units, ICEUs. Moreover, they indicate that human autoantibodies can be useful tools for localizing the proteins responsible for formation of ICEUs and modulation of their function. Thus, it appears that the proteins associated with the Z-disks and M-lines may participate in formation of ICEUs and that binding of IgG to these proteins decreases the access of exogenous adenine nucleotides to mitochondria, which manifests as decreased rate of ADP-dependent respiration.
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Affiliation(s)
- Lumme Kadaja
- Department of Pathophysiology, Faculty of Medicine, University of Tartu, Tartu, Estonia
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Abstract
BACKGROUND Colchicine has been used for patients with primary biliary cirrhosis because of its immunomodulatory and antifibrotic potential. The therapeutical responses to colchicine in randomised clinical trials were inconsistent. OBJECTIVES To evaluate the beneficial and harmful effects of colchicine in patients with primary biliary cirrhosis. SEARCH STRATEGY We identified trials through electronic searches of The Cochrane Hepato-Biliary Group Controlled Trials Register, The Cochrane Central Register of Controlled Trials on The Cochrane Library, MEDLINE, EMBASE (September 2003), and manual searches of bibliographies. We contacted authors of trials and pharmaceutical companies. SELECTION CRITERIA Randomised clinical trials comparing colchicine with any kind of control therapy were included irrespective of language, year of publication, and publication status. DATA COLLECTION AND ANALYSIS The primary outcomes were the number of deaths and the number of death and/or patients who underwent liver transplantation. Dichotomous outcomes were reported as relative risk (RR) with 95% confidence interval (CI). We examined intervention effects by using both a fixed effect model and a random effects model. Heterogeneity was investigated by subgroup analyses and sensitivity analyses. MAIN RESULTS Eleven randomised clinical trials involving 716 patients with primary biliary cirrhosis fulfilled the inclusion criteria. No significant differences were detected between colchicine and placebo/no intervention on the number of deaths (RR 1.21, 95% CI 0.71 to 2.06), the number of deaths and/or patients who underwent liver transplantation (RR 1.00, 95% CI 0.67 to 1.49), liver complications, liver biochemical variables, liver histological measurements, and adverse events. Trial methodology was generally low and some trials had high drop-out rate. A best-worst-case-scenario analysis showed no significant effect of colchicine on mortality (RR 0.59, 95%CI 0.30 to 1.15), while a worst-best-case-scenario analysis showed a significant detrimental effect of colchicine on mortality (RR 2.28, 95% CI 1.17 to 4.44). Colchicine significantly decreased the number of patients without improvement of pruritus (RR 0.75, 95% CI 0.65 to 0.87). However, this estimate was based on only 156 patients from three trials. The effect of the combined treatment with ursodeoxycholic acid was not significantly different from that of colchicine alone. REVIEWERS' CONCLUSIONS We did not find evidence either to support or refute the use of colchicine for patients with primary biliary cirrhosis. As we are not able to exclude a detrimental effect of colchicine, we suggest that it is only used in randomised clinical trials.
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Affiliation(s)
- Y Gong
- Copenhagen Trial Unit, Centre for Clinical Intervention Research, Copenhagen University Hospital, Dept. 7102, Blegdamsvej 9, H:S Rigshospitalet, Copenhagen, Denmark, DK-2100
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14
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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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15
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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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