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Gao X, Ma H, Niu J, Li D. FcγRIIB expression increases during primary biliary cholangitis. Mol Immunol 2023; 162:30-37. [PMID: 37634276 DOI: 10.1016/j.molimm.2023.08.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Revised: 08/07/2023] [Accepted: 08/09/2023] [Indexed: 08/29/2023]
Abstract
Primary biliary cholangitis (PBC) is a severe disease with unknown aetiology and poor prognosis owing to ineffective treatment. B-cell antibodies play a regulatory role during immune responses; therefore, their role in PBC should not be overlooked. Fcγ receptors (FcγRs) of IgG and cell surface glycoproteins play an important role in autoimmune and infectious disease prevention. In this study, 60 patients with PBC and 35 healthy controls (HCs) were recruited. The number of B cells and the expression of the FcγRIIB on the peripheral blood mononuclear cells of patients with PBC were evaluated using FACS. The concentrations of soluble FcγRs were determined using ELISA, and intrahepatic FcγRIIB and CD19 expressions in patients with PBC were visualised using IHC. FcγRIIB expression in B cells was significantly higher in patients with PBC than in HCs (P < 0.0001). The soluble FcγRIIB levels in the plasma were higher in patients with PBC than in HCs (P = 0.0009). Notably, these levels were reduced by treatment with ursodeoxycholic acid (P = 0.0236). CD19 and FcγRIIB expression increased in the liver of patients with PBC relative to that in HCs. These findings can provide new insights into PBC pathogenesis and can aid the future development of treatment strategies.
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Affiliation(s)
- Xiuzhu Gao
- Department of Hepatology, First Hospital of Jilin University, Jilin University, 71 Xinmin Street, Changchun, Jilin Province 130021, China
| | - Heming Ma
- Department of Hepatology, First Hospital of Jilin University, Jilin University, 71 Xinmin Street, Changchun, Jilin Province 130021, China
| | - Junqi Niu
- Department of Hepatology, First Hospital of Jilin University, Jilin University, 71 Xinmin Street, Changchun, Jilin Province 130021, China.
| | - Dong Li
- Department of Hepatology, First Hospital of Jilin University, Jilin University, 71 Xinmin Street, Changchun, Jilin Province 130021, China; Department of Immunology, College of Basic Medical Sciences, Jilin University, 126 Xinmin Street, Changchun 130021, China.
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Zhao Y, Wei S, Chen L, Zhou X, Ma X. Primary biliary cholangitis: molecular pathogenesis perspectives and therapeutic potential of natural products. Front Immunol 2023; 14:1164202. [PMID: 37457696 PMCID: PMC10349375 DOI: 10.3389/fimmu.2023.1164202] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2023] [Accepted: 06/05/2023] [Indexed: 07/18/2023] Open
Abstract
Primary biliary cirrhosis (PBC) is a chronic cholestatic immune liver disease characterized by persistent cholestasis, interlobular bile duct damage, portal inflammation, liver fibrosis, eventual cirrhosis, and death. Existing clinical and animal studies have made a good progress in bile acid metabolism, intestinal flora disorder inflammatory response, bile duct cell damage, and autoimmune response mechanisms. However, the pathogenesis of PBC has not been clearly elucidated. We focus on the pathological mechanism and new drug research and development of PBC in clinical and laboratory in the recent 20 years, to discuss the latest understanding of the pathological mechanism, treatment options, and drug discovery of PBC. Current clinical treatment mode and symptomatic drug support obviously cannot meet the urgent demand of patients with PBC, especially for the patients who do not respond to the current treatment drugs. New treatment methods are urgently needed. Drug candidates targeting reported targets or signals of PBC are emerging, albeit with some success and some failure. Single-target drugs cannot achieve ideal clinical efficacy. Multitarget drugs are the trend of future research and development of PBC drugs.
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Affiliation(s)
- Yanling Zhao
- Department of Pharmacy, Chinese People's Liberation Army (PLA) General Hospital, Beijing, China
| | - Shizhang Wei
- Department of Anatomy, Histology and Embryology, School of Basic Medical Sciences, Peking University, Beijing, China
| | - Lisheng Chen
- Department of Pharmacy, Chinese People's Liberation Army (PLA) General Hospital, Beijing, China
- College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Xuelin Zhou
- Department of Pharmacology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Xiao Ma
- College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
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Cançado GGL, Braga MH, Ferraz MLG, Villela-Nogueira CA, Terrabuio DRB, Cançado ELR, Nardelli MJ, Faria LC, de Faria Gomes NM, Oliveira EMG, Rotman V, Oliveira MB, da Cunha SMCF, Cunha-Silva M, Mendes LSC, Ivantes CAP, Codes L, de Almeida E Borges VF, de Lima Pace FH, Pessoa MG, Signorelli IV, Coral GP, Bittencourt PL, Levy C, Couto CA. Anti-mitochondrial Antibody-Negative Primary Biliary Cholangitis Is Part of the Same Spectrum of Classical Primary Biliary Cholangitis. Dig Dis Sci 2022; 67:3305-3312. [PMID: 34181166 DOI: 10.1007/s10620-021-07122-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Accepted: 06/16/2021] [Indexed: 12/11/2022]
Abstract
BACKGROUND Primary biliary cholangitis (PBC) is a chronic cholestatic liver disease in which anti-mitochondrial antibodies (AMA) are the diagnostic hallmark. Whether AMA-negative PBC patients represent a different phenotype of disease is highly debated. AIMS The purpose of our study was to compare AMA-positive and AMA-negative PBC patients in a large non-white admixed Brazilian cohort. METHODS The Brazilian Cholestasis Study Group multicentre database was reviewed to assess demographics, clinical features and treatment outcomes of Brazilian PBC patients, stratifying data according to AMA status. RESULTS A total of 464 subjects (95.4% females, mean age 56 ± 5 years) with PBC were included. Three hundred and eighty-four (83%) subjects were AMA-positive, whereas 80 (17%) had AMA-negative PBC. Subjects with AMA-negative PBC were significantly younger (52.2 ± 14 vs. 59.6 ± 11 years, p = 0.001) and had their first symptom at an earlier age (43.2 ± 13 vs. 49.5 ± 12 years, p = 0.005). Frequency of type 2 diabetes was significantly increased in subjects with AMA-negative PBC (22.5% vs. 12.2%, p = 0.03). Lower IgM (272.2 ± 183 vs. 383.2 ± 378 mg/dL, p = 0.01) and triglycerides (107.6 ± 59.8 vs.129.3 ± 75.7 mg/dL, p = 0.025) and higher bilirubin (3.8 ± 13.5 vs. 1.8 ± 3.4 mg/dL, p = 0.02) levels were also observed in this subgroup. Response to ursodeoxycholic acid varied from 40.5 to 63.3% in AMA-positive and 34 to 62.3% in AMA-negative individuals, according to different response criteria. Outcomes such as development of liver-related complications, death and requirement for liver transplantation were similar in both groups. CONCLUSIONS AMA-negative PBC patients are similar to their AMA-positive counterparts with subtle differences observed in clinical and laboratory features.
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Affiliation(s)
- Guilherme Grossi Lopes Cançado
- Instituto Alfa de Gastroenterologia, Hospital das Clínicas, Universidade Federal de Minas Gerais, Av. Professor Alfredo Balena 110, Belo Horizonte, Minas Gerais, 30130-100, Brazil.
- Hospital da Polícia Militar de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.
| | - Michelle Harriz Braga
- Departamento de Gastroenterologia, Faculdade de Medicina da Universidade de São Paulo, São Paulo, São Paulo, Brazil
| | - Maria Lucia Gomes Ferraz
- Disciplina de Gastroenterologia, Universidade Federal de São Paulo, São Paulo, São Paulo, Brazil
| | - Cristiane Alves Villela-Nogueira
- Hospital Universitário Clementino Fraga Filho e Departamento de Clínica Médica da Faculdade de Medicina, Universidade Federal Do Rio de Janeiro, Rio de Janeiro, Rio de Janeiro, Brazil
| | | | - Eduardo Luiz Rachid Cançado
- Departamento de Gastroenterologia, Faculdade de Medicina da Universidade de São Paulo, São Paulo, São Paulo, Brazil
| | - Mateus Jorge Nardelli
- Instituto Alfa de Gastroenterologia, Hospital das Clínicas, Universidade Federal de Minas Gerais, Av. Professor Alfredo Balena 110, Belo Horizonte, Minas Gerais, 30130-100, Brazil
| | - Luciana Costa Faria
- Instituto Alfa de Gastroenterologia, Hospital das Clínicas, Universidade Federal de Minas Gerais, Av. Professor Alfredo Balena 110, Belo Horizonte, Minas Gerais, 30130-100, Brazil
| | | | | | - Vivian Rotman
- Hospital Universitário Clementino Fraga Filho e Departamento de Clínica Médica da Faculdade de Medicina, Universidade Federal Do Rio de Janeiro, Rio de Janeiro, Rio de Janeiro, Brazil
| | - Maria Beatriz Oliveira
- Ambulatório Municipal de Hepatites Virais de São José Dos Campos, São José dos Campos, São Paulo, Brazil
| | | | - Marlone Cunha-Silva
- Divisão de Gastroenterologia (Gastrocentro), Faculdade de Ciências Médicas, Universidade Estadual de Campinas, Campinas, São Paulo, Brazil
| | | | | | - Liana Codes
- Hospital Universitário Professor Edgard Santos, Universidade Federal da Bahia, Salvador, Bahia, Brazil
- Hospital Português, Salvador, Bahia, Brazil
| | - Valéria Ferreira de Almeida E Borges
- Instituto de Gastroenterologia, Endoscopia e Proctologia, Uberlândia, Minas Gerais, Brazil
- Universidade Federal de Uberlândia, Uberlândia, Minas Gerais, Brazil
| | - Fabio Heleno de Lima Pace
- Serviço de Gastroenterologia e Hepatologia, Universidade Federal de Juiz de Fora, Juiz de Fora, Minas Gerais, Brazil
| | - Mario Guimarães Pessoa
- Departamento de Gastroenterologia, Faculdade de Medicina da Universidade de São Paulo, São Paulo, São Paulo, Brazil
| | - Izabelle Venturini Signorelli
- Hospital Universitário Cassiano Antônio Moraes, Universidade Federal do Espírito Santo, Vitória, Espírito Santo, Brazil
| | - Gabriela Perdomo Coral
- Irmandade da Santa Casa de Misericórdia de Porto Alegre, Porto Alegre, Rio Grande do Sul, Brazil
| | - Paulo Lisboa Bittencourt
- Hospital Português, Salvador, Bahia, Brazil
- Escola Bahiana de Medicina e Saúde Pública, Salvador, Bahia, Brazil
| | - Cynthia Levy
- Division of Digestive Health and Liver Diseases, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Cláudia Alves Couto
- Instituto Alfa de Gastroenterologia, Hospital das Clínicas, Universidade Federal de Minas Gerais, Av. Professor Alfredo Balena 110, Belo Horizonte, Minas Gerais, 30130-100, Brazil
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Early histopathologic changes in primary biliary cholangitis: does 'minimal change' primary biliary cholangitis exist? A pathologist's view. Eur J Gastroenterol Hepatol 2021; 33:e7-e12. [PMID: 32804848 DOI: 10.1097/meg.0000000000001876] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Primary biliary cholangitis (PBC), formerly known as primary biliary cirrhosis, is an autoimmune, slowly progressive, cholestatic liver disease characterized by nonsuppurative destructive cholangitis, and interlobular bile duct destruction. Necroinflammatory activities of the hepatic parenchyma and limiting plates of milder form along with late liver fibrosis may develop. Serum liver tests include elevated serum alkaline phosphatase along with a positive antimitochondrial antibody (AMA) in nearly 95% of patients. Liver biopsies are an important confirmatory and staging tool and are additionally very helpful when AMA is negative. More specifically, the earliest changes in liver biopsy suspicious for PBC can be detected, namely loss of the canals of Hering (CoH), as proposed by various authors recently. CoH loss has been described as an early feature of PBC. We focus on early histologic features of PBC, investigating through the literature the possible role of 'minimal change' supporting the clinical diagnosis of PBC, even in the absence of characteristic granulomatous duct destructive lesions.
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Clinical significance of IgG antimitochondrial M2 antibody levels in primary biliary cholangitis: A single center study from China. PLoS One 2020; 15:e0242164. [PMID: 33180817 PMCID: PMC7661052 DOI: 10.1371/journal.pone.0242164] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2020] [Accepted: 10/27/2020] [Indexed: 11/25/2022] Open
Abstract
Background and objective The relationship between antimitochondrial antibody (AMA) levels and the severity or prognosis of primary biliary cholangitis (PBC) is unclear. This study explored the clinical significance of serum IgG antimitochondrial M2 antibody (IgG-M2) levels. Methods From 2008 to 2017, a retrospective analysis was conducted with PBC patients who had available quantitative values of serum IgG-M2 levels obtained with ELISA based on triple expression hybrid clones. The patients were divided into two groups based on high and low concentrations of IgG-M2. Baseline parameters, the incidence of adverse events, and prognosis were compared. Results Among the 530 PBC patients, the levels of albumin, cholinesterase, hemoglobin, fibrinogen and triglycerides and the red blood cell count were significantly lower in the high-concentration group than in the low-concentration group (n = 263, 49.6%). The red cell distribution width (RDW) and levels of serum immunoglobulin (Ig) G, IgM and IgA were significantly higher in the high-concentration group than in the low-concentration group. Spearman’s correlation analysis suggested that the correlation between the above baseline indicators and IgG-M2 levels was statistically significant but weak (r < 0.2, P < 0.05). In total, 203 patients were followed up, of whom 87 (42.9%) were in the high-concentration group. During the median follow-up period of 52 months (range: 28–75), 121 (59.6%) experienced hepatic decompensation, and 37 (18.2%) died or underwent liver transplantation. There was no significant difference in the incidence of complications or survival (log-rank test: P = 0.079) between the two groups. One year after ursodeoxycholic acid (UDCA) treatment, the two groups had similar responses. In addition, the levels of IgG-M2 did not fluctuate significantly during treatment. Conclusion IgG-M2 levels were not related to the disease severity, prognosis or efficacy of UDCA. The levels of IgG-M2 did not change significantly during treatment.
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Dalekos GN, Gatselis NK. Variant and Specific Forms of Autoimmune Cholestatic Liver Diseases. Arch Immunol Ther Exp (Warsz) 2019; 67:197-211. [PMID: 31165900 DOI: 10.1007/s00005-019-00550-9] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2019] [Accepted: 05/31/2019] [Indexed: 12/12/2022]
Abstract
Primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) are the main autoimmune cholestatic liver diseases. IgG4-associated sclerosing cholangitis is another distinct immune-mediated cholestatic disorder of unknown aetiology that is frequently associated with autoimmune pancreatitis or other IgG4-related diseases. Although the majority of PBC and PSC patients have a typical presentation, there are common and uncommon important variants or specific subgroups that observed in everyday routine clinical practice. In this updated review, we summarize the published data giving also our own experience on the variants and specific groups of autoimmune cholestatic liver diseases. Actually, we give in detail the underlining difficulties and the rising dilemmas concerning the diagnosis and management of these special conditions in the clinical spectrum of autoimmune cholestatic liver diseases including the IgG4-associated sclerosing cholangitis highlighting also the uncertainties and the potential new eras of the research agenda.
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Affiliation(s)
- George N Dalekos
- Institute of Internal Medicine and Hepatology, Larissa, Greece.
- Department of Medicine and Research Laboratory of Internal Medicine, University Hospital of Larissa, 41110, Larissa, Greece.
| | - Nikolaos K Gatselis
- Institute of Internal Medicine and Hepatology, Larissa, Greece
- Department of Medicine and Research Laboratory of Internal Medicine, University Hospital of Larissa, 41110, Larissa, Greece
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Deng CW, Wang L, Fei YY, Hu CJ, Yang YJ, Peng LY, Zeng XF, Zhang FC, Li YZ. Exploring pathogenesis of primary biliary cholangitis by proteomics: A pilot study. World J Gastroenterol 2017; 23:8489-8499. [PMID: 29358857 PMCID: PMC5752709 DOI: 10.3748/wjg.v23.i48.8489] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2017] [Revised: 11/21/2017] [Accepted: 11/28/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To explore the pathogenesis of primary biliary cholangitis (PBC) by identifying candidate autoantibodies in serum samples by proteomics and bioinformatics. METHODS Nine antimitochondrial antibody (AMA)-positive PBC patients and nine age- and sex-matched AMA-negative PBC patients were recruited. Antigen enrichment technology was applied to capture autoantigens of human intrahepatic biliary epithelial cells (HiBECs) that are recognized by autoantibodies from the sera of PBC patients. Candidate autoantigens were identified by label-free mass spectrometry. Bioinformatics analysis with MaxQuant software (version 1.5.2.8), DAVID platform, and Cytoscape v.3.0 allowed illustration of pathways potentially involved in the pathogenesis of PBC. RESULTS In total, 1081 candidate autoantigen proteins were identified from the PBC patient pool. Among them, 371 were determined to be significantly differentially expressed between AMA-positive and -negative PBC patients (P < 0.05). Fisher's exact test was performed for enrichment analysis of Gene Ontology protein annotations (biological processes, cellular components, and molecular functions) and the Kyoto Encyclopedia of Genes and Genomes pathways. Significantly different protein categories were revealed between AMA-positive and -negative PBC patients. As expected, autoantigens related to mitochondria were highly enriched in AMA-positive PBC patients. However, lower levels of AMA were also detected in AMA-negative PBC patients. In addition, autoantigens of AMA-negative PBC patients were mainly involved in B-cell activation, recognition of phagocytosis, and complement activation. CONCLUSION AMA-negative PBC individuals may not exist, but rather, those patients exhibit pathogenesis pathways different from those of AMA-positive PBC. Comprehensive research is needed to confirm these observations.
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Affiliation(s)
- Chui-Wen Deng
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
- Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing 100730, China
| | - Li Wang
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
- Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing 100730, China
| | - Yun-Yun Fei
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
- Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing 100730, China
| | - Chao-Jun Hu
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
- Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing 100730, China
| | - Yun-Jiao Yang
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
- Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing 100730, China
| | - Lin-Yi Peng
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
- Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing 100730, China
| | - Xiao-Feng Zeng
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
- Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing 100730, China
| | - Feng-Chun Zhang
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
- Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing 100730, China
| | - Yong-Zhe Li
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
- Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing 100730, China
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Burman BE, Jhaveri MA, Kowdley KV. An Update on the Treatment and Follow-up of Patients with Primary Biliary Cholangitis. Clin Liver Dis 2017; 21:709-723. [PMID: 28987258 DOI: 10.1016/j.cld.2017.06.005] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Primary biliary cholangitis (PBC) is an autoimmune liver disease characterized by chronic granulomatous lymphocytic cholangitis of the small bile ducts. PBC was a leading indication for liver transplant in the United States; with early diagnosis and treatment, the majority of patients with PBC have a normal life expectancy. Pathogenesis involves inflammatory damage of bile duct epithelium secondary to innate and adaptive immune responses, and toxicity from accumulated bile acids. Cholestasis and disease progression can lead to cirrhosis. Extrahepatic complications include dyslipidemia, metabolic bone disease, and fat-soluble vitamin deficiency. Ursodeoxycholic acid is a well-established therapy. Novel targeted therapeutics are being developed.
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Affiliation(s)
- Blaire E Burman
- Division of Gastroenterology and Hepatology, Virginia Mason Medical Center, 1100 Ninth Avenue, Seattle, WA 98101, USA
| | - Manan A Jhaveri
- Department of Organ Transplant & Liver Center, Liver Care Network and Organ Care Research, Swedish Medical Center, Seattle, 1124 Columbia Street, WA 98101, USA
| | - Kris V Kowdley
- Department of Organ Transplant & Liver Center, Liver Care Network and Organ Care Research, Swedish Medical Center, Seattle, 1124 Columbia Street, WA 98101, USA.
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Minuk GY, Pollock G, Uhanova J. Adult idiopathic cholestasis: a condition more common in the Canadian Inuit? Int J Circumpolar Health 2017; 76:1388104. [PMID: 29034810 PMCID: PMC5645770 DOI: 10.1080/22423982.2017.1388104] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Despite extensive investigations, some patients have no identifiable cause for their cholestatic liver enzyme abnormalities. The aim of this study was to document the clinical, laboratory, radiologic and histologic features of adult patients with idiopathic cholestasis (AIC). A computerised database of referred patients to a tertiary care hospital outpatient department for assessment of hepatobiliary disorders between 2005 and 2015 was employed to identify and describe features associated with AIC. Of 6,560 patient referrals, sufficient documentation to warrant a diagnosis of AIC was present in 17 (0.26%) cases. Of the 17, a disproportionate number were Canadian Inuit (7/60, 12% Inuit referrals vs. 10/6,500, 0.16% non-Inuit referrals, p<0.0001). The median age of the 17 subjects was 57 years and nine (53%) were female. Clinical and/or laboratory evidence of autoimmune disorders was present in six (35%) cases. Clinical features of hepatic decompensation, radiologic findings in keeping with cirrhosis and histologic confirmation of cirrhosis were present in 47%, 31% and 42% of individuals, respectively. There were no significant improvements in cholestatic liver enzymes and function tests in those treated with ursodiol and/or immunomodulants (n=7) compared to those left untreated (n=10). In conclusion, AIC is a rare condition diagnosed by exclusion. It appears to be more common in the Canadian Inuit population and those with autoimmune disorders. Advanced liver disease is a frequent finding at presentation. Intervention with ursodiol and/or immunomodulants does not appear to be of therapeutic value.
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Affiliation(s)
- Gerald Y Minuk
- a Section of Hepatology, Department of Medicine , College of Medicine, University of Manitoba , Winnipeg , Canada.,b Department of Pharmacology and Therapeutics , College of Medicine, University of Manitoba , Winnipeg , Canada
| | - Galia Pollock
- a Section of Hepatology, Department of Medicine , College of Medicine, University of Manitoba , Winnipeg , Canada
| | - Julia Uhanova
- a Section of Hepatology, Department of Medicine , College of Medicine, University of Manitoba , Winnipeg , Canada
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Fan X, Wang T, Shen Y, Xi X, Yang L. Underestimated Male Prevalence of Primary Biliary Cholangitis in China: Results of a 16-yr cohort study involving 769 patients. Sci Rep 2017; 7:6560. [PMID: 28747696 PMCID: PMC5529550 DOI: 10.1038/s41598-017-06807-7] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2017] [Accepted: 06/16/2017] [Indexed: 02/05/2023] Open
Abstract
For primary biliary cholangitis (PBC), a sex ratio was reported to be significantly lower than previously cited in the West; we sought to evaluate sex ratio and long-term outcomes in PBC by studying a PBC cohort at a high-volume hospital from January 2001 to July 2016. A retrospective analysis including 769 PBC patients was conducted. The gender ratio was 6.1:1. Of the patients, 30.6% had one or more extrahepatic autoimmune (EHA) conditions. The proportion of patients with decompensated PBC at diagnosis increased from 25.0% in period 1 to 47.0% in period 4 (p < 0.05). Of the 420 patients without complications on presentation, the Kaplan-Meier estimate revealed distinct outcomes between non-cirrhotic PBC and cirrhotic PBC, with estimated mean survival times of 145.1 months and 104.5 months, respectively (p < 0.001). According to a subgroup analysis, gender and anti-mitochondrial antibody (AMA) status did not affect long-term prognosis, whereas patients with EHA conditions showed better prognoses. This study reveals evolving trends in male prevalence similar to their Western counterparts. Cirrhotic PBC patients were distinct from those with non-cirrhotic PBC at diagnosis based on difference in long-term outcome.
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Affiliation(s)
- Xiaoli Fan
- Division of Gastroenterology & Hepatology, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Tingting Wang
- Division of Gastroenterology & Hepatology, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Yi Shen
- Division of Gastroenterology & Hepatology, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Xiaotan Xi
- Division of Gastroenterology & Hepatology, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Li Yang
- Division of Gastroenterology & Hepatology, West China Hospital, Sichuan University, Chengdu, 610041, China.
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Juliusson G, Imam M, Björnsson ES, Talwalkar JA, Lindor KD. Long-term outcomes in antimitochondrial antibody negative primary biliary cirrhosis. Scand J Gastroenterol 2016; 51:745-52. [PMID: 26776319 DOI: 10.3109/00365521.2015.1132337] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVES Antimitochondrial antibodies (AMA) are a sensitive and specific marker for primary biliary cirrhosis (PBC). AMAs are present in 95% of patients with PBC. However, 5% do not have AMAs and data on these patients is scarce. We aim to evaluate the long-term outcomes of patients with AMA negative PBC. METHODS A retrospective chart review of 71 AMA negative PBC patients. Disease presentation, laboratory results, and clinical endpoints were recorded. AMA negative patients were matched on year of diagnosis to a control group of 71 AMA positive patients. RESULTS Ninety-six percent of the AMA negative patients were of female gender with a median age at diagnosis of 55 years and a length of follow-up of 7.5 years vs. 86% females, a median age of 56 and a follow-up of 8.3 years in the control group. Mean total bilirubin and alkaline phosphatase levels were 0.7 mg/dL vs. 0.6 and 570 U/L vs 341, in AMA negative vs. AMA positive patients at presentation, respectively (p = NS). AMA negative patients did not differ in terms of age, serum IgM levels, ANA status, or length of follow-up. Notably, AMA negative patients had a significantly reduced survival free of liver-related complications including transplantation and death compared to AMA positive patients (p = 0.0182). CONCLUSION In this large experience, AMA negative PBC patients had a significantly worse prognosis compared to AMA positive PBC patients. The reason for the difference in prognosis is unclear, as it may be true difference or reflect delays in case detection among AMA negative patients.
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Affiliation(s)
- Gunnar Juliusson
- a Faculty of Medicine , University of Iceland , Reykjavík , Iceland
| | - Mohamad Imam
- b Division of Gastroenterology and Hepatology , Mayo Clinic , Rochester , MN , USA
| | - Einar S Björnsson
- a Faculty of Medicine , University of Iceland , Reykjavík , Iceland ;,c Department of Gastroenterology and Hepatology , Landspitali University Hospital , Reykjavík , Iceland
| | - Jayant A Talwalkar
- b Division of Gastroenterology and Hepatology , Mayo Clinic , Rochester , MN , USA
| | - Keith D Lindor
- d Arizona State University , College of Health Solutions , Phoenix , AZ , USA
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Ozaslan E, Efe C, Gokbulut Ozaslan N. The diagnosis of antimitochondrial antibody-negative primary biliary cholangitis. Clin Res Hepatol Gastroenterol 2016; 40:553-561. [PMID: 27567165 DOI: 10.1016/j.clinre.2016.06.001] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2016] [Revised: 06/12/2016] [Accepted: 06/23/2016] [Indexed: 02/04/2023]
Abstract
Autoimmune liver diseases are heterogenous disorders that share largely non-specific clinical, serological and pathological features. The correct diagnosis requires discriminative features which are highly specific, for example high-titer antimitochondrial antibodies (AMA) and florid duct lesion in primary biliary cholangitis (PBC). However, the imperfect sensitivities of these characteristic features and abuse of scoring systems led to many artificial diagnoses such as overlap syndromes and outliers for example "autoimmune cholangitis" which is now called as "AMA-negative PBC". Patients lacking detectable AMA (up to 20% in indirect immunofluorescence - IF), but otherwise presenting signs and symptoms of PBC should be regarded as affected by "AMA-negative PBC" because they seem to follow a natural history similar to that of their AMA positive counterparts. The complementary use of IF, ELISA and immunoblotting have disclosed that the majority of patients initially considered AMA-negative are in fact AMA positive. Moreover, the use of PBC-specific ANA's like Gp210 and sp100 have diminished the AMA-negative cases (if truly exists!) to less than 5%. The histological spectrum of PBC includes typical florid duct lesions and/or compatible features such as non-specific hepatitic and biliary findings. In the absence of florid duct lesion and AMA positivity, histology alone cannot differentiate PBC from other biliary disorders. However, the analysis of compatible histological features with the clinical, serological and imaging findings usually points to a specific diagnosis. In this review, we present serological, clinical and pathological pitfalls regarding AMA-negative PBC including illustrative cases and a diagnostic algorithm.
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Affiliation(s)
- Ersan Ozaslan
- Numune Education and Research Hospital, Department of Gastroenterology, Ankara, Turkey.
| | - Cumali Efe
- Batman State Hospital, Department of Gastroenterology, Batman, Turkey
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13
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Abstract
Primary biliary cirrhosis is a chronic cholestatic liver disease characterised by destruction of small intrahepatic bile ducts, leading to fibrosis and potential cirrhosis through resulting complications. The serological hallmark of primary biliary cirrhosis is the antimitochondrial antibody, a highly disease-specific antibody identified in about 95% of patients with primary biliary cirrhosis. These patients usually have fatigue and pruritus, both of which occur independently of disease severity. The typical course of primary biliary cirrhosis has changed substantially with the introduöction of ursodeoxycholic acid (UDCA). Several randomised placebo-controlled studies have shown that UDCA improves transplant-free survival in primary biliary cirrhosis. However, about 40% of patients do not have a biochemical response to UDCA and would benefit from new therapies. Liver transplantation is a life-saving surgery with excellent outcomes for those with decompensated cirrhosis. Meanwhile, research on nuclear receptor hormones has led to the development of exciting new potential treatments. This Seminar will review the current understanding of the epidemiology, pathogenesis, and natural history of primary biliary cirrhosis, discuss management of the disease and its sequelae, and introduce research on new therapeutic options.
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Affiliation(s)
- Elizabeth J Carey
- Division of Gastroenterology and Hepatology, Mayo Clinic, Phoenix, AZ, USA
| | - Ahmad H Ali
- Division of Gastroenterology and Hepatology, Mayo Clinic, Phoenix, AZ, USA
| | - Keith D Lindor
- Division of Gastroenterology and Hepatology, Mayo Clinic, Phoenix, AZ, USA; Arizona State University, College of Health Solutions, Phoenix, AZ, USA.
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14
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Lian JS, Liu W, Hao SR, Chen DY, Wang YY, Yang JL, Jia HY, Huang JR. A serum metabolomic analysis for diagnosis and biomarker discovery of primary biliary cirrhosis and autoimmune hepatitis. Hepatobiliary Pancreat Dis Int 2015; 14:413-21. [PMID: 26256087 DOI: 10.1016/s1499-3872(15)60393-9] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
BACKGROUND Because of the diversity of the clinical and laboratory manifestations, the diagnosis of autoimmune liver disease (AILD) remains a challenge in clinical practice. The value of metabolomics has been studied in the diagnosis of many diseases. The present study aimed to determine whether the metabolic profiles, based on ultraperformance liquid chromatography-mass spectrometry (UPLC-MS), differed between autoimmune hepatitis (AIH) and primary biliary cirrhosis (PBC), to identify specific metabolomic markers, and to establish a model for the diagnosis of AIH and PBC. METHODS Serum samples were collected from 20 patients with PBC, 19 patients with AIH, and 25 healthy individuals. UPLC-MS data of the samples were analyzed using principal component analysis, partial least squares discrimination analysis and orthogonal partial least squares discrimination analysis. RESULTS The partial least squares discrimination analysis model (R2Y=0.991, Q2=0.943) was established between the AIH and PBC groups and exhibited both sensitivity and specificity of 100%. Five groups of biomarkers were identified, including bile acids, free fatty acids, phosphatidylcholines, lysolecithins and sphingomyelin. Bile acids significantly increased in the AIH and PBC groups compared with the healthy control group. The other biomarkers decreased in the AIH and PBC groups compared with those in the healthy control group. In addition, the biomarkers were downregulated in the AIH group compared with the PBC group. CONCLUSIONS The biomarkers identified revealed the pathophysiological changes in AILD and helped to discriminate between AIH and PBC. The predictability of this method suggests its potential application in the diagnosis of AILD.
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Affiliation(s)
- Jiang-Shan Lian
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases; State Key Laboratory for Diagnosis and Treatment of Infectious Disease, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China.
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15
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Purohit T, Cappell MS. Primary biliary cirrhosis: Pathophysiology, clinical presentation and therapy. World J Hepatol 2015; 7:926-941. [PMID: 25954476 PMCID: PMC4419097 DOI: 10.4254/wjh.v7.i7.926] [Citation(s) in RCA: 67] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2014] [Revised: 02/09/2015] [Accepted: 03/05/2015] [Indexed: 02/06/2023] Open
Abstract
Primary biliary cirrhosis (PBC) is an autoimmune, slowly progressive, cholestatic, liver disease characterized by a triad of chronic cholestasis, circulating anti-mitochondrial antibodies (AMA), and characteristic liver biopsy findings of nonsuppurative destructive cholangitis and interlobular bile duct destruction. About 10% of PBC patients, however, lack AMA. A variant, called PBC-autoimmune hepatitis (AIH) overlap, is characterized by the above findings of PBC together with findings of elevated serum alanine aminotransferase, elevated serum immunoglobulin G, and circulating anti-smooth muscle antibodies, with liver biopsy demonstrating periportal or periseptal, lymphocytic, piecemeal necrosis. PBC is hypothesized to be related to environmental exposure in genetically vulnerable individuals. It typically occurs in middle-aged females. Prominent clinical features include fatigue, pruritis, jaundice, xanthomas, osteoporosis, and dyslipidemia. The Mayo Risk score is the most widely used and best prognostic system. Ursodeoxycholic acid is the primary therapy. It works partly by reducing the concentration and injury from relatively toxic bile acids. PBC-AIH overlap syndrome is treated with ursodeoxycholic acid and corticosteroids, especially budesonide. Obeticholic acid and fibrate are promising new, but incompletely tested, therapies. Liver transplantation is the definitive therapy for advanced disease, with about 70% 10-year survival after transplantation. Management of pruritis includes local skin care, dermatologist referral, avoiding potential pruritogens, cholestyramine, and possibly opioid antagonists, sertraline, or rifaximin. Management of osteoporosis includes life-style modifications, administration of calcium and vitamin D, and alendronate. Statins are relatively safe to treat the osteopenia associated with PBC. Associated Sjogren's syndrome is treated by artificial tears, cyclosporine ophthalmic emulsion to stimulate tear production; and saliva substitutes, cholinergic agents, and scrupulous oral and dental care. Complications of cirrhosis from advanced PBC include esophageal varices, ascites, spontaneous bacterial peritonitis, hepatorenal syndrome, and hepatoma formation.
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Affiliation(s)
- Treta Purohit
- Treta Purohit, Mitchell S Cappell, Division of Gastroenterology and Hepatology, William Beaumont Hospital, Royal Oak, MI 48073, United States
| | - Mitchell S Cappell
- Treta Purohit, Mitchell S Cappell, Division of Gastroenterology and Hepatology, William Beaumont Hospital, Royal Oak, MI 48073, United States
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16
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Ali AH, Carey EJ, Lindor KD. Diagnosis and management of primary biliary cirrhosis. Expert Rev Clin Immunol 2014; 10:1667-78. [DOI: 10.1586/1744666x.2014.979792] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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17
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Hagymási K, Tulassay Z. [Review of overlap syndromes in autoimmune liver diseases. Diagnostic and therapeutic difficulties]. Orv Hetil 2013; 154:923-929. [PMID: 23752047 DOI: 10.1556/oh.2013.29640] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Overlap syndromes are biochemical, serological, histological and radiological overlaps across the classic autoimmune liver diseases in the presence of autoimmun hepatitis and primary biliary cirrhosis or primary sclerosing cholangitis. The exact prevalence of the disease is not known, but it may vary between 5% and 20%. Because it has no generally accepted diagnostic criteria, clinical signs, biochemical, serological, radiological and histological findings are evaluated together. Treatment depends on the predominant feature of the overlap syndrome; ursodeoxycholic acid and/or immunsuppressive (corticosteroid) treatment are used, based on observations from retrospective, non-randomized studies.
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Affiliation(s)
- Krisztina Hagymási
- Semmelweis Egyetem, Általános Orvostudományi Kar, II. Belgyógyászati Klinika, Budapest.
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18
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Portmann B, Zen Y. Inflammatory disease of the bile ducts-cholangiopathies: liver biopsy challenge and clinicopathological correlation. Histopathology 2011; 60:236-48. [PMID: 21668470 DOI: 10.1111/j.1365-2559.2011.03853.x] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Liver biopsy challenge and clinicopathological correlation Liver biopsy interpretation in inflammatory diseases of the bile ducts or chronic cholangiopathies may be challenging, especially for pathologists working outside referral centres, where there is a limited exposure to relatively uncommon conditions. In view of the importance of sampling errors resulting from the patchy distribution of pathognomonic bile duct injuries and the misleading absence of cholestasis in the early stages, there is a need to recognize surrogate markers and subtle changes, in particular the early periportal deposition of copper and mild biliary interface activity. Such findings may either constitute the first indication of a primarily biliary disorder or be supportive of a clinically suspected diagnosis. Histological changes common to chronic cholangiopathies are reviewed at the variable stages of development that patients may first present to clinicians. As awareness of the protean clinical manifestations is essential for histological interpretation, the major and distinctive anatomoclinical features of primary biliary cirrhosis and primary and acquired sclerosing cholangitis are revisited, together with so-called overlapping syndromes and less common variants and associations, including more recently documented conditions, such as IgG4-related disease and the rarer multidrug resistance 3 deficiency. The review stresses the importance of evaluating histological changes in conjunction with clinical information.
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Affiliation(s)
- Bernard Portmann
- Institute of Liver Studies, King's College Hospital, London, UK.
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Tanaka A, Ohira H, Kikuchi K, Nezu S, Shibuya A, Bianchi I, Podda M, Invernizzi P, Takikawa H. Genetic association of Fc receptor-like 3 polymorphisms with susceptibility to primary biliary cirrhosis: ethnic comparative study in Japanese and Italian patients. ACTA ACUST UNITED AC 2011; 77:239-43. [PMID: 21299530 DOI: 10.1111/j.1399-0039.2010.01600.x] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
A functional variant in the Fc receptor-like 3 (FCRL3) gene is associated with the susceptibility to several autoimmune diseases. In this study, we examined whether the FCRL3 is associated with susceptibility to primary biliary cirrhosis (PBC) by comparing the two different ethnic groups, Japanese and Italians. We enrolled 232 patients with PBC and 230 controls in Japanese, and 216 PBC and 180 controls in Italians. Minor allele frequency of fcrl3_3 (-169 T>C) in the patients with PBC and controls was 0.20 and 0.09 in Japanese and 0.24 and 0.21 in Italians, respectively. We found a significant association of fcrl3_3 with PBC only in Japanese (P = 9.64 × 10(-7) ). These findings support the presence of common FCRL3-related pathological pathways in several autoimmune diseases, especially in Asians.
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Affiliation(s)
- A Tanaka
- Department of Medicine, Teikyo University School of Medicine, Tokyo, Japan.
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20
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Abstract
Primary biliary cirrhosis (PBC) is a chronic, progressive, cholestatic, organ-specific autoimmune disease of unknown etiology. It predominantly affects middle-aged women, and is characterized by autoimmune-mediated destruction of small- and medium-size intrahepatic bile ducts, portal inflammation and progressive scarring, which without proper treatment can ultimately lead to fibrosis and hepatic failure. Serum autoantibodies are crucial tools for differential diagnosis of PBC. While it is currently accepted that antimitochondrial antibodies are the most important serological markers of PBC, during the last five decades more than sixty autoantibodies have been explored in these patients, some of which had previously been thought to be specific for other autoimmune diseases.
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Juran BD, Atkinson EJ, Larson JJ, Schlicht EM, Liu X, Heathcote EJ, Hirschfield GM, Siminovitch KA, Lazaridis KN. Carriage of a tumor necrosis factor polymorphism amplifies the cytotoxic T-lymphocyte antigen 4 attributed risk of primary biliary cirrhosis: evidence for a gene-gene interaction. Hepatology 2010; 52:223-9. [PMID: 20578265 PMCID: PMC2922843 DOI: 10.1002/hep.23667] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/07/2022]
Abstract
UNLABELLED Common genetic variants significantly influence complex diseases such as primary biliary cirrhosis (PBC). We recently reported an association between PBC and a single nucleotide polymorphism (rs231725) of the immunoreceptor gene cytotoxic T-lymphocyte antigen 4 (CTLA4). We hypothesized that PBC risk attributed to this polymorphism might be increased by propensity to an overly robust inflammatory response. Thus, we examined its potential interaction with the commonly studied -308AG promoter polymorphism (rs1800629) of the tumor necrosis factor (TNF) gene for which the variant TNF2A allele causes increased TNF production. The polymorphisms were genotyped in 866 PBC patients and 761 controls from independent US and Canadian registries; the effects of individual single nucleotide polymorphisms (SNPs) and their interaction on PBC risk was assessed by logistic regression. The reported association of PBC with the CTLA4 "A/A" genotype was replicated in the Canadian cohort and significant for PBC risk in the combined data (odds ratio [OR], 1.68; P = 0.0005). TNF2A allele frequency was elevated in PBC patients, but only reached borderline significance using the combined data (OR, 1.21; P = 0.042). Analysis showed that TNF2A carriage was significantly increased in CTLA4 "A/A" PBC patients compared with CTLA4 "A/A" controls (39.7% versus 16.5%, P = 0.0004); no apparent increase of TNF2A carriage was noted in CTLA4 "A/G" or "G/G" individuals. Finally, interaction under a logistic model was highly significant, as TNF2A carriage in combination with the CTLA4 "A/A" genotype was present in 6.5% of PBC patients, compared with 1.7% of controls (OR, 3.98; P < 0.0001). CONCLUSION TNF2A amplifies the CTLA4 rs231725 "A/A" genotype risk for PBC. Although the mechanisms remain unclear, the premise that deficiency in T-cell regulation resulting in an increased risk of PBC is amplified by overexpression of an important proinflammatory cytokine provides a basis for future functional studies.
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Affiliation(s)
- Brian D. Juran
- Center for Basic Research in Digestive Diseases, Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN
| | | | - Joseph J. Larson
- Division of Biostatistics, Mayo Clinic College of Medicine, Rochester, MN
| | - Erik M. Schlicht
- Center for Basic Research in Digestive Diseases, Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN
| | - Xiangdong Liu
- Mount Sinai Hospital, SLRI, Toronto, Ontario, Canada
| | - E. Jenny Heathcote
- University of Toronto and Liver Center, Toronto Western Hospital, Toronto, Canada
| | | | | | - Konstantinos N. Lazaridis
- Center for Basic Research in Digestive Diseases, Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN
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Silveira MG, Lindor KD. 38-year-old woman with abnormal liver enzymes and hyperlipidemia. Mayo Clin Proc 2009; 84:551-4. [PMID: 19483172 PMCID: PMC2688629 DOI: 10.4065/84.6.551] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/25/2023]
Affiliation(s)
- Marina G Silveira
- Mayo School of Graduate Medical Education, Mayo Clinic, Rochester, MN 55905, USA
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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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