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Geographical region and clinical outcomes of patients with primary biliary cholangitis from Western Europe. Eur J Gastroenterol Hepatol 2023; 35:112-119. [PMID: 36468575 DOI: 10.1097/meg.0000000000002464] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
BACKGROUND AND AIMS The are geographic variations in the incidence and prevalence of primary biliary cholangitis (PBC). The aim was to explore whether clinical outcomes of patients within Western Europe differ according to geographical region. METHODS Ursodeoxycholic acid-treated patients from European centers from the Global PBC database diagnosed from 1990 onwards were included. Patients with a time lag > 1 year from diagnosis to start of follow-up were excluded. Differences in baseline characteristics were studied according to North/South and East/West, whereas outcomes (transplant-free survival and decompensation) were studied with center latitude and longitude. Cox regression analyses were adjusted for age, sex, diagnosis year, biochemical markers, and cirrhosis as a time-dependent covariate. RESULTS One thousand eight hundred seventy-eight patients were included, and there were no geographical differences in age or sex, with a mean age of 54 years and 89% female patients. Those in North Europe were more often of a moderately advanced/advanced Rotterdam biochemical stage (28.4%) compared with South Europe (20.6%). Additionally, they exhibited higher median alkaline phosphatase (2.0 ×ULN vs. 1.4 ×ULN) and transaminases. In multivariable analysis, there was a significant interaction between center latitude and longitude for decompensation (P < 0.001) and a trend for transplant-free survival, in which the Northwestern area demonstrated an increased risk for poor outcomes as compared to the reference (Paris). CONCLUSION We describe geographic variations in outcomes for patients across Europe from specialist centers in the Global PBC Study Group. Further study is important to explore the potential individual, environmental, and healthcare-related factors that may be contributors.
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Galoosian A, Hanlon C, Zhang J, Holt EW, Yimam KK. Clinical Updates in Primary Biliary Cholangitis: Trends, Epidemiology, Diagnostics, and New Therapeutic Approaches. J Clin Transl Hepatol 2020; 8:49-60. [PMID: 32274345 PMCID: PMC7132015 DOI: 10.14218/jcth.2019.00049] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2019] [Revised: 12/21/2019] [Accepted: 01/01/2020] [Indexed: 12/12/2022] Open
Abstract
Primary biliary cholangitis, formerly known as primary biliary cirrhosis, is a chronic, autoimmune, and cholestatic disease ameliorating the biliary epithelial system causing fibrosis and end-stage liver disease, over time. Patients range from an asymptomatic phase early in the disease course, to symptoms of decompensated cirrhosis later in its course. This review focuses on the current consensus on the epidemiology, diagnosis, and management of patients with primary biliary cholangitis. We also discuss established medical management as well as novel and investigational therapeutics in the pipeline for management of PBC.
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Affiliation(s)
- Artin Galoosian
- Department of Medicine, California Pacific Medical Center, San Francisco, CA, USA
| | - Courtney Hanlon
- Department of Medicine, University of Southern California Keck School of Medicine, Los Angeles, CA, USA
| | - Julia Zhang
- Department of Medicine, California Pacific Medical Center, San Francisco, CA, USA
| | - Edward W. Holt
- Department of Transplant, Division of Hepatology, California Pacific Medical Center, San Francisco, CA, USA
| | - Kidist K. Yimam
- Director of the Autoimmune Liver Disease Program, Department of Transplant, Division of Hepatology, California Pacific Medical Center, San Francisco, CA, USA
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Young GR, Abdelghany TM, Leitch AC, Dunn MP, Blain PG, Lanyon C, Wright MC. Changes in the gut microbiota of mice orally exposed to methylimidazolium ionic liquids. PLoS One 2020; 15:e0229745. [PMID: 32163446 PMCID: PMC7067480 DOI: 10.1371/journal.pone.0229745] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2019] [Accepted: 02/13/2020] [Indexed: 12/12/2022] Open
Abstract
Ionic liquids are salts used in a variety of industrial processes, and being relatively non-volatile, are proposed as environmentally-friendly replacements for existing volatile liquids. Methylimidazolium ionic liquids resist complete degradation in the environment, likely because the imidazolium moiety does not exist naturally in biological systems. However, there is limited data available regarding their mammalian effects in vivo. This study aimed to examine the effects of exposing mice separately to 2 different methylimidazolium ionic liquids (BMI and M8OI) through their addition to drinking water. Potential effects on key target organs-the liver and kidney-were examined, as well as the gut microbiome. Adult male mice were exposed to drinking water containing ionic liquids at a concentration of 440 mg/L for 18 weeks prior to examination of tissues, serum, urine and the gut microbiome. Histopathology was performed on tissues and clinical chemistry on serum for biomarkers of hepatic and renal injury. Bacterial DNA was isolated from the gut contents and subjected to targeted 16S rRNA sequencing. Mild hepatic and renal effects were limited to glycogen depletion and mild degenerative changes respectively. No hepatic or renal adverse effects were observed. In contrast, ionic liquid exposure altered gut microbial composition but not overall alpha diversity. Proportional abundance of Lachnospiraceae, Clostridia and Coriobacteriaceae spp. were significantly greater in ionic liquid-exposed mice, as were predicted KEGG functional pathways associated with xenobiotic and amino acid metabolism. Exposure to ionic liquids via drinking water therefore resulted in marked changes in the gut microbiome in mice prior to any overt pathological effects in target organs. Ionic liquids may be an emerging risk to health through their potential effects on the gut microbiome, which is implicated in the causes and/or severity of an array of chronic disease in humans.
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Affiliation(s)
- Gregory R. Young
- Faculty of Health and Life Sciences, Northumbria University, Newcastle upon Tyne, England, United Kingdom
| | - Tarek M. Abdelghany
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt
- Health Protection Research Unit, Institute of Cellular Medicine, Newcastle University, Newcastle Upon Tyne, England, United Kingdom
| | - Alistair C. Leitch
- Health Protection Research Unit, Institute of Cellular Medicine, Newcastle University, Newcastle Upon Tyne, England, United Kingdom
| | - Michael P. Dunn
- Health Protection Research Unit, Institute of Cellular Medicine, Newcastle University, Newcastle Upon Tyne, England, United Kingdom
| | - Peter G. Blain
- Health Protection Research Unit, Institute of Cellular Medicine, Newcastle University, Newcastle Upon Tyne, England, United Kingdom
| | - Clare Lanyon
- Faculty of Health and Life Sciences, Northumbria University, Newcastle upon Tyne, England, United Kingdom
| | - Matthew C. Wright
- Health Protection Research Unit, Institute of Cellular Medicine, Newcastle University, Newcastle Upon Tyne, England, United Kingdom
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Tanaka A, Leung PSC, Gershwin ME. Pathogen infections and primary biliary cholangitis. Clin Exp Immunol 2019; 195:25-34. [PMID: 30099750 PMCID: PMC6300644 DOI: 10.1111/cei.13198] [Citation(s) in RCA: 53] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2018] [Revised: 08/02/2018] [Accepted: 08/03/2018] [Indexed: 12/14/2022] Open
Abstract
Primary biliary cholangitis (PBC) is a multi-factorial disease caused by the interaction of both genetic predisposition and environmental triggers. Bacterial infection has been investigated most intensively, both epidemiologically and experimentally, as a prime environmental aetiology in PBC. The association of recurrent history of urinary tract infection (UTI) with PBC has been frequently confirmed by several large-scale, case-control studies, despite variation in geographic area or case-finding methods. Escherichia coli is a predominant pathogen in most cases with UTI. Animal studies and molecular mimicry analysis between the human and E. coli E2 subunit of the 2-oxo-acid dehydrogenase complexes demonstrated that E. coli infection is a key factor in breaking immunological tolerance against the mitochondria, resulting in the production of anti-mitochondrial autoantibodies (AMA), the disease-specific autoantibodies of PBC. Novosphingobium aromaticivorans, a ubiquitous xenobiotic-metabolizing bacterium, is another candidate which may be involved in the aetiology of PBC. Meanwhile, improved environmental hygiene and increased prevalence of PBC, especially in males, may argue against the aetiological role of bacterial infection in PBC. Multiple mechanisms can result in the loss of tolerance to mitochondrial autoantigens in PBC; nonetheless, bacterial infection is probably one of the dominant pathways, especially in female patients. Notably, there is a rising prevalence of male patients with PBC. With increasing exposure to environmental xenobiotics in both genders, studies directed towards identifying the environmental culprit with systematically designed case-control studies are much needed to further determine the environmental factors and role of bacterial infections in PBC.
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Affiliation(s)
- A. Tanaka
- Department of MedicineTeikyo University School of MedicineTokyoJapan
| | - P. S. C. Leung
- Division of Rheumatology Allergy and Clinical ImmunologyUniversity of California School of MedicineDavisCAUSA
| | - M. E. Gershwin
- Division of Rheumatology Allergy and Clinical ImmunologyUniversity of California School of MedicineDavisCAUSA
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Tanaka A, Leung PSC, Gershwin ME. The Genetics and Epigenetics of Primary Biliary Cholangitis. Clin Liver Dis 2018; 22:443-455. [PMID: 30259846 DOI: 10.1016/j.cld.2018.03.002] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Both genetic background and environmental factors contribute to primary biliary cholangitis (PBC). Recent innovative technologies, such as genome-wide association studies, identified a remarkable number of susceptible nonhuman leukocyte antigen genes contributing to the development of PBC; however, they are primarily indicators of active immunologic responses commonly involved in autoimmune reactions. Thus, recent studies have focused on epigenetic mechanisms that would link genetic predisposition and environmental triggering factors. In PBC, methylation profiling and altered X chromosome architecture have been intensively explored in conjunction with a striking female predominance. Further, microRNAs have been found to be associated with the etiology of PBC.
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Affiliation(s)
- Atsushi Tanaka
- Department of Medicine, Teikyo University School of Medicine, 2-11-1, Kaga, Itabashi-ku, Tokyo 173-8605, Japan
| | - Patrick S C Leung
- Division of Rheumatology, Allergy and Clinical Immunology, UC Davis School of Medicine, 451 Health Sciences Drive, Suite 6510, Davis 95616, CA
| | - Merrill Eric Gershwin
- Division of Rheumatology, Allergy and Clinical Immunology, UC Davis School of Medicine, 451 Health Sciences Drive, Suite 6510, Davis 95616, CA.
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Tanaka A, Leung PS, Gershwin ME. Environmental basis of primary biliary cholangitis. Exp Biol Med (Maywood) 2018; 243:184-189. [PMID: 29307284 DOI: 10.1177/1535370217748893] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Autoimmunity is a consequence of both genetic and environmental factors, occurring in genetically susceptible hosts with environmental triggers. While genome-wide association studies have revealed a number of susceptible genes contributing to etiology, the environmental triggers remain poorly understood. Primary biliary cholangitis, formally known as primary biliary cirrhosis, is considered a model autoimmune disease for which our group has extensively evaluated environmental factors involved in its etiology. Bacterial infection and xenobiotics have been proposed as candidate environmental factors that may explain tolerance breakdown and production of primary biliary cholangitis-specific antimitochondrial autoantibodies. Large-scale case-control studies have consistently detected an association of primary biliary cholangitis with urinary tract infections caused by Escherichia coli, as E. coli PDC-E2 is molecularly similar to human PDC-E2, the immunodominant target of AMAs. Another bacterium of interest is Novosphingobium aromaticivorans, a ubiquitous xenobiotic-metabolizing bacterium that produces lipoylated proteins, which are highly reactive with sera from primary biliary cholangitis patients. Regarding xenobiotics, case-control studies have suggested that frequent use of nail polish is associated with an increased susceptibility to primary biliary cholangitis. We found that 2-octynamide, the conjugate derived from 2-octynoic acid present in cosmetics, lipsticks, and some chewing gums, was unique in both its quantitative structure-activity relationship analysis and reactivity with primary biliary cholangitis sera. 2-nonyamide is another xenobiotic that also has the optimal chemical structure for xenobiotic modification of the PDC-E2 epitope, as demonstrated by the enhanced epitope recognition with AMA-positive PBC sera. Moreover, we found that C57BL/6 mice immunized with 2-octynoic acid-BSA possess many of the features characteristic to primary biliary cholangitis. Impact statement Autoimmunity is believed to develop in genetically susceptible hosts with triggers from the environment. Researchers have recently demonstrated that bacteria and xenobiotics commonly present in our environment are potential triggers of tolerance breakdown against autoantigens and autoimmunity, particularly in primary biliary cholangitis (PBC). The link between xenobiotics and PBC has been further confirmed with the establishment of PBC model mice by immunizing mice with xenobiotics.
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Affiliation(s)
- Atsushi Tanaka
- 1 Department of Medicine, School of Medicine, Teikyo University, Tokyo 1738606, Japan
| | - Patrick Sc Leung
- 2 Division of Rheumatology Allergy and Clinical Immunology, University of California School of Medicine, Davis, CA 95616, USA
| | - M Eric Gershwin
- 2 Division of Rheumatology Allergy and Clinical Immunology, University of California School of Medicine, Davis, CA 95616, USA
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Begum R, Mahtab MA, Al Mamun A, Kumar Saha B, Shahadat Hossain SM, Chandra Das D, Fazle Akbar SM, Kamal M, Rahman S. A Case of Antimitochondrial Antibody Negative Primary Biliary Cirrhosis from Bangladesh and Review of Literature. Euroasian J Hepatogastroenterol 2015; 5:122-126. [PMID: 29201708 PMCID: PMC5578542 DOI: 10.5005/jp-journals-10018-1150] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2015] [Accepted: 04/05/2015] [Indexed: 11/23/2022] Open
Abstract
Primary biliary cirrhosis (PBC) is very closely associated with the presence of antimitochondrial antibodies (AMA). Nevertheless, 5 to 10% of patients with typical features of primary biliary cirrhosis do not have detectable AMA. They are referred to as AMA negative PBC. We report a case of PBC who was AMA-negative. The patient was a middle-aged woman seeking help of dermatologist for her complaint of itching. The diagnosis was confirmed by histopathology, whereas other possible causes of cirrhosis were excluded. How to cite this article Begum R, Mahtab MA, Mamun AA, Saha BK, Hossain SMS, Saha DC, Akbar SMF, Kamal M, Rahman S. A Case of Antimitochondrial Antibody Negative Primary Biliary Cirrhosis from Bangladesh and Review of Literature. Euroasian J Hepato-Gastroenterol 2015;5(2):122-126.
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Affiliation(s)
- Roksana Begum
- Department of Hepatology, Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh
| | - Mamun-Al Mahtab
- Department of Hepatology, Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh
| | - Ayub Al Mamun
- Department of Hepatology, Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh
| | - Biplob Kumar Saha
- Department of Hepatology, Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh
| | | | - Dulal Chandra Das
- Department of Hepatology, Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh
| | | | - Mohammad Kamal
- Department of Pathology, Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh
| | - Salimur Rahman
- Department of Hepatology, Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh
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Abstract
The etiology of the autoimmune liver disease primary biliary cirrhosis (PBC) remains largely unresolved, owing in large part to the complexity of interaction between environmental and genetic contributors underlying disease development. Observations of disease clustering, differences in geographical prevalence, and seasonality of diagnosis rates suggest the environmental component to PBC is strong, and epidemiological studies have consistently found cigarette smoking and history of urinary tract infection to be associated with PBC. Current evidence implicates molecular mimicry as a primary mechanism driving loss of tolerance and subsequent autoimmunity in PBC, yet other environmentally influenced disease processes are likely to be involved in pathogenesis. In this review, the authors provide an overview of current findings and touch on potential mechanisms behind the environmental component of PBC.
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Affiliation(s)
- Brian D. Juran
- Division of Gastroenterology and Hepatology, Center for Basic Research in Digestive Diseases, Mayo Clinic, Rochester, Minnesota Semin Liver Dis 2014;34:265–272
| | - Konstantinos N. Lazaridis
- Division of Gastroenterology and Hepatology, Center for Basic Research in Digestive Diseases, Mayo Clinic, Rochester, Minnesota Semin Liver Dis 2014;34:265–272
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Koulentaki M, Mantaka A, Sifaki-Pistolla D, Thalassinos E, Tzanakis N, Kouroumalis E. Geoepidemiology and space-time analysis of Primary biliary cirrhosis in Crete, Greece. Liver Int 2014; 34:e200-7. [PMID: 24502439 DOI: 10.1111/liv.12479] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2013] [Accepted: 01/31/2014] [Indexed: 12/18/2022]
Abstract
BACKGROUND & AIMS The prevalence of Primary biliary cirrhosis varies in different geographical areas. This might reflect genetic or environmental risk factors. We aimed to define Primary biliary cirrhosis prevalence and incidence, describe patient's spatial distribution, generate prediction maps and detect any possible routing pattern of time-spatial appearance of the disease in Crete, Greece. METHODS From 1990-2010, 245 Primary biliary cirrhosis patients diagnosed and followed up at the Gastroenterology Department of the University Hospital and the District Hospitals of the island, were contacted and 222 were included in the time-spatial analysis. To map their spatial distribution per 5-year periods, geospatial models were applied in Gis-ArcMap 9.3 software. Kriging Interpolation methods were used to generate prediction maps for the disease in Crete. Areas of high and low probability of disease occurrence were estimated through multicriteria modelling. The disease route was defined by Gis-ArcMap's toolbox. RESULTS Prevalence was found to be 365 cases per million, with a mean incidence of 20.88 (range 3.79-35.99). Prediction map estimates from 1.22 to 11 patients per 50 km2 all over Crete. Areas of high risk of disease occurrence are located in the Eastern part, while low risk in the Western part of the island. DISCUSSION Prevalence and incidence of Primary biliary cirrhosis in Crete are among the higher published in Europe. Given the homogeneous and stable study population and the geopolitics of the island, the heterogeneity in the time-spatial distribution and the route of disease appearance strongly suggest a role for environmental causative agents.
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Affiliation(s)
- M Koulentaki
- Department of Gastroenterology & Hepatology, University Hospital of Crete, Heraklion, Crete, Greece
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Invernizzi P, Alessio MG, Smyk DS, Lleo A, Sonzogni A, Fabris L, Candusso M, Bogdanos DP, Iorio R, Torre G. Autoimmune hepatitis type 2 associated with an unexpected and transient presence of primary biliary cirrhosis-specific antimitochondrial antibodies: a case study and review of the literature. BMC Gastroenterol 2012; 12:92. [PMID: 22816667 PMCID: PMC3464927 DOI: 10.1186/1471-230x-12-92] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2012] [Accepted: 07/20/2012] [Indexed: 12/14/2022] Open
Abstract
Background Unlike other autoimmune liver diseases, primary biliary cirrhosis (PBC) has never been reported in early childhood, while type 2 autoimmune hepatitis (AIH) is eminently a paediatric disease. Case presentation We describe a case of type 2 AIH with serological positivity for PBC-specific anti-mitochondrial antibodies (AMA) in a 3-year old girl. We found this observation intriguing as AMA and indeed an overlap with PBC are virtually absent in Type 2 AIH, a pediatric form of AIH which is distinct precisely because it is characterized by pathognomonic anti-liver kidney microsomal type 1 (LKM-1) showing a remarkable antigen-specificity directed against cytochrome P4502D6. We also review the literature in relation to AMA positivity in paediatric age and adolescence. In our case, the presence of AIH-2-specific anti-LKM-1 and PBC-specific AMA was confirmed by indirect immunofluorescence (IIF), and immunoblotting and ELISA based on recombinant mitochondrial antigens. The clinical, laboratory and histological features of the child are given in detail. Interestingly the mother was AMA positive without other features of PBC. The child was successfully treated with immunosuppression and five years after the original diagnosis is on a low dose of prednisolone and azathioprine, with no signs of relapse. Anti-LKM-1 antibodies are still present in low titres. AMA were detectable for the first 4 years after the diagnosis and disappeared later. Conclusion This is the first case report in the literature of AIH type 2 with an unexpected PBC-specific AMA positivity in a young child. Response to immunosuppressive treatment was satisfactory and similar to that described in AIH. A review of published reports on AMA positivity in paediatric age shows that the antibody may arise in the context of immunodeficiency and is variably associated with liver damage.
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Affiliation(s)
- Pietro Invernizzi
- Center for Autoimmune Liver Diseases, Humanitas Clinical and Research Center, Via Manzoni 56, 20089, Rozzano(MI), Italy.
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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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Abstract
Primary biliary cirrhosis (PBC) is a chronic cholestatic liver disease in which an immune-mediated injury targets the small intrahepatic bile ducts. PBC is further characterized by highly specific serum antimitochondrial autoantibodies (AMA) and autoreactive T cells, a striking female predominance, a strong genetic susceptibility, and a plethora of candidate environmental factors to trigger the disease onset. For these reasons PBC appears ideal to represent the developments of the clonal selection theory over the past decades. First, a sufficiently potent autoimmunogenic stimulus in PBC would require the coexistence of numerous pre-existing conditions (mostly genetic, as recently illustrated by genome-wide association studies and animal models) to perpetuate the destruction of the biliary epithelium by the immune system via the persistence of forbidden clones. Second, the proposed modifications of mitochondrial autoantigens caused by infectious agents and/or xenobiotics well illustrate the possibility that peculiar changes in the antigen structure and flexibility may contribute to tolerance breakdown. Third, the unique apoptotic features demonstrated for cholangiocytes are the ideal setting for the development of mitochondrial autoantigen presentation to the immune system through macrophages and AMA thus turning the non traditional mitochondrial antigen into a traditional one. This article will review the current knowledge on PBC etiology and pathogenesis in light of the clonal selection theory developments.
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Yanagisawa M, Takagi H, Takahashi H, Uehara M, Otsuka T, Yuasa K, Hosonuma K, Mori M. Familial clustering and genetic background of primary biliary cirrhosis in Japan. Dig Dis Sci 2010; 55:2651-8. [PMID: 20012485 DOI: 10.1007/s10620-009-1057-0] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/23/2009] [Accepted: 11/13/2009] [Indexed: 12/17/2022]
Abstract
BACKGROUND Primary biliary cirrhosis (PBC) is regarded as an autoimmune liver disease and familial clustering of PBC could represent some genetic predisposition to the disease. AIMS To elucidate the genetic background of PBC by investigating familial cases of PBC. METHODS Familial cases were picked out from 171 PBC patients who enrolled in this study. We analyzed them and their family members, and compared them clinically and immunogenetically to non-familial cases. RESULTS Out of 171 PBC patients, ten (5.8%) were identified as familial PBC in five families. The clinical features of familial PBC were almost comparable to those of non-familial PBC. The distribution of human leukocyte antigens (HLA)-A, -B and -DR in familial PBC showed no specificity. Two new PBC patients were identified in one family in addition to the two originally enrolled PBC patients, resulting in four patients with PBC within the same family. The two new PBC patients had an identical HLA haplotype. On the other hand, one HLA-identical sister of a PBC patient in another family did not develop PBC. CONCLUSIONS Primary biliary cirrhosis can exhibit familial clustering without any HLA predisposition, however, a survey of families for PBC could be useful for identifying new patients with PBC in the asymptomatic stage for earlier diagnosis and treatment.
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Affiliation(s)
- Masatoshi Yanagisawa
- Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan.
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Selmi C, Diana A, Cocchi CA, Zuin M, Gershwin ME. Environmental factors and the induction of autoimmunity in primary biliary cirrhosis. Expert Rev Clin Immunol 2010; 4:239-45. [PMID: 20477053 DOI: 10.1586/1744666x.4.2.239] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
Primary biliary cirrhosis (PBC) is a chronic cholestatic disease with an autoimmune pathogenesis and an unknown etiology, predominantly affecting postmenopausal women. The term PBC is a misnomer since most cases currently diagnosed have limited probability to develop cirrhosis. Antimitochondrial autoantibodies, elevated IgM and selective destruction of the intrahepatic bile ducts are the hallmarks of PBC. A permissive genetic background is critical in producing susceptibility despite limited associations with alleles within the MHC. The disease has incomplete concordance in monozygotic twins and its geoepidemiology suggests a role for environmental factors in the induction of PBC. This hypothesis is further supported by clinical (risk factors) and experimental evidence. Some of the factors incriminated model molecular mimicry by infectious agents and xenobiotic chemicals. Additional candidates are being proposed through large screening; all proposed associations ultimately require confirmation in animal models and clinical practice.
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Affiliation(s)
- Carlo Selmi
- University of Milan, Internal Medicine and Liver Unit, DIMCO San Paolo Hospital School of Medicine, Italy
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Poupon R. Primary biliary cirrhosis: a 2010 update. J Hepatol 2010; 52:745-58. [PMID: 20347176 DOI: 10.1016/j.jhep.2009.11.027] [Citation(s) in RCA: 198] [Impact Index Per Article: 13.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2009] [Revised: 11/27/2009] [Accepted: 11/30/2009] [Indexed: 12/14/2022]
Abstract
Primary biliary cirrhosis (PBC) is a chronic inflammatory autoimmune disease that mainly targets the cholangiocytes of the interlobular bile ducts in the liver. The condition primarily affects middle-aged women. Without treatment, PBC generally progresses to cirrhosis and eventually liver failure over a period of 10-20 years. PBC is a rare disease with prevalence of less than 1/2000. PBC is thought to result from a combination of multiple genetic factors and superimposed environmental triggers. The contribution of the genetic predisposition is evidenced by the familial clustering. Several risk factors, including exposure to infectious agents and chemical xenobiotics, have been suggested. Ursodeoxycholic acid (UDCA) is currently the only FDA-approved medical treatment for PBC. When administered at doses of 13-15 mg/kg/day, a majority of patients with PBC have a normal life expectancy without additional therapeutic measures. One out of three patients does not adequately respond to UDCA therapy and may need additional medical therapy and/or liver transplantation. This review summarises current knowledge on the epidemiology, ethiopathogenesis, clinical, and therapeutic aspects of PBC.
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Affiliation(s)
- Raoul Poupon
- UPMC Univ Paris 06, France; INSERM, UMR_S 938, Paris, France.
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Abstract
Autoimmune disease (AD) affects approximately 3% of the population. This is an enormous number, but ironically the study of autoimmunity has not taken on the significance of many other diseases because so many of the ADs are relatively uncommon. Indeed, despite enormous advances in the diagnosis and the treatment of AD, there is still a paucity of data on the etiological events that lead to the clinical pathology. For most other human diseases, the etiology is addressed and often solved by the use of epidemiology. Epidemiology consists of the study of prevalence of a disease, coupled with analysis of genetic factors and detection of environmental agents. In the context of autoimmune conditions, preclinical epidemiology has recently been favored, as a consequence of the discovery that autoantibody precedes overt disease. The idea of a North-South gradient in the prevalence of ADs, with a reciprocal gradient in that of infectious injuries has proven to be debatable. More importantly, environmentally-induced changes have been shown to modify certain diseases giving rise to the key concept of epigenetics. However, it is clear that major voids exist. Some of these voids were hoped to be solved by the use of genome-wide associations. This, however, has proven very problematic, as the genetic basis of AD is considerably more complicated than once believed. We now base our hopes on next generational sequencing as a brut force undertaking to partially decipher the genetic code that predisposes individuals to AD. This volume is a compilation of papers in Autoimmunity Reviews and the Journal of Autoimmunity and presented as part of the 7th International Congress on Autoimmunity in Ljubljana, Slovenia. It is clearly impossible to present data on the geoepidemiology of all of the AD. Instead, we attempted to generate interest amongst immunologists to generate papers that are thought provoking but also contemporary reviews.
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Selmi C, Gershwin ME. The role of environmental factors in primary biliary cirrhosis. Trends Immunol 2009; 30:415-20. [PMID: 19643668 DOI: 10.1016/j.it.2009.05.006] [Citation(s) in RCA: 52] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2009] [Revised: 05/06/2009] [Accepted: 05/07/2009] [Indexed: 01/12/2023]
Abstract
The etiology of primary biliary cirrhosis (PBC) is enigmatic, although it is clearly related to a combination of genetic predisposition and environmental stimulation. PBC is a chronic autoimmune cholestatic liver disease that occurs throughout the world with a reported latitudinal gradient in prevalence and incidence. PBC is also characterized by a 60% concordance in monozygotic twins and is considered a model autoimmune disease because of several features common to other conditions and the relatively homogeneous serological and biochemical features. Several risk factors have been suggested to be associated with PBC, including exposure to infectious agents and chemical xenobiotics. This review will attempt to place such factors in perspective.
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Affiliation(s)
- Carlo Selmi
- Department of Internal Medicine, IRCCS Istituto Clinico Humanitas, University of Milan, Rozzano, Milan 20089, Italy
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Juran BD, Atkinson EJ, Larson JJ, Schlicht EM, Lazaridis KN. Common genetic variation and haplotypes of the anion exchanger SLC4A2 in primary biliary cirrhosis. Am J Gastroenterol 2009; 104:1406-11. [PMID: 19491853 PMCID: PMC2853916 DOI: 10.1038/ajg.2009.103] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVES Deficiencies of the anion exchanger SLC4A2 are thought to play a pathogenic role in primary biliary cirrhosis (PBC), as the evidenced by decreased expression and activity in PBC patients and development of disease features in SLC4A2 knockout mice. We hypothesized that genetic variation in SLC4A2 might influence this pathogenic contribution. Thus, we aimed to perform a comprehensive assessment of SLC4A2 genetic variation in PBC using a linkage disequilibrium (LD)-based haplotype-tagging approach. METHODS Twelve single nucleotide polymorphisms (SNPs) across SLC4A2 were genotyped in 409 PBC patients and 300 controls and evaluated for association with disease, as well as with prior orthotopic liver transplant and antimitochondrial antibody (AMA) status among the PBC patients, both individually and as inferred haplotypes, using logistic regression. RESULTS All SNPs were in Hardy-Weinberg equilibrium. No associations with disease or liver transplantation were detected, but two variants, rs2303929 and rs3793336, were associated with negativity for antimitochondrial antibodies among the PBC patients. CONCLUSIONS The common genetic variation of SLC4A2 does not directly affect the risk of PBC or its clinical outcome. Whether the deficiency of SLC4A2 expression and activity observed earlier in PBC patients is an acquired epiphenomenon of underlying disease or is because of heritable factors in unappreciated regulatory regions remains uncertain. Of note, two SLC4A2 variants appear to influence AMA status among PBC patients. The mechanisms behind this finding are unclear.
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Affiliation(s)
- Brian D. Juran
- Division of Gastroenterology and Hepatology, Center for Basic Research in Digestive Diseases, Mayo Clinic College of Medicine, Rochester, Minnesota, USA
| | - Elizabeth J. Atkinson
- Division of Biostatistics, Mayo Clinic College of Medicine, Rochester, Minnesota, USA
| | - Joseph J. Larson
- Division of Biostatistics, Mayo Clinic College of Medicine, Rochester, Minnesota, USA
| | - Erik M. Schlicht
- Division of Gastroenterology and Hepatology, Center for Basic Research in Digestive Diseases, Mayo Clinic College of Medicine, Rochester, Minnesota, USA
| | - Konstantinos N. Lazaridis
- Division of Gastroenterology and Hepatology, Center for Basic Research in Digestive Diseases, Mayo Clinic College of Medicine, Rochester, Minnesota, USA
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Abstract
Infectious agents have been postulated to play a pathogenic role in the loss of immunological tolerance and the induction of primary biliary cirrhosis, an immune-mediated cholestatic liver disease characterized by progressive destruction of the small intrahepatic bile ducts and subsequent cirrhosis and liver failure. This review discusses emerging issues implicating infectious agents such as Escherichia coli, mycobacteria, chlamydia, helicobacter species, lactobacilli, Novosphingobium aromaticivorans, and betaretroviruses in the pathogenesis of primary biliary cirrhosis. We also review the immunopathological mechanisms responsible for the induction of the disease with special emphasis on the role of molecular mimicry and microbial/self immunological cross-reactivity.
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Abstract
In nearly every multifactorial human disease, there are three periods that characterize our understanding and definition. First, there is a period in which there is rapid accumulation of descriptive data. Second, there is a longer and slower period as information is obtained that redefines and expands basic and clinical knowledge that lacks the final and important area of understanding aetiology and therapeutic intervention. Third, which is much less common for most diseases, is the vigorous definition of pathobiology and treatment. These phases are well illustrated by our current understanding of primary biliary cirrhosis (PBC). The term PBC was first used nearly 60 years ago and for the first 40 or so years, the primary research efforts were directed at clinical definitions and pathology. Subsequently, with the advent of molecular biology, there began a rigorous dissection of the immune response and, in particular, a better understanding of anti-mitochondrial antibodies. These efforts have greatly helped in our understanding of not only the effector mechanisms of disease, but also the uniqueness of the primary target tissue, biliary epithelium. However, this research has still not led to successful translation for specific therapy.
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Affiliation(s)
- Carlo Selmi
- Division of Internal Medicine and Liver Unit, San Paolo Hospital School of Medicine, University of Milan, Italy
- Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis School of Medicine, Davis, CA 95616
| | - Massimo Zuin
- Division of Internal Medicine and Liver Unit, San Paolo Hospital School of Medicine, University of Milan, Italy
| | - M. Eric Gershwin
- Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis School of Medicine, Davis, CA 95616
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Abstract
Since initial reports in the mid-1970s provided epidemiology data on primary biliary cirrhosis (PBC), many studies have characterized the variable frequency of this disease in diverse populations worldwide and sought to identify associated risk factors. Recent research confirms earlier work suggesting that the incidence and prevalence of PBC are on the rise, although geographic variation persists. Analysis of familial and geographic clustering supports the hypothesis that development and progression of the disease hinge on a complex interplay between genetic and environmental risk factors. International clinical data systems are needed to advance PBC epidemiologic research. Given this complexity, international clinical data systems are needed to advance PBC epidemiologic research.
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Abstract
Primary biliary cirrhosis (PBC) is a chronic cholestatic liver disease more commonly found in women (with most cases being diagnosed in the fourth to fifth decades of life) that share peculiar features. Among these, serum antimitochondrial autoantibodies (AMA), serum hyper-immunoglobulin M, and progressive destruction of intrahepatic bile ducts are the most common clinical findings. The pathogenesis of the selective destruction of small-duct biliary epithelial cells is still unknown, although an autoimmune mechanism appears likely due to the detection of autoreactive T and B cells. Genetic background is critical in determining susceptibility to the disease, despite the limited associations with alleles within the major histocompatibility complex. However, among other observations, incomplete concordance of the disease in monozygotic twins and epidemiology strongly support a role for environmental factors in PBC onset. Molecular mimicry by either infectious agents or chemicals has been proposed to induce breakdown of immune tolerance in genetically predisposed individuals. This hypothesis is further supported by clinical (risk factors) and experimental evidence obtained also in animal models.
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Affiliation(s)
- Carlo Selmi
- Division of Internal Medicine, "Luigi Sacco" Department of Clinical Sciences, University of Milan, Milan, Italy and Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, Davis, California, USA
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Abstract
The clustering of patients in a representative family as well as relatively high concordance rate in monozygotic twins strongly indicate that genetic factors play a crucial role in modulating primary biliary cirrhosis (PBC) by conferring susceptibility to, or providing protection from, the disease. Therefore, much like other autoimmune diseases, intensive investigations have attempted to elucidate which genes are incriminated in the etiology of PBC. So far, a number of genes, including major histocompatibility complex (MHC) class I and II, cytokines and cell surface molecules, have been examined to seek the possibility of whether single nucleotide polymorphisms (SNP) of the gene might be associated with susceptibility to PBC. Nevertheless, it appears that methodologicaldifficulties, mainly the limitation of the number of individuals tested in each study, hamper the detection of a convincing and reproducible link between genetic polymorphisms and the etiology of PBC. Also, the difference in genetic background among several ethnic groups may play a role in concealing the association. In this review, I will highlight the genetic association in PBC, and review the association of genetic polymorphisms with the etiology of PBC, which have been reported in various ethnicities.
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Affiliation(s)
- Atsushi Tanaka
- Department of Medicine, Teikyo University School of Medicine, Tokyo, Japan
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Abstract
Primary biliary cirrhosis (PBC) is a disease of unknown etiology leading to progressive destruction of small intrahepatic bile ducts and eventually to liver cirrhosis and failure. It is characterised by female predominance and serum auto-antibodies to mitochondrial antigens targeting the E2 components of the 2-oxoacid dehydrogenase complex. Although they are associated with disease pathogenesis, no concrete evidence has been presented so far. Epidemiological data indicate that a geographical clustering of cases and possible environmental factors are implicated in pathogenesis. A number of genetic factors play a role in determining disease susceptibility or progression, although no definitive conclusion has been reached so far. A key factor to immune pathogenesis is considered to be the breakdown of immune tolerance, either through molecular mimicry or through the so called determinant density model. In this review, the available data regarding the pathogenesis of primary biliary cirrhosis are described and discussed. A new unifying hypothesis based on early endothelin overproduction in primary biliary cirrhosis (PBC) is presented and discussed.
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Gershwin ME, Selmi C, Worman HJ, Gold EB, Watnik M, Utts J, Lindor KD, Kaplan MM, Vierling JM. Risk factors and comorbidities in primary biliary cirrhosis: a controlled interview-based study of 1032 patients. Hepatology 2005; 42:1194-202. [PMID: 16250040 PMCID: PMC3150736 DOI: 10.1002/hep.20907] [Citation(s) in RCA: 429] [Impact Index Per Article: 21.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Primary biliary cirrhosis (PBC) is an autoimmune disease of unknown etiology, often associated with other autoimmune conditions. Controlled studies have so far provided conflicting data on risk factors and comorbidity rates in PBC. We enrolled patients with PBC (n = 1032) from 23 tertiary referral centers for liver diseases in the United States and random-digit-dialed controls (n = 1041) matched for sex, age, race, and geographical location. Patients and controls were administered a modified version of the US National Health and Nutrition Examination Study (NHANES III) questionnaire by trained personnel to evaluate associations between PBC and social, demographic, personal and family medical histories, lifestyle, and reproductive factors and the rates of comorbidity in affected individuals. Data indicate that having a first-degree relative with PBC (adjusted odds ratio [AOR] 10.736; 95% confidence interval 4.227-27.268), history of urinary tract infections (AOR 1.511, 95% CI 1.192-1.915), past smoking (AOR 1.569, 95% CI 1.292-1.905), or use of hormone replacement therapies (AOR 1.548, 95% CI 1.273-1.882) were significantly associated with increased risk of PBC. The frequent use of nail polish slightly increased the risk of having PBC. Other autoimmune diseases were found in 32% of cases and 13% of controls (P<0.0001). In conclusion, environmental factors, possibly including infectious agents through urinary tract infections or chemicals contained in cigarette smoke, may induce PBC in genetically susceptible individuals. Exogenous estrogens may also contribute to explain the female predominance of the disease.
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Affiliation(s)
- M Eric Gershwin
- Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis School of Medicine, Davis, CA 95616, USA.
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Invernizzi P, Selmi C, Mackay IR, Podda M, Gershwin ME. From bases to basis: linking genetics to causation in primary biliary cirrhosis. Clin Gastroenterol Hepatol 2005; 3:401-10. [PMID: 15880308 DOI: 10.1016/s1542-3565(04)00678-0] [Citation(s) in RCA: 71] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Primary biliary cirrhosis (PBC) is a multifactorial autoimmune disease with inherited and environmental components in pathogenesis. It is exceptional among autoimmune diseases in showing strong heritability according to familial occurrence and monozygotic twins concordance, yet with weak associations with the usual genetic risk elements for autoimmunity, such as the HLA alleles. Among the latter, there is risk (at least in some populations) conferred by HLA DRB1*08 and possibly some protection by DRB1*11. However, the inconsistency among studies on HLA is surprising, given that PBC is a relatively homogenous disease entity. Among non-HLA genes, some studies implicate polymorphisms of genes for cytotoxic T-lymphocyte antigen-4, interleukin-2, or interleukin-10; polymorphisms of the vitamin D receptor could synergize with low sunlight exposure to create deficiency of the immunoregulatory factor, activated vitamin D. A new lead is available from the finding in female subjects with PBC of an increase in the degree of monosomy of the X chromosome that is presumed to carry immune response genes. A further suggested source of inquiry is the apparent protection of African-American women from PBC. Finally, data on inheritance should be sought in PBC by descent methodology, rather than by cross-sectional association studies in cases and control subjects, and based on analysis of a large number of families with an affected member through a worldwide effort.
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Affiliation(s)
- Pietro Invernizzi
- Division of Internal Medicine, Department of Medicine, Surgery and Dentistry, San Paolo School of Medicine, University of Milan, Italy
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Nakamura T, Kawagoe Y, Ueda Y, Koide H. Antineutrophil cytoplasmic autoantibody-associated rapidly progressive glomerulonephritis in a patient with primary biliary cirrhosis. Am J Med Sci 2004; 328:176-9. [PMID: 15367878 DOI: 10.1097/00000441-200409000-00009] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
A 72-year-old woman with primary biliary cirrhosis (PBC) and antineutrophil cytoplasmic autoantibody (ANCA)-associated rapidly progressive glomerulonephritis is described. She had a 6-year history of PBC diagnosed histologically, with a positive test finding for antimitochondrial antibodies and elevated biliary enzyme activity. The myeloperoxidase-ANCA test result was negative. The patient was treated with ursodeoxycholic acid (600 mg/day) and had been stable for 6 years. She was admitted to our hospital because of general fatigue, exertional dyspnea, and peripheral edema. Her serum level of creatinine was increased (4.4 mg/dL), and her hemoglobin concentration was reduced (8.0 g/dL). The patient was diagnosed as having rapidly progressive glomerulonephritis. Test results for serum antinuclear antibody and myeloperoxidase-ANCA were positive. The diagnosis by renal biopsy was necrotizing crescentic glomerulonephritis. Prednisolone followed by methylprednisolone pulse therapy and cyclophosphamide were administered. The patient underwent plasma exchange twice weekly for 4 weeks. After 4 weeks, her serum creatinine level fell to 1.8 mg/dL, and she recovered renal function without hemodialysis. After 24 weeks, her renal function (serum creatinine level, 1.6 mg/dL) was stable.
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Affiliation(s)
- Tsukasa Nakamura
- Department of Medicine, Shinmatsudo Central General Hospital, Chiba, Japan
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Selmi C, Ross SR, Ansari AA, Invernizzi P, Podda M, Coppel RL, Gershwin ME. Lack of immunological or molecular evidence for a role of mouse mammary tumor retrovirus in primary biliary cirrhosis. Gastroenterology 2004; 127:493-501. [PMID: 15300582 DOI: 10.1053/j.gastro.2004.05.033] [Citation(s) in RCA: 87] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
BACKGROUND & AIMS Recent observations, including a pilot clinical trial, have suggested that a human mouse mammary tumor virus (MMTV) causes primary biliary cirrhosis (PBC). We attempted to confirm such data. METHODS We obtained sera from 101 patients (53 with PBC and 48 controls), fixed liver sections from 10 patients (8 PBC and 2 controls), fresh liver specimens (6 PBC and 6 controls), and fresh peripheral blood lymphocytes (PBLs) (10 PBC and 10 controls). We studied sera for reactivities against 3 different strains of MMTV virions, MMTV(C3H), MMTV(FM), and MMTV(LA), including goat polyclonal antibodies against MMTV virions, gp52, and p27 as positive controls. We stained liver specimens using polyclonal antibodies against MMTV and gp52 and further examined tissue samples and PBLs for specific MMTV genome sequences. RESULTS By Western blot analysis, no detectable reactivity in any of the PBC sera against any of the 3 MMTV strains or MMTV gp52 or p27 was observed. However, viral proteins were recognized by our control positive polyclonal antibodies. We note that 13%-60% of PBC sera presented low reactivity against 2 proteins of approximately 57 and 74 kilodaltons. Such reactivity is related to the trace amounts of mitochondrial antigens in the virus preparations derived from murine mammary tumor tissue. No detectable immunohistochemical or molecular evidence for MMTV was found in the liver specimens or PBLs. CONCLUSIONS We were unable to recapitulate the data on this specific retroviral etiology of PBC and suggest that such data could be the result of contamination.
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Affiliation(s)
- Carlo Selmi
- Division of Rheumatology, Allergy, and Clinical Immunology, University of California at Davis, 95616, USA
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