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Chen Y, Chen R, Li H, Shuai Z. Clinical management of autoimmune liver diseases: juncture, opportunities, and challenges ahead. Immunol Res 2025; 73:67. [PMID: 40195209 PMCID: PMC11976385 DOI: 10.1007/s12026-025-09622-9] [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: 11/27/2024] [Accepted: 03/14/2025] [Indexed: 04/09/2025]
Abstract
The three major autoimmune liver diseases are autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), and primary sclerosing cholangitis (PSC).These conditions are assumed to result from a breakdown in immunological tolerance, which leads to an inflammatory process that causes liver damage.The self-attack is started by T-helper cell-mediated identification of liver autoantigens and B-cell production of autoantibodies,and it is maintained by a reduction in the number and activity of regulatory T-cells.Infections and environmental factors have been explored as triggering factors for these conditions, in addition to a genetic predisposition.Allelic mutations in the HLA locus have been linked to vulnerability, as have relationships with single nucleotide polymorphisms in non-HLA genes.Despite the advances in the management of these diseases, there is no curative treatment for these disorders, and a significant number of patients eventually progress to an end-stage liver disease requiring liver transplantation.In this line, tailored immune-therapeutics have emerged as possible treatments to control the disease.In addition, early diagnosis and treatment are pivotal for reducing the long-lasting effects of these conditions and their burden on quality of life.Herein we present a review of the etiology, clinical presentation, diagnosis, and challenges on ALDs and the feasible solutions for these complex diseases.
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MESH Headings
- Humans
- Hepatitis, Autoimmune/therapy
- Hepatitis, Autoimmune/diagnosis
- Hepatitis, Autoimmune/immunology
- Hepatitis, Autoimmune/etiology
- Cholangitis, Sclerosing/therapy
- Cholangitis, Sclerosing/diagnosis
- Cholangitis, Sclerosing/immunology
- Liver Cirrhosis, Biliary/therapy
- Liver Cirrhosis, Biliary/diagnosis
- Liver Cirrhosis, Biliary/immunology
- Animals
- Immunotherapy/methods
- Autoimmune Diseases/therapy
- Autoimmune Diseases/diagnosis
- Disease Management
- Genetic Predisposition to Disease
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Affiliation(s)
- Yangfan Chen
- Department of Rheumatology and Immunology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China
| | - Ruofei Chen
- Department of Rheumatology and Immunology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China
| | - Haiyan Li
- Department of Rheumatology and Immunology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China
| | - Zongwen Shuai
- Department of Rheumatology and Immunology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China.
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, 230032, China.
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Bauer A, Habior A. Antibodies directed against bacterial antigens in sera of Polish patients with primary biliary cholangitis. Front Cell Infect Microbiol 2025; 14:1410282. [PMID: 39844835 PMCID: PMC11752878 DOI: 10.3389/fcimb.2024.1410282] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2024] [Accepted: 12/04/2024] [Indexed: 01/24/2025] Open
Abstract
Background Primary biliary cholangitis (PBC) is a cholestatic, autoimmune liver disease with the presence of characteristic autoantibodies. The aim of the work was to determine the level of antibodies directed against bacterial antigens: Chlamydia pneumoniae (anti-Cpn), Yersinia enterolitica (anti-Y.e), Helicobacter pylori (anti-Hp), Mycoplasma pneumoniae (anti- Mp.) and Escherichia coli (E.coli) in sera of PBC patients. We also performed in vitro studies on the impact of the bacterial peptides on the specific antigen-antibody binding. Method We screened 92 Polish PBC patients and sera samples from healthy donors and pathological controls. Autoantibodies and anti-bacterial antibodies were determined by commercially available ELISA kits. Specific inhibition of antibody binding was also detected by the in house ELISA method. Results Anti-Cpn, anti-Y. enterolitica, anti-Hp, anti-M. pneumoniae and anti-E. coli antibodies were significantly more common in the group of PBC patients than in the pathological and healthy control groups: 74%, 40%, 84%, 39% and 69% respectively. The mean level of anti-Cpn, anti- Y.e, anti-Hp and anti- M.p in the PBC group was significantly higher than those in the healthy group (p < 0.001). and in patients with other liver diseases. In sera of patients with the presence of positive anti-mitochondrial antibodies (AMA), specific for PBC, anti-bacterial antibodies have been found in 80% vs. 50% in sera with AMA negative. We observed inhibition of specific antigen-antibody binding by the bacterial peptide: EClpP (E. coli caseinolytic protease) and adenine glycosylase from E. coli caseinolytic protease P, ClpP Y.e from peptide of Y. enterolitica, Mp PDC from M. pneumonia peptide and adenine glycosylase of E. coli. Bacterial factors influence the specific binding of antibodies to pyruvate dehydrogenase (PDC-E2), gp210 and KLHL12 (kelch-like peptide 12) antigens. Conclusion Microbial mimics may be the major targets of cross-reactivity with human pyruvate dehydrogenase, gp210, and KLHL12 in PBC.
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Affiliation(s)
- Alicja Bauer
- Department of Biochemistry and Molecular Biology, Centre of Postgraduate Medical Education, Warsaw, Poland
| | - Andrzej Habior
- Clinic of Polish Gastroenterology Foundation, Warsaw, Poland
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Zhou S, Li J, Liu J, Dong S, Chen N, Ran Y, Liu H, Wang X, Yang H, Liu M, Chu H, Wang B, Li Y, Guo L, Zhou L. Depressive symptom as a risk factor for cirrhosis in patients with primary biliary cholangitis: Analysis based on Lasso-logistic regression and decision tree models. Brain Behav 2024; 14:e3639. [PMID: 39099389 PMCID: PMC11298689 DOI: 10.1002/brb3.3639] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2023] [Revised: 05/06/2024] [Accepted: 07/09/2024] [Indexed: 08/06/2024] Open
Abstract
BACKGROUND Depressive symptoms are frequently observed in patients with primary biliary cholangitis (PBC). The role of depressive symptoms on cirrhosis has not been fully noticed in PBC. We aimed to establish a risk model for cirrhosis that took depressive symptoms into account. METHODS Depressive symptoms were assessed by the 17-item Hamilton Depression Rating Scale (HAMD-17). HAMD-17 score was analyzed in relation to clinical parameters. Least absolute shrinkage and selection operator (Lasso)-logistic regression and decision tree models were used to explore the effect of depressive symptoms on cirrhosis. RESULTS The rate of depressive symptom in patients with PBC (n = 162) was higher than in healthy controls (n = 180) (52.5% vs. 16.1%; p < .001). HAMD-17 score was negatively associated with C4 levels and positively associated with levels of alkaline phosphatase (ALP), γ-glutamyl transpeptidase (GGT), total bilirubin (TB), Immunoglobulin (Ig) G, and IgM (r = -0.162, 0.197, 0.355, 0.203, 0.182, 0.314, p < .05). In Lasso-logistic regression analysis, HAMD-17 score, human leukocyte antigen (HLA)-DRB1*03:01 allele, age, ALP levels, and IgM levels (odds ratio [OR] = 1.087, 7.353, 1.075, 1.009, 1.005; p < 0.05) were independent risk factors for cirrhosis. Elevated HAMD-17 score was also a discriminating factor for high risk of cirrhosis in patients with PBC in decision tree model. CONCLUSIONS Depressive symptoms were associated with disease severity. Elevated HAMD-17 score was a risk factor for cirrhosis in patients with PBC.
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Affiliation(s)
- Simin Zhou
- Department of Gastroenterology and Hepatology, General HospitalTianjin Medical UniversityTianjinChina
| | - Jiwen Li
- Department of Gastroenterology and Hepatology, General HospitalTianjin Medical UniversityTianjinChina
| | - Jiangpeng Liu
- Department of Gastroenterology and Hepatology, General HospitalTianjin Medical UniversityTianjinChina
| | - Shijing Dong
- Department of Gastroenterology and Hepatology, General HospitalTianjin Medical UniversityTianjinChina
| | - Nian Chen
- Department of Gastroenterology and Hepatology, General HospitalTianjin Medical UniversityTianjinChina
| | - Ying Ran
- Department of Gastroenterology and Hepatology, General HospitalTianjin Medical UniversityTianjinChina
| | - Haifeng Liu
- Department of Gastroenterology and Hepatology, General HospitalTianjin Medical UniversityTianjinChina
| | - Xiaoyi Wang
- Department of Gastroenterology and Hepatology, General HospitalTianjin Medical UniversityTianjinChina
| | - Hui Yang
- Department of Gastroenterology and Hepatology, General HospitalTianjin Medical UniversityTianjinChina
| | - Man Liu
- Department of Gastroenterology and Hepatology, General HospitalTianjin Medical UniversityTianjinChina
| | - Hongyu Chu
- Department of Gastroenterology and Hepatology, General HospitalTianjin Medical UniversityTianjinChina
| | - Bangmao Wang
- Department of Gastroenterology and Hepatology, General HospitalTianjin Medical UniversityTianjinChina
| | - Yanni Li
- Department of Gastroenterology and Hepatology, General HospitalTianjin Medical UniversityTianjinChina
| | - Liping Guo
- Department of Gastroenterology and Hepatology, General HospitalTianjin Medical UniversityTianjinChina
| | - Lu Zhou
- Department of Gastroenterology and Hepatology, General HospitalTianjin Medical UniversityTianjinChina
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Mihai IR, Rezus C, Burlui MA, Cardoneanu A, Macovei LA, Richter P, Bratoiu I, Rezus E. Autoimmune Liver Diseases and Rheumatoid Arthritis-Is There an Etiopathogenic Link? Int J Mol Sci 2024; 25:3848. [PMID: 38612658 PMCID: PMC11011907 DOI: 10.3390/ijms25073848] [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: 02/07/2024] [Revised: 02/28/2024] [Accepted: 03/23/2024] [Indexed: 04/14/2024] Open
Abstract
Rheumatoid arthritis (RA) is a systemic immune-mediated disease that, in addition to the articular involvement, can have extra-articular manifestations. Even though liver damage in RA is not very common, associated autoimmune liver diseases (AILDs) may occur. The most common AILD associated with RA is primary biliary cirrhosis (PBC), followed by autoimmune hepatitis (AIH) and primary sclerosing cholangitis (PSC). There are common underlying mechanisms that play a role in the emergence of autoimmunity and inflammation in both rheumatic and autoimmune liver diseases. Genetic studies have revealed the existence of several common disease-associated genes shared between RA and AILDs, and infectious triggers, particularly those associated with recurrent or complicated urinary tract infections, are also speculated to be potential triggers for these conditions. Moreover, these diseases share common serologic patterns characterized by the presence of specific autoantibodies and hyper-gammaglobulinemia. In this study, we focus on reviewing the association between RA and AILDs regarding the prevalence and possible etiopathogenic link.
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Affiliation(s)
- Ioana Ruxandra Mihai
- Department of Rheumatology, Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania (L.A.M.); (E.R.)
- Clinical Rehabilitation Hospital, 700661 Iasi, Romania
| | - Ciprian Rezus
- Department of Internal Medicine, Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania
- “Sfantul Spiridon” Emergency Hospital, 700111 Iasi, Romania
| | - Maria Alexandra Burlui
- Department of Rheumatology, Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania (L.A.M.); (E.R.)
- Clinical Rehabilitation Hospital, 700661 Iasi, Romania
| | - Anca Cardoneanu
- Department of Rheumatology, Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania (L.A.M.); (E.R.)
- Clinical Rehabilitation Hospital, 700661 Iasi, Romania
| | - Luana Andreea Macovei
- Department of Rheumatology, Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania (L.A.M.); (E.R.)
- Clinical Rehabilitation Hospital, 700661 Iasi, Romania
| | - Patricia Richter
- Department of Rheumatology, Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania (L.A.M.); (E.R.)
- Clinical Rehabilitation Hospital, 700661 Iasi, Romania
| | - Ioana Bratoiu
- Department of Rheumatology, Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania (L.A.M.); (E.R.)
- Clinical Rehabilitation Hospital, 700661 Iasi, Romania
| | - Elena Rezus
- Department of Rheumatology, Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania (L.A.M.); (E.R.)
- Clinical Rehabilitation Hospital, 700661 Iasi, Romania
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Floreani A, Gabbia D, De Martin S. Current Perspectives on the Molecular and Clinical Relationships between Primary Biliary Cholangitis and Hepatocellular Carcinoma. Int J Mol Sci 2024; 25:2194. [PMID: 38396870 PMCID: PMC10888596 DOI: 10.3390/ijms25042194] [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: 01/18/2024] [Revised: 02/07/2024] [Accepted: 02/09/2024] [Indexed: 02/25/2024] Open
Abstract
Primary biliary cholangitis (PBC) is an autoimmune liver disease characterised by the immune-mediated destruction of small and medium intrahepatic bile ducts, with variable outcomes and progression. This review summarises the state of the art regarding the risk of neoplastic progression in PBC patients, with a particular focus on the molecular alterations present in PBC and in hepatocellular carcinoma (HCC), which is the most frequent liver cancer in these patients. Major risk factors are male gender, viral infections, e.g., HBV and HCV, non-response to UDCA, and high alcohol intake, as well as some metabolic-associated factors. Overall, HCC development is significantly more frequent in patients with advanced histological stages, being related to liver cirrhosis. It seems to be of fundamental importance to unravel eventual dysfunctional molecular pathways in PBC patients that may be used as biomarkers for HCC development. In the near future, this will possibly take advantage of artificial intelligence-designed algorithms.
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Affiliation(s)
- Annarosa Floreani
- University of Padova, 35122 Padova, Italy;
- Scientific Consultant IRCCS Negrar, 37024 Verona, Italy
| | - Daniela Gabbia
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, 35131 Padova, Italy;
| | - Sara De Martin
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, 35131 Padova, Italy;
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Villani R, Serviddio G, Avolio C, Cassano T, D'Amico E. Autoimmune liver disease and multiple sclerosis: state of the art and future perspectives. Clin Exp Med 2023; 23:3321-3338. [PMID: 37421590 PMCID: PMC10618321 DOI: 10.1007/s10238-023-01128-8] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2022] [Accepted: 06/23/2023] [Indexed: 07/10/2023]
Abstract
Clinical observations suggest that the prevalence of autoimmune diseases is changing over time. Both autoimmune liver diseases and multiple sclerosis have shown a significant increase in the last decades. Although the coexistence of autoimmune diseases within individuals and families is a common phenomenon, the extent to which liver disease and multiple sclerosis co-occur is not clear. Case reports and few studies have reported the possible coexistence of multiple sclerosis with thyroid diseases, inflammatory bowel disease, psoriasis, and rheumatoid arthritis. It is unknown whether there is a definite association between multiple sclerosis and autoimmune liver diseases. We reviewed the literature to summarize the available studies on the association between different autoimmune liver diseases (autoimmune hepatitis, primary biliary cholangitis, and primary sclerosing cholangitis) and treated or untreated multiple sclerosis.
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Affiliation(s)
- Rosanna Villani
- Liver Unit, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy.
| | - Gaetano Serviddio
- Liver Unit, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | - Carlo Avolio
- Department of Medical and Surgical Sciences, Multiple Sclerosis Center, University of Foggia, Foggia, Italy
| | - Tommaso Cassano
- Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | - Emanuele D'Amico
- Department of Medical and Surgical Sciences, Multiple Sclerosis Center, University of Foggia, Foggia, Italy
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7
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Zhao J, Li K, Liao X, Zhao Q. Causal associations between inflammatory bowel disease and primary biliary cholangitis: a two-sample bidirectional Mendelian randomization study. Sci Rep 2023; 13:10950. [PMID: 37414807 PMCID: PMC10326252 DOI: 10.1038/s41598-023-35785-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2023] [Accepted: 05/23/2023] [Indexed: 07/08/2023] Open
Abstract
Inflammatory bowel disease (IBD) has been reported to be associated with hepatobiliary diseases. Previous observational and Mendelian randomization (MR) studies have suggested a causal association between IBD and primary sclerosing cholangitis (PSC). However, it is unclear whether IBD has a causal association with primary biliary cholangitis (PBC): another autoimmune liver disease. We obtained genome-wide association study (GWAS) statistics from published GWASs for PBC, UC, and CD. We screened qualified instrumental variables (IVs) based on the three major assumptions of MR. To determine the causal relationships between UC or CD and PBC, two-sample MR analyses were performed using inverse variance-weighted (IVW), MR-Egger, and weighted median (WM) methods, and sensitivity analyses were conducted to validate the robustness of the results. We also conducted reverse MR analysis to reveal the causal association between PBC and UC or CD. UC was associated with a higher risk of PBC (OR 1.35, 95% CI 1.05-1.73, P = 0.02) in the IVW method, and CD was associated with an increased risk of PBC (OR 1.18, 95% CI 1.03-1.36, P = 0.02) in IVW. The weighted median and MR-Egger regression of both diseases showed a consistent direction but were not statistically significant. Results of the reverse MR analysis did not suggest genetic susceptibility that PBC was associated with an increased risk of UC (OR 1.05, 95% CI 0.95-1.17, P = 0.34) or CD (OR 1.1, 95% CI 0.99-1.20, P = 0.06). The present study revealed that IBD subtypes could increase the incidence of PBC, but in turn, PBC did not increase the incidence of IBD subtypes. Understanding that IBD and PBC constitute mutual risk factors can help with the clinical management of both diseases.
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Affiliation(s)
- Jiaxi Zhao
- Department of General Practice, General Practice Medical Center, West China Hospital, West China School of Medicine, Sichuan University, Chengdu, Sichuan, China
| | - Kaixin Li
- Huadong Hospital Affiliated to Fudan University, Shanghai, 200040, China
| | - Xiaoyang Liao
- Department of General Practice, General Practice Medical Center, West China Hospital, West China School of Medicine, Sichuan University, Chengdu, Sichuan, China
| | - Qian Zhao
- Department of General Practice, General Practice Medical Center, West China Hospital, West China School of Medicine, Sichuan University, Chengdu, Sichuan, China.
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Khor SS, Ueno K, Nishida N, Kawashima M, Kawai Y, Aiba Y, Hitomi Y, Nagasaki M, Nakamura M, Tokunaga K. Novel HLA allele associations with susceptibility, staging, symptomatic state, autoimmune hepatitis and hepatocellular carcinoma events for primary biliary cholangitis in the Japanese population. Front Immunol 2023; 14:1151502. [PMID: 37325616 PMCID: PMC10264690 DOI: 10.3389/fimmu.2023.1151502] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2023] [Accepted: 05/18/2023] [Indexed: 06/17/2023] Open
Abstract
Primary biliary cholangitis (PBC) is a rare autoimmune disease with a clear predisposition for human leukocyte antigen (HLA)-DR/DQ-associated loss of immune tolerance for the E2 component of the pyruvate dehydrogenase complex. Three-field-resolution HLA imputation of 1,670 Japanese PBC patients and 2,328 healthy controls was conducted using Japanese population-specific HLA reference panels. Eighteen previously reported Japanese PBC-associated HLA alleles were confirmed and extended to 3-field-resolution, including HLA-DRB1*08:03 to HLA-DRB1*08:03:02, HLA-DQB1*03:01 to HLA-DQB1*03:01:01, HLA-DQB1*04:01 to HLA-DQB1*04:01:01 and HLA-DQB1*06:04 to HLA-DQB1*06:04:01. In addition, additional significant novel HLA alleles were identified, including 3 novel susceptible HLA-DQA1 alleles: HLA-DQA1*03:03:01, HLA-DQA1*04:01:01, HLA-DQA1*01:04:01 and 1 novel protective HLA-DQA1 allele, HLA-DQA1*05:05:01. In addition, PBC patients carrying HLA-DRB1*15:01:01 and HLA-DQA1*03:03:01 would have a higher predisposition toward developing concomitant autoimmune hepatitis (AIH). Further, late-stage and symptomatic PBC shared the same susceptible HLA alleles of HLA-A*26:01:01, HLA-DRB1*09:01:02 and HLA-DQB1*03:03:02. Lastly, HLA-DPB1*05:01:01 was identified as a potential risk HLA allele for development of hepatocellular carcinoma (HCC) in PBC patients. In conclusion, we have extended the current knowledge of HLA allele associations to 3-field resolution and identified novel HLA allele associations with predisposition risk, staging, symptomatic state, and AIH and HCC events for Japanese PBC patients.
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Affiliation(s)
- Seik-Soon Khor
- Genome Medical Science Project, National Center for Global Health and Medicine, Tokyo, Japan
| | - Kazuko Ueno
- Genome Medical Science Project, National Center for Global Health and Medicine, Tokyo, Japan
| | - Nao Nishida
- Genome Medical Science Project, National Center for Global Health and Medicine, Tokyo, Japan
- The Research Center for Hepatitis and Immunology, Research Institute, National Center for Global Health and Medicine, Ichikawa, Japan
| | - Minae Kawashima
- Database Center for Life Science (DBCLS), Research Organization of Information and Systems, Chiba, Japan
| | - Yosuke Kawai
- Genome Medical Science Project, National Center for Global Health and Medicine, Tokyo, Japan
| | - Yoshihiro Aiba
- Clinical Research Center, National Hospital Organization (NHO) Nagasaki Medical Center, Omura, Japan
| | - Yuki Hitomi
- Department of Human Genetics, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan
| | - Masao Nagasaki
- Medical Research Center for High Depth Omics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan
- Center for Genomic Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Minoru Nakamura
- Clinical Research Center, National Hospital Organization (NHO) Nagasaki Medical Center, Omura, Japan
- Department of Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Omura, Japan
- Headquarters of Primary Biliary Cholangitis (PBC) Research in NHO Study Group for Liver Disease in Japan (NHOSLJ), Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
| | - Katsushi Tokunaga
- Genome Medical Science Project, National Center for Global Health and Medicine, Tokyo, Japan
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Yamashita Y, Umemura T, Kimura T, Joshita S, Hirohara J, Nakano T, Komori A, Tanaka A. Prognostic utility of albumin-bilirubin grade in Japanese patients with primary biliary cholangitis. JHEP Rep 2023; 5:100662. [PMID: 36873419 PMCID: PMC9976453 DOI: 10.1016/j.jhepr.2022.100662] [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: 08/18/2022] [Revised: 12/07/2022] [Accepted: 12/09/2022] [Indexed: 12/26/2022] Open
Abstract
Background & Aims The albumin-bilirubin (ALBI) score is calculated using serum levels of total bilirubin and albumin as a simple method to assess liver function. This study investigated the ability of baseline ALBI score/grade measurements to assess histological stage and disease progression in individuals with primary biliary cholangitis (PBC) in a large Japanese nationwide cohort. Methods A total of 8,768 Japanese patients with PBC were enrolled between 1980 and 2016 from 469 institutions, among whom 83% received ursodeoxycholic acid (UDCA) only, 9% received UDCA and bezafibrate, and 8% were given neither drug. Baseline clinical and laboratory parameters were retrospectively retrieved and reviewed from a central database. Associations of ALBI score/grade with histological stage, mortality, and need for liver transplantation (LT) were evaluated using Cox proportional hazards models. Results During the median follow-up period of 5.3 years, 1,227 patients died (including 789 from liver-related causes) and 113 underwent LT. ALBI score and ALBI grade were significantly associated with Scheuer's classification (both p <0.0001). ALBI grade 2 or 3 had significant associations with all-cause mortality or need for LT as well as liver-related mortality or need for LT according to Cox proportional hazards regression analysis (hazard ratio 3.453, 95% CI 2.942-4.052 and hazard ratio 4.242, 95% CI 3.421-5.260, respectively; both p <0.0001). Cumulative LT-free survival rates at 5 years in the ALBI grade 1, 2, and 3 groups were 97.2%, 82.4%, and 38.8%, respectively, while respective non-liver-related survival rates were 98.1%, 86.0%, and 42.0% (both p <0.0001, log-rank test). Conclusions This large nationwide study of patients with PBC suggested that baseline measurements of ALBI grade were a simple non-invasive predictor of prognosis in PBC. Impact and implications Primary biliary cholangitis (PBC) is an autoimmune liver disease characterized by progressive destruction of intrahepatic bile ducts. This study examined the ability of albumin-bilirubin (ALBI) score/grade to estimate histological findings and disease progression in PBC by means of a large-scale nationwide cohort in Japan. ALBI score/grade were significantly associated with Scheuer's classification stage. Baseline ALBI grade measurements may be a simple non-invasive predictor of prognosis in PBC.
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Key Words
- ALBI, albumin-bilirubin
- ALP, alkaline phosphatase
- AMA, anti-mitochondrial autoantibody
- AUC, area under the ROC curve
- BZF, bezafibrate
- HR, hazard ratio
- LSM, liver stiffness measurement
- LT, liver transplantation
- M2BPGi, Mac-2-binding protein glycosylation isomer
- PBC, primary biliary cholangitis
- Prognosis
- ROC, receiver-operating characteristic
- Transplantation
- UDCA, ursodeoxycholic acid
- ULN, upper limit of normal
- Ursodeoxycholic acid
- pc, corrected p
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Affiliation(s)
- Yuki Yamashita
- Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Takeji Umemura
- Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, Matsumoto, Japan.,Consultation Center for Liver Diseases, Shinshu University Hospital, Matsumoto, Japan
| | - Takefumi Kimura
- Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Satoru Joshita
- Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Junko Hirohara
- The Third Department of Internal Medicine, Kansai Medical University, Osaka, Japan
| | - Toshiaki Nakano
- The Third Department of Internal Medicine, Kansai Medical University, Osaka, Japan
| | - Atsumasa Komori
- Clinical Research Center, National Hospital Organization (NHO) Nagasaki Medical Center, Nagasaki, Japan
| | - Atsushi Tanaka
- Department of Medicine, Teikyo University School of Medicine, Tokyo, Japan
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10
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Hitomi Y, Nakamura M. The Genetics of Primary Biliary Cholangitis: A GWAS and Post-GWAS Update. Genes (Basel) 2023; 14:405. [PMID: 36833332 PMCID: PMC9957238 DOI: 10.3390/genes14020405] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Revised: 01/27/2023] [Accepted: 02/01/2023] [Indexed: 02/09/2023] Open
Abstract
Primary biliary cholangitis (PBC) is a chronic, progressive cholestatic liver disease in which the small intrahepatic bile ducts are destroyed by autoimmune reactions. Among autoimmune diseases, which are polygenic complex traits caused by the combined contribution of genetic and environmental factors, PBC exhibits the strongest involvement of genetic heritability in disease development. As at December 2022, genome-wide association studies (GWASs) and associated meta-analyses identified approximately 70 PBC susceptibility gene loci in various populations, including those of European and East Asian descent. However, the molecular mechanisms through which these susceptibility loci affect the pathogenesis of PBC are not fully understood. This study provides an overview of current data regarding the genetic factors of PBC as well as post-GWAS approaches to identifying primary functional variants and effector genes in disease-susceptibility loci. Possible mechanisms of these genetic factors in the development of PBC are also discussed, focusing on four major disease pathways identified by in silico gene set analyses, namely, (1) antigen presentation by human leukocyte antigens, (2) interleukin-12-related pathways, (3) cellular responses to tumor necrosis factor, and (4) B cell activation, maturation, and differentiation pathways.
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Affiliation(s)
- Yuki Hitomi
- Department of Human Genetics, Research Institute, National Center for Global Health and Medicine, 1-21-1 Toyama, Shinjuku-ku, Tokyo 162-8655, Japan
| | - Minoru Nakamura
- Clinical Research Center, National Hospital Organization (NHO) Nagasaki Medical Center, 2-1001-1 Kubara, Omura 856-8562, Japan
- Department of Hepatology, Nagasaki University Graduate School of Biomedical Sciences, 2-1001-1 Kubara, Omura 856-8562, Japan
- Headquarters of PBC Research in NHO Study Group for Liver Disease in Japan (NHOSLJ), Clinical Research Center, National Hospital Organization (NHO) Nagasaki Medical Center, 2-1001-1 Kubara, Omura 856-8562, Japan
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11
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Abstract
Primary biliary cholangitis (PBC) is a cholestatic liver disease with potential evolution to liver cirrhosis when left untreated. Despite being rare, PBC has a substantial impact on the quality of life and survival of affected patients. Women are the most diagnosed worldwide; however, male subjects seem to have more aggressive disease and worse prognosis. Changing epidemiologic trends are emerging in PBC, with increasing global prevalence and slight smoothing of sex differences. In this review we present available data on incidence rates and prevalence of PBC worldwide, highlighting geographic differences and factors impacting clinical outcomes.
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Affiliation(s)
- Francesca Colapietro
- Division of Internal Medicine and Hepatology, Department of Gastroenterology, IRCCS Humanitas Research Hospital, Via A. Manzoni 56, Rozzano 20089, Italy; Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy
| | - Arianna Bertazzoni
- Division of Internal Medicine and Hepatology, Department of Gastroenterology, IRCCS Humanitas Research Hospital, Via A. Manzoni 56, Rozzano 20089, Italy; Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy
| | - Ana Lleo
- Division of Internal Medicine and Hepatology, Department of Gastroenterology, IRCCS Humanitas Research Hospital, Via A. Manzoni 56, Rozzano 20089, Italy; Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy.
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12
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Mulinacci G, Palermo A, Gerussi A, Asselta R, Gershwin ME, Invernizzi P. New insights on the role of human leukocyte antigen complex in primary biliary cholangitis. Front Immunol 2022; 13:975115. [PMID: 36119102 PMCID: PMC9471323 DOI: 10.3389/fimmu.2022.975115] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2022] [Accepted: 08/11/2022] [Indexed: 01/04/2023] Open
Abstract
Primary Biliary Cholangitis (PBC) is a rare autoimmune cholangiopathy. Genetic studies have shown that the strongest statistical association with PBC has been mapped in the human leukocyte antigen (HLA) locus, a highly polymorphic area that mostly contribute to the genetic variance of the disease. Furthermore, PBC presents high variability throughout different population groups, which may explain the different geoepidemiology of the disease. A major role in defining HLA genetic contribution has been given by genome-wide association studies (GWAS) studies; more recently, new technologies have been developed to allow a deeper understanding. The study of the altered peptides transcribed by genetic alterations also allowed the development of novel therapeutic strategies in the context of immunotolerance. This review summarizes what is known about the immunogenetics of PBC with a focus on the HLA locus, the different distribution of HLA alleles worldwide, and how HLA modifications are associated with the pathogenesis of PBC. Novel therapeutic strategies are also outlined.
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Affiliation(s)
- Giacomo Mulinacci
- Division of Gastroenterology, Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, Monza, Italy
| | - Andrea Palermo
- Division of Gastroenterology, Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, Monza, Italy
| | - Alessio Gerussi
- Division of Gastroenterology, Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, Monza, Italy
| | - Rosanna Asselta
- Department of Biomedical Sciences, Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS) Humanitas Research Hospital, Milan, Italy
- Department of Biomedical Sciences, Humanitas University, Milan, Italy
| | - Merrill Eric Gershwin
- Division of Rheumatology, Allergy and Clinical Immunology, University of California, Davis, Davis, CA, United States
| | - Pietro Invernizzi
- Division of Gastroenterology, Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, Monza, Italy
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13
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Terziroli Beretta-Piccoli B, Mieli-Vergani G, Vergani D. HLA, gut microbiome and hepatic autoimmunity. Front Immunol 2022; 13:980768. [PMID: 36059527 PMCID: PMC9433828 DOI: 10.3389/fimmu.2022.980768] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Accepted: 07/25/2022] [Indexed: 12/12/2022] Open
Abstract
Genetic susceptibility to autoimmune liver diseases is conferred mainly by polymorphisms of genes encoding for the human leukocyte antigens (HLA). The strongest predisposition to autoimmune hepatitis type 1 (AIH-1) is linked to the allele DRB1*03:01, possession of which is associated with earlier disease onset and more severe course. In populations where this allele is very rare, such as in Asia, and in DRB1*03-negative patients, risk of AIH-1 is conferred by DRB1*04, which is associated with later disease onset and milder phenotype. AIH type 2 (AIH-2) is associated with DRB1*07. The pediatric condition referred to as autoimmune sclerosing cholangitis (ASC), is associated with the DRB1*13 in populations of Northern European ancestry. DRB1*1501 is protective from AIH-1, AIH-2 and ASC in Northern European populations. Possession of the DRB1*08 allele is associated with an increased risk of primary biliary cholangitis (PBC) across different populations. DRB1*03:01 and B*08:01 confer susceptibility to primary sclerosing cholangitis (PSC), as well as DRB1*13 and DRB1*15 in Europe. The hepatic blood supply is largely derived from the splanchnic circulation, suggesting a pathophysiological role of the gut microbiome. AIH appears to be associated with dysbiosis, increased gut permeability, and translocation of intestinal microbial products into the circulation; molecular mimicry between microbial and host antigens may trigger an autoaggressive response in genetically-predisposed individuals. In PBC an altered enteric microbiome may affect intestinal motility, immunological function and bile secretion. Patients with PSC have a gut microbial profile different from health as well as from patients with inflammatory bowel disease without PSC.
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Affiliation(s)
- Benedetta Terziroli Beretta-Piccoli
- Faculty of Biomedical Sciences, Epatocentro Ticino and Università della Svizzera Italiana, Lugano, Switzerland
- MowatLabs, Faculty of Life Sciences and Medicine, King’s College London, King’s College Hospital, London, United Kingdom
- *Correspondence: Benedetta Terziroli Beretta-Piccoli,
| | - Giorgina Mieli-Vergani
- MowatLabs, Faculty of Life Sciences and Medicine, King’s College London, King’s College Hospital, London, United Kingdom
| | - Diego Vergani
- MowatLabs, Faculty of Life Sciences and Medicine, King’s College London, King’s College Hospital, London, United Kingdom
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Park JW, Kim JH, Kim SE, Jung JH, Jang MK, Park SH, Lee MS, Kim HS, Suk KT, Kim DJ. Primary Biliary Cholangitis and Primary Sclerosing Cholangitis: Current Knowledge of Pathogenesis and Therapeutics. Biomedicines 2022; 10:1288. [PMID: 35740310 PMCID: PMC9220082 DOI: 10.3390/biomedicines10061288] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Revised: 05/24/2022] [Accepted: 05/28/2022] [Indexed: 02/07/2023] Open
Abstract
Cholangiopathies encompass various biliary diseases affecting the biliary epithelium, resulting in cholestasis, inflammation, fibrosis, and ultimately liver cirrhosis. Primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) are the most important progressive cholangiopathies in adults. Much research has broadened the scope of disease biology to genetic risk, epigenetic changes, dysregulated mucosal immunity, altered biliary epithelial cell function, and dysbiosis, all of which interact and arise in the context of ill-defined environmental triggers. An in-depth understanding of the molecular pathogenesis of these cholestatic diseases will help clinicians better prevent and treat diseases. In this review, we focus on the main underlying mechanisms of disease initiation and progression, and novel targeted therapeutics beyond currently approved treatments.
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Affiliation(s)
- Ji-Won Park
- Department of Internal Medicine, College of Medicine, Hallym University, Chuncheon-si 24252, Korea; (J.-W.P.); (J.-H.K.); (S.-E.K.); (J.H.J.); (M.-K.J.); (S.-H.P.); (M.-S.L.); (H.-S.K.); (K.T.S.)
- Institute for Liver and Digestive Diseases, Hallym University, Chuncheon 200-010, Korea
| | - Jung-Hee Kim
- Department of Internal Medicine, College of Medicine, Hallym University, Chuncheon-si 24252, Korea; (J.-W.P.); (J.-H.K.); (S.-E.K.); (J.H.J.); (M.-K.J.); (S.-H.P.); (M.-S.L.); (H.-S.K.); (K.T.S.)
- Institute for Liver and Digestive Diseases, Hallym University, Chuncheon 200-010, Korea
| | - Sung-Eun Kim
- Department of Internal Medicine, College of Medicine, Hallym University, Chuncheon-si 24252, Korea; (J.-W.P.); (J.-H.K.); (S.-E.K.); (J.H.J.); (M.-K.J.); (S.-H.P.); (M.-S.L.); (H.-S.K.); (K.T.S.)
- Institute for Liver and Digestive Diseases, Hallym University, Chuncheon 200-010, Korea
| | - Jang Han Jung
- Department of Internal Medicine, College of Medicine, Hallym University, Chuncheon-si 24252, Korea; (J.-W.P.); (J.-H.K.); (S.-E.K.); (J.H.J.); (M.-K.J.); (S.-H.P.); (M.-S.L.); (H.-S.K.); (K.T.S.)
- Institute for Liver and Digestive Diseases, Hallym University, Chuncheon 200-010, Korea
| | - Myoung-Kuk Jang
- Department of Internal Medicine, College of Medicine, Hallym University, Chuncheon-si 24252, Korea; (J.-W.P.); (J.-H.K.); (S.-E.K.); (J.H.J.); (M.-K.J.); (S.-H.P.); (M.-S.L.); (H.-S.K.); (K.T.S.)
- Institute for Liver and Digestive Diseases, Hallym University, Chuncheon 200-010, Korea
| | - Sang-Hoon Park
- Department of Internal Medicine, College of Medicine, Hallym University, Chuncheon-si 24252, Korea; (J.-W.P.); (J.-H.K.); (S.-E.K.); (J.H.J.); (M.-K.J.); (S.-H.P.); (M.-S.L.); (H.-S.K.); (K.T.S.)
| | - Myung-Seok Lee
- Department of Internal Medicine, College of Medicine, Hallym University, Chuncheon-si 24252, Korea; (J.-W.P.); (J.-H.K.); (S.-E.K.); (J.H.J.); (M.-K.J.); (S.-H.P.); (M.-S.L.); (H.-S.K.); (K.T.S.)
| | - Hyoung-Su Kim
- Department of Internal Medicine, College of Medicine, Hallym University, Chuncheon-si 24252, Korea; (J.-W.P.); (J.-H.K.); (S.-E.K.); (J.H.J.); (M.-K.J.); (S.-H.P.); (M.-S.L.); (H.-S.K.); (K.T.S.)
- Institute for Liver and Digestive Diseases, Hallym University, Chuncheon 200-010, Korea
| | - Ki Tae Suk
- Department of Internal Medicine, College of Medicine, Hallym University, Chuncheon-si 24252, Korea; (J.-W.P.); (J.-H.K.); (S.-E.K.); (J.H.J.); (M.-K.J.); (S.-H.P.); (M.-S.L.); (H.-S.K.); (K.T.S.)
- Institute for Liver and Digestive Diseases, Hallym University, Chuncheon 200-010, Korea
| | - Dong Joon Kim
- Department of Internal Medicine, College of Medicine, Hallym University, Chuncheon-si 24252, Korea; (J.-W.P.); (J.-H.K.); (S.-E.K.); (J.H.J.); (M.-K.J.); (S.-H.P.); (M.-S.L.); (H.-S.K.); (K.T.S.)
- Institute for Liver and Digestive Diseases, Hallym University, Chuncheon 200-010, Korea
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Abenavoli L, Procopio AC, Cinaglia P, Zanza C, Grazie CD, Longhitano Y, Libicherova P, Luzza F. Clinical Patterns of Primary Biliary Cholangitis: Comparison Between Two European Case Series. Rev Recent Clin Trials 2022; 17:136-142. [PMID: 35718979 DOI: 10.2174/1574887117666220617095856] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2021] [Revised: 03/22/2022] [Accepted: 04/07/2022] [Indexed: 12/14/2022]
Abstract
BACKGROUND Primary biliary cholangitis (PBC) is a chronic autoimmune cholestatic liver disease characterized by progressive destruction of the intrahepatic bile ducts, followed by fibrous substitution of the ducts and potential evolution in cirrhosis. The geographical disparity in the prevalence of PBC suggests a possible role of environmental factors in developing the disease. We analyzed two groups of patients with different geographical prevalence. METHODS This study concerned the analysis of 14 Caucasian patients in two groups: ten patients enrolled in the Digestive Diseases Unit, University of Catanzaro (Italy), and four patients enrolled in the Department of Hepatology, University Hospital Kràlovskè Vinohrady of Prague (Czech Republic). The statistical analysis was performed using the software IBM SPSS (v. 20, Windows). RESULTS The Italian group showed a statistically significant difference in the total bilirubin values at diagnosis and during the last control (0.74±0.267 vs. 0.56±0.246; p-value: 0.013). Moreover, the comparison between the two groups showed a statistically significant difference in the serum albumin values at the time of the last control (4.6±0.231 vs. 4.15±0.532; p-value: 0.048). CONCLUSION Our data indicate an effective difference in the onset and clinical presentation between our two groups. More epidemiologic, prospective, and multicenter research projects are warranted to advance PBC knowledge in Europe.
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Affiliation(s)
- Ludovico Abenavoli
- Department of Health Sciences, University, Magna Graecia, Catanzaro Italy
| | | | - Pietro Cinaglia
- Department of Health Sciences, University, Magna Graecia, Catanzaro Italy
| | - Christian Zanza
- Ospedale Alba-Bra Onlus, Department of Emergency Medicine, Anesthesia and Critical Care Medicine, Michele and Pietro Ferrero Hospital, Verduno (CN), Italy
| | | | - Yaroslava Longhitano
- Ospedale Alba-Bra Onlus, Department of Emergency Medicine, Anesthesia and Critical Care Medicine, Michele and Pietro Ferrero Hospital, Verduno (CN), Italy
| | - Pavla Libicherova
- Department of Hepatology, Third Faculty of Medicine and University Hospital Královské Vinohrady, Charles University, Prague, Czech Republic
| | - Francesco Luzza
- Department of Health Sciences, University, Magna Graecia, Catanzaro Italy
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Li Y, Liu X, Wang Y, Zhou Y, Hu S, Yang H, Zhong W, Zhao J, Wang X, Chu H, Zheng Y, Zhang J, Zhou L, Wang B. Novel HLA-DRB1 alleles contribute risk for disease susceptibility in primary biliary cholangitis. Dig Liver Dis 2022; 54:228-236. [PMID: 34016546 DOI: 10.1016/j.dld.2021.04.010] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2021] [Revised: 04/07/2021] [Accepted: 04/08/2021] [Indexed: 12/11/2022]
Abstract
BACKGROUND Primary biliary cholangitis (PBC) is a complex disease with high heritability. We investigated the association between human leukocyte antigen (HLA)-DRB1 alleles and PBC in families and sporadic cases to evaluate the genetic components of the disease. METHODS We performed whole exome sequencing in three PBC families. We genotyped HLA-DRB1 and calculated the association between HLA-DRB1 alleles and the encoding amino acid sequences with the clinical features. RESULTS Ten variants harboured the HLA-DRB1 gene associated with PBC. DRB1×07:01, 14:01 and 14:05 were highly increased in PBC. Ten coding region polymorphisms were associated with PBC that encode the amino acid variants of HLA-DR β54, β59 and β66 located in the peptide-binding site of the MHC molecule. Glutamine at position 54 was confirmed as a risk amino acid, verifying the results of familial aggregation analysis of PBC families. DISCUSSION Familial aggregation analysis indicated that HLA-DRB1 is a candidate gene for the risk of disease course. Considering that amino acid variations are critical to peptide-binding properties, they underlie the major component of MHC association with PBC.
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Affiliation(s)
- Yanni Li
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin, China; Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center Groningen, Groningen, the Netherlands
| | - Xin Liu
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin, China
| | - Yi Wang
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin, China; Department of General Surgery, YouAn Hospital, Capital Medical University, Beijing, China
| | - Yi Zhou
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin, China
| | - Shixian Hu
- Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center Groningen, Groningen, the Netherlands
| | - Hui Yang
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin, China
| | - Weilong Zhong
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin, China
| | - Jingwen Zhao
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin, China
| | - Xiaoyi Wang
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin, China
| | - Hongyu Chu
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin, China
| | - Yanping Zheng
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin, China
| | - Jie Zhang
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin, China
| | - Lu Zhou
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin, China; Department of Gastroenterology and Hepatology, People's Hospital of Hetian District, Xinjiang Uygur Autonomous Region, China.
| | - Bangmao Wang
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin, China.
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17
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Montano-Loza AJ, Allegretti JR, Cheung A, Ebadi M, Jones D, Kerkar N, Levy C, Rizvi S, Vierling JM, Alvarez F, Bai W, Gilmour S, Gulamhusein A, Guttman O, Hansen BE, MacParland S, Mason A, Onofrio F, Santamaria P, Stueck A, Swain M, Vincent C, Ricciuto A, Hirschfield G. Single Topic Conference on Autoimmune Liver Disease from the Canadian Association for the Study of the Liver. CANADIAN LIVER JOURNAL 2021; 4:401-425. [PMID: 35989897 PMCID: PMC9235119 DOI: 10.3138/canlivj-2021-0006] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Accepted: 02/09/2021] [Indexed: 11/20/2022]
Abstract
Autoimmune liver disease (AILD) spans a spectrum of chronic disorders affecting the liver parenchyma and biliary system. Three main categories of AILD are autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC), and primary sclerosing cholangitis (PSC). This review condenses the presentation and discussions of the Single Topic Conference (STC) on AILD that was held in Ottawa, Ontario, in November 2019. We cover generalities regarding disease presentation and clinical diagnosis; mechanistic themes; treatment paradigms; clinical trials, including approaches and challenges to new therapies; and looking beyond traditional disease boundaries. Although these diseases are considered autoimmune, the etiology and role of environmental triggers are poorly understood. AILDs are progressive and chronic conditions that affect survival and quality of life. Advances have been made in PBC treatment because second-line treatments are now available (obeticholic acid, bezafibrate); however, a significant proportion still present suboptimal response. AIH treatment has remained unchanged for several decades, and data suggest that fewer than 50% of patients achieve a complete response and as many as 80% develop treatment-related side effects. B-cell depletion therapy to treat AIH is in an early stage of development and has shown promising results. An effective treatment for PSC is urgently needed. Liver transplant remains the best option for patients who develop decompensated cirrhosis or hepatocellular carcinoma within specific criteria, but recurrent AILD might occur. Continued efforts are warranted to develop networks for AILD aimed at assessing geo-epidemiological, clinical, and biochemical differences to capture the new treatment era in Canada.
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Affiliation(s)
- Aldo J Montano-Loza
- Division of Gastroenterology and Liver Unit, University of Alberta, Edmonton, Alberta, Canada
| | - Jessica R Allegretti
- Division of Gastroenterology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Angela Cheung
- Mayo Clinic College of Medicine and Science, Rochester, Minnesota, USA
| | - Maryam Ebadi
- Division of Gastroenterology and Liver Unit, University of Alberta, Edmonton, Alberta, Canada
| | - David Jones
- Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Nanda Kerkar
- Division of Gastroenterology, Hepatology and Nutrition, Golisano Children’s Hospital at Strong, University of Rochester Medical Center, New York, USA
| | - Cynthia Levy
- Schiff Center for Liver Diseases, University of Miami, Miami, Florida, USA
| | - Sumera Rizvi
- Mayo Clinic College of Medicine and Science, Rochester, Minnesota, USA
| | | | - Fernando Alvarez
- Department of Pediatrics, Hôpital Sainte-Justine, University of Montreal, Montreal, Quebec, Canada
| | - Wayne Bai
- Division of Gastroenterology and Liver Unit, University of Alberta, Edmonton, Alberta, Canada
| | - Susan Gilmour
- Stollery Children’s Hospital, University of Alberta, Edmonton, Alberta, Canada
| | - Aliya Gulamhusein
- Ajmera Family Transplant Centre, Toronto General Research Institute, Departments of Laboratory Medicine and Pathobiology and Immunology, University of Toronto, Toronto, Ontario, Canada
| | - Orlee Guttman
- Division of Gastroenterology, Hepatology and Nutrition, British Columbia Children’s Hospital, Vancouver, British Columbia, Canada
| | - Bettina E Hansen
- Ajmera Family Transplant Centre, Toronto General Research Institute, Departments of Laboratory Medicine and Pathobiology and Immunology, University of Toronto, Toronto, Ontario, Canada
| | - Sonya MacParland
- Ajmera Family Transplant Centre, Toronto General Research Institute, Departments of Laboratory Medicine and Pathobiology and Immunology, University of Toronto, Toronto, Ontario, Canada
| | - Andrew Mason
- Division of Gastroenterology and Liver Unit, University of Alberta, Edmonton, Alberta, Canada
| | - Fernanda Onofrio
- Ajmera Family Transplant Centre, Toronto General Research Institute, Departments of Laboratory Medicine and Pathobiology and Immunology, University of Toronto, Toronto, Ontario, Canada
| | - Pere Santamaria
- Department of Microbiology, Immunology & Infectious Diseases, University of Calgary, Calgary, Alberta, Canada
| | - Ashley Stueck
- Department of Pathology, Dalhousie University, Halifax, Nova Scotia, Canada
| | - Mark Swain
- Calgary Liver Unit, Division of Gastroenterology and Hepatology, University of Calgary, Calgary, Alberta, Canada
| | - Catherine Vincent
- Department of Medicine, University of Montreal, Montreal, Quebec, Canada
| | - Amanda Ricciuto
- Division of Gastroenterology, Hepatology and Nutrition, Hospital for Sick Children, Toronto, Ontario, Canada
| | - Gideon Hirschfield
- Toronto Centre for Liver Disease, University Health Network & Institute of Health Policy Management and Evaluation, University of Toronto, Toronto, Ontario, Canada
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18
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The genetic architecture of primary biliary cholangitis. Eur J Med Genet 2021; 64:104292. [PMID: 34303876 DOI: 10.1016/j.ejmg.2021.104292] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2021] [Revised: 07/03/2021] [Accepted: 07/21/2021] [Indexed: 12/12/2022]
Abstract
Primary biliary cholangitis (PBC) is a rare autoimmune disease of the liver affecting the small bile ducts. From a genetic point of view, PBC is a complex trait and several genetic and environmental factors have been called in action to explain its etiopathogenesis. Similarly to other complex traits, PBC has benefited from the introduction of genome-wide association studies (GWAS), which identified many variants predisposing or protecting toward the development of the disease. While a progressive endeavour toward the characterization of candidate loci and downstream pathways is currently ongoing, there is still a relatively large portion of heritability of PBC to be revealed. In addition, genetic variation behind progression of the disease and therapeutic response are mostly to be investigated yet. This review outlines the state-of-the-art regarding the genetic architecture of PBC and provides some hints for future investigations, focusing on the study of gene-gene interactions, the application of whole-genome sequencing techniques, and the investigation of X chromosome that can be helpful to cover the missing heritability gap in PBC.
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Asselta R, Paraboschi EM, Gerussi A, Cordell HJ, Mells GF, Sandford RN, Jones DE, Nakamura M, Ueno K, Hitomi Y, Kawashima M, Nishida N, Tokunaga K, Nagasaki M, Tanaka A, Tang R, Li Z, Shi Y, Liu X, Xiong M, Hirschfield G, Siminovitch KA, Carbone M, Cardamone G, Duga S, Gershwin ME, Seldin MF, Invernizzi P. X Chromosome Contribution to the Genetic Architecture of Primary Biliary Cholangitis. Gastroenterology 2021; 160:2483-2495.e26. [PMID: 33675743 PMCID: PMC8169555 DOI: 10.1053/j.gastro.2021.02.061] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2020] [Revised: 02/15/2021] [Accepted: 02/25/2021] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Genome-wide association studies in primary biliary cholangitis (PBC) have failed to find X chromosome (chrX) variants associated with the disease. Here, we specifically explore the chrX contribution to PBC, a sexually dimorphic complex autoimmune disease. METHODS We performed a chrX-wide association study, including genotype data from 5 genome-wide association studies (from Italy, United Kingdom, Canada, China, and Japan; 5244 case patients and 11,875 control individuals). RESULTS Single-marker association analyses found approximately 100 loci displaying P < 5 × 10-4, with the most significant being a signal within the OTUD5 gene (rs3027490; P = 4.80 × 10-6; odds ratio [OR], 1.39; 95% confidence interval [CI], 1.028-1.88; Japanese cohort). Although the transethnic meta-analysis evidenced only a suggestive signal (rs2239452, mapping within the PIM2 gene; OR, 1.17; 95% CI, 1.09-1.26; P = 9.93 × 10-8), the population-specific meta-analysis showed a genome-wide significant locus in East Asian individuals pointing to the same region (rs7059064, mapping within the GRIPAP1 gene; P = 6.2 × 10-9; OR, 1.33; 95% CI, 1.21-1.46). Indeed, rs7059064 tags a unique linkage disequilibrium block including 7 genes: TIMM17B, PQBP1, PIM2, SLC35A2, OTUD5, KCND1, and GRIPAP1, as well as a superenhancer (GH0XJ048933 within OTUD5) targeting all these genes. GH0XJ048933 is also predicted to target FOXP3, the main T-regulatory cell lineage specification factor. Consistently, OTUD5 and FOXP3 RNA levels were up-regulated in PBC case patients (1.75- and 1.64-fold, respectively). CONCLUSIONS This work represents the first comprehensive study, to our knowledge, of the chrX contribution to the genetics of an autoimmune liver disease and shows a novel PBC-related genome-wide significant locus.
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Affiliation(s)
- Rosanna Asselta
- Department of Biomedical Sciences, Humanitas University, Milan, Italy; IRCCS Humanitas Research Hospital, Milan, Italy
| | - Elvezia M Paraboschi
- Department of Biomedical Sciences, Humanitas University, Milan, Italy; IRCCS Humanitas Research Hospital, Milan, Italy
| | - Alessio Gerussi
- Division of Gastroenterology and Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy; European Reference Network on Hepatological Diseases, San Gerardo Hospital, Monza, Italy
| | - Heather J Cordell
- Population Health Sciences Institute, Faculty of Medical Sciences, Newcastle University, United Kingdom
| | - George F Mells
- Academic Department of Medical Genetics, Cambridge University, Cambridge, United Kingdom
| | - Richard N Sandford
- Academic Department of Medical Genetics, Cambridge University, Cambridge, United Kingdom
| | - David E Jones
- Faculty of Medical Sciences, Newcastle University, Newcastle, United Kingdom
| | - Minoru Nakamura
- Clinical Research Center, National Hospital Organization, Nagasaki Medical Center, Nagasaki, Japan; Department of Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Omura, Nagasaki, Japan
| | - Kazuko Ueno
- Genome Medical Science Project, National Center for Global Health and Medicine, Tokyo, Japan
| | - Yuki Hitomi
- Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Minae Kawashima
- Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Nao Nishida
- Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Katsushi Tokunaga
- Genome Medical Science Project, National Center for Global Health and Medicine, Tokyo, Japan; Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Masao Nagasaki
- Human Biosciences Unit for the Top Global Course Center for the Promotion of Interdisciplinary Education and Research, Kyoto University, Kyoto, Japan; Center for Genomic Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Atsushi Tanaka
- Department of Medicine, Teikyo University School of Medicine, Tokyo, Japan
| | - Ruqi Tang
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Shanghai, China
| | - Zhiqiang Li
- Affiliated Hospital of Qingdao University and Biomedical Sciences Institute of Qingdao University (Qingdao Branch of SJTU Bio-X Institutes), Qingdao University, Qingdao, China; Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Collaborative Innovation Center for Brain Science, Shanghai Jiao Tong University, Shanghai, China
| | - Yongyong Shi
- Affiliated Hospital of Qingdao University and Biomedical Sciences Institute of Qingdao University (Qingdao Branch of SJTU Bio-X Institutes), Qingdao University, Qingdao, China; Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Collaborative Innovation Center for Brain Science, Shanghai Jiao Tong University, Shanghai, China
| | - Xiangdong Liu
- Key Laboratory of Developmental Genes and Human Diseases, Institute of Life Sciences, Southeast University, Nanjing, Jiangsu, China
| | - Ma Xiong
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Shanghai, China
| | - Gideon Hirschfield
- Toronto General Hospital Research Institute, Toronto, Ontario, Canada; Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Katherine A Siminovitch
- Department of Medicine, University of Toronto, Toronto, Ontario, Canada; Mount Sinai Hospital, Lunenfeld Tanenbaum Research Institute and Toronto General Research Institute, Toronto, Canada; Department of Immunology, University of Toronto, Toronto, Ontario, Canada; Institute of Medical Sciences, University of Toronto, Toronto, Ontario, Canada
| | - Marco Carbone
- Division of Gastroenterology and Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy; European Reference Network on Hepatological Diseases, San Gerardo Hospital, Monza, Italy
| | - Giulia Cardamone
- Department of Biomedical Sciences, Humanitas University, Milan, Italy; IRCCS Humanitas Research Hospital, Milan, Italy
| | - Stefano Duga
- Department of Biomedical Sciences, Humanitas University, Milan, Italy; IRCCS Humanitas Research Hospital, Milan, Italy
| | | | | | - Pietro Invernizzi
- Division of Gastroenterology and Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy; European Reference Network on Hepatological Diseases, San Gerardo Hospital, Monza, Italy.
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20
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Leung KK, Deeb M, Hirschfield GM. Review article: pathophysiology and management of primary biliary cholangitis. Aliment Pharmacol Ther 2020; 52:1150-1164. [PMID: 32813299 DOI: 10.1111/apt.16023] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2020] [Revised: 05/13/2020] [Accepted: 07/18/2020] [Indexed: 12/13/2022]
Abstract
BACKGROUND Primary biliary cholangitis (PBC), an immune-mediated disease characterised by destruction of intrahepatic bile ducts, results in progressive damage to the biliary tree, cholestasis and ultimately advanced liver disease. In the last decade, advances in practice have improved clinical care, driven novel therapeutic options and improved risk stratification tools. AIMS To provide an overview of the disease characteristics of PBC and review a patient-centred management approach for the clinical team caring for those with PBC. METHODS We reviewed the current literature and guidelines on PBC with a focus on management and therapies. RESULTS A confident diagnosis of PBC is usually made based on serum liver tests and immune serology. Management of PBC should focus on three main 'process' pillars: (a) treat and risk-stratify through use of biochemical and prognostic criteria; (b) manage concurrent symptoms and other associated diseases; and (c) stage disease, monitor progression and prevent complications. With ongoing complexities in management, including a newly licensed therapy (obeticholic acid) and alternative non-licensed treatments and ongoing clinical trials, discussion with PBC expert centres is encouraged. CONCLUSIONS PBC is a dynamic disease wherein current treatment goals have become appropriately ambitious. Goals of care should prioritise prevention of end-stage liver disease and amelioration of patient symptom burden for all.
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Affiliation(s)
- Kristel K Leung
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Toronto, Toronto, ON, Canada.,Toronto Centre for Liver Disease, University Health Network, University of Toronto, Toronto, Ontario, Canada
| | - Maya Deeb
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Toronto, Toronto, ON, Canada.,Toronto Centre for Liver Disease, University Health Network, University of Toronto, Toronto, Ontario, Canada
| | - Gideon M Hirschfield
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Toronto, Toronto, ON, Canada.,Toronto Centre for Liver Disease, University Health Network, University of Toronto, Toronto, Ontario, Canada
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21
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Richardson N, Ng STH, Wraith DC. Antigen-Specific Immunotherapy for Treatment of Autoimmune Liver Diseases. Front Immunol 2020; 11:1586. [PMID: 32793226 PMCID: PMC7385233 DOI: 10.3389/fimmu.2020.01586] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2020] [Accepted: 06/15/2020] [Indexed: 12/11/2022] Open
Abstract
The liver is a critical organ in controlling immune tolerance. In particular, it is now clear that targeting antigens for presentation by antigen presenting cells in the liver can induce immune tolerance to either autoantigens from the liver itself or tissues outside of the liver. Here we review immune mechanisms active within the liver that contribute both to the control of infectious diseases and tolerance to self-antigens. Despite its extraordinary capacity for tolerance induction, the liver remains a target organ for autoimmune diseases. In this review, we compare and contrast known autoimmune diseases of the liver. Currently patients tend to receive strong immunosuppressive treatments and, in many cases, these treatments are associated with deleterious side effects, including a significantly higher risk of infection and associated health complications. We propose that, in future, antigen-specific immunotherapies are adopted for treatment of liver autoimmune diseases in order to avoid such adverse effects. We describe various therapeutic approaches that either are in or close to the clinic, highlight their mechanism of action and assess their suitability for treatment of autoimmune liver diseases.
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Affiliation(s)
| | | | - David C. Wraith
- Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom
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22
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Gulamhusein AF, Hirschfield GM, Milovanovic J, Arsenijevic D, Arsenijevic N, Milovanovic M. Primary biliary cholangitis: pathogenesis and therapeutic opportunities. Nat Rev Gastroenterol Hepatol 2020; 17:93-110. [PMID: 31819247 DOI: 10.1038/s41575-019-0226-7] [Citation(s) in RCA: 183] [Impact Index Per Article: 36.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 10/09/2019] [Indexed: 02/08/2023]
Abstract
Primary biliary cholangitis is a chronic, seropositive and female-predominant inflammatory and cholestatic liver disease, which has a variable rate of progression towards biliary cirrhosis. Substantial progress has been made in patient risk stratification with the goal of personalized care, including early adoption of next-generation therapy with licensed use of obeticholic acid or off-label fibrate derivatives for those with insufficient benefit from ursodeoxycholic acid, the current first-line drug. The disease biology spans genetic risk, epigenetic changes, dysregulated mucosal immunity and altered biliary epithelial cell function, all of which interact and arise in the context of ill-defined environmental triggers. A current focus of research on nuclear receptor pathway modulation that specifically and potently improves biliary excretion, reduces inflammation and attenuates fibrosis is redefining therapy. Patients are benefiting from pharmacological agonists of farnesoid X receptor and peroxisome proliferator-activated receptors. Immunotherapy remains a challenge, with a lack of target definition, pleiotropic immune pathways and an interplay between hepatic immune responses and cholestasis, wherein bile acid-induced inflammation and fibrosis are dominant clinically. The management of patient symptoms, particularly pruritus, is a notable goal reflected in the development of rational therapy with apical sodium-dependent bile acid transporter inhibitors.
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Affiliation(s)
- Aliya F Gulamhusein
- Toronto Centre for Liver Disease, University Health Network and Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Gideon M Hirschfield
- Toronto Centre for Liver Disease, University Health Network and Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
| | - Jelena Milovanovic
- Center for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, Kragujevac 34000, Serbia.,Department of Histology, Faculty of Medical Sciences, University of Kragujevac, Kragujevac 34000, Serbia
| | - Dragana Arsenijevic
- Department of Pharmacy, Faculty of Medical Sciences, University of Kragujevac, Kragujevac 34000, Serbia
| | - Nebojsa Arsenijevic
- Center for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, Kragujevac 34000, Serbia
| | - Marija Milovanovic
- Center for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, Kragujevac 34000, Serbia
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23
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Liberal R, Gaspar R, Lopes S, Macedo G. Primary biliary cholangitis in patients with inflammatory bowel disease. Clin Res Hepatol Gastroenterol 2020; 44:e5-e9. [PMID: 31171469 DOI: 10.1016/j.clinre.2019.05.002] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2019] [Revised: 04/24/2019] [Accepted: 05/09/2019] [Indexed: 02/04/2023]
Abstract
BACKGROUND & AIMS Inflammatory bowel diseases (IBD) are associated with various hepatobiliary disorders. There is a strong association for primary sclerosing cholangitis (PSC). Primary biliary cholangitis (PBC), another autoimmune cholestatic liver disease, is not usually associated with IBD. The aim of this study is to report cases of PBC-associated IBD, their clinical features, response to therapy, and long-term outcome. METHODS Retrospective analysis of a prospectively collated database identified patients presenting with PBC-associated IBD from 2006 to 2016. PBC has been diagnosed according to accepted criteria, and staged according to Ludwig classification. A magnetic resonance cholangiopancreatography (MRCP) was performed to rule out PSC. Response to ursodeoxycholic acid (UDCA) therapy has been assessed by using the Paris II criteria. RESULTS A total of six patients (five females) with PBC-associated IBD were identified. Median age at IBD diagnosis was 44.7 years (range 22.5-48.8). Three had Crohn's disease and three ulcerative colitis. PBC was diagnosed in all after IBD had been diagnosed. All patients presented with cholestasis, all were positive for anti-mitochondrial antibodies. MRCP was normal in all. Liver biopsy was consistent with PBC (stage I in one, stage II in five). One year after initiation of UDCA, all patients responded to therapy. CONCLUSION Herein we describe the largest series reported to date of PBC-associated IBD. Although the coexistence of the two conditions is rare, PBC should be considered during the work-up of abnormal liver function tests in patients with IBD.
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Affiliation(s)
- Rodrigo Liberal
- Gastroenterology and Hepatology Department, Centro Hospitalar Sao Joao, Alameda Prof. Hernani Monteiro, 4200-319 Porto, Portugal.
| | - Rui Gaspar
- Gastroenterology and Hepatology Department, Centro Hospitalar Sao Joao, Alameda Prof. Hernani Monteiro, 4200-319 Porto, Portugal
| | - Susana Lopes
- Gastroenterology and Hepatology Department, Centro Hospitalar Sao Joao, Alameda Prof. Hernani Monteiro, 4200-319 Porto, Portugal
| | - Guilherme Macedo
- Gastroenterology and Hepatology Department, Centro Hospitalar Sao Joao, Alameda Prof. Hernani Monteiro, 4200-319 Porto, Portugal
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24
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Wang C, Zheng X, Tang R, Han C, Jiang Y, Wu J, Shao Y, Gao Y, Yu J, Hu Z, Zang Z, Zhao Y, Dai N, Liu L, Wu X, Nie J, Jiang B, Lin M, Li L, Wei Y, Li Y, Gong Y, Dai Y, Wang L, Ding N, Xu P, Chen S, Jiang P, Wang L, Qiu F, Wu Q, Zhang M, Jawed R, Chen R, Zhang Y, Shi X, Zhu Z, Pei H, Huang L, Tian Y, Zhang K, Qiu H, Zhao W, Gershwin ME, Chen W, Seldin MF, Liu X, Ma X, Sun L. Fine mapping of the MHC region identifies major independent variants associated with Han Chinese primary biliary cholangitis. J Autoimmun 2020; 107:102372. [PMID: 31810856 DOI: 10.1016/j.jaut.2019.102372] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2019] [Revised: 11/03/2019] [Accepted: 11/14/2019] [Indexed: 02/08/2023]
Abstract
The genetic association of primary biliary cholangitis with major histocompatibility complex (MHC) has been widely confirmed among different ethnicities. To map specific MHC region variants associated with PBC in a Han Chinese cohort, we imputed HLA antigens and amino acids (AA) in 1126 PBC cases and 1770 healthy control subjects using a Han-MHC reference database. We demonstrate that HLA-DRB1 and/or HLA-DQB1 contributed the strongest signals, and that HLA-DPB1 was a separate independent locus. Regression analyses with classical HLA alleles indicate that HLA-DQB1*03:01 or HLA-DQβ1-Pro55, HLA-DPB1*17:01 or HLA-DPβ1-Asp84 and HLA-DRB1*08:03 could largely explain MHC association with PBC. Forward stepwise regression analyses with HLA amino acid variants localize the major signals to HLA-DRβ1-Ala74, HLA-DQβ1-Pro55 and HLA-DPβ1-Asp84. Electrostatic potential calculations implicated AA variations at HLA-DQβ1 position 55 and HLA-DPβ1 position 84 as critical to peptide binding properties. Furthermore, although several critical Han Chinese AA variants differed from those shown in European populations, the predicted effects on antigen binding are likely to be very similar or identical and underlie the major component of MHC association with PBC.
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Affiliation(s)
- Chan Wang
- Key Laboratory of Developmental Genes and Human Diseases, Institute of Life Sciences, Southeast University, 2 Sipailou Road, Nanjing, Jiangsu, 210096, China
| | - Xiaodong Zheng
- Department of Dermatology, The First Affiliated Hospital of Anhui Medical University, Hefei, China, Key Laboratory of Dermatology (Anhui Medical University), Ministry of Education, Hefei, China, Key Laboratory of Major Autoimmune Diseases, Anhui Province, Hefei, China, 218 Jixi Road, Hefei, Anhui, 230022, China
| | - Ruqi Tang
- Department of Gastroenterology and Hepatology, Shanghai Institute of Digestive Diseases, Shanghai Jiao Tong University School of Medicine Affiliated Renji Hospital, 145 Shandong Middle Road, Shanghai, 200001, China
| | - Chongxu Han
- Department of Laboratory Medicine, Subei People's Hospital, Clinical Medical College, Yangzhou University, 98 Nantong West Road, Yangzhou, Jiangsu, 225001, China
| | - Yuzhang Jiang
- Department of Laboratory Medicine, Huai'an First People's Hospital, Nanjing Medical University, 1 Huanghe West Road, Huai'an, Jiangsu, 223300, China
| | - Jian Wu
- Department of Rheumatology, First Affiliated Hospital of Soochow University, 188 Shizi Road, Suzhou, Jiangsu, 215006, China
| | - Youlin Shao
- Department of Hepatology, The Third People's Hospital of Changzhou, 300 Lanling North Road, Changzhou, Jiangsu, 213001, China
| | - Yueqiu Gao
- Department of Liver Disease, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, 528 Zhangheng Road, Shanghai, 201203, China
| | - Jianjiang Yu
- Department of Laboratory Medicine, Jiangyin People's Hospital, Southeast University, 163 Shoushan Road, Jiangyin, Jiangsu, 214400, China
| | - Zhigang Hu
- Department of Laboratory Medicine, Affiliated Wuxi People's Hospital of Nanjing Medical University, 299 Qingyang Road, Wuxi, Jiangsu, 214023, China
| | - Zhidong Zang
- Department of Hepatology, The Second Hospital of Nanjing, Southeast University, 1 Zhongfu Road, Nanjing, jiangsu, 210003, China
| | - Yi Zhao
- Department of Gastrointestinal Endoscopy, Eastern Hepatobiliary Surgery Hospital, 700 Moyu North Road, Shanghai, 201800, China
| | - Na Dai
- Department of Gastroenterology, Jiangsu University Affiliated Kunshan Hospital, 91 Qianjin West Road, Kunshan, Jiangsu, 215300, China
| | - Lei Liu
- Department of Gastroenterology, Yixing People's Hospital, 75 Tongzhenguan Road, Yixing, Jiangsu, 214200, China
| | - Xudong Wu
- Department of Gastroenterology, Yancheng First People's Hospital, 66 Renmin South Road, Yancheng, Jiangsu, 224005, China
| | - Jinshan Nie
- Department of Gastroenterology, Taicang First People's Hospital, Soochow University, 58 Changsheng South Road, Taicang, Jiangsu, 215400, China
| | - Bo Jiang
- Department of Hepatology, Jingjiang Second People's Hospital, 1 Chengxiqiao Jiangping Road, Jingjiang, Jiangsu, 214500, China
| | - Maosong Lin
- Department of Gastroenterology, Taizhou People's Hospital, 210 Yingchun Road, Taizhou, Jiangsu, 225300, China
| | - Li Li
- Department of Laboratory Medicine, Zhongda Hospital, Southeast University, 87 Dingjiaqiao Road, Nanjing, Jiangsu, 210009, China
| | - Yiran Wei
- Department of Gastroenterology and Hepatology, Shanghai Institute of Digestive Diseases, Shanghai Jiao Tong University School of Medicine Affiliated Renji Hospital, 145 Shandong Middle Road, Shanghai, 200001, China
| | - You Li
- Department of Gastroenterology and Hepatology, Shanghai Institute of Digestive Diseases, Shanghai Jiao Tong University School of Medicine Affiliated Renji Hospital, 145 Shandong Middle Road, Shanghai, 200001, China
| | - Yuhua Gong
- Department of Laboratory Medicine, The Third People's Hospital of Zhenjiang, 300 Daijiamen, Zhenjiang, Jiangsu, 212021, China
| | - Yaping Dai
- Department of Laboratory Medicine, The Fifth People's Hospital of Wuxi, 1215 Guangrui Road, Wuxi, Jiangsu, 214000, China
| | - Lan Wang
- Department of Laboratory Medicine, The 81st Hospital of PLA, 34 Yanggongjing Nanjing, Jiangsu, 210002, China
| | - Ningling Ding
- Department of Hepatology, Department of Laboratory Medicine, The Fifth People's Hospital of Suzhou, Soochow University, 10 Guangqian Road, Suzhou, Jiangsu, 215131, China
| | - Ping Xu
- Department of Radiology, The Second Affiliated Hospital of Soochow University, 1055 Sanxiang Road, Suzhou, Jiangsu, 215004, China
| | - Sufang Chen
- Department of Hepatology, Department of Laboratory Medicine, The Fifth People's Hospital of Suzhou, Soochow University, 10 Guangqian Road, Suzhou, Jiangsu, 215131, China
| | - Peng Jiang
- Key Laboratory of Developmental Genes and Human Diseases, Institute of Life Sciences, Southeast University, 2 Sipailou Road, Nanjing, Jiangsu, 210096, China
| | - Lu Wang
- Key Laboratory of Developmental Genes and Human Diseases, Institute of Life Sciences, Southeast University, 2 Sipailou Road, Nanjing, Jiangsu, 210096, China
| | - Fang Qiu
- Key Laboratory of Developmental Genes and Human Diseases, Institute of Life Sciences, Southeast University, 2 Sipailou Road, Nanjing, Jiangsu, 210096, China
| | - Qiuyuan Wu
- Key Laboratory of Developmental Genes and Human Diseases, Institute of Life Sciences, Southeast University, 2 Sipailou Road, Nanjing, Jiangsu, 210096, China
| | - Mingming Zhang
- Key Laboratory of Developmental Genes and Human Diseases, Institute of Life Sciences, Southeast University, 2 Sipailou Road, Nanjing, Jiangsu, 210096, China
| | - Rohil Jawed
- Key Laboratory of Developmental Genes and Human Diseases, Institute of Life Sciences, Southeast University, 2 Sipailou Road, Nanjing, Jiangsu, 210096, China
| | - Ru Chen
- Key Laboratory of Developmental Genes and Human Diseases, Institute of Life Sciences, Southeast University, 2 Sipailou Road, Nanjing, Jiangsu, 210096, China
| | - Yu Zhang
- Key Laboratory of Developmental Genes and Human Diseases, Institute of Life Sciences, Southeast University, 2 Sipailou Road, Nanjing, Jiangsu, 210096, China
| | - Xingjuan Shi
- Key Laboratory of Developmental Genes and Human Diseases, Institute of Life Sciences, Southeast University, 2 Sipailou Road, Nanjing, Jiangsu, 210096, China
| | - Zhen Zhu
- Department of Hepatology, The Third People's Hospital of Changzhou, 300 Lanling North Road, Changzhou, Jiangsu, 213001, China
| | - Hao Pei
- Department of Laboratory Medicine, The Fifth People's Hospital of Wuxi, 1215 Guangrui Road, Wuxi, Jiangsu, 214000, China
| | - Lihua Huang
- Department of Laboratory Medicine, The Fifth People's Hospital of Wuxi, 1215 Guangrui Road, Wuxi, Jiangsu, 214000, China
| | - Ye Tian
- Department of Laboratory Medicine, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, 321 Zhongshan Road, Nanjing, Jiangsu, 210008, China
| | - Kui Zhang
- Department of Hepatology, First Affiliated Hospital of Soochow University, 188 Shizi Road, Suzhou, Jiangsu, 215006, China
| | - Hong Qiu
- Department of Laboratory Medicine, The 81st Hospital of PLA, 34 Yanggongjing Nanjing, Jiangsu, 210002, China
| | - Weifeng Zhao
- Department of Hepatology, First Affiliated Hospital of Soochow University, 188 Shizi Road, Suzhou, Jiangsu, 215006, China
| | - M Eric Gershwin
- Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis School of Medicine, Genome and Biomedical Sciences Facility Building, 451 Health Sciences Drive, Suite 6510, Davis, CA, 95616, USA
| | - Weichang Chen
- Department of Gastroenterology, First Affiliated Hospital of Soochow University, 188 Shizi Road, Suzhou, Jiangsu, 215006, China
| | - Michael F Seldin
- Department of Biochemistry and Molecular Medicine, University of California at Davis School of Medicine, 4327 Tupper Hall, Davis, CA, 95616, USA
| | - Xiangdong Liu
- Key Laboratory of Developmental Genes and Human Diseases, Institute of Life Sciences, Southeast University, 2 Sipailou Road, Nanjing, Jiangsu, 210096, China.
| | - Xiong Ma
- Department of Gastroenterology and Hepatology, Shanghai Institute of Digestive Diseases, Shanghai Jiao Tong University School of Medicine Affiliated Renji Hospital, 145 Shandong Middle Road, Shanghai, 200001, China.
| | - Liangdan Sun
- Department of Dermatology, The First Affiliated Hospital of Anhui Medical University, Hefei, China, Key Laboratory of Dermatology (Anhui Medical University), Ministry of Education, Hefei, China, Key Laboratory of Major Autoimmune Diseases, Anhui Province, Hefei, China, 218 Jixi Road, Hefei, Anhui, 230022, China.
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25
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Gerussi A, Cristoferi L, Carbone M, Asselta R, Invernizzi P. The immunobiology of female predominance in primary biliary cholangitis. J Autoimmun 2018; 95:124-132. [DOI: 10.1016/j.jaut.2018.10.015] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2018] [Accepted: 10/17/2018] [Indexed: 12/21/2022]
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26
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Darlay R, Ayers KL, Mells GF, Hall LS, Liu JZ, Almarri MA, Alexander GJ, Jones DE, Sandford RN, Anderson CA, Cordell HJ. Amino acid residues in five separate HLA genes can explain most of the known associations between the MHC and primary biliary cholangitis. PLoS Genet 2018; 14:e1007833. [PMID: 30507971 PMCID: PMC6292650 DOI: 10.1371/journal.pgen.1007833] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2018] [Revised: 12/13/2018] [Accepted: 11/13/2018] [Indexed: 12/15/2022] Open
Abstract
Primary Biliary Cholangitis (PBC) is a chronic autoimmune liver disease characterised by progressive destruction of intrahepatic bile ducts. The strongest genetic association is with HLA-DQA1*04:01, but at least three additional independent HLA haplotypes contribute to susceptibility. We used dense single nucleotide polymorphism (SNP) data in 2861 PBC cases and 8514 controls to impute classical HLA alleles and amino acid polymorphisms using state-of-the-art methodologies. We then demonstrated through stepwise regression that association in the HLA region can be largely explained by variation at five separate amino acid positions. Three-dimensional modelling of protein structures and calculation of electrostatic potentials for the implicated HLA alleles/amino acid substitutions demonstrated a correlation between the electrostatic potential of pocket P6 in HLA-DP molecules and the HLA-DPB1 alleles/amino acid substitutions conferring PBC susceptibility/protection, highlighting potential new avenues for future functional investigation.
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Affiliation(s)
- Rebecca Darlay
- Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Kristin L. Ayers
- Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - George F. Mells
- Academic Department of Medical Genetics, University of Cambridge, Cambridge, United Kingdom
| | - Lynsey S. Hall
- Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom
- Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, United Kingdom
| | - Jimmy Z. Liu
- Human Genetics, Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridgeshire, United Kingdom
| | - Mohamed A. Almarri
- Human Genetics, Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridgeshire, United Kingdom
- Department of Forensic Science and Criminology, Dubai Police HQ, Dubai, United Arab Emirates
| | - Graeme J. Alexander
- Department of Hepatology, Cambridge University Hospitals National Health Service (NHS) Foundation Trust, Cambridge, United Kingdom
| | - David E. Jones
- Institute of Cellular Medicine, Medical School, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Richard N. Sandford
- Academic Department of Medical Genetics, University of Cambridge, Cambridge, United Kingdom
| | - Carl A. Anderson
- Human Genetics, Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridgeshire, United Kingdom
| | - Heather J. Cordell
- Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom
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Abstract
Primary cholangitis (cirrhosis) is a chronic cholestatic disease with an unquestionable female predominance. It is characterised by inflammation of the small and medium size bile ducts, and can eventually progress to cirrhosis. Most patients remain asymptomatic and are diagnosed by the casual finding of an anicteric biochemical cholestasis with increased alkaline phosphatase. The pathogenesis is unknown and of presumed autoimmune origin in genetic susceptible subjects. M2-type antimitochondrial antibodies, and specific antinuclear antibodies (gp210 and Sp100) are typical and specific of the disease. The positivity of these antibodies and a biochemical cholestasis are sufficient for diagnosis, without the need for liver biopsy. Ursodeoxycholic acid is the specific treatment with an excellent response in more than 60% of patients. When this optimal response is not observed, it can be combined with new agents, but those that have shown to be effective are those that improve cholestasis such as fibrates and obeticholic acid.
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Affiliation(s)
- Albert Parés
- Unidad de Hepatología, Hospital Clinic, Universidad de Barcelona, IDIBAPS, CIBERehd, Barcelona, España.
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28
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Rosa R, Cristoferi L, Tanaka A, Invernizzi P. Geoepidemiology and (epi-)genetics in primary biliary cholangitis. Best Pract Res Clin Gastroenterol 2018; 34-35:11-15. [PMID: 30343705 DOI: 10.1016/j.bpg.2018.05.011] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2018] [Accepted: 05/14/2018] [Indexed: 01/31/2023]
Abstract
Primary biliary cholangitis (PBC) is a rare female preponderant chronic autoimmune cholestatic liver disease, characterized by intrahepatic ductopenia and progressive fibrosis. During last decades incidence and prevalence showed an increasing rate which vary widely worldwide demonstrating an important interaction between environmental and genetic factors. Heritability suggested by familial occurrence and monozygotic twins concordance have been confirmed in more studies. Epigenetics mechanisms such as histone modification and DNA methylation can partially explain predisposition and inheritance of this disease. Nevertheless, an association with specific class II human leukocyte antigen (HLA) variants have been reported, showing an increase risk in susceptibility. More recently, data regarding a strong protective association between PBC and HLA alleles confirmed this association. After recent genome-wide association studies (GWAS), a more intricate interaction between PBC and the HLA region has been shown. Furthermore, GWAS also identified several immune-related-genes implicated. More genome-wide association studies on this disease are needed to reach a complete and systematic knowledge of this disease. In this review we discuss more recent issued data on geoepidemiology of PBC and the role of (epi-)genetic mechanisms in its pathogenesis.
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Affiliation(s)
- Roberto Rosa
- Division of Gastroenterology and Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milan-Bicocca, Milan, Italy
| | - Laura Cristoferi
- Division of Gastroenterology and Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milan-Bicocca, Milan, Italy
| | - Atsushi Tanaka
- Department of Medicine, Teikyo University School of Medicine, 2-11-1, Kaga, Itabashi-ku, Tokyo, Japan
| | - Pietro Invernizzi
- Division of Gastroenterology and Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milan-Bicocca, Milan, Italy.
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Gulamhusein AF, Hirschfield GM. Pathophysiology of primary biliary cholangitis. Best Pract Res Clin Gastroenterol 2018; 34-35:17-25. [PMID: 30343706 DOI: 10.1016/j.bpg.2018.05.012] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2018] [Accepted: 05/22/2018] [Indexed: 01/31/2023]
Abstract
Primary biliary cholangitis is a prototypical autoimmune disease characterized by an overwhelming female predominance, a distinct clinical phenotype, and disease specific anti-mitochondrial antibodies targeted against a well-defined auto-antigen. In a genetically susceptible host, multi-lineage loss of tolerance to the E2 component of the 2-oxo-dehydrogenase pathway and dysregulated immune pathways directed at biliary epithelial cells leads to cholestasis, progressive biliary fibrosis, and cirrhosis in a subset of patients. Several key insights have shed light on the complex pathogenesis of disease. First, characteristic anti-mitochondrial antibodies (AMAs) target lipoic acid containing immunodominant epitopes, particularly pyruvate dehydrogenase complex (PDC-E2), on the inner mitochondrial membrane of BECs. Next, breakdown of the protective apical bicarbonate rich umbrella may sensitize BECs to aberrant apoptotic pathways leaving the antigenic PDC-E2 epitope immunologically tact within an apoptotic bleb. A multi-lineage immune response ensues characterized by an imbalance between effector and regulatory activity resulting in progressive and self-perpetuating biliary injury. Genome wide studies shed light on important pathways involved in disease, key among them being IL-12. Epigenetic mechanisms and microRNAs may play help shed light on the missing heritability and female preponderance of disease. Taken together, these findings have dramatically advanced our understanding of disease and may lead to important therapeutic advances.
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Affiliation(s)
- Aliya F Gulamhusein
- Toronto Centre for Liver Disease, 200 Elizabeth Street, Toronto, ON, Canada.
| | - Gideon M Hirschfield
- Centre for Liver Research and NIHR Birmingham Biomedical Research Centre, University of Birmingham, Birmingham, UK.
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30
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Genetics and epigenetics in the pathogenesis of primary biliary cholangitis. Clin J Gastroenterol 2017; 11:11-18. [PMID: 29159718 DOI: 10.1007/s12328-017-0799-z] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2017] [Accepted: 11/05/2017] [Indexed: 02/07/2023]
Abstract
Primary biliary cholangitis (PBC) is a chronic, slowly progressive cholestatic autoimmune liver disease predominantly afflicting women. PBC is characterized by the presence of disease-specific antimitochondrial antibodies and the histological destruction of intrahepatic bile ducts, which eventually lead to cirrhosis and hepatic failure. Fortunately, ursodeoxycholic acid therapy has improved the outcome of the vast majority of PBC cases. Although the etiology of PBC has not yet been elucidated, human leukocyte antigen (HLA) class II alleles have been consistently associated with disease onset for decades. PBC patients may also have genetically determined risk factors in non-HLA regions. Meanwhile, exposure to environmental factors, such as infectious diseases and harmful chemicals, can produce epigenetic alterations in some individuals and subsequent PBC onset. In this review, we describe the influence of HLA alleles and other gene polymorphisms on PBC along with the results of genome-wide association studies on this disease and its future prospects in terms of epigenetics.
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Yasunami M, Nakamura H, Tokunaga K, Kawashima M, Nishida N, Hitomi Y, Nakamura M. Principal contribution of HLA-DQ alleles, DQB1*06:04 and DQB1*03:01, to disease resistance against primary biliary cholangitis in a Japanese population. Sci Rep 2017; 7:11093. [PMID: 28894202 PMCID: PMC5593890 DOI: 10.1038/s41598-017-11148-6] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2017] [Accepted: 08/21/2017] [Indexed: 01/07/2023] Open
Abstract
Identification of the primary allele(s) in HLA class II associated diseases remains challenging because of a tight linkage between alleles of HLA-DR and -DQ loci. In the present study, we determined the genotypes of seven HLA loci (HLA-A, -B, -DRB1, -DQA1, -DQB1, -DPA1 and -DPB1) for 1200 Japanese patients with primary biliary cholangitis and 1196 controls. Observation of recombination derivatives facilitated an evaluation of the effects of individual HLA alleles consisting of disease-prone/disease-resistant HLA haplotypes. Consequently, a primary contribution of DQB1*06:04 (odds ratio: 0.19, p = 1.91 × 10−22), DQB1*03:01 (odds ratio: 0.50, p = 6.76 × 10−10), DRB1*08:03 (odds ratio: 1.75, p = 1.01 × 10−7) and DQB1*04:01 (odds ratio: 1.50, p = 9.20 × 10−6) was suggested. Epistasis of the protective DQB1*06:04 to risk conferred by DRB1*08:03 was demonstrated by subpopulation analysis, implicating the presence of an active immunological mechanism that alleviates pathogenic autoimmune reactions. Further, the contribution of the aforementioned HLA alleles as well as an HLA-DP allele, DPB1*02:01 to the association signals of 304 loci among 4103 SNPs in the HLA region at the genome-wide level of significance (p values less than 5 × 10−8) was demonstrated by the stepwise exclusion of the individuals possessing these HLA alleles from the comparison.
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Affiliation(s)
- Michio Yasunami
- Department of Medical Genomics, Life Science Institute, Saga-Ken Medical Centre Koseikan, Saga, 840-8571, Japan. .,Department of Clinical Medicine, Institute of Tropical Medicine, Nagasaki University, Nagasaki, 852-8523, Japan.
| | - Hitomi Nakamura
- Department of Clinical Medicine, Institute of Tropical Medicine, Nagasaki University, Nagasaki, 852-8523, Japan.,Clinical Research Center, National Hospital Organization (NHO) Nagasaki Medical Center and Department of Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Omura, 856-8562, Japan
| | - Katsushi Tokunaga
- Department of Human Genetics, Graduate School of Medicine, the University of Tokyo, Tokyo, 113-0033, Japan
| | - Minae Kawashima
- Department of Human Genetics, Graduate School of Medicine, the University of Tokyo, Tokyo, 113-0033, Japan
| | - Nao Nishida
- Department of Human Genetics, Graduate School of Medicine, the University of Tokyo, Tokyo, 113-0033, Japan.,The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa, 272-8516, Japan
| | - Yuki Hitomi
- Department of Human Genetics, Graduate School of Medicine, the University of Tokyo, Tokyo, 113-0033, Japan
| | - Minoru Nakamura
- Clinical Research Center, National Hospital Organization (NHO) Nagasaki Medical Center and Department of Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Omura, 856-8562, Japan. .,Headquarters of PBC Research in the NHO Study Group for Liver Disease in Japan (NHOSLJ), Omura, 856-8562, Japan. .,Headquarters of gp210 Working Group in Intractable Hepatobiliary Disease Study Group supported by the Ministry of Health, Labour and Welfare of Japan (gp210WG), Omura, 856-8562, Japan.
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Genetic Contribution to the Pathogenesis of Primary Biliary Cholangitis. J Immunol Res 2017; 2017:3073504. [PMID: 28255561 PMCID: PMC5309396 DOI: 10.1155/2017/3073504] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2016] [Accepted: 01/12/2017] [Indexed: 12/14/2022] Open
Abstract
Formerly termed primary biliary cirrhosis, primary biliary cholangitis (PBC) is a chronic and progressive cholestatic liver disease characterized by the presence of antimitochondrial antibodies. Ursodeoxycholic acid (UDCA) therapy is the most effective and approved treatment for PBC and leads to a favorable outcome in the vast majority of cases. Although the etiology of PBC has not yet been elucidated, human leukocyte antigen (HLA) class II alleles have been consistently associated with disease onset for decades. Individuals in different geographic regions of the world may have varying susceptibility alleles that reflect indigenous triggering antigens. In this review, we describe the influence of HLA alleles and other gene polymorphisms on PBC along with the results of genome-wide association studies (GWAS) on this disease.
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Almasio PL, Licata A, Maida M, Macaluso FS, Costantino A, Alessi N, Grimaudo S, Accardi G, Caruso C, Craxi A. Clinical Course and Genetic Susceptibility of Primary Biliary Cirrhosis: Analysis of a Prospective Cohort. HEPATITIS MONTHLY 2016; 16:e31681. [PMID: 28070198 PMCID: PMC5203613 DOI: 10.5812/hepatmon.31681] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/20/2015] [Revised: 11/28/2015] [Accepted: 12/19/2015] [Indexed: 12/11/2022]
Abstract
BACKGROUND Natural history of primary biliary cirrhosis (PBC) is partially characterized in patients from the Mediterranean area whose genetic background differs from that of Northern Europeans. OBJECTIVES We aimed to describe genetic susceptibility and clinical course of PBC in patients from Southern Italy. METHODS Socio-demographic, clinical, biochemical and histological data at diagnosis as well as disease progression of 81 PBC consecutive patients were collected. All subjects were treated with Ursodeoxycholic acid at a dose of 15 mg/kg. HLA class II DRB1 alleles were compared with those of 237 healthy control subjects. IL28B genotyping for IL28B rs12979860 C/T and rs80899917 G/T was performed in a sub-group of patients. RESULTS HLA-DRB1*07 (RR 5.3, P = 0.0008) and HLA-DRB1*08 (RR n.c. P = 0.0005) were significantly associated with the risk of PBC development. Patients younger than 45 years had significantly higher alanine aminotransferase (P = 0.038) and alkaline phosphatase levels (P = 0.047) than older cases. In comparison to non-CC rs12979860, patients with CC rs12979860 genotype showed an early histological stage at onset (93.8% vs. 62.5%, P = 0.03). After a mean follow-up of 61 months, three patients died, one underwent liver transplantation and sixteen (21.9%) had progression of the disease. At multivariate analysis, extrahepatic autoimmune disease (P = 0.04), pruritus (P = 0.008) and advanced histological stage (P < 0.0001) were independent risk factors for disease progression. CONCLUSIONS HLA-DRB1*07 and HLA-DRB1*08 alleles increase susceptibility to disease development. At onset, higher biochemical activity was observed in younger patients, whereas rs12979860 CC genotype was associated with milder histological stage. Pruritus and coexistence of extrahepatic autoimmune diseases were significantly associated with poorer prognosis.
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Affiliation(s)
- Piero Luigi Almasio
- Sezione di Gastroenterologia ed Epatologia, Dipartimento Biomedico di Medicina Interna e Specialistica, University of Palermo, Palermo, Italy
| | - Anna Licata
- Sezione di Gastroenterologia ed Epatologia, Dipartimento Biomedico di Medicina Interna e Specialistica, University of Palermo, Palermo, Italy
| | - Marcello Maida
- Sezione di Gastroenterologia ed Epatologia, Dipartimento Biomedico di Medicina Interna e Specialistica, University of Palermo, Palermo, Italy
| | - Fabio Salvatore Macaluso
- Sezione di Gastroenterologia ed Epatologia, Dipartimento Biomedico di Medicina Interna e Specialistica, University of Palermo, Palermo, Italy
| | - Andrea Costantino
- Sezione di Gastroenterologia ed Epatologia, Dipartimento Biomedico di Medicina Interna e Specialistica, University of Palermo, Palermo, Italy
| | - Nicola Alessi
- Sezione di Gastroenterologia ed Epatologia, Dipartimento Biomedico di Medicina Interna e Specialistica, University of Palermo, Palermo, Italy
| | - Stefania Grimaudo
- Sezione di Gastroenterologia ed Epatologia, Dipartimento Biomedico di Medicina Interna e Specialistica, University of Palermo, Palermo, Italy
| | - Giulia Accardi
- Dipartimento di Biopatologia e Biotecnologie Mediche, University of Palermo, Palermo, Italy
| | - Calogero Caruso
- Dipartimento di Biopatologia e Biotecnologie Mediche, University of Palermo, Palermo, Italy
| | - Antonio Craxi
- Sezione di Gastroenterologia ed Epatologia, Dipartimento Biomedico di Medicina Interna e Specialistica, University of Palermo, Palermo, Italy
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34
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Liberal R, Grant CR. Cirrhosis and autoimmune liver disease: Current understanding. World J Hepatol 2016; 8:1157-1168. [PMID: 27729952 PMCID: PMC5055585 DOI: 10.4254/wjh.v8.i28.1157] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2016] [Revised: 05/14/2016] [Accepted: 08/08/2016] [Indexed: 02/06/2023] Open
Abstract
Primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC) and autoimmune hepatitis (AIH) constitute the classic autoimmune liver diseases (AILDs). While AIH target the hepatocytes, in PBC and PSC the targets of the autoimmune attack are the biliary epithelial cells. Persistent liver injury, associated with chronic AILD, leads to un-resolving inflammation, cell proliferation and the deposition of extracellular matrix proteins by hepatic stellate cells and portal myofibroblasts. Liver cirrhosis, and the resultant loss of normal liver function, inevitably ensues. Patients with cirrhosis have higher risks or morbidity and mortality, and that in the decompensated phase, complications of portal hypertension and/or liver dysfunction lead to rapid deterioration. Accurate diagnosis and monitoring of cirrhosis is, therefore of upmost importance. Liver biopsy is currently the gold standard technique, but highly promising non-invasive methodology is under development. Liver transplantation (LT) is an effective therapeutic option for the management of end-stage liver disease secondary to AIH, PBC and PSC. LT is indicated for AILD patients who have progressed to end-stage chronic liver disease or developed intractable symptoms or hepatic malignancy; in addition, LT may also be indicated for patients presenting with acute liver disease due to AIH who do not respond to steroids.
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Clemente MG, Frau F, Bernasconi M, Macis MD, Cicotto L, Pilleri G, De Virgiliis S, Castiglia P, Farci P. Distinctive HLA-II association with primary biliary cholangitis on the Island of Sardinia. United European Gastroenterol J 2016; 5:527-531. [PMID: 28588884 DOI: 10.1177/2050640616665030] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2016] [Accepted: 07/26/2016] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND The HLA DRB1*08 allele associated with primary biliary cholangitis (PBC) among Caucasians is of low frequency in the Sardinian population. OBJECTIVE The aim of our study was to type a cohort of PBC patients from the island of Sardinia for HLA class II antigens. METHODS Twenty Sardinian patients affected by PBC, 14 with autoimmune hepatitis (AIH) and 89 healthy controls (HCs) were typed for HLA class II alleles by dot-blot analysis. RESULTS The PBC-associated HLA DRB1*08 allele was detected in none of the studied individuals. The DRB1*0301-DQB1*0201 was the prevalent HLA haplotype, detected in 19 (47.5%) out of 40 PBC haplotypes (OR = 3.0; 95% CI 1.5-6.2) and in 11 (39.3%) out of 28 AIH haplotypes (OR = 2.2; 95% CI 0.94-5.0), but in only 41 (23%) out of 178 HC haplotypes. Moreover, PBC patients showed an increased frequency of homozygosity for the DQB1*0201 allele (35% compared with 6.7% of the HCs; OR = 7.5; 95% CI 2.2-25.7). The frequency of the DRB1*11 allele in the PBC group was about half of that seen in the Sardinian HCs (7.5% vs 15.7%) (p = ns). CONCLUSIONS Our study confirmed the low frequency of the HLA DRB1*08 allele among Sardinians, either in the general population or PBC patients. The high prevalence of the HLA DRB1*0301-DQB1*0201 haplotype is a distinctive genetic feature of PBC among Sardinians. Our study strengthens the hypothesis that still unknown genetic, epigenetic, and environmental factors must be involved in the pathogenesis of different HLA-associated liver diseases, and it represents a pathfinder that warrants exploration in a future extensive study.
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Affiliation(s)
- Maria Grazia Clemente
- Department of Biomedical Sciences and Biotechnologies, University of Cagliari, Cagliari, Italy.,Present address: Department of Surgical, Microsurgical and Medical Sciences, University of Sassari, Sassari, Italy
| | - Fulvia Frau
- Department of Biomedical Sciences and Biotechnologies, University of Cagliari, Cagliari, Italy
| | | | - Maria Doloretta Macis
- Department of Biomedical Sciences and Biotechnologies, University of Cagliari, Cagliari, Italy
| | - Lucia Cicotto
- Department of Biomedical Sciences and Biotechnologies, University of Cagliari, Cagliari, Italy
| | - Giampaolo Pilleri
- 2nd Division of Medicine, Azienda Ospedaliera Brotzu, Cagliari, Italy
| | - Stefano De Virgiliis
- Department of Biomedical Sciences and Biotechnologies, University of Cagliari, Cagliari, Italy
| | - Paolo Castiglia
- Department of Biomedical Sciences, University of Sassari, Sassari, Italy
| | - Patrizia Farci
- Department of Medical Sciences "Mario Aresu", University of Cagliari, Cagliari, Italy.,Present address: Hepatic Pathogenesis Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
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36
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Bekki N, Bae SK, Yoshizawa S, Shiota A, Gushima T, Motoshita J, Shimoda S, Aiba Y, Komori A, Nakamura M, Takahashi K. A case of primary biliary cirrhosis in a patient with rheumatoid arthritis. Clin Case Rep 2016; 4:90-4. [PMID: 26783445 PMCID: PMC4706410 DOI: 10.1002/ccr3.449] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2015] [Revised: 09/09/2015] [Accepted: 10/25/2015] [Indexed: 01/26/2023] Open
Abstract
The true prevalence of PBC in RA is not well known. Herein, we report an unusual case of a patient with PBC and RA, and discuss the association between these two diseases. PBC should be ruled out in the differential diagnosis of patients with RA having abnormal liver function tests.
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Affiliation(s)
- Norifumi Bekki
- The center for liver disease Hamanomachi Hospital 3-3-1 Nagahama Chuo-ku Fukuoka 810-8539 Japan
| | - Sung Kwan Bae
- The center for liver disease Hamanomachi Hospital 3-3-1 Nagahama Chuo-ku Fukuoka 810-8539 Japan
| | - Seiji Yoshizawa
- Department of Rheumatology Hamanomachi Hospital Fukuoka Japan
| | - Ayaka Shiota
- The center for liver disease Hamanomachi Hospital 3-3-1 Nagahama Chuo-ku Fukuoka 810-8539 Japan
| | - Toshifumi Gushima
- The center for liver disease Hamanomachi Hospital 3-3-1 Nagahama Chuo-ku Fukuoka 810-8539 Japan
| | | | - Shinji Shimoda
- Medicine and Biosystemic Science Kyushu University Fukuoka Japan
| | - Yoshihiro Aiba
- Clinical Research Center National Hospital Organization (NHO) Nagasaki Medical Center Nagasaki Japan
| | - Atsumasa Komori
- Clinical Research Center National Hospital Organization (NHO) Nagasaki Medical Center Nagasaki Japan
| | - Minoru Nakamura
- Clinical Research Center National Hospital Organization (NHO) Nagasaki Medical Center Nagasaki Japan
| | - Kazuhiro Takahashi
- The center for liver disease Hamanomachi Hospital 3-3-1 Nagahama Chuo-ku Fukuoka 810-8539 Japan
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37
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Zhang AP, Yang JH. Advances in understanding pathogenesis of primary biliary cholangitis. Shijie Huaren Xiaohua Zazhi 2016; 24:169-175. [DOI: 10.11569/wcjd.v24.i2.169] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Primary biliary cholangitis (PBC) is an autoimmune liver disease characterized by chronic and progressive cholestasis. In recent years, the incidence and prevalence of PBC are increasing year by year. However, the etiology and pathogenesis are not fully understood. It is believed that genetic susceptibility, environmental factors, and immunologic tolerance are related with the pathogenesis of PBC. This article reviews the progress in the understanding of the pathogenesis of PBC.
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38
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Abstract
Genome-wide association studies (GWASs) have been a significant technological advance in our ability to evaluate the genetic architecture of complex diseases such as primary biliary cirrhosis (PBC). To date, six large-scale studies have been performed that have identified 27 risk loci in addition to human leukocyte antigen (HLA) associated with PBC. The identified risk variants emphasize important disease concepts; namely, that disturbances in immunoregulatory pathways are important in the pathogenesis of PBC and that such perturbations are shared among a diverse number of autoimmune diseases-suggesting the risk architecture may confer a generalized propensity to autoimmunity not necessarily specific to PBC. Furthermore, the impact of non-HLA risk variants, particularly in genes involved with interleukin-12 signaling, and ethnic variation in conferring susceptibility to PBC have been highlighted. Although GWASs have been a critical stepping stone in understanding common genetic variation contributing to PBC, limitations pertaining to power, sample availability, and strong linkage disequilibrium across genes have left us with an incomplete understanding of the genetic underpinnings of disease pathogenesis. Future efforts to gain insight into this missing heritability, the genetic variation that contributes to important disease outcomes, and the functional consequences of associated variants will be critical if practical clinical translation is to be realized.
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Affiliation(s)
- Aliya F. Gulamhusein
- Division of Gastroenterology and Hepatology and the Mayo Clinic Center for Cell Signaling, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, Minnesota 55905
| | - Brian D. Juran
- Division of Gastroenterology and Hepatology and the Mayo Clinic Center for Cell Signaling, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, Minnesota 55905
| | - Konstantinos N. Lazaridis
- Division of Gastroenterology and Hepatology and the Mayo Clinic Center for Cell Signaling, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, Minnesota 55905. Phone: (507) 538-4877. Fax: (507) 284-0762
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Webb GJ, Siminovitch KA, Hirschfield GM. The immunogenetics of primary biliary cirrhosis: A comprehensive review. J Autoimmun 2015; 64:42-52. [PMID: 26250073 PMCID: PMC5014907 DOI: 10.1016/j.jaut.2015.07.004] [Citation(s) in RCA: 90] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2015] [Accepted: 07/06/2015] [Indexed: 12/20/2022]
Abstract
Primary biliary cirrhosis (PBC), a classic autoimmune liver disease, is characterised by a progressive T cell predominant lymphocytic cholangitis, and a serologic pattern of reactivity in the form of specific anti-mitochondrial antibodies (AMA). CD4+ T cells are particularly implicated by PBC's cytokine signature, the presence of CD4+ T cells specific to mitochondrial auto-antigens, the expression of MHC II on injured biliary epithelial cells, and PBC's coincidence with other similar T cell mediated autoimmune conditions. CD4+ T cells are also central to current animal models of PBC, and their transfer typically also transfers disease. The importance of genetic risk to developing PBC is evidenced by a much higher concordance rate in monozygotic than dizygotic twins, increased AMA rates in asymptomatic relatives, and disproportionate rates of disease in siblings of PBC patients, PBC family members and certain genetically defined populations. Recently, high-throughput genetic studies have greatly expanded our understanding of the gene variants underpinning risk for PBC development, so linking genetics and immunology. Here we summarize genetic association data that has emerged from large scale genome-wide association studies and discuss the evidence for the potential functional significance of the individual genes and pathways identified; we particularly highlight associations in the IL-12-STAT4-Th1 pathway. HLA associations and epigenetic effects are specifically considered and individual variants are linked to clinical phenotypes where data exist. We also consider why there is a gap between calculated genetic risk and clinical data: so-called missing heritability, and how immunogenetic observations are being translated to novel therapies. Ultimately whilst genetic risk factors will only account for a proportion of disease risk, ongoing efforts to refine associations and understand biologic links to disease pathways are hoped to drive more rational therapy for patients.
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Affiliation(s)
- G J Webb
- NIHR Birmingham Liver Biomedical Research Unit, University of Birmingham, Birmingham, UK
| | - K A Siminovitch
- Mount Sinai Hospital, Lunenfeld-Tanenbaum Research Institute, Toronto General Research Institute, and Departments of Immunology and Molecular Genetics, University of Toronto, Toronto, Ontario, Canada
| | - G M Hirschfield
- NIHR Birmingham Liver Biomedical Research Unit, University of Birmingham, Birmingham, UK.
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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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Mackie SL, Taylor JC, Haroon-Rashid L, Martin S, Dasgupta B, Gough A, Green M, Hordon L, Jarrett S, Pease CT, Barrett JH, Watts R, Morgan AW. Association of HLA-DRB1 amino acid residues with giant cell arteritis: genetic association study, meta-analysis and geo-epidemiological investigation. Arthritis Res Ther 2015; 17:195. [PMID: 26223536 PMCID: PMC4520081 DOI: 10.1186/s13075-015-0692-4] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2014] [Accepted: 06/18/2015] [Indexed: 12/15/2022] Open
Abstract
INTRODUCTION Giant cell arteritis (GCA) is an autoimmune disease commonest in Northern Europe and Scandinavia. Previous studies report various associations with HLA-DRB1*04 and HLA-DRB1*01; HLA-DRB1 alleles show a gradient in population prevalence within Europe. Our aims were (1) to determine which amino acid residues within HLA-DRB1 best explained HLA-DRB1 allele susceptibility and protective effects in GCA, seen in UK data combined in meta-analysis with previously published data, and (2) to determine whether the incidence of GCA in different countries is associated with the population prevalence of the HLA-DRB1 alleles that we identified in our meta-analysis. METHODS GCA patients from the UK GCA Consortium were genotyped by using single-strand oligonucleotide polymerization, allele-specific polymerase chain reaction, and direct sequencing. Meta-analysis was used to compare and combine our results with published data, and public databases were used to identify amino acid residues that may explain observed susceptibility/protective effects. Finally, we determined the relationship of HLA-DRB1*04 population carrier frequency and latitude to GCA incidence reported in different countries. RESULTS In our UK data (225 cases and 1378 controls), HLA-DRB1*04 carriage was associated with GCA susceptibility (odds ratio (OR) = 2.69, P = 1.5×10(-11)), but HLA-DRB1*01 was protective (adjusted OR = 0.55, P = 0.0046). In meta-analysis combined with 14 published studies (an additional 691 cases and 4038 controls), protective effects were seen from HLA-DR2, which comprises HLA-DRB1*15 and HLA-DRB1*16 (OR = 0.65, P = 8.2×10(-6)) and possibly from HLA-DRB1*01 (OR = 0.73, P = 0.037). GCA incidence (n = 17 countries) was associated with population HLA-DRB1*04 allele frequency (P = 0.008; adjusted R(2) = 0.51 on univariable analysis, adjusted R(2) = 0.62 after also including latitude); latitude also made an independent contribution. CONCLUSIONS We confirm that HLA-DRB1*04 is a GCA susceptibility allele. The susceptibility data are best explained by amino acid risk residues V, H, and H at positions 11, 13, and 33, contrary to previous suggestions of amino acids in the second hypervariable region. Worldwide, GCA incidence was independently associated both with population frequency of HLA-DRB1*04 and with latitude itself. We conclude that variation in population HLA-DRB1*04 frequency may partly explain variations in GCA incidence and that HLA-DRB1*04 may warrant investigation as a potential prognostic or predictive biomarker.
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Affiliation(s)
- Sarah Louise Mackie
- School of Medicine and NIHR-Leeds Biomedical Research Unit, Chapel Allerton Hospital, Leeds, LS7 4SA, West Yorkshire, UK.
| | - John C Taylor
- School of Medicine and NIHR-Leeds Biomedical Research Unit, Chapel Allerton Hospital, Leeds, LS7 4SA, West Yorkshire, UK.
| | - Lubna Haroon-Rashid
- School of Medicine and NIHR-Leeds Biomedical Research Unit, Chapel Allerton Hospital, Leeds, LS7 4SA, West Yorkshire, UK.
| | - Stephen Martin
- School of Medicine and NIHR-Leeds Biomedical Research Unit, Chapel Allerton Hospital, Leeds, LS7 4SA, West Yorkshire, UK.
| | - Bhaskar Dasgupta
- Department of Rheumatology, Southend University Hospital, Prittlewell Chase, Southend, SS0 0RY, Essex, UK.
| | - Andrew Gough
- Department of Rheumatology, Harrogate and District Foundation NHS Trust, Lancaster Park Road, Harrogate, HG2 7SX, North Yorkshire, UK.
| | - Michael Green
- Department of Rheumatology, York Teaching Hospital NHS Foundation Trust, Wigginton Road, York, YO31 8HE, North Yorkshire, UK.
| | - Lesley Hordon
- Department of Rheumatology, Dewsbury and District Hospital, Halifax Road, Dewsbury, WF13 4HS, West Yorkshire, UK.
| | - Stephen Jarrett
- Department of Rheumatology, Pinderfields General Hospital, Aberford Road, Wakefield, WF1 4DG, West Yorkshire, UK.
| | - Colin T Pease
- Department of Rheumatology, Chapel Allerton Hospital, Leeds, Leeds, LS7 4SA, West Yorkshire, UK.
| | - Jennifer H Barrett
- School of Medicine and NIHR-Leeds Biomedical Research Unit, Chapel Allerton Hospital, Leeds, LS7 4SA, West Yorkshire, UK.
| | - Richard Watts
- Department of Rheumatology, Ipswich Hospital NHS Trust, Heath Road, Ipswich, IP4 5PD, Suffolk, UK.
| | - Ann W Morgan
- School of Medicine and NIHR-Leeds Biomedical Research Unit, Chapel Allerton Hospital, Leeds, LS7 4SA, West Yorkshire, UK.
- Wellcome Trust Brenner Building, St. James's University Hospital, Beckett Street, Leeds, LS9 7TF, West Yorkshire, UK.
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Tang R, Chen H, Miao Q, Bian Z, Ma W, Feng X, Seldin MF, Invernizzi P, Gershwin ME, Liao W, Ma X. The cumulative effects of known susceptibility variants to predict primary biliary cirrhosis risk. Genes Immun 2015; 16:193-8. [PMID: 25569263 PMCID: PMC5553973 DOI: 10.1038/gene.2014.76] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2014] [Revised: 09/25/2014] [Accepted: 10/02/2014] [Indexed: 12/12/2022]
Abstract
Multiple genetic variants influence the risk for development of primary biliary cirrhosis (PBC). To explore the cumulative effects of known susceptibility loci on risk, we utilized a weighted genetic risk score (wGRS) to evaluate whether genetic information can predict susceptibility. The wGRS was created using 26 known susceptibility loci and investigated in 1840 UK PBC and 5164 controls. Our data indicate that the wGRS was significantly different between PBC and controls (P=1.61E-142). Moreover, we assessed predictive performance of wGRS on disease status by calculating the area under the receiver operator characteristic curve. The area under curve for the purely genetic model was 0.72 and for gender plus genetic model was 0.82, with confidence limits substantially above random predictions. The risk of PBC using logistic regression was estimated after dividing individuals into quartiles. Individuals in the highest disclosed risk group demonstrated a substantially increased risk for PBC compared with the lowest risk group (odds ratio: 9.3, P=1.91E-084). Finally, we validated our findings in an analysis of an Italian PBC cohort. Our data suggested that the wGRS, utilizing genetic variants, was significantly associated with increased risk for PBC with consistent discriminant ability. Our study is a first step toward risk prediction for PBC.
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Affiliation(s)
- Ruqi Tang
- State Key Laboratory for Oncogenes and Related Genes, Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Cancer Institute, Shanghai Institute of Digestive Disease, China
| | - Haoyan Chen
- State Key Laboratory for Oncogenes and Related Genes, Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Cancer Institute, Shanghai Institute of Digestive Disease, China
- Department of Dermatology, University of California San Francisco, San Francisco, CA, USA
| | - Qi Miao
- State Key Laboratory for Oncogenes and Related Genes, Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Cancer Institute, Shanghai Institute of Digestive Disease, China
| | - Zhaolian Bian
- State Key Laboratory for Oncogenes and Related Genes, Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Cancer Institute, Shanghai Institute of Digestive Disease, China
| | - Wansu Ma
- Department of Anesthesia and Perioperative Care, University of California, San Francisco, San Francisco, CA, USA
| | - Xiaomei Feng
- Division of Gastroenterology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Michael F. Seldin
- Department of Biochemistry and Molecular Medicine, University of California at Davis, Davis, CA, USA
- Department of Medicine, Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, Davis, CA, USA
| | - Pietro Invernizzi
- Clinical Immunology, IRCCS Istituto Clinico Humanitas, Rozzano, Milan, Italy
| | - M. Eric Gershwin
- Department of Medicine, Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, Davis, CA, USA
| | - Wilson Liao
- Department of Dermatology, University of California San Francisco, San Francisco, CA, USA
| | - Xiong Ma
- State Key Laboratory for Oncogenes and Related Genes, Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Cancer Institute, Shanghai Institute of Digestive Disease, China
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Quarneti C, Muratori P, Lalanne C, Fabbri A, Menichella R, Granito A, Masi C, Lenzi M, Cassani F, Pappas G, Muratori L. Fatigue and pruritus at onset identify a more aggressive subset of primary biliary cirrhosis. Liver Int 2015; 35:636-641. [PMID: 24698666 DOI: 10.1111/liv.12560] [Citation(s) in RCA: 55] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2014] [Accepted: 03/28/2014] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS In recent years, primary biliary cirrhosis is mostly diagnosed in patients who are asymptomatic; however, a proportion of cases still present with typical complaints such as fatigue and/or pruritus. We compared biochemical, histological and immunological features of patients with or without fatigue and/or pruritus at onset to see whether the different clinical presentation may eventually impact on disease progression. METHODS We analysed the Bologna cohort of 216 patients with primary biliary cirrhosis referred to our Centre between 1997 and 2007, according to symptomatic (fatigue and/or pruritus) or asymptomatic presentation. Clinical, biochemical, histological and immunological feature at diagnosis, response to ursodeoxycholic acid and progression of the disorder were compared after a mean follow-up of 81 ± 75 months. RESULTS At diagnosis, symptomatic patients were significantly more often women (98.6% vs. 87.2%, P = 0.004), younger (mean age 49 ± 12 vs. 55 ± 12 years, P = 0.003) and with more pronounced biochemical activity, as indicated by higher alkaline phosphatase (mean 2.93 ± 2 vs. 2.12, P = 0.002) and aminotransferase (mean 1.92 ± 1 vs. 1.47 ± 1.27, P = 0.014) levels, whereas histological stage and autoantibody profile were similar. Symptomatic patients were less likely to respond to ursodeoxycholic acid therapy (63% vs. 81%, P = 0.006) and developed more often cirrhosis and its complications (31% vs. 13%, P = 0.004). CONCLUSIONS Fatigue and/or pruritus at onset identify a subset of patients with primary biliary cirrhosis who preferentially are women, younger, with a particularly active disease, less responsive to ursodeoxycholic acid treatment, and more inclined to evolve to cirrhosis and its complications.
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Affiliation(s)
- Chiara Quarneti
- Department of Medical and Surgical Sciences, Alma Mater Studiorum - University of Bologna, Azienda Ospedaliera Universitaria Sant'Orsola-Malpighi, Bologna, Italy
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Umemura T, Katsuyama Y, Yoshizawa K, Kimura T, Joshita S, Komatsu M, Matsumoto A, Tanaka E, Ota M. Human leukocyte antigen class II haplotypes affect clinical characteristics and progression of type 1 autoimmune hepatitis in Japan. PLoS One 2014; 9:e100565. [PMID: 24956105 PMCID: PMC4067340 DOI: 10.1371/journal.pone.0100565] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2014] [Accepted: 05/25/2014] [Indexed: 12/31/2022] Open
Abstract
Although we earlier demonstrated that the human leukocyte antigen (HLA) DRB1*04:05 allele was associated with susceptibility to autoimmune hepatitis (AIH) in Japan, the precise relationship of HLA haplotype and the role of amino acid alignment with disease susceptibility and progression has not been fully clarified. We reinvestigated HLA class I A, B, and C and HLA class II DRB1, DQB1, and DPB1 alleles and haplotypes in a larger new cohort of 156 Japanese patients with type 1 AIH and compared them with the published data of 210 healthy subjects. The DRB1*04:05-DQB1*04:01 haplotype was significantly associated with AIH susceptibility (30% vs. 11%, P = 1.2×10−10; odds ratio [OR] = 3.51) and correlated with elevated serum IgG (3042 vs. 2606 mg/dL, P = 0.041) and anti-smooth muscle antigen positivity (77% vs. 34%, P = 0.000006). No associations with HLA-DPB1 alleles were found. The HLA A*24:02 and C*01:02 alleles were associated with disease susceptibility (corrected P = 0.0053 and 0.036, respectively), but this likely constituents of a long ranged haplotype including DRB1*04:05-DQB1*04:01 haplotype. Conversely, the DRB1*15:01-DQB1*06:02 haplotype was associated with protection from both disease onset (5% vs. 13%, P = 0.00057; OR = 0.38) and the development of hepatocellular carcinoma (25% vs. 5%, P = 0.017; OR = 6.81). The frequency of the DRB1*08:03-DQB1*06:01 haplotype was significantly higher in patients who developed hepatic failure (22% vs. 6%, P = 0.034; OR = 4.38). In conclusion, this study established the role of HLA haplotypes in determining AIH susceptibility and progression in the Japanese population. Additional sequencing of the entire HLA region is required to more precisely identify the genetic components of AIH.
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Affiliation(s)
- Takeji Umemura
- Department of Medicine, Division of Hepatology and Gastroenterology, Shinshu University School of Medicine, Matsumoto, Japan
| | | | - Kaname Yoshizawa
- Department of Medicine, Division of Hepatology and Gastroenterology, Shinshu University School of Medicine, Matsumoto, Japan; Department of Gastroenterology, NHO Ueda Medical Center, Ueda, Japan
| | - Takefumi Kimura
- Department of Medicine, Division of Hepatology and Gastroenterology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Satoru Joshita
- Department of Medicine, Division of Hepatology and Gastroenterology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Michiharu Komatsu
- Department of Medicine, Division of Hepatology and Gastroenterology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Akihiro Matsumoto
- Department of Medicine, Division of Hepatology and Gastroenterology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Eiji Tanaka
- Department of Medicine, Division of Hepatology and Gastroenterology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Masao Ota
- Department of Legal Medicine, Shinshu University School of Medicine, Matsumoto, Japan
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Li M, Zheng H, Tian QB, Rui MN, Liu DW. HLA-DR polymorphism and primary biliary cirrhosis: evidence from a meta-analysis. Arch Med Res 2014; 45:270-9. [PMID: 24657596 DOI: 10.1016/j.arcmed.2014.03.002] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2013] [Accepted: 02/26/2014] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIMS We undertook this study to review and quantitatively analyze the association between human leukocyte antigen (HLA) DR polymorphisms and susceptibility of primary biliary cirrhosis (PBC). METHODS All relevant publications on the association between HLA-DR polymorphisms and PBC were searched through June 2013. Odds ratios (OR) and confidence intervals (CI) for the comparisons between case and control group were calculated. Statistical analysis was performed using Stata 11.0 software. RESULTS Nineteen articles (or 20 studies including the substudies) were identified. For DR*7 allele, the ORs (95% CIs) were 1.530 (1.310, 1.788), 1.757 (1.285, 2.403) and 1.495 (1.211, 1.845) in overall, Asian and European populations, respectively. For DR*8 alleles, the ORs (95% CIs) were 3.158 (1.822, 5.475), 2.803 (2.420, 3.247) and 3.056 (2.573, 3.629) in Asian, American and European subgroups, respectively. The subgroup analysis for DR*11 and DR*13 showed a significant association in Asian and European population. For DR*12 and *15 alleles, the overall ORs (95% CIs) were 0.551 (0.404, 0.753) and 0.721 (0.607, 0.857). However, in subgroup analysis for DR*12 allele, the association was only found in Asian population. In addition, statistical significance exists in American and European populations in the subgroup analysis for DR*15 allele. CONCLUSION Our meta-analysis suggested that HLA-DR *7 and *8 allele polymorphisms contributed to the susceptibility of PBC, whereas DR*11, *12, *13 and *15 allele polymorphisms are protective factors in certain population.
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Affiliation(s)
- Man Li
- Department of Epidemiology and Statistics, School of Public Health, Hebei Medical University, Shijiazhuang, China
| | - Hao Zheng
- Department of Ultrasonography, Hebei Chest Hospital, Shijiazhuang, China
| | - Qing-bao Tian
- Department of Epidemiology and Statistics, School of Public Health, Hebei Medical University, Shijiazhuang, China
| | - Mei-na Rui
- Department of Epidemiology and Statistics, School of Public Health, Hebei Medical University, Shijiazhuang, China
| | - Dian-wu Liu
- Department of Epidemiology and Statistics, School of Public Health, Hebei Medical University, Shijiazhuang, China.
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Mo C, Lu Y, Deng Y, Wang J, Xie L, Li T, He Y, Qin X, Li S. Lack of association between vitamin D receptor gene ApaI, BsmI, and TaqI polymorphisms and primary biliary cirrhosis risk: a meta-analysis. Tumour Biol 2014; 35:4913-20. [PMID: 24526415 DOI: 10.1007/s13277-014-1645-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2013] [Accepted: 01/12/2014] [Indexed: 12/31/2022] Open
Abstract
Previous studies have reported the association between vitamin D receptor (VDR) polymorphisms and the risk of primary biliary cirrhosis (PBC), although these results remain controversial. The aim of this meta-analysis was to evaluate the association of three polymorphisms in VDR with PBC risk. The relevant studies were identified through an electronic database search carried out in September 2013. The crude odds ratio (OR) and 95% confidence interval (CI) were calculated to assess the association between VDR polymorphisms and PBC risk. Six eligible studies which met our selection criteria were included. Overall, the ApaI, BsmI, and TaqI polymorphisms in the VDR gene were not associated with PBC risk (ApaI A vs a OR = 1.132, 95% CI = 0.870-1.472, p = 0.355; BsmI B vs b OR = 1.148, 95% CI = 0.697-1.891, p = 0.589; TaqI t vs T OR = 1.1432, 95% CI = 0.709-1.841, p = 0.584). Furthermore, in subgroup analysis by ethnicity for the ApaI, BsmI, and TaqI polymorphisms, there were no significant results in either Caucasians or Asians under the allele contrast and recessive and dominant models. This meta-analysis indicated that VDR polymorphisms were not a risk factor for PBC. Larger and more carefully designed studies are needed to verify our results.
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Affiliation(s)
- Cuiju Mo
- Department of Clinical Laboratory, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, 530021, China
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Zhao DT, Liao HY, Zhang X, Liu YM, Zhao Y, Zhang HP, Sun LM, Ma YX, Yan HP. Human leucocyte antigen alleles and haplotypes and their associations with antinuclear antibodies features in Chinese patients with primary biliary cirrhosis. Liver Int 2014; 34:220-6. [PMID: 23809616 DOI: 10.1111/liv.12236] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2012] [Accepted: 05/28/2013] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS Primary biliary cirrhosis (PBC) is an autoimmune liver disease. Genetic factors are critical in determining susceptibility to PBC. Among human leuocyte antigen (HLA) genes, an association between the DRB1*08 allele and PBC has been reported in many populations, but not in Chinese patients. METHODS We investigated HLA-A, B, DRB1, and DQB1 alleles and haplotypes in 145 PBC patients and 500 healthy subjects. Patients were also stratified according to autoantibody features, and associations between these and HLA alleles were analyzed. RESULTS Significant associations existed between HLA-DRB1*08:03 (22.1% vs. 9.0%, Pc < 0.0001, OR = 2.86), DQ2 (41.4% vs. 25.4%, Pc < 0.0001, OR = 2.07) and DQB1*06:01 (31.0% vs. 17.8%, Pc = 0.014, OR = 2.08) alleles and PBC. DRB1*08:03-DQB1*06:01 (22.1% vs. 8.2%, P < 0.0001, OR = 3.17) and DRB1*07:01-DQB1*02:02 haplotypes (28.3% vs. 17.6%, P = 0.005, OR = 1.85) were also associated with PBC susceptibility. In contrast, the DQB1*03:01 allele (21.4% vs. 39.2%, Pc < 0.0001, OR = 0.42) and DRB1*12:02-DQB1*03:01 haplotype (6.9% vs. 14.6%, P = 0.015, OR = 0.43) were significantly decreased in PBC patients compared with controls. DRB1*14:54 and DQ5(1) protected against antinuclear antibody (ANA) (OR = 0.25) and anti-gp210 antibody (OR = 0.39) production, respectively, while HLA-B*44:03 predisposed patients to anti-gp210 antibody (OR = 5.70) production. CONCLUSION These results suggest that Chinese patients with PBC have a distinct genetic background in eastern Asia, and we confirmed the role of HLA genes in determining PBC susceptibility and autoantibody features in the Chinese population.
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Affiliation(s)
- Dan-Tong Zhao
- Clinical Research Center for Autoimmune Liver Disease, Beijing You'an Hospital, Capital Medical University, Beijing, China
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Qin B, Wang J, Chen J, Liang Y, Yang Z, Zhong R. Association of human leukocyte antigen class II with susceptibility to primary biliary cirrhosis: a systematic review and meta-analysis. PLoS One 2013; 8:e79580. [PMID: 24265779 PMCID: PMC3827176 DOI: 10.1371/journal.pone.0079580] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2013] [Accepted: 09/27/2013] [Indexed: 12/26/2022] Open
Abstract
Purpose Several previous studies suggested that HLA-ClassII may be associated with susceptibility to primary biliary cirrhosis (PBC), but data from individual studies remain controversial. Therefore, a systematic review and meta-analysis is needed to comprehensively evaluate the association between HLA-ClassII and PBC risk. Methods All published reports of an association between HLA class II and PBC risk were searched in PubMed, EMBASE (updated to 22 May 2012). ORs with 95% confidence intervals (CIs) were extracted from each included study and the meta-analysis was performed using the fixed- or random-effects model. Results A total of 3,732 PBC patients and 11,031 controls from 34 studies were included in the meta-analysis. An assessment of study quality revealed that the majority of studies included (18 studies) were of high quality. The serological group DR8 was found to be a risk factor for PBC (OR = 2.82, 95%CI: 1.84–4.30). At the allelic level, HLA-DR*08 and HLA-DR*0801 were identified as risk factors for PBC (OR = 2.30, 95%CI: 1.76-3.00; OR = 3.23, 95%CI: 2.22–4.70, respectively), whereas HLA-DR*11 and HLA-DR*13 were potent protective factors (OR = 0.31, 95%CI: 0.27-0.38; OR = 0.62, 95%CI: 0.48-0.81, respectively). HLA-DQB1 and HLA-DQB1*0402 conferred a predisposition to PBC development (OR = 3.47, 95%CI: 2.35–5.13), whereas HLA-DQB1*0604 was protective against PBC (OR = 0.3, 95%CI: 0.18–0.58). No HLA-DPB1 allele was observed to be associated with PBC susceptibility (P > 0.05). Conclusions The present study revealed that HLA-ClassII components are closely associated with the development of PBC.
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Affiliation(s)
- Baodong Qin
- Department of Laboratory Diagnostics, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Jiaqi Wang
- Department of Stomatology, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Jia Chen
- Department of Laboratory Diagnostics, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Yan Liang
- Department of Laboratory Diagnostics, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Zaixing Yang
- Department of Laboratory Diagnostics, Changzheng Hospital, Second Military Medical University, Shanghai, China
- * E-mail: (ZXY); (RQZ)
| | - Renqian Zhong
- Department of Laboratory Diagnostics, Changzheng Hospital, Second Military Medical University, Shanghai, China
- * E-mail: (ZXY); (RQZ)
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Inamine T, Higa S, Noguchi F, Kondo S, Omagari K, Yatsuhashi H, Tsukamoto K, Nakamura M. Association of genes involved in bile acid synthesis with the progression of primary biliary cirrhosis in Japanese patients. J Gastroenterol 2013; 48:1160-70. [PMID: 23354620 DOI: 10.1007/s00535-012-0730-9] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2012] [Accepted: 11/26/2012] [Indexed: 02/04/2023]
Abstract
BACKGROUND Patients with primary biliary cirrhosis (PBC) exhibit a variety of clinical manifestations and patterns of disease progression. The aim of this study was to identify genetic determinants of PBC progression. METHODS A total of 52 tag single nucleotide polymorphisms (SNPs) of 11 candidate genes involved in regulating bile acid synthesis were analyzed by polymerase chain reaction (PCR)-restriction fragment length polymorphism, -high resolution melting curve analysis, or -direct DNA sequencing in 315 Japanese patients with PBC. RESULTS In this study, four tag SNPs of CYP7A1 (rs1457043, rs8192870, rs3808607, and rs3824260), two tag SNPs of HNF4A (rs6017340 and 6031587), and one SNP of PPARGC1A (rs8192678) showed a significant association with PBC progression. In addition, a dual luciferase assay revealed that the polymorphism of rs3808607 in CYP7A1 altered the expression of CYP7A1 in HepG2. Specifically, the CYP7A1 promoter carrying the risk G allele for PBC progression induced higher expression of CYP7A1 under both the normal and cholestatic conditions in vitro as compared to another promoter carrying the non-risk T allele. CONCLUSION These results suggested that the genetic variants of CYP7A1 and its transcriptional activators (HNF4A and PPARGC1A) may activate bile acid synthesis, resulting in the accumulation of bile acids in hepatocytes and eventually leading to the predisposition to PBC progression. Thus, the regulation of CYP7A1 expression may represent an attractive therapeutic target for cholestatic liver diseases including PBC.
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Affiliation(s)
- Tatsuo Inamine
- Department of Pharmacotherapeutics, Nagasaki University Graduate School of Biomedical Sciences, 1-14 Bunkyo-machi, Nagasaki, 852-8521, Japan
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Hirschfield GM, Gershwin ME. The immunobiology and pathophysiology of primary biliary cirrhosis. ANNUAL REVIEW OF PATHOLOGY-MECHANISMS OF DISEASE 2013; 8:303-30. [PMID: 23347352 DOI: 10.1146/annurev-pathol-020712-164014] [Citation(s) in RCA: 225] [Impact Index Per Article: 18.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Primary biliary cirrhosis (PBC) is an autoimmune disease characterized by clinical homogeneity among patients, an overwhelming female predominance, production of a multilineage immune response to mitochondrial autoantigens, inflammation of small bile ducts, and in some patients the development of fibrosis and cirrhosis. The targets in this disease are small bile ducts, and the prototypic serologic response includes antimitochondrial antibodies (AMAs). Several key observations have greatly advanced our understanding of PBC. First, the multilineage immune response, including AMAs, is directed at the E2 component of the 2-oxo-dehydrogenase pathway, particularly PDC-E2. Second, such autoantibodies may be identified years before the clinical diagnosis of disease. Third, the autoreactive T cell precursor frequency for both CD4 and CD8 cells is significantly higher in liver and regional lymph node than in blood, so the multilineage antimitochondrial response may be required for the development of this disease. Fourth, the apotope of biliary cells contains intact PDC-E2; this apotope, in a setting that includes granulocyte macrophage colony-stimulating factor-stimulated macrophages and AMAs, produces an intense proinflammatory response. Fifth, several mouse models of PBC highlight the importance of loss of tolerance to PDC-E2 as well as a critical role for the interleukin (IL)-12 signaling pathway. Finally, genome-wide association studies suggest an important role for the IL-12 pathway in disease susceptibility. Taken together, these findings have resulted in a better understanding of the mechanism for selective biliary cell destruction and have also suggested unique pathways for therapeutic intervention.
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Affiliation(s)
- Gideon M Hirschfield
- Centre for Liver Research, NIHR Biomedical Research Unit, University of Birmingham, Birmingham, United Kingdom
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