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1
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Ronca V, Gerussi A, Collins P, Parente A, Oo YH, Invernizzi P. The liver as a central "hub" of the immune system: pathophysiological implications. Physiol Rev 2025; 105:493-539. [PMID: 39297676 DOI: 10.1152/physrev.00004.2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2023] [Revised: 09/05/2024] [Accepted: 09/08/2024] [Indexed: 01/16/2025] Open
Abstract
The purpose of this review is to describe the immune function of the liver, guiding the reader from the homeostatic tolerogenic status to the aberrant activation demonstrated in chronic liver disease. An extensive description of the pathways behind the inflammatory modulation of the healthy liver will be provided focusing on the complex immune cell network residing within the liver. The limit of tolerance will be presented in the context of organ transplantation, seizing the limits of homeostatic mechanisms that fail in accepting the graft, progressing eventually toward rejection. The triggers and mechanisms behind chronic activation in metabolic liver conditions and viral hepatitis will be discussed. The last part of the review will be dedicated to one of the greatest paradoxes for a tolerogenic organ, developing autoimmunity. Through the description of the three most common autoimmune liver diseases, the autoimmune reaction against hepatocytes and biliary epithelial cells will be dissected.
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Affiliation(s)
- Vincenzo Ronca
- Centre for Liver and Gastro Research and National Institute for Health and Care Research (NIHR) Biomedical Research Centre, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
- Liver Unit, Queen Elizabeth Hospital University Hospital Birmingham National Health Service (NHS) Foundation Trust, Birmingham, United Kingdom
- Centre for Rare Diseases, European Reference Network Centre-Rare Liver, Birmingham, United Kingdom
- Department of Biomedical Sciences, Humanitas University, Milan, Italy
- Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Humanitas Research Hospital, Milan, Italy
| | - Alessio Gerussi
- Division of Gastroenterology, Center for Autoimmune Liver Diseases, European Reference Network on Hepatological Diseases (ERN RARE-LIVER), IRCCS Fondazione San Gerardo dei Tintori, Monza, Italy
- Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
| | - Paul Collins
- VIB-UGent Center for Inflammation Research, Ghent, Belgium
- Department of Biomedical Molecular Biology, Faculty of Sciences, Ghent University, Ghent, Belgium
| | - Alessandro Parente
- Liver Unit, Queen Elizabeth Hospital University Hospital Birmingham National Health Service (NHS) Foundation Trust, Birmingham, United Kingdom
- Institute of Liver Studies, King's College Hospital NHS Foundation Trust, London, United Kingdom
| | - Ye Htun Oo
- Centre for Liver and Gastro Research and National Institute for Health and Care Research (NIHR) Biomedical Research Centre, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
- Liver Unit, Queen Elizabeth Hospital University Hospital Birmingham National Health Service (NHS) Foundation Trust, Birmingham, United Kingdom
- Centre for Rare Diseases, European Reference Network Centre-Rare Liver, Birmingham, United Kingdom
| | - Pietro Invernizzi
- Division of Gastroenterology, Center for Autoimmune Liver Diseases, European Reference Network on Hepatological Diseases (ERN RARE-LIVER), IRCCS Fondazione San Gerardo dei Tintori, Monza, Italy
- Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
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2
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Mol B, Werner E, Culver EL, van der Meer AJ, Bogaards JA, Ponsioen CY. Epidemiological and economical burden of cholestatic liver disease. Hepatology 2025:01515467-990000000-01224. [PMID: 40168457 DOI: 10.1097/hep.0000000000001341] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/02/2025] [Accepted: 03/24/2025] [Indexed: 04/03/2025]
Abstract
The main cholestatic liver diseases comprise primary sclerosing cholangitis, primary biliary cholangitis, and IgG4-related cholangitis. Despite being classified as rare diseases, these are becoming gradually more important in the field of hepatology since their incidence is slowly rising while the viral hepatitis burden is declining. Cholestatic liver diseases now rank among the 3 most frequent indications for liver transplantation in many Western countries. An accurate understanding of the epidemiology and burden of disease on both the individual and society of cholestatic diseases is of great importance. This review aims to provide a comprehensive overview of the current literature on the epidemiology, health-related quality of life, and economic burden of primary sclerosing cholangitis, primary biliary cholangitis, and IgG4-related cholangitis.
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Affiliation(s)
- Bregje Mol
- Department of Gastroenterology and Hepatology, Amsterdam University Medical Centre, Amsterdam, The Netherlands
- Endocrinology and Metabolism, Amsterdam Institute of Gastroenterology, Amsterdam, The Netherlands
| | - Ellen Werner
- Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center Rotterdam, The Netherlands
| | - Emma L Culver
- Oxford Liver Unit, John Radcliffe Hospital, Oxford, UK
| | - Adriaan J van der Meer
- Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center Rotterdam, The Netherlands
| | - Johannes A Bogaards
- Department of Epidemiology and Data Science, Amsterdam University Medical Centre, Amsterdam, The Netherlands
| | - Cyriel Y Ponsioen
- Department of Gastroenterology and Hepatology, Amsterdam University Medical Centre, Amsterdam, The Netherlands
- Endocrinology and Metabolism, Amsterdam Institute of Gastroenterology, Amsterdam, The Netherlands
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3
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Zhang JW, Zhang N, Lyu Y, Zhang XF. Influence of Sex in the Development of Liver Diseases. Semin Liver Dis 2025; 45:15-32. [PMID: 39809453 DOI: 10.1055/a-2516-0261] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/16/2025]
Abstract
The liver is a sexually dimorphic organ. Sex differences in prevalence, progression, prognosis, and treatment prevail in most liver diseases, and the mechanism of how liver diseases act differently among male versus female patients has not been fully elucidated. Biological sex differences in normal physiology and disease arise principally from sex hormones and/or sex chromosomes. Sex hormones contribute to the development and progression of most liver diseases, with estrogen- and androgen-mediated signaling pathways mechanistically involved. In addition, genetic factors in sex chromosomes have recently been found to contribute to the sex disparity of many liver diseases, which might explain, to some extent, the difference in gene expression pattern, immune response, and xenobiotic metabolism between men and women. Although increasing evidence suggests that sex is one of the most important modulators of disease prevalence and outcomes, at present, basic and clinical studies have long been sex unbalanced, with female subjects underestimated. As such, this review focuses on sex disparities of liver diseases and summarizes the current understanding of sex-specific mechanisms, including sex hormones, sex chromosomes, etc. We anticipate that understanding sex-specific pathogenesis will aid in promoting personalized therapies for liver disease among male versus female patients.
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Affiliation(s)
- Jie-Wen Zhang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, People's Republic of China
- Institute of Advanced Surgical Technology and Engineering, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, People's Republic of China
- National-Local Joint Engineering Research Center for Precision Surgery and Regenerative Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi Province, People's Republic of China
| | - Nan Zhang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, People's Republic of China
- Institute of Advanced Surgical Technology and Engineering, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, People's Republic of China
- National-Local Joint Engineering Research Center for Precision Surgery and Regenerative Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi Province, People's Republic of China
| | - Yi Lyu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, People's Republic of China
- Institute of Advanced Surgical Technology and Engineering, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, People's Republic of China
- National-Local Joint Engineering Research Center for Precision Surgery and Regenerative Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi Province, People's Republic of China
| | - Xu-Feng Zhang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, People's Republic of China
- Institute of Advanced Surgical Technology and Engineering, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, People's Republic of China
- National-Local Joint Engineering Research Center for Precision Surgery and Regenerative Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi Province, People's Republic of China
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4
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Terracina S, Caronti B, Lucarelli M, Francati S, Piccioni MG, Tarani L, Ceccanti M, Caserta M, Verdone L, Venditti S, Fiore M, Ferraguti G. Alcohol Consumption and Autoimmune Diseases. Int J Mol Sci 2025; 26:845. [PMID: 39859557 PMCID: PMC11766456 DOI: 10.3390/ijms26020845] [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: 11/26/2024] [Revised: 12/31/2024] [Accepted: 01/04/2025] [Indexed: 01/27/2025] Open
Abstract
Alcohol is the second-most misused substance after tobacco. It has been identified as a causal factor in more than 200 diseases and 5.3% of all deaths and is associated with significant behavioral, social, and economic difficulties. As alcohol consumption may modulate the immune system's regulatory mechanisms to avoid attacking the body's tissues, it has been proven to play a dichotomic role in autoimmune diseases (ADs) based on the quantity of consumption. In this review, we report updated evidence on the role of alcohol in ADs, with a focus on alcohol addiction and the human biological immune system and the relationship between them, with alcohol as a risk or protective factor. Then, in this narrative review, we report the main evidence on the most studied ADs where alcohol represents a key modulator, including autoimmune thyroiditis, multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, diabetes, allergic rhinitis, and primary biliary cholangitis. Alcohol at low-moderate dosages seems mostly to have a protective role in these diseases, while at higher dosages, the collateral risks surpass possible benefits. The specific mechanisms by which low-to-moderate alcohol intake relieves AD symptoms are not yet fully understood; however, emerging studies suggest that alcohol may have a systemic immunomodulatory effect, potentially altering the balance of anti-inflammatory innate and adaptive immune cells, as well as cytokines (via the NF-κB or NLRP3 pathways). It might influence the composition of the gut microbiome (increasing amounts of beneficial gut microbes) and the production of their fatty acid metabolites, such as short-chain fatty acids (SCFAs) and polyunsaturated fatty acids (PUFAs), as well as elevated concentrations of acetate, high-density lipoprotein (HDL), and nitric oxide (NO). Unfortunately, a definite acceptable daily intake (ADI) of ethanol is complicated to establish because of the many mechanisms associated with alcohol consumption such that despite the interesting content of these findings, there is a limit to their applicability and risks should be weighed in cases of alcoholic drinking recommendations. The aim of future studies should be to modulate those beneficial pathways involved in the alcohol-protective role of ADs with various strategies to avoid the risks associated with alcohol intake.
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Affiliation(s)
- Sergio Terracina
- Department of Experimental Medicine, Sapienza University of Rome, 00161 Rome, Italy; (S.T.); (M.L.); (S.F.)
| | - Brunella Caronti
- Department of Human Neurosciences, Sapienza University Hospital of Rome, 00185 Rome, Italy
| | - Marco Lucarelli
- Department of Experimental Medicine, Sapienza University of Rome, 00161 Rome, Italy; (S.T.); (M.L.); (S.F.)
- Pasteur Institute, Cenci Bolognetti Foundation, Sapienza University of Rome, 00161 Rome, Italy
| | - Silvia Francati
- Department of Experimental Medicine, Sapienza University of Rome, 00161 Rome, Italy; (S.T.); (M.L.); (S.F.)
| | - Maria Grazia Piccioni
- Department of Maternal Infantile and Urological Sciences, Sapienza University of Rome, 00161 Rome, Italy; (M.G.P.); (L.T.)
| | - Luigi Tarani
- Department of Maternal Infantile and Urological Sciences, Sapienza University of Rome, 00161 Rome, Italy; (M.G.P.); (L.T.)
| | - Mauro Ceccanti
- SITAC, Società Italiana per il Trattamento dell’Alcolismo e le sue Complicanze, 00185 Rome, Italy;
| | - Micaela Caserta
- Institute of Molecular Biology and Pathology (IBPM-CNR), 00161 Rome, Italy; (M.C.); (L.V.)
| | - Loredana Verdone
- Institute of Molecular Biology and Pathology (IBPM-CNR), 00161 Rome, Italy; (M.C.); (L.V.)
| | - Sabrina Venditti
- Department of Biology and Biotechnologies “Charles Darwin”, Sapienza University of Rome, 00161 Rome, Italy;
| | - Marco Fiore
- Institute of Biochemistry and Cell Biology (IBBC-CNR), c/o Department of Sensory Organs, Sapienza University of Rome, 00161 Rome, Italy
| | - Giampiero Ferraguti
- Department of Experimental Medicine, Sapienza University of Rome, 00161 Rome, Italy; (S.T.); (M.L.); (S.F.)
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Tanaka A, Ma X, Takahashi A, Vierling JM. Primary biliary cholangitis. Lancet 2024; 404:1053-1066. [PMID: 39216494 DOI: 10.1016/s0140-6736(24)01303-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2024] [Revised: 06/04/2024] [Accepted: 06/17/2024] [Indexed: 09/04/2024]
Abstract
Primary biliary cholangitis is a chronic, autoimmune, cholestatic disease that mainly affects women aged 40-70 years. Recent epidemiological studies have shown an increasing incidence worldwide despite geographical heterogeneity and a decrease in the female-to-male ratio of those the disease affects. Similar to other autoimmune diseases, primary biliary cholangitis occurs in genetically predisposed individuals upon exposure to environmental triggers, specifically xenobiotics, smoking, and the gut microbiome. Notably, the diversity of the intestinal microbiome is diminished in individuals with primary biliary cholangitis. The intricate interplay among immune cells, cytokines, chemokines, and biliary epithelial cells is postulated as the underlying pathogenic mechanism involved in the development and progression of primary biliary cholangitis, and extensive research has been dedicated to comprehending these complex interactions. Following the official approval of obeticholic acid as second-line treatment for patients with an incomplete response or intolerance to ursodeoxycholic acid, clinical trials have indicated that peroxisome proliferator activator receptor agonists are promising additional second-line drugs. Future dual or triple drug regimens might reach a new treatment goal of normalisation of alkaline phosphatase levels, rather than a decrease to less than 1·67 times the upper limit of normal levels, and potentially improve long-term outcomes. Improvement of health-related quality of life with better recognition and care of subjective symptoms, such as pruritus and fatigue, is also an important treatment goal. Promising clinical investigations are underway to alleviate these symptoms. Efforts to facilitate better access to medical care and dissemination of current knowledge should enable diagnosis at an earlier stage of primary biliary cholangitis and ensure access to treatments based on risk stratification for all patients.
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Affiliation(s)
- Atsushi Tanaka
- Department of Medicine, Teikyo University School of Medicine, Tokyo, Japan.
| | - Xiong Ma
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, NHC Key Laboratory of Digestive Diseases, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Shanghai, China
| | - Atsushi Takahashi
- Department of Gastroenterology, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - John M Vierling
- Department of Medicine and Surgery, Section of Gastroenterology, Baylor College of Medicine, Houston, TX, USA; Hepatology, and Division of Abdominal Transplantation, Baylor College of Medicine, Houston, TX, USA
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6
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de Veer RC, van Hooff MC, Werner E, Beuers U, Drenth JP, Cuperus FJ, van Hoek B, Veldt BJ, Klemt-Kropp M, van Meer S, Verdonk RC, Flink HJ, Vrolijk JM, Gevers TJ, Ponsioen CY, ter Borg MJ, Soufidi K, Boersma F, de Jonge HJ, Wolfhagen FH, Baak L, Onderwater SL, van Bergeijk JD, van Putten PG, de Bruin GJ, Adang RP, Aparicio-Pages MN, de Boer W, Borg FT, van Soest H, Janssen HL, Hansen BE, Erler NS, van der Meer AJ. Incidence and prevalence of primary biliary cholangitis in the Netherlands - A nationwide cohort study. JHEP Rep 2024; 6:101132. [PMID: 39113899 PMCID: PMC11304051 DOI: 10.1016/j.jhepr.2024.101132] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2024] [Revised: 05/28/2024] [Accepted: 05/30/2024] [Indexed: 08/10/2024] Open
Abstract
BACKGROUND & AIMS Although primary biliary cholangitis (PBC) is considered a rare disorder, accurate determination of its incidence and prevalence remains challenging due to limited comprehensive population-based registries. We aimed to assess the incidence and prevalence of PBC in the Netherlands over time through the nationwide Dutch PBC Cohort Study (DPCS). METHODS DPCS retrospectively included every identifiable patient with PBC in the Netherlands from 1990 onwards in all 71 Dutch hospitals. Incidence and prevalence were assessed between 2008-2018 by Poisson regression between sex and age groups over time. RESULTS On the 1st of January 2008, there were 1,458 patients with PBC in the Netherlands. Between 2008-2018, 2,187 individuals were newly diagnosed, 46 were transplanted and 468 died. The yearly incidence of PBC in 2008 was 1.38, increasing to 1.74 per 100,000 persons in 2018. When compared to those aged <45 years, females aged 45-64 years (adjusted incidence rate ratio 4.21, 95% CI 3.76-4.71, p <0.001) and males ≥65 years (adjusted incidence rate ratio 14.41, 95% CI 9.62-21.60, p <0.001) were at the highest risk of being diagnosed with PBC. The male-to-female ratio of patients newly diagnosed with PBC during the study period was 1:14 in those <45 years, 1:10 in patients aged 45-64 years, and 1:4 in those ≥65 years. Point prevalence increased from 11.9 in 2008 to 21.5 per 100,000 persons in 2018. Average annual percent change in this time period was 5.94% (95% CI 5.77-6.15, p <0.05), and was the highest among the population aged ≥65 years (5.69%, 95% CI 5.32-6.36, p <0.001). CONCLUSIONS In this nationwide cohort study, we observed an increase in both the incidence and prevalence of PBC in the Netherlands over the past decade, with marked age and sex differences. IMPACT AND IMPLICATIONS This nationwide Dutch primary biliary cholangitis (PBC) Cohort Study, including all hospitals in the Netherlands, showed that the incidence and prevalence of PBC have increased over the last decade. The age-dependent PBC incidence rate differed for males (highest risk ≥65 years) and females (highest risk between 45 and 65 years), which may be related to a difference in the timing of exposure to environmental triggers of PBC. The largest increase in PBC prevalence over time was observed in the population aged ≥65 years, which may have implications for the use of second-line therapies. These results therefore indicate that further studies are needed to elaborate on the advantages and disadvantages of add-on therapies in the elderly population.
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Affiliation(s)
- Rozanne C. de Veer
- Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - Maria C.B. van Hooff
- Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - Ellen Werner
- Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - Ulrich Beuers
- Department of Gastroenterology and Hepatology, Amsterdam University Medical Center, Amsterdam, the Netherlands
| | - Joost P.H. Drenth
- Department of Gastroenterology and Hepatology, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Frans J.C. Cuperus
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, Groningen, the Netherlands
| | - Bart van Hoek
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, the Netherlands
| | - Bart J. Veldt
- Department of Gastroenterology and Hepatology Reinier de Graaf Gasthuis, Delft, the Netherlands
| | - Michael Klemt-Kropp
- Department of Gastroenterology and Hepatology, Noordwest Ziekenhuisgroep, Alkmaar, the Netherlands
| | - Suzanne van Meer
- Department of Gastroenterology and Hepatology, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Robert C. Verdonk
- Department of Gastroenterology and Hepatology, St. Antonius Hospital, Nieuwegein, the Netherlands
| | - Hajo J. Flink
- Department of Gastroenterology and Hepatology, Catharina Hospital, Eindhoven, the Netherlands
| | - Jan Maarten Vrolijk
- Department of Gastroenterology and Hepatology, Rijnstate, Arnhem, the Netherlands
| | - Tom J.G. Gevers
- Department of Gastroenterology and Hepatology, Maastricht University Medical Center, Maastricht, the Netherlands
| | - Cyriel Y. Ponsioen
- Department of Gastroenterology and Hepatology, Amsterdam University Medical Center, Amsterdam, the Netherlands
| | - Martijn J. ter Borg
- Department of Gastroenterology and Hepatology, Maxima Medical Center, Eindhoven, the Netherlands
| | - Khalida Soufidi
- Department of Gastroenterology and Hepatology, Zuyderland Medical Center, Heerlen, the Netherlands
| | - Femke Boersma
- Department of Gastroenterology and Hepatology, Gelre Hospitals, Apeldoorn-Zutphen, the Netherlands
| | - Hendrik J.M. de Jonge
- Department of Gastroenterology and Hepatology, Jeroen Bosch Hospital, Den Bosch, the Netherlands
| | - Frank H.J. Wolfhagen
- Department of Gastroenterology and Hepatology, Albert Schweitzer Hospital, Dordrecht, the Netherlands
| | - L.C. Baak
- Department of Gastroenterology and Hepatology, Onze Lieve Vrouwe Gasthuis, Amsterdam, the Netherlands
| | - Susanne L. Onderwater
- Department of Gastroenterology and Hepatology, Diakonessenhuis, Utrecht, the Netherlands
| | - Jeroen D. van Bergeijk
- Department of Gastroenterology and Hepatology, Hospital De Gelderse Vallei, Ede, the Netherlands
| | - Paul G. van Putten
- Department of Gastroenterology and Hepatology, Medical Center Leeuwarden, Leeuwarden, the Netherlands
| | - Gijs J. de Bruin
- Department of Gastroenterology and Hepatology, Tergooi Hospital, Hilversum-Blaricum, the Netherlands
| | - Rob P.R. Adang
- Department of Gastroenterology and Hepatology, VieCuri, Venlo, the Netherlands
| | - Maria N. Aparicio-Pages
- Department of Gastroenterology and Hepatology, Canisius/Wilhemina Hospital, Nijmegen, the Netherlands
| | - Wink de Boer
- Department of Gastroenterology and Hepatology, Bernhoven, Uden, the Netherlands
| | - Frank ter Borg
- Department of Gastroenterology and Hepatology, Deventer Hospital, Deventer, the Netherlands
| | - Hanneke van Soest
- Department of Gastroenterology and Hepatology, Medical Center Haaglanden, Den Haag, the Netherlands
| | - Harry L.A. Janssen
- Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, the Netherlands
- Department of Gastroenterology and Hepatology, Toronto Centre for Liver Disease, University of Toronto, Ontario, Canada
| | - Bettina E. Hansen
- Department of Biostatistics, Erasmus University Medical Center, Rotterdam, the Netherlands
- Department of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - Nicole S. Erler
- Department of Biostatistics, Erasmus University Medical Center, Rotterdam, the Netherlands
- Department of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - Adriaan J. van der Meer
- Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, the Netherlands
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7
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Trivedi PJ, Hirschfield GM, Adams DH, Vierling JM. Immunopathogenesis of Primary Biliary Cholangitis, Primary Sclerosing Cholangitis and Autoimmune Hepatitis: Themes and Concepts. Gastroenterology 2024; 166:995-1019. [PMID: 38342195 DOI: 10.1053/j.gastro.2024.01.049] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Revised: 01/21/2024] [Accepted: 01/28/2024] [Indexed: 02/13/2024]
Abstract
Autoimmune liver diseases include primary biliary cholangitis, primary sclerosing cholangitis, and autoimmune hepatitis, a family of chronic immune-mediated disorders that target hepatocytes and cholangiocytes. Treatments remain nonspecific, variably effective, and noncurative, and the need for liver transplantation is disproportionate to their rarity. Development of effective therapies requires better knowledge of pathogenic mechanisms, including the roles of genetic risk, and how the environment and gut dysbiosis cause immune cell dysfunction and aberrant bile acid signaling. This review summarizes key etiologic and pathogenic concepts and themes relevant for clinical practice and how such learning can guide the development of new therapies for people living with autoimmune liver diseases.
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Affiliation(s)
- Palak J Trivedi
- National Institute for Health Research Birmingham Biomedical Research Centre, Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom; Liver Unit, University Hospitals Birmingham, Birmingham, United Kingdom; Institute of Translational Medicine, University of Birmingham, Birmingham, United Kingdom.
| | - Gideon M Hirschfield
- Division of Gastroenterology and Hepatology, Toronto Centre for Liver Disease, University of Toronto, Toronto, Ontario, Canada
| | - David H Adams
- National Institute for Health Research Birmingham Biomedical Research Centre, Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom; Liver Unit, University Hospitals Birmingham, Birmingham, United Kingdom
| | - John M Vierling
- Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine, Houston, Texas; Division of Abdominal Transplantation, Department of Surgery, Baylor College of Medicine, Houston, Texas.
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8
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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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9
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Ma D, Ma J, Zhao C, Tai W. Reasons why women are more likely to develop primary biliary cholangitis. Heliyon 2024; 10:e25634. [PMID: 38384574 PMCID: PMC10878884 DOI: 10.1016/j.heliyon.2024.e25634] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2023] [Revised: 01/29/2024] [Accepted: 01/31/2024] [Indexed: 02/23/2024] Open
Abstract
Primary biliary cholangitis (PBC) is a chronic autoimmune disease of biliary stasis in which immune factors cause the gradual destruction of small bile ducts, biliary stasis, and eventually the development of liver fibrosis, cirrhosis, and even liver failure. One of the main characteristics of PBC is that it primarily affects middle-aged women, but the precise cause is still unknown. This article analyzes the unique causes and mechanisms of the female predominance of PBC and summarizes the potential causes.The female domination of PBC is reported to be primarily caused by sex hormones, environmental circumstances, and epigenetic changes, each of which has a different subtle impact on patients' gender disparities.
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Affiliation(s)
- Di Ma
- Clinical Laboratory Department, The Second Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Jiaxuan Ma
- Clinical Laboratory Department, The Second Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Chunmei Zhao
- Clinical Laboratory Department, The Second Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Wenlin Tai
- Clinical Laboratory Department, The Second Affiliated Hospital of Kunming Medical University, Kunming, China
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10
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Tao T, Tang A, Lv L, Yuan J, Wu L, Zhao L, Chen J. Investigating the causal relationship and potential shared diagnostic genes between primary biliary cholangitis and systemic lupus erythematosus using bidirectional Mendelian randomization and transcriptomic analyses. Front Immunol 2024; 15:1270401. [PMID: 38464525 PMCID: PMC10921416 DOI: 10.3389/fimmu.2024.1270401] [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: 07/31/2023] [Accepted: 02/05/2024] [Indexed: 03/12/2024] Open
Abstract
Background The co-occurrence of primary biliary cholangitis (PBC) and systemic lupus erythematosus (SLE) has been consistently reported in observational studies. Nevertheless, the underlying causal correlation between these two conditions still needs to be established. Methods We performed a bidirectional two-sample Mendelian randomization (MR) study to assess their causal association. Five MR analysis methods were utilized for causal inference, with inverse-variance weighted (IVW) selected as the primary method. The Mendelian Randomization Pleiotropy RESidual Sum and Outlier (MR-PRESSO) and the IVW Radial method were applied to exclude outlying SNPs. To assess the robustness of the MR results, five sensitivity analyses were carried out. Multivariable MR (MVMR) analysis was also employed to evaluate the effect of possible confounders. In addition, we integrated transcriptomic data from PBC and SLE, employing Weighted Gene Co-expression Network Analysis (WGCNA) to explore shared genes between the two diseases. Then, we used Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment methods to perform on the shared genes. The Least Absolute Shrinkage and Selection Operator (LASSO) regression algorithm was utilized to identify potential shared diagnostic genes. Finally, we verified the potential shared diagnostic genes in peripheral blood mononuclear cells (PBMCs)-specific cell populations of SLE patients by single-cell analysis. Results Our MR study provided evidence that PBC had a causal relationship with SLE (IVW, OR: 1.347, 95% CI: 1.276 - 1.422, P < 0.001) after removing outliers (MR-PRESSO, rs35464393, rs3771317; IVW Radial, rs11065987, rs12924729, rs3745516). Conversely, SLE also had a causal association with PBC (IVW, OR: 1.225, 95% CI: 1.141 - 1.315, P < 0.001) after outlier correction (MR-PRESSO, rs11065987, rs3763295, rs7774434; IVW Radial, rs2297067). Sensitivity analyses confirmed the robustness of the MR findings. MVMR analysis indicated that body mass index (BMI), smoking and drinking were not confounding factors. Moreover, bioinformatic analysis identified PARP9, ABCA1, CEACAM1, and DDX60L as promising diagnostic biomarkers for PBC and SLE. These four genes are highly expressed in CD14+ monocytes in PBMCs of SLE patients and potentially associated with innate immune responses and immune activation. Conclusion Our study confirmed the bidirectional causal relationship between PBC and SLE and identified PARP9, ABCA1, CEACAM1, and DDX60L genes as the most potentially shared diagnostic genes between the two diseases, providing insights for the exploration of the underlying mechanisms of these disorders.
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Affiliation(s)
- Tian Tao
- Department of Nephrology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Anqi Tang
- Department of Nephrology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Lizeyu Lv
- Department of Nephrology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Jianhua Yuan
- Department of Cardiovascular Medicine, Chengdu Second People’s Hospital, Chengdu, Chengdu, China
| | - Ling Wu
- Department of Nephrology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Liangbin Zhao
- Department of Nephrology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Jun Chen
- Department of Intensive Care Medicine, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
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11
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Abstract
Primary biliary cholangitis (PBC) is the most common of the autoimmune liver diseases, in which there is chronic small bile duct inflammation. The pathophysiology of PBC is multifactorial, involving immune dysregulation and damage to biliary epithelial cells, with influences from genetic factors, epigenetics, the gut-liver axis, and environmental exposures.
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Affiliation(s)
- Inbal Houri
- Division of Gastroenterology and Hepatology, Toronto Centre for Liver Disease, University of Toronto, 9th Floor Eaton Building, North Wing 219-B, 200 Elizabeth Street, Toronto, Ontario M5G 2C4, Canada
| | - Gideon M Hirschfield
- Division of Gastroenterology and Hepatology, Toronto Centre for Liver Disease, University of Toronto, 9th Floor Eaton Building, North Wing 219-B, 200 Elizabeth Street, Toronto, Ontario M5G 2C4, Canada.
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12
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Rodrigues SG, van der Merwe S, Krag A, Wiest R. Gut-liver axis: Pathophysiological concepts and medical perspective in chronic liver diseases. Semin Immunol 2024; 71:101859. [PMID: 38219459 DOI: 10.1016/j.smim.2023.101859] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Revised: 10/11/2023] [Accepted: 12/04/2023] [Indexed: 01/16/2024]
Affiliation(s)
- Susana G Rodrigues
- Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Switzerland
| | - Schalk van der Merwe
- Department of Gastroenterology and Hepatology, University hospital Gasthuisberg, University of Leuven, Belgium
| | - Aleksander Krag
- Institute of Clinical Research, University of Southern Denmark, Odense, Denmark; Centre for Liver Research, Department of Gastroenterology and Hepatology, Odense University Hospital, Odense, Denmark, University of Southern Denmark, Odense, Denmark
| | - Reiner Wiest
- Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Switzerland.
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13
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Ichikawa M, Okada H, Nakamoto N, Taniki N, Chu PS, Kanai T. The gut-liver axis in hepatobiliary diseases. Inflamm Regen 2024; 44:2. [PMID: 38191517 PMCID: PMC10773109 DOI: 10.1186/s41232-023-00315-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2023] [Accepted: 12/17/2023] [Indexed: 01/10/2024] Open
Abstract
Recent advances in the analysis of intestinal bacteria have led to reports of variations in intestinal bacterial levels among hepatobiliary diseases. The mechanisms behind the changes in intestinal bacteria in various hepatobiliary diseases include the abnormal composition of intestinal bacteria, weakening of the intestinal barrier, and bacterial translocation outside the intestinal tract, along with their metabolites, but many aspects remain unresolved. Further research employing clinical studies and animal models is expected to clarify the direct relationship between intestinal bacteria and hepatobiliary diseases and to validate the utility of intestinal bacteria as a diagnostic biomarker and potential therapeutic target. This review summarizes the involvement of the microbiota in the pathogenesis of hepatobiliary diseases via the gut-liver axis.
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Affiliation(s)
- Masataka Ichikawa
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Shinanomachi, Tokyo, 1608582, Japan
| | - Haruka Okada
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Shinanomachi, Tokyo, 1608582, Japan
| | - Nobuhiro Nakamoto
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Shinanomachi, Tokyo, 1608582, Japan.
| | - Nobuhito Taniki
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Shinanomachi, Tokyo, 1608582, Japan
| | - Po-Sung Chu
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Shinanomachi, Tokyo, 1608582, Japan
| | - Takanori Kanai
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Shinanomachi, Tokyo, 1608582, Japan.
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14
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Wang X, Wei Y, Yang Y, Yang Y, Li H, Li Y, Zhang F, Wang L. Animal models of primary biliary cholangitis: status and challenges. Cell Biosci 2023; 13:214. [PMID: 37993960 PMCID: PMC10664283 DOI: 10.1186/s13578-023-01170-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2023] [Accepted: 11/08/2023] [Indexed: 11/24/2023] Open
Abstract
BACKGROUND Primary biliary cholangitis (PBC) is an autoimmune liver disease. The aetiology of PBC remains unclear, and its pathogenesis is complex. Animal models are essential to clarify the pathogenesis of PBC and explore the occurrence of early events. MAIN BODY Herein, we review recent research progress in PBC animal models, including genetically modified, chemically inducible, biologically inducible, and protein-immunised models. Although these animal models exhibit several immunological and pathological features of PBC, they all have limitations that constrain further research and weaken their connection with clinical practice. CONCLUSION The review will benefit efforts to understand and optimise animal models in order to further clarify PBC pathogenesis and molecular targets for therapeutic interventions.
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Affiliation(s)
- Xu Wang
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, National Clinical Research Center for Dermatologic and Immunologic Diseases, Beijing, China
| | - Yi Wei
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, National Clinical Research Center for Dermatologic and Immunologic Diseases, Beijing, China
| | - Yanlei Yang
- Clinical Biobank, Department Medical Research Central, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yunjiao Yang
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, National Clinical Research Center for Dermatologic and Immunologic Diseases, Beijing, China
| | - Haolong Li
- Department of Clinical Laboratory, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
| | - Yongzhe Li
- Department of Clinical Laboratory, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
| | - Fengchun Zhang
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, National Clinical Research Center for Dermatologic and Immunologic Diseases, Beijing, China
| | - Li Wang
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, National Clinical Research Center for Dermatologic and Immunologic Diseases, Beijing, China.
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15
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Trivella J, John BV, Levy C. Primary biliary cholangitis: Epidemiology, prognosis, and treatment. Hepatol Commun 2023; 7:02009842-202306010-00027. [PMID: 37267215 DOI: 10.1097/hc9.0000000000000179] [Citation(s) in RCA: 30] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2023] [Accepted: 04/10/2023] [Indexed: 06/04/2023] Open
Abstract
Primary biliary cholangitis (PBC) is a chronic cholestatic autoimmune liver disease characterized by a destructive, small duct, and lymphocytic cholangitis, and marked by the presence of antimitochondrial antibodies. The incidence and prevalence of PBC vary widely in different regions and time periods, and although disproportionally more common among White non-Hispanic females, contemporary data show a higher prevalence in males and racial minorities than previously described. Outcomes largely depend on early recognition of the disease and prompt institution of treatment, which, in turn, are directly influenced by provider bias and socioeconomic factors. Ursodeoxycholic acid remains the initial treatment of choice for PBC, with obeticholic acid and fibrates (off-label therapy) reserved as add-on therapy for the management of inadequate responders or those with ursodeoxycholic acid intolerance. Novel and repurposed drugs are currently at different stages of clinical development not only for the treatment of PBC but also for its symptomatic management. Here, we summarize the most up-to-date data regarding the epidemiology, prognosis, and treatment of PBC, providing clinically useful information for its holistic management.
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Affiliation(s)
- Juan Trivella
- Department of Medicine, Division of Gastroenterology and Hepatology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| | - Binu V John
- Department of Medicine, Division of Gastroenterology and Hepatology, Miami VA Medical System, Miami, Florida, USA
- Department of Medicine, Division of Digestive Health and Liver Diseases, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - Cynthia Levy
- Department of Medicine, Division of Digestive Health and Liver Diseases, University of Miami Miller School of Medicine, Miami, Florida, USA
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16
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Abstract
BACKGROUND Autoimmune hepatitis has an unknown cause and genetic associations that are not disease-specific or always present. Clarification of its missing causality and heritability could improve prevention and management strategies. AIMS Describe the key epigenetic and genetic mechanisms that could account for missing causality and heritability in autoimmune hepatitis; indicate the prospects of these mechanisms as pivotal factors; and encourage investigations of their pathogenic role and therapeutic potential. METHODS English abstracts were identified in PubMed using multiple key search phases. Several hundred abstracts and 210 full-length articles were reviewed. RESULTS Environmental induction of epigenetic changes is the prime candidate for explaining the missing causality of autoimmune hepatitis. Environmental factors (diet, toxic exposures) can alter chromatin structure and the production of micro-ribonucleic acids that affect gene expression. Epistatic interaction between unsuspected genes is the prime candidate for explaining the missing heritability. The non-additive, interactive effects of multiple genes could enhance their impact on the propensity and phenotype of autoimmune hepatitis. Transgenerational inheritance of acquired epigenetic marks constitutes another mechanism of transmitting parental adaptations that could affect susceptibility. Management strategies could range from lifestyle adjustments and nutritional supplements to precision editing of the epigenetic landscape. CONCLUSIONS Autoimmune hepatitis has a missing causality that might be explained by epigenetic changes induced by environmental factors and a missing heritability that might reflect epistatic gene interactions or transgenerational transmission of acquired epigenetic marks. These unassessed or under-evaluated areas warrant investigation.
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Affiliation(s)
- Albert J Czaja
- Mayo Clinic College of Medicine and Science, Rochester, MN, USA.
- Professor Emeritus of Medicine, Mayo Clinic College of Medicine and Science, 200 First Street SW, Rochester, MN, 55905, USA.
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17
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Rigopoulou EI, Bogdanos DP. Role of autoantibodies in the clinical management of primary biliary cholangitis. World J Gastroenterol 2023; 29:1795-1810. [PMID: 37032725 PMCID: PMC10080701 DOI: 10.3748/wjg.v29.i12.1795] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2022] [Revised: 01/04/2023] [Accepted: 03/14/2023] [Indexed: 03/28/2023] Open
Abstract
Primary biliary cholangitis (PBC) is a chronic cholestatic liver disease characterized by immune-driven destruction of small intrahepatic bile ducts leading a proportion of patients to hepatic failure over the years. Diagnosis at early stages in concert with ursodeoxycholic acid treatment has been linked with prevention of disease progression in the majority of cases. Diagnosis of PBC in a patient with cholestasis relies on the detection of disease-specific autoantibodies, including anti-mitochondrial antibodies, and disease-specific anti-nuclear antibodies targeting sp100 and gp210. These autoantibodies assist the diagnosis of the disease, and are amongst few autoantibodies the presence of which is included in the diagnostic criteria of the disease. They have also become important tools evaluating disease prognosis. Herein, we summarize existing data on detection of PBC-related autoantibodies and their clinical significance. Moreover, we provide insight on novel autoantibodies and their possible prognostic role in PBC patients.
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Affiliation(s)
- Eirini I Rigopoulou
- Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, Larissa 41110, Greece
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), General University Hospital of Larissa, Larissa 41110, Greece
| | - Dimitrios P Bogdanos
- Department of Rheumatology and Clinical Immunology, Faculty of Medicine, School of Health Sciences, University of Thessaly, Larissa 41110, Greece
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18
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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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19
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Nevalainen A, Nevalainen OPO. Autoimmune and immune-mediated inflammatory diseases after exposure to acid-suppressive medication: A systematic review and meta-analysis. INTERNATIONAL JOURNAL OF RISK & SAFETY IN MEDICINE 2023; 34:207-225. [PMID: 36442213 DOI: 10.3233/jrs-220012] [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] [Indexed: 11/24/2022]
Abstract
BACKGROUND Pharmacovigilance risk signals have proposed a relationship between the use of acid-suppressive medications and the development of certain autoimmune and immune-mediated inflammatory diseases. OBJECTIVE A systematic review and a meta-analysis was performed. METHODS We reviewed MEDLINE (Ovid) and Scopus for comparative observational studies between these diseases and previous exposure to proton-pump inhibitors (PPI), H2-receptor antagonists (H2RA), and antacids. The protocol was registered on the PROSPERO database (CRD42020192715). RESULTS From 3,191 citations, 25 articles were eligible and covered 16 diseases. Microscopic colitis (MC) was studied the most (7 studies). In a random-effects meta-analysis, there was low certainty evidence (GRADE approach) of a non-significant relationship between exposure to any PPIs and MC (meta-OR 3.28, 95% CI 0.98-11.0, I2 98.2%, six studies, 4,436 PPI-exposed MC patients). Moderate certainty evidence pointed towards large odds of collagenous colitis after exposure to lansoprazole (meta-OR 14.5, 95% CI 9.37-22.3, I2 10.2%, three studies, 1,725 lansoprazole-exposed patients). After PPI exposure, the risk of rheumatoid arthritis was slightly increased based on low certainty evidence from two cohort studies totaling 475 diagnoses (meta-RR 1.62, 95% CI 1.12-2.34, I2 34.5%). CONCLUSIONS In patients with MC, it would be reasonable to carefully review the indication of PPI, especially in CC patients using lansoprazole.
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Affiliation(s)
| | - Olli P O Nevalainen
- Hatanpää Health Centre, City of Tampere, Tampere, Finland
- Health Sciences, Faculty of Social Sciences, Tampere University, Tampere, Finland
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20
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Abstract
Primary biliary cholangitis (PBC) is a rare disease of the liver characterized by an autoimmune attack on the small bile ducts. PBC is a complex trait, meaning that a large list of genetic factors interacts with environmental agents to determine its onset. Genome-wide association studies have had a huge impact in fostering research in PBC, but many steps need still to be done compared with other autoimmune diseases of similar prevalence. This review presents the state-of-the-art regarding the genetic architecture of PBC and provides some thoughtful reflections about possible future lines of research, which can be helpful to fill the missing heritability gap in PBC.
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Affiliation(s)
- Alessio Gerussi
- Division of Gastroenterology and Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milano-Bicocca, Via Cadore 48, 20900 Monza (MB), Italy; European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, Monza, Italy.
| | - Rosanna Asselta
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, Pieve Emanuele 20072, Italy; Humanitas Clinical and Research Center, IRCCS, Via Manzoni 56, Rozzano 20089, Italy
| | - Pietro Invernizzi
- Division of Gastroenterology and Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milano-Bicocca, Via Cadore 48, 20900 Monza (MB), Italy; European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, Monza, Italy.
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21
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Shaker M, Mansour N, John BV. Primary Biliary Cholangitis in Males: Pathogenesis, Clinical Presentation, and Prognosis. Clin Liver Dis 2022; 26:643-655. [PMID: 36270721 DOI: 10.1016/j.cld.2022.06.008] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Primary biliary cholangitis (PBC) is an immune-mediated chronic liver disease characterized by progressive cholestasis, bile duct destruction, biliary fibrosis, and cirrhosis. Patients who respond to ursodeoxycholic acid have an expected survival similar to the general population. Although PBC primarily affects females, the prevalence in males is higher than was previously believed, with contemporary studies suggesting a female-to-male ratio of 4-6:1. A diagnosis of PBC is often delayed among males because of the myth that PBC is rare in males.
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Affiliation(s)
- Mina Shaker
- Division of Hepatology, Miami VA Medical Center 1201 NW 16th Street, Miami, FL 33125 USA.
| | - Natalie Mansour
- Division of Hepatology, Miami VA Medical Center 1201 NW 16th Street, Miami, FL 33125 USA
| | - Binu V John
- Division of Hepatology, Miami VA Medical Center 1201 NW 16th Street, Miami, FL 33125 USA; Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, USA
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22
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Chen R, Tang R, Ma X, Gershwin ME. Immunologic Responses and the Pathophysiology of Primary Biliary Cholangitis. Clin Liver Dis 2022; 26:583-611. [PMID: 36270718 DOI: 10.1016/j.cld.2022.06.003] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Primary biliary cholangitis (PBC) is an autoimmune liver disease with a female predisposition and selective destruction of intrahepatic small bile ducts leading to nonsuppurative destructive cholangitis. It is characterized by seropositivity of antimitochondrial antibodies or PBC-specific antinuclear antibodies, progressive cholestasis, and typical liver histologic manifestations. Destruction of the protective bicarbonate-rich umbrella is attributed to the decreased expression of membrane transporters in biliary epithelial cells (BECs), leading to the accumulation of hydrophobic bile acids and sensitizing BECs to apoptosis. A recent X-wide association study reveals a novel risk locus on the X chromosome, which reiterates the importance of Treg cells.
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Affiliation(s)
- Ruiling Chen
- 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 JiaoTong University, Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai, China
| | - 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 JiaoTong University, Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai, China
| | - Xiong Ma
- 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 JiaoTong University, Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai, China.
| | - M Eric Gershwin
- Division of Rheumatology-Allergy and Clinical Immunology, University of California at Davis, 451 Health Sciences Drive, Suite 6510, Davis, CA 95616, USA.
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23
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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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24
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French JA, Gow P, Simpson-Yap S, Collins K, Ng J, Angus PW, van der Mei IAF. Alcohol intake is associated with a decreased risk of developing primary biliary cholangitis. World J Hepatol 2022; 14:1747-1756. [PMID: 36185715 PMCID: PMC9521450 DOI: 10.4254/wjh.v14.i9.1747] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2022] [Revised: 06/13/2022] [Accepted: 08/26/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Primary biliary cholangitis (PBC) is a chronic progressive liver disease of unknown aetiology characterised by immune-mediated destruction of small and medium-sized intrahepatic bile ducts. There are few well-established risk factors and epidemiological studies are needed to further evaluate the pathogenesis of the disease.
AIM To evaluate the relationship between alcohol intake, smoking and marijuana use with PBC development.
METHODS We conducted a prevalent case control study of 200 cases and 200 age (within a five year age band) and sex-matched controls, identified from the Victorian PBC prevalence study. We assessed lifetime alcohol intake and smoking behaviour (both tobacco and marijuana) prior to PBC onset and used conditional logistic regression for analyses.
RESULTS Alcohol intake consistently showed a dose-dependent inverse association with case status, and this was most substantial for 21-30 years and 31-40 years (Ptrend < 0.001). Smoking was associated with PBC, with a stronger association with a longer duration of smoking [e.g., adjusted OR 2.27 (95%CI: 1.12- 4.62) for those who had smoked for 20-35 years]. There was no association between marijuana use and PBC.
CONCLUSION Alcohol appears to have an inverse relationship with PBC. Smoking has been confirmed as an environmental risk factor for PBC. There was no association between marijuana use and PBC.
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Affiliation(s)
| | - Paul Gow
- Department of Gastroenterology, Austin Hospital, Heidelberg 3084, Australia
| | - Steven Simpson-Yap
- Melbourne School of Population and Global Health, University of Melbourne, Carlton 3053, Australia
- Menzies Institute for Medical Research, University of Tasmania, Hobart 7000, Australia
| | - Kate Collins
- Department of Gastroenterology, Austin Hospital, Heidelberg 3084, Australia
| | - Justin Ng
- Department of Gastroenterology, Austin Hospital, Heidelberg 3084, Australia
| | - Peter W Angus
- Department of Gastroenterology, Austin Hospital, Heidelberg 3084, Australia
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25
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Marti-Aguado D, Clemente-Sanchez A, Bataller R. Cigarette smoking and liver diseases. J Hepatol 2022; 77:191-205. [PMID: 35131406 DOI: 10.1016/j.jhep.2022.01.016] [Citation(s) in RCA: 72] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2021] [Revised: 01/14/2022] [Accepted: 01/25/2022] [Indexed: 01/27/2023]
Abstract
Cigarette smoking is a preventable risk factor for premature morbidity and mortality. A history of smoking is observed in approximately 40% of patients with liver disease, while a growing number of studies are investigating the potential impact of smoking in chronic liver diseases. This review discusses the effects of smoking on liver diseases, at multiple levels, with a focus on its potential causal role. Clinical evidence indicates that cigarette smoking negatively impacts the incidence and severity of fatty liver disease, fibrosis progression, hepatocellular carcinoma development, and the outcomes of patients with advanced liver disease. The underlying mechanisms are complex and involve different pathophysiological pathways including oxidative stress and oncogenic signals. Importantly, smoking promotes cardiovascular disease and extrahepatic cancers in patients with steatohepatitis and in transplant recipients. We discuss how promoting smoking cessation could improve the rates of treatment response (in clinical trials) and fibrosis regression, while reducing the risk of hepatocellular carcinoma and improving liver transplant outcomes. Finally, we discuss current challenges such as the referral of smokers to specialised units for smoking cessation.
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Affiliation(s)
- David Marti-Aguado
- Digestive Disease Department, Clinic University Hospital, INCLIVA Health Research Institute, Valencia, Spain; Center for Liver Diseases, Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, Pittsburgh Liver Research Center, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Ana Clemente-Sanchez
- Center for Liver Diseases, Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, Pittsburgh Liver Research Center, University of Pittsburgh Medical Center, Pittsburgh, PA, USA; Liver Unit and Digestive Department, Hospital General Universitario Gregorio Marañon, CIBERehd, Instituto de Salud Carlos III, Madrid, Spain
| | - Ramon Bataller
- Center for Liver Diseases, Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, Pittsburgh Liver Research Center, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
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26
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El Jamaly H, Eslick GD, Weltman M. Primary biliary cholangitis in pregnancy: A systematic review with meta-analysis. Hepatobiliary Pancreat Dis Int 2022; 21:218-225. [PMID: 35361530 DOI: 10.1016/j.hbpd.2022.03.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Accepted: 03/01/2022] [Indexed: 02/05/2023]
Abstract
BACKGROUND The outcomes and disease associations in pregnant women with primary biliary cholangitis (PBC) have not been largely explored. This study aimed to determine the level of evidence associated with maternal and fetal outcomes and other disease associations in female patients with PBC. DATA SOURCES A comprehensive literature search was conducted. Maternal and fetal outcomes were obtained from patients with a previous, current or subsequent diagnosis of PBC. A random-effects model was employed, using odds ratios (ORs) with 95% confidence intervals (CIs). RESULTS Eleven studies, with 2179 female PBC patients were included. Pregnant women with PBC were significantly more likely to have a miscarriage (OR = 1.27, 95% CI: 1.02-1.58; P = 0.03), and a history of abortion (OR = 1.50, 95% CI: 1.09-2.07; P = 0.01), with absent heterogeneity (I2 = 0%). PBC pregnant women were significantly more likely to deliver via vaginal birth (OR = 1.69, 95% CI: 1.33-2.14; P < 0.001) with low level heterogeneity (I2 < 0.001%). Patients had a statistically significant increased likelihood of lifetime smoking (OR = 1.95, 95% CI: 1.17-3.23; P = 0.01). Egger's regression revealed no evidence of publication bias. CONCLUSIONS This meta-analysis provides pooled evidence that a PBC pregnancy is associated with fetal morbidity and maternal lifestyle associations that may influence pregnancy outcomes. More studies are needed to establish disease associations that may directly affect pregnancy outcomes. These data are essential for clinicians managing these patients before, during or after pregnancy.
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Affiliation(s)
- Hydar El Jamaly
- Department of Gastroenterology and Hepatology, Nepean Hospital, Penrith, New South Wales, Australia; Nepean Clinical School, The University of Sydney, Penrith, New South Wales, Australia.
| | - Guy D Eslick
- NHMRC Centre for Research Excellence in Digestive Health, Hunter Medical Research Institute, The University of Newcastle, Newcastle, New South Wales, Australia
| | - Martin Weltman
- Department of Gastroenterology and Hepatology, Nepean Hospital, Penrith, New South Wales, Australia; Nepean Clinical School, The University of Sydney, Penrith, New South Wales, Australia
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27
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Gerussi A, Paraboschi EM, Cappadona C, Caime C, Binatti E, Cristoferi L, Asselta R, Invernizzi P. The Role of Epigenetics in Primary Biliary Cholangitis. Int J Mol Sci 2022; 23:4873. [PMID: 35563266 PMCID: PMC9105933 DOI: 10.3390/ijms23094873] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2022] [Revised: 04/25/2022] [Accepted: 04/26/2022] [Indexed: 12/12/2022] Open
Abstract
Primary Biliary Cholangitis (PBC) is a rare autoimmune disease of the liver, affecting mostly females. There is evidence that epigenetic changes have a pathogenic role in PBC. Epigenetic modifications are related to methylation of CpG DNA islands, post-translational modifications of histone proteins, and non-coding RNAs. In PBC, there are data showing a dysregulation of all these levels, especially in immune cells. In addition, epigenetics seems to be involved in complex phenomena such as X monosomy or abnormalities in the process of X chromosome inactivation, which have been reported in PBC and appear to influence its sex imbalance and pathogenesis. We review here historical data on epigenetic modifications in PBC, present new data, and discuss possible links among X-chromosome abnormalities at a genetic and epigenetic level, PBC pathogenesis, and PBC sex imbalance.
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Affiliation(s)
- Alessio Gerussi
- Division of Gastroenterology, Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milano-Bicocca, 20900 Monza, Italy; (A.G.); (C.C.); (E.B.); (L.C.)
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, 20900 Monza, Italy
| | - Elvezia Maria Paraboschi
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20072 Pieve Emanuele, Italy; (E.M.P.); (C.C.); (R.A.)
- Humanitas Clinical and Research Center, IRCCS, Via Manzoni 56, 20089 Rozzano, Italy
| | - Claudio Cappadona
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20072 Pieve Emanuele, Italy; (E.M.P.); (C.C.); (R.A.)
- Humanitas Clinical and Research Center, IRCCS, Via Manzoni 56, 20089 Rozzano, Italy
| | - Chiara Caime
- Division of Gastroenterology, Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milano-Bicocca, 20900 Monza, Italy; (A.G.); (C.C.); (E.B.); (L.C.)
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, 20900 Monza, Italy
| | - Eleonora Binatti
- Division of Gastroenterology, Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milano-Bicocca, 20900 Monza, Italy; (A.G.); (C.C.); (E.B.); (L.C.)
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, 20900 Monza, Italy
| | - Laura Cristoferi
- Division of Gastroenterology, Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milano-Bicocca, 20900 Monza, Italy; (A.G.); (C.C.); (E.B.); (L.C.)
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, 20900 Monza, Italy
| | - Rosanna Asselta
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20072 Pieve Emanuele, Italy; (E.M.P.); (C.C.); (R.A.)
- Humanitas Clinical and Research Center, IRCCS, Via Manzoni 56, 20089 Rozzano, Italy
| | - Pietro Invernizzi
- Division of Gastroenterology, Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milano-Bicocca, 20900 Monza, Italy; (A.G.); (C.C.); (E.B.); (L.C.)
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, 20900 Monza, Italy
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28
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Cariello M, Gadaleta RM, Moschetta A. The gut-liver axis in cholangiopathies: focus on bile acid based pharmacological treatment. Curr Opin Gastroenterol 2022; 38:136-143. [PMID: 35034082 PMCID: PMC10826921 DOI: 10.1097/mog.0000000000000807] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
PURPOSE OF REVIEW This review analyses the main features of primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) and provides an overview of the currently available (bile acid) bile acid related treatments. RECENT FINDINGS In PBC, biliary injury is the consequence of a dysregulated intrahepatic and systemic immune response. Given the close association between PSC and inflammatory bowel disease (IBD), the microbiota represents an important factor in the development of PSC. Bile acid based pharmacological treatments could represent promising therapeutic strategies in the management of cholangiopathies. SUMMARY Cholangiopathies include a spectrum of diseases resulting in cholestasis, an impairment of bile flow in the biliary tree, leading to biliary obstruction and damage as well as liver inflammation and fibrosis. PSC and PBC are highly heterogeneous cholangiopathies and progressive disorders with defined pathophysiological mechanisms. Curative treatments have not been established, and although their prevalence is low, they are a frequent indication for liver transplantation in the advanced stages of cholangiopathies. These diseases still present with unmet therapeutic strategies, also taking into account that on average 30-40% of patients undergoing liver transplantation will have recurrence of the original illness.
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Affiliation(s)
- Marica Cariello
- INBB, National Institute for Biostructures and Biosystems, Rome
| | - Raffaella M. Gadaleta
- Department of Interdisciplinary Medicine, ‘Aldo Moro’ University of Bari, Bari, Italy
| | - Antonio Moschetta
- INBB, National Institute for Biostructures and Biosystems, Rome
- Department of Interdisciplinary Medicine, ‘Aldo Moro’ University of Bari, Bari, Italy
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29
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Yang Y, Choi J, Chen Y, Invernizzi P, Yang G, Zhang W, Shao TH, Jordan F, Nemeria NS, Coppel RL, Ridgway WM, Kurth M, Ansari AA, Leung PSC, Gershwin ME. E. coli and the etiology of human PBC: Antimitochondrial antibodies and spreading determinants. Hepatology 2022; 75:266-279. [PMID: 34608663 DOI: 10.1002/hep.32172] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2021] [Revised: 08/31/2021] [Accepted: 09/21/2021] [Indexed: 12/16/2022]
Abstract
BACKGROUND AND AIMS The increased frequency of urinary tract infections in patients with primary biliary cholangitis (PBC) and the cross-reactivity between the lipoyl domains (LD) of human pyruvate dehydrogenase complex (hPDC-E2) and Escherichia coli PDC-E2 (ePDC-E2) have long suggested a role of E. coli in causality of PBC. This issue, however, has remained speculative. We hypothesized that by generating specific constructs of human and E. coli PDC-E2, we would be able to assess the specificity of autoantibody responses and define whether exposure to E. coli in susceptible hosts is the basis for the antimitochondrial antibody (AMA) response. APPROACH AND RESULTS Importantly, the reactivity of hPDC-E2 LD (hPDC-E2LD) affinity-purified antibodies against hPDC-E2LD could only be removed by prior absorption with hPDC-E2LD and not ePDC-E2, suggesting the presence of unique human PDC-E2 epitopes distinct from E. coli PDC-E2. To identify the autoepitope(s) present in hPDC-E2LD, a more detailed study using a variety of PDC-E2 constructs was tested, including the effect of lipoic acid (LA) on ePDC-E2 conformation and AMA recognition. Individual recombinant ePDCE2 LD domains LD1, LD2 and LD3 did not react with either AMA or antibodies to LA (anti-LA), but in contrast, anti-LA was readily reactive against purified recombinant LD1, LD2, and LD3 expressed in tandem (LP); such reactivity increased when LP was precultured with LA. Moreover, when the three LD (LD1, LD2, LD3) domains were expressed in tandem in pET28a or when LD1 was expressed in another plasmid pGEX, they were lipoylated and reactive to PBC sera. CONCLUSIONS In conclusion, our data are consistent with an exposure to E. coli that elicits specific antibody to ePDC-E2 resulting in determinant spreading and the classic autoantibody to hPDC-E2LD. We argue this is the first step to development of human PBC.
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Affiliation(s)
- Yao Yang
- Division of Rheumatology, Allergy and Clinical ImmunologyUniversity of California DavisDavisCaliforniaUSA
- School of Food Science and Pharmaceutical EngineeringNanjing Normal UniversityNanjingChina
| | - Jinjung Choi
- Division of Rheumatology, Allergy and Clinical ImmunologyUniversity of California DavisDavisCaliforniaUSA
- Division of RheumatologyCHA University Medical CenterBundangKorea
| | - Ying Chen
- School of Food Science and Pharmaceutical EngineeringNanjing Normal UniversityNanjingChina
| | - Pietro Invernizzi
- International Center for Digestive HealthDepartment of Medicine and SurgeryUniversity of Milan-BicoccaMilanItaly
| | - Guoxiang Yang
- Division of Rheumatology, Allergy and Clinical ImmunologyUniversity of California DavisDavisCaliforniaUSA
| | - Weici Zhang
- Division of Rheumatology, Allergy and Clinical ImmunologyUniversity of California DavisDavisCaliforniaUSA
| | - Ti-Hong Shao
- Division of Rheumatology, Allergy and Clinical ImmunologyUniversity of California DavisDavisCaliforniaUSA
| | - Frank Jordan
- Department of ChemistryRutgers UniversityNewarkNew JerseyUSA
| | | | - Ross L Coppel
- Department of Microbiology, Nursing and Health SciencesMonash UniversityClaytonVictoriaAustralia
| | - William M Ridgway
- Division of Rheumatology, Allergy and Clinical ImmunologyUniversity of California DavisDavisCaliforniaUSA
| | - Mark Kurth
- Department of ChemisrtyUniversity of California DavisDavisCaliforniaUSA
| | - Aftab A Ansari
- Department of PathologyEmory University School of MedicineAtlantaGeorgiaUSA
| | - Patrick S C Leung
- Division of Rheumatology, Allergy and Clinical ImmunologyUniversity of California DavisDavisCaliforniaUSA
| | - M Eric Gershwin
- Division of Rheumatology, Allergy and Clinical ImmunologyUniversity of California DavisDavisCaliforniaUSA
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30
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You H, Ma X, Efe C, Wang G, Jeong SH, Abe K, Duan W, Chen S, Kong Y, Zhang D, Wei L, Wang FS, Lin HC, Yang JM, Tanwandee T, Gani RA, Payawal DA, Sharma BC, Hou J, Yokosuka O, Dokmeci AK, Crawford D, Kao JH, Piratvisuth T, Suh DJ, Lesmana LA, Sollano J, Lau G, Sarin SK, Omata M, Tanaka A, Jia J. APASL clinical practice guidance: the diagnosis and management of patients with primary biliary cholangitis. Hepatol Int 2022; 16:1-23. [PMID: 35119627 PMCID: PMC8843914 DOI: 10.1007/s12072-021-10276-6] [Citation(s) in RCA: 55] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Accepted: 11/08/2021] [Indexed: 12/14/2022]
Affiliation(s)
- Hong You
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, 95 Yong-an Road, Beijing, Mainland, China
| | - Xiong Ma
- Department of Gastroenterology and Hepatology, Renji Hospital, Shanghai Jiao Tong University, Shanghai, Mainland, China
| | - Cumali Efe
- Department of Gastroenterology, Gazi Yaşargil Education and Research Hospital, Diyarbakir, Turkey
| | - Guiqiang Wang
- Department of Infectious Diseases and Center for Liver Diseases, Peking University First Hospital, Beijing, Mainland, China
| | - Sook-Hyang Jeong
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seoul, South Korea
| | - Kazumichi Abe
- Department of Gastroenterology, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Weijia Duan
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, 95 Yong-an Road, Beijing, Mainland, China
| | - Sha Chen
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, 95 Yong-an Road, Beijing, Mainland, China
| | - Yuanyuan Kong
- Clinical Epidemiology and EBM Unit, Beijing Friendship Hospital, Capital Medical University, Beijing, Mainland, China
| | - Dong Zhang
- Experimental and Translational Research Center, Beijing Clinical Research Institute, Beijing, Mainland, China
| | - Lai Wei
- Hepatobiliary Pancreatic Center, Tsinghua Changgung Hospital, Tsinghua University, Beijing, Mainland, China
| | - Fu-Sheng Wang
- Treatment and Research Center for Infectious Diseases, The Fifth Medical Center of PLA General Hospial, Beijing, Mainland, China
| | - Han-Chieh Lin
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Jin Mo Yang
- Division of Hepatology, Department of Internal Medicine, College of Medicine, St. Vincent’s Hospital, The Catholic University of Korea, Suwon, South Korea
| | - Tawesak Tanwandee
- Division of Gastroenterology, Department of Medicine, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Rino A. Gani
- Department of Internal Medicine, Cipto Mangunkusumo Hospital, University of Indonesia, Jakarta, Indonesia
| | - Diana A. Payawal
- Department of Medicine, Fatima University Medical Center, Manila, Philippines
| | | | - Jinlin Hou
- Department of Infectious Disease and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, Mainland, China
| | - Osamu Yokosuka
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - A. Kadir Dokmeci
- Department of Medicine, Ankara University School of Medicine, Ankara, Turkey
| | - Darrell Crawford
- School of Medicine, University of Queensland, Brisbane, Australia
| | - Jia-Horng Kao
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Teerha Piratvisuth
- NKC Institute of Gastroenterology and Hepatology, Faculty of Medicine, Prince of Songkla University, Hatyai, Thailand
| | - Dong Jin Suh
- Department of Gastroenterology, University of Ulsan College of Medicine, Seoul, South Korea
| | | | - Jose Sollano
- Department of Medicine, University of Santo Tomas, Manila, Philippines
| | - George Lau
- Humanity and Health Clinical Trial Center, Humanity and Health Medical Group, Hong Kong SAR, China
| | - Shiv K. Sarin
- Department of Hepatology, Institute of Liver and Biliary Sciences, Vasant Kunj, New Delhi, India
| | - Masao Omata
- Department of Gastroenterology, Yamanashi Central Hospital, Yamanashi, Japan
- University of Tokyo, Tokyo, Japan
| | - Atsushi Tanaka
- Department of Medicine, Teikyo University School of Medicine, Tokyo, Japan
| | - Jidong Jia
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, 95 Yong-an Road, Beijing, Mainland, China
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31
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Selected transgenic murine models of human autoimmune liver diseases. Pharmacol Rep 2022; 74:263-272. [PMID: 35032321 PMCID: PMC8964654 DOI: 10.1007/s43440-021-00351-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Revised: 12/22/2021] [Accepted: 12/23/2021] [Indexed: 12/19/2022]
Abstract
Murine models of human diseases are of outmost importance for both studying molecular mechanisms driving their development and testing new treatment strategies. In this review, we first discuss the etiology and risk factors for autoimmune liver disease, including primary biliary cholangitis, autoimmune hepatitis and primary sclerosing cholangitis. Second, we highlight important features of murine transgenic models that make them useful for basic scientists, drug developers and clinical researchers. Next, a brief description of each disease is followed by the characterization of selected animal models.
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32
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Kim W. Chronic Liver Disease. SEX/GENDER-SPECIFIC MEDICINE IN THE GASTROINTESTINAL DISEASES 2022:209-227. [DOI: 10.1007/978-981-19-0120-1_14] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Matsumoto K, Ohfuji S, Abe M, Komori A, Takahashi A, Fujii H, Kawata K, Noritake H, Tadokoro T, Honda A, Asami M, Namisaki T, Ueno M, Sato K, Kakisaka K, Arakawa M, Ito T, Tanaka K, Matsui T, Setsu T, Takamura M, Yasuda S, Katsumi T, Itakura J, Sano T, Tamura Y, Miura R, Arizumi T, Asaoka Y, Uno K, Nishitani A, Ueno Y, Terai S, Takikawa Y, Morimoto Y, Yoshiji H, Mochida S, Ikegami T, Masaki T, Kawada N, Ohira H, Tanaka A. Environmental factors, medical and family history, and comorbidities associated with primary biliary cholangitis in Japan: a multicenter case-control study. J Gastroenterol 2022; 57:19-29. [PMID: 34796398 DOI: 10.1007/s00535-021-01836-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2021] [Accepted: 11/04/2021] [Indexed: 02/04/2023]
Abstract
BACKGROUND Primary biliary cholangitis (PBC) is considered to be caused by the interaction between genetic background and environmental triggers. Previous case-control studies have indicated the associations of environmental factors (tobacco smoking, a history of urinary tract infection, and hair dye) use with PBC. Therefore, we conducted a multicenter case-control study to identify the environmental factors associated with the development of PBC in Japan. METHODS From 21 participating centers in Japan, we prospectively enrolled 548 patients with PBC (male/female = 78/470, median age 66), and 548 age- and sex-matched controls. These participants completed a questionnaire comprising 121 items with respect to demographic, anthropometric, socioeconomic features, lifestyle, medical/familial history, and reproductive history in female individuals. The association was determined using conditional multivariate logistic regression analysis. RESULTS The identified factors were vault toilet at home in childhood [odds ratio (OR), 1.63; 95% confidence interval (CI), 1.01-2.62], unpaved roads around the house in childhood (OR, 1.43; 95% CI, 1.07-1.92), ever smoking (OR, 1.70; 95% CI, 1.28-2.25), and hair dye use (OR, 1.57; 95% CI, 1.15-2.14) in the model for lifestyle factors, and a history of any type of autoimmune disease (OR, 8.74; 95% CI, 3.99-19.13), a history of Cesarean section (OR, 0.20; 95% CI, 0.077-0.53), and presence of PBC in first-degree relatives (OR, 21.1; 95% CI, 6.52-68.0) in the model for medical and familial factors. CONCLUSIONS These results suggest that poor environmental hygiene in childhood (vault toilets and unpaved roads) and chronic exposure to chemicals (smoking and hair dye use) are likely to be risk factors for the development of PBC in Japan.
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Affiliation(s)
- Kosuke Matsumoto
- Department of Medicine, Teikyo University School of Medicine, 2-11-1, Kaga, Itabashi-ku, Tokyo, Japan.
| | - Satoko Ohfuji
- Department of Public Health, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Masanori Abe
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Ehime, Japan
| | - Atsumasa Komori
- Clinical Research Center, National Hospital Organization (NHO) Nagasaki Medical Center, Nagasaki, Japan
| | - Atsushi Takahashi
- Department of Gastroenterology, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Hideki Fujii
- Department of Premier Preventive Medicine, Graduate School of Medicine, Osaka City University, Osaka, Japan
- Department of Hepatology, Graduate School of Medicine, Osaka City University, Osaka, Japan
| | - Kazuhito Kawata
- Hepatology Division, Department of Internal Medicine II, Hamamatsu University School of Medicine, Shizuoka, Japan
| | - Hidenao Noritake
- Hepatology Division, Department of Internal Medicine II, Hamamatsu University School of Medicine, Shizuoka, Japan
| | - Tomoko Tadokoro
- Department of Gastroenterology and Neurology, Kagawa University School of Medicine, Kagawa, Japan
| | - Akira Honda
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Tokyo Medical University Ibaraki Medical Center, Ibaraki, Japan
| | - Maiko Asami
- Department of Gastroenterology and Hepatology, Faculty of Medicine, Saitama Medical University, Saitama, Japan
| | - Tadashi Namisaki
- Department of Gastroenterology, Nara Medical University, Nara, Japan
| | - Masayuki Ueno
- Department of Gastroenterology and Hepatology, Kurashiki Central Hospital, Okayama, Japan
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Ken Sato
- Department of Gastroenterology and Hepatology, Gunma University Graduate School of Medicine, Gunma, Japan
| | - Keisuke Kakisaka
- Division of Hepatology, Department of Internal Medicine, Iwate Medical University, Iwate, Japan
| | - Mie Arakawa
- Department of Gastroenterology, Faculty of Medicine, Oita University, Oita, Japan
| | - Takanori Ito
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Aichi, Japan
| | - Kazunari Tanaka
- Center for Gastroenterology, Teine-Keijinkai Hospital, Hokkaido, Japan
| | - Takeshi Matsui
- Center for Gastroenterology, Teine-Keijinkai Hospital, Hokkaido, Japan
| | - Toru Setsu
- Division of Gastroenterology and Hepatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Masaaki Takamura
- Division of Gastroenterology and Hepatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Satoshi Yasuda
- Department of Gastroenterology and Hepatology, Ogaki Municipal Hospital, Gifu, Japan
| | - Tomohiro Katsumi
- Department of Gastroenterology, Yamagata University Faculty of Medicine, Yamagata, Japan
| | - Jun Itakura
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Tomoya Sano
- Division of Gastroenterology, Department of Internal Medicine, Kurume University School of Medicine, Fukuoka, Japan
| | - Yamato Tamura
- Department of Medicine, Teikyo University School of Medicine, 2-11-1, Kaga, Itabashi-ku, Tokyo, Japan
| | - Ryo Miura
- Department of Medicine, Teikyo University School of Medicine, 2-11-1, Kaga, Itabashi-ku, Tokyo, Japan
| | - Toshihiko Arizumi
- Department of Medicine, Teikyo University School of Medicine, 2-11-1, Kaga, Itabashi-ku, Tokyo, Japan
| | - Yoshinari Asaoka
- Department of Medicine, Teikyo University School of Medicine, 2-11-1, Kaga, Itabashi-ku, Tokyo, Japan
| | - Kiyoko Uno
- Teikyo Academic Research Center, Teikyo University, Tokyo, Japan
| | - Ai Nishitani
- Teikyo Academic Research Center, Teikyo University, Tokyo, Japan
| | - Yoshiyuki Ueno
- Department of Gastroenterology, Yamagata University Faculty of Medicine, Yamagata, Japan
| | - Shuji Terai
- Division of Gastroenterology and Hepatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Yasuhiro Takikawa
- Division of Hepatology, Department of Internal Medicine, Iwate Medical University, Iwate, Japan
| | - Youichi Morimoto
- Department of Gastroenterology and Hepatology, Kurashiki Central Hospital, Okayama, Japan
| | - Hitoshi Yoshiji
- Department of Gastroenterology, Nara Medical University, Nara, Japan
| | - Satoshi Mochida
- Department of Gastroenterology and Hepatology, Faculty of Medicine, Saitama Medical University, Saitama, Japan
| | - Tadashi Ikegami
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Tokyo Medical University Ibaraki Medical Center, Ibaraki, Japan
| | - Tsutomu Masaki
- Department of Gastroenterology and Neurology, Kagawa University School of Medicine, Kagawa, Japan
| | - Norifumi Kawada
- Department of Hepatology, Graduate School of Medicine, Osaka City University, Osaka, Japan
| | - Hiromasa Ohira
- Department of Gastroenterology, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Atsushi Tanaka
- Department of Medicine, Teikyo University School of Medicine, 2-11-1, Kaga, Itabashi-ku, Tokyo, Japan
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The Epidemiology of UK Autoimmune Liver Disease Varies With Geographic Latitude. Clin Gastroenterol Hepatol 2021; 19:2587-2596. [PMID: 33493696 PMCID: PMC8661127 DOI: 10.1016/j.cgh.2021.01.029] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Revised: 01/05/2021] [Accepted: 01/18/2021] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS The epidemiology of autoimmune liver disease (AILD) is challenging to study because of the diseases' rarity and because of cohort selection bias. Increased incidence farther from the Equator has been reported for multiple sclerosis, another autoimmune disease. We assessed the incidence of primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), and autoimmune hepatitis (AIH) in relation to latitude. METHODS We performed a retrospective cohort study using anonymized UK primary care records from January 1, 2002, to May 10, 2016. All adults without a baseline diagnosis of AILD were included and followed up until the first occurrence of an AILD diagnosis, death, or they left the database. Latitude was measured as registered general practice rounded down to whole degrees. RESULTS The cohort included 8,590,421 records with 53.3 × 107 years of follow-up evaluation from 694 practices. There were 1314 incident cases of PBC, 396 of PSC, and 1034 of AIH. Crude incidences were as follows: PBC, 2.47 (95% CI, 2.34-2.60); PSC, 0.74 (95% CI, 0.67-0.82); and AIH, 1.94 (95% CI, 1.83-2.06) per 100,000 per year. PBC incidence correlated with female sex, smoking, and deprivation; PSC incidence correlated with male sex and non-smoking; AIH incidence correlated with female sex and deprivation. A more northerly latitude was associated strongly with incidence of PBC: 2.16 (95% CI, 1.79-2.60) to 4.86 (95% CI, 3.93-6.00) from 50°N to 57°N (P = .002) and incidence of AIH: 2.00 (95% CI, 1.65-2.43) to 3.28 (95% CI, 2.53-4.24) (P = .003), but not incidence of PSC: 0.82 (95% CI, 0.60-1.11) to 1.02 (95% CI, 0.64-1.61) (P = .473). Incidence after adjustment for age, sex, smoking, and deprivation status showed similar positive correlations for PBC and AIH with latitude, but not PSC. Incident AIH cases were younger at more northerly latitude. CONCLUSIONS We describe an association in the United Kingdom between more northerly latitude and the incidence of PBC and AIH that requires both confirmation and explanation.
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Early histopathologic changes in primary biliary cholangitis: does 'minimal change' primary biliary cholangitis exist? A pathologist's view. Eur J Gastroenterol Hepatol 2021; 33:e7-e12. [PMID: 32804848 DOI: 10.1097/meg.0000000000001876] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Primary biliary cholangitis (PBC), formerly known as primary biliary cirrhosis, is an autoimmune, slowly progressive, cholestatic liver disease characterized by nonsuppurative destructive cholangitis, and interlobular bile duct destruction. Necroinflammatory activities of the hepatic parenchyma and limiting plates of milder form along with late liver fibrosis may develop. Serum liver tests include elevated serum alkaline phosphatase along with a positive antimitochondrial antibody (AMA) in nearly 95% of patients. Liver biopsies are an important confirmatory and staging tool and are additionally very helpful when AMA is negative. More specifically, the earliest changes in liver biopsy suspicious for PBC can be detected, namely loss of the canals of Hering (CoH), as proposed by various authors recently. CoH loss has been described as an early feature of PBC. We focus on early histologic features of PBC, investigating through the literature the possible role of 'minimal change' supporting the clinical diagnosis of PBC, even in the absence of characteristic granulomatous duct destructive lesions.
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Lammert C, Chalasani SN, Atkinson EJ, McCauley BM, Lazaridis KN. Environmental risk factors are associated with autoimmune hepatitis. Liver Int 2021; 41:2396-2403. [PMID: 33978301 PMCID: PMC8496440 DOI: 10.1111/liv.14944] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2020] [Revised: 04/20/2021] [Accepted: 04/26/2021] [Indexed: 12/17/2022]
Abstract
BACKGROUND Failure of immunologic homeostasis and resultant hepatocyte destruction in autoimmune hepatitis (AIH) is likely the result of environmental triggers within a permissive genetic architecture. AIMS We aimed to identify risk factors associated with AIH in a well-phenotyped AIH cohort. METHODS We prospectively collected environmental questionnaires from 358 AIH cases and 563 healthy controls. Response frequencies were compared using logistic regression, adjusting for age at recruitment, sex and education. RESULTS AIH cases were more likely to ever have a urinary tract infection (UTI) (53.6% vs 33.9%, P < .001) and recurrent UTI (more than 1 per year) (23.5% vs 15.9%, P = .002) compared to controls. Female cases more frequently had ever used oral contraceptives (83.0% vs 73.7%, P = .006), fewer pregnancies (median = 1 vs 3, P < .001) and less often used hormone replacement therapy compared to controls (28.5% vs 60.1%, P < .001). Current smoking was more prevalent in cases (18.9% vs 7.4%, P = .022), yet no difference according to historical smoking behaviours was observed. Finally, cases were less likely to have history of mumps (32.4% vs 53.1%, P = .011) and rheumatic fever (1.1% vs 4.4%, P = .028), but reported higher vaccination frequency to chicken pox (38% vs 28.1%), measles (66.5% vs 39.3%), mumps (58.7% vs 34.6%), rubella (55.3% vs 32.7%), pertussis (59.8% vs 40.1%) and pneumococcus (47.2% VS 39.4%) (P < .002). CONCLUSIONS Environmental factors are important in AIH pathogenesis. Replication of these findings and prospective examination may provide new insight into AIH onset and outcomes.
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Affiliation(s)
- Craig Lammert
- Division of Gastroenterology and HepatologyIndiana University School of MedicineIndianapolisINUSA
| | - Sai N. Chalasani
- Division of Gastroenterology and HepatologyIndiana University School of MedicineIndianapolisINUSA
| | - Elizabeth J. Atkinson
- Division of Gastroenterology and HepatologyMayo Clinic College of MedicineRochesterMNUSA
| | - Bryan M. McCauley
- Division of Gastroenterology and HepatologyMayo Clinic College of MedicineRochesterMNUSA
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Trivedi PJ, Hirschfield GM. Recent advances in clinical practice: epidemiology of autoimmune liver diseases. Gut 2021; 70:1989-2003. [PMID: 34266966 DOI: 10.1136/gutjnl-2020-322362] [Citation(s) in RCA: 129] [Impact Index Per Article: 32.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2021] [Accepted: 06/24/2021] [Indexed: 12/13/2022]
Abstract
Autoimmune liver diseases are chronic inflammatory hepatobiliary disorders that when classically defined encompass three distinctive clinical presentations; primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC) and autoimmune hepatitis (AIH). Meaningful changes in disease epidemiology are reported, with increasing incidence and prevalence of AIH and PSC in Europe, and rising prevalence of PBC across Europe, North America and the Asia-Pacific region. However, there appears to be very significant global variation with contemporary incidence rates of disease per 100 000 ranging from 0.84 to 2.75 for PBC, 0.1 to 4.39 for PSC and 0.4 to 2.39 for AIH. Prevalence corresponds, and per 100 000 estimates for PBC range from 1.91 to 40.2, for PSC between 0.78 and 31.7 and for AIH from 4.8 to 42.9. Population-based studies and multicentre observational cohort series provide improved understanding of the clinical course that patients experience, highlighting variations in presenting phenotypes geographically and temporally. Collectively, while autoimmune liver diseases are rare, the clinical burden is disproportionately high relative to population incidence and prevalence. Age, sex and race also impact clinical outcomes, and patient morbidity and mortality are reflected by high need for gastroenterology, hepatology and organ transplant services.
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Affiliation(s)
- Palak J Trivedi
- National Institute for Health Research (NIHR) Birmingham Liver Biomedical Research Centre, University of Birmingham College of Medical and Dental Sciences, Birmingham, Birmingham, UK
- Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK
- Institute of Applied Health Research, University of Birmingham, Birmingham, UK
- Liver Unit, University Hospitals Birmingham National Health Service Foundation Trust Queen Elizabeth, Birmingham, UK
| | - Gideon M Hirschfield
- Toronto Centre for Liver Disease, Division of Gastroenterology and Hepatology, University of Toronto, Toronto, Ontario, Canada
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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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Gazda J, Drazilova S, Janicko M, Jarcuska P. The Epidemiology of Primary Biliary Cholangitis in European Countries: A Systematic Review and Meta-Analysis. Can J Gastroenterol Hepatol 2021; 2021:9151525. [PMID: 34239845 PMCID: PMC8238597 DOI: 10.1155/2021/9151525] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Revised: 05/27/2021] [Accepted: 06/09/2021] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Primary biliary cholangitis (PBC) is a chronic autoimmune cholestatic liver disease with wide ranges of reported incidence and prevalence. AIM To map the incidence and prevalence of PBC in European countries from 2000 through 2020. METHODS Following PRISMA recommendations, we searched the Medline and Scopus databases for studies with information on either the incidence or prevalence of PBC. After data extraction, we used a random-effects model to estimate both the pooled annual incidence rate and pooled point-prevalence rate and performed subgroup analyses to identify components contributing to between-study heterogeneity. RESULTS We performed a qualitative and quantitative analysis of 18 studies. The pooled point-prevalence rate was 22.27 cases per 100,000 inhabitants (95% CI: 17.98-27.01), and the pooled annual incidence rate was 1.87 new cases per 100,000 inhabitants (95% CI: 1.46-2.34). In the subgroup analyses, we proved that a small part of the between-study heterogeneity is significantly associated with a history of being part of the Eastern Bloc.
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Affiliation(s)
- Jakub Gazda
- 2nd Department of Internal Medicine, PJ Safarik University in Kosice and L. Pasteur University Hospital, Trieda SNP 1, Kosice 040 11, Slovakia
| | - Sylvia Drazilova
- 2nd Department of Internal Medicine, PJ Safarik University in Kosice and L. Pasteur University Hospital, Trieda SNP 1, Kosice 040 11, Slovakia
| | - Martin Janicko
- 2nd Department of Internal Medicine, PJ Safarik University in Kosice and L. Pasteur University Hospital, Trieda SNP 1, Kosice 040 11, Slovakia
| | - Peter Jarcuska
- 2nd Department of Internal Medicine, PJ Safarik University in Kosice and L. Pasteur University Hospital, Trieda SNP 1, Kosice 040 11, Slovakia
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French J, Simpson-Yap S, van der Mei I, Ng J, Angus P, Gow PJ. Identification of a Latitude Gradient in the Prevalence of Primary Biliary Cholangitis. Clin Transl Gastroenterol 2021; 12:e00357. [PMID: 34003806 PMCID: PMC8345914 DOI: 10.14309/ctg.0000000000000357] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2021] [Accepted: 04/05/2021] [Indexed: 12/03/2022] Open
Abstract
INTRODUCTION The prevalence of primary biliary cholangitis (PBC) reported in different countries varies significantly and seems to have a latitudinal gradient with the highest prevalence reported in higher latitudes, as has been observed with other autoimmune diseases. This study aimed to determine whether there is a latitudinal gradient of PBC prevalence in Australia using 2 methods of case ascertainment. METHODS We investigated the latitudinal variation of PBC prevalence across the states and territories of Australia (latitudinal range 18.0°-42.7°S) using pathology-based (private pathology antimitochondrial antibody results and PBC-specific prescription databases (prescriptions for ursodeoxycholic acid, the only publicly subsidized treatment for this disease). RESULTS PBC prevalence was significantly positively associated with latitude, and the postcodes in the highest quintile of latitude (encompassing the south coastal areas of the Australian mainland and Tasmania; latitude range -37.75° to -42.72°) had a prevalence estimate that was 1.78 times higher using the pathology-based prevalence estimation than those in the lowest quintile (encompassing tropical and southern Queensland; latitude range -18.02° to -27.59°). Comparing prevalence estimates between states/territories, the result was 2.53 and 2.21 times higher in Tasmania compared with Queensland when using the pathology-based and prescription-based methods, respectively. DISCUSSION Using 2 different case-ascertainment methods, we have demonstrated that prevalence estimates of PBC vary significantly with latitude in Australia. Further studies are needed to determine whether factors such as variations in ultraviolet radiation exposure and/or vitamin D levels are responsible for this observation and to investigate the latitudinal prevalence of PBC in other populations.
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Affiliation(s)
- Janine French
- Department of Gastroenterology, Austin Hospital, Heidelberg, Australia
| | - Steve Simpson-Yap
- Department of Biostatistics and Epidemiology, Melbourne School of Population and Global Health, University of Melbourne, Carlton, Australia
- Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia
| | - Ingrid van der Mei
- Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia
| | - Justin Ng
- Department of Gastroenterology, Austin Hospital, Heidelberg, Australia
| | - Peter Angus
- Department of Gastroenterology, Austin Hospital, Heidelberg, Australia
| | - Paul J. Gow
- Department of Gastroenterology, Austin Hospital, Heidelberg, Australia
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Wu H, Chen C, Ziani S, Nelson LJ, Ávila MA, Nevzorova YA, Cubero FJ. Fibrotic Events in the Progression of Cholestatic Liver Disease. Cells 2021; 10:1107. [PMID: 34062960 PMCID: PMC8147992 DOI: 10.3390/cells10051107] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Revised: 04/28/2021] [Accepted: 04/30/2021] [Indexed: 02/07/2023] Open
Abstract
Cholestatic liver diseases including primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) are associated with active hepatic fibrogenesis, which can ultimately lead to the development of cirrhosis. However, the exact relationship between the development of liver fibrosis and the progression of cholestatic liver disease remains elusive. Periductular fibroblasts located around the bile ducts seem biologically different from hepatic stellate cells (HSCs). The fibrotic events in these clinical conditions appear to be related to complex crosstalk between immune/inflammatory mechanisms, cytokine signalling, and perturbed homeostasis between cholangiocytes and mesenchymal cells. Several animal models including bile duct ligation (BDL) and the Mdr2-knockout mice have improved our understanding of mechanisms underlying chronic cholestasis. In the present review, we aim to elucidate the mechanisms of fibrosis in order to help to identify potential diagnostic and therapeutic targets.
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Affiliation(s)
- Hanghang Wu
- Department of Immunology, Ophthalmology & ENT, Complutense University School of Medicine, 28040 Madrid, Spain; (H.W.); (C.C.); (S.Z.); (Y.A.N.)
| | - Chaobo Chen
- Department of Immunology, Ophthalmology & ENT, Complutense University School of Medicine, 28040 Madrid, Spain; (H.W.); (C.C.); (S.Z.); (Y.A.N.)
- Health Research Institute Gregorio Marañón (IiSGM), 28007 Madrid, Spain
- Department of General Surgery, Wuxi Xishan People’s Hospital, Wuxi 214000, China
| | - Siham Ziani
- Department of Immunology, Ophthalmology & ENT, Complutense University School of Medicine, 28040 Madrid, Spain; (H.W.); (C.C.); (S.Z.); (Y.A.N.)
| | - Leonard J. Nelson
- Institute for Bioengineering (IBioE), School of Engineering, Faraday Building, The University of Edinburgh, Edinburgh EH9 3 JL, Scotland, UK;
- Institute of Biological Chemistry, Biophysics and Bioengineering (IB3), School of Engineering and Physical Sciences (EPS), Heriot-Watt University, Edinburgh EH14 4AS, Scotland, UK
| | - Matías A. Ávila
- Hepatology Program, Center for Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Spain;
- Centro de Investigacion Biomedica en Red, Enfermedades Hepáticas y Digestivas (CIBERehd), 28029 Madrid, Spain
- Instituto de Investigaciones Sanitarias de Navarra IdiSNA, 31008 Pamplona, Spain
| | - Yulia A. Nevzorova
- Department of Immunology, Ophthalmology & ENT, Complutense University School of Medicine, 28040 Madrid, Spain; (H.W.); (C.C.); (S.Z.); (Y.A.N.)
- Health Research Institute Gregorio Marañón (IiSGM), 28007 Madrid, Spain
- Centro de Investigacion Biomedica en Red, Enfermedades Hepáticas y Digestivas (CIBERehd), 28029 Madrid, Spain
- Department of Internal Medicine III, University Hospital RWTH Aachen, 52074 Aachen, Germany
| | - Francisco Javier Cubero
- Department of Immunology, Ophthalmology & ENT, Complutense University School of Medicine, 28040 Madrid, Spain; (H.W.); (C.C.); (S.Z.); (Y.A.N.)
- Health Research Institute Gregorio Marañón (IiSGM), 28007 Madrid, Spain
- Centro de Investigacion Biomedica en Red, Enfermedades Hepáticas y Digestivas (CIBERehd), 28029 Madrid, Spain
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Blesl A, Stadlbauer V. The Gut-Liver Axis in Cholestatic Liver Diseases. Nutrients 2021; 13:nu13031018. [PMID: 33801133 PMCID: PMC8004151 DOI: 10.3390/nu13031018] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Revised: 03/12/2021] [Accepted: 03/18/2021] [Indexed: 12/12/2022] Open
Abstract
The gut-liver axis describes the physiological interplay between the gut and the liver and has important implications for the maintenance of health. Disruptions of this equilibrium are an important factor in the evolution and progression of many liver diseases. The composition of the gut microbiome, the gut barrier, bacterial translocation, and bile acid metabolism are the key features of this cycle. Chronic cholestatic liver diseases include primary sclerosing cholangitis, the generic term secondary sclerosing cholangitis implying the disease secondary sclerosing cholangitis in critically ill patients and primary biliary cirrhosis. Pathophysiology of these diseases is not fully understood but seems to be multifactorial. Knowledge about the alterations of the gut-liver axis influencing the pathogenesis and the outcome of these diseases has considerably increased. Therefore, this review aims to describe the function of the healthy gut-liver axis and to sum up the pathological changes in these cholestatic liver diseases. The review compromises the actual level of knowledge about the gut microbiome (including the mycobiome and the virome), the gut barrier and the consequences of increased gut permeability, the effects of bacterial translocation, and the influence of bile acid composition and pool size in chronic cholestatic liver diseases. Furthermore, therapeutic implications and future scientific objectives are outlined.
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Affiliation(s)
- Andreas Blesl
- Division for Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, 8036 Graz, Austria;
- Correspondence:
| | - Vanessa Stadlbauer
- Division for Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, 8036 Graz, Austria;
- Center for Biomarker Research in Medicine (CBmed), 8010 Graz, Austria
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Kim KA, Kim YS, Park SH, Chung WJ, Choi DH, Jang ES, Jeong SH. Environmental risk factors and comorbidities of primary biliary cholangitis in Korea: a case-control study. Korean J Intern Med 2021; 36:313-321. [PMID: 32204000 PMCID: PMC7969053 DOI: 10.3904/kjim.2019.234] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2019] [Accepted: 09/05/2019] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND/AIMS The risk factors for the development of primary biliary cholangitis (PBC) is unclear. This study aimed to investigate the risk factors associated with PBC in Korea through a questionnaire survey. METHODS Consecutively enrolled 103 PBC patients from six referral hospitals and 100 age- and sex-matched community controls participated in this study. A standardized questionnaire survey including demographics, lifestyle, individual and familial medical history and reproductive history was prospectively collected and analyzed. RESULTS The PBC patients had a mean age of 58.3 years and a female proportion of 86.4%. The age- and sex-matched controls had a similar educational level and economic status to the PBC patients. Among the lifestyle factors, the multivariable analysis showed smoking including both first-hand and second-hand (odds ratio [OR], 2.03; 95% confidence interval [CI], 1.06 to 3.93), history of autoimmune diseases (OR, 2.46; 95% CI, 1.06 to 6.35), and family history of PBC (OR, 17.76; 95% CI, 1.77 to 2,418.74) were significantly associated with PBC, whereas alcohol intake was negatively associated with PBC. Among reproductive factors, the number of induced abortions was significantly associated with PBC, while the number of full-term deliveries was negatively associated with PBC. CONCLUSION A family history of PBC, accompanying autoimmune diseases, and smoking were significantly associated with PBC. More induced abortions and less full-term deliveries were associated with PBC in women. In contrast, mild to moderate alcohol intake was negatively associated with PBC. Further studies are warranted to validate the results of this study and to search for clues about the pathogenesis of PBC.
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Affiliation(s)
- Kyung-Ah Kim
- Department of Internal Medicine, Inje University Ilsan Paik Hospital, Goyang, Korea
| | - Young Seok Kim
- Department of Internal Medicine, Soonchunhyang University Bucheon Hospital, Bucheon, Korea
| | - Sang Hoon Park
- Division of Gastroenterology and Hepatology, Hallym University Kangnam Sacred Heart Hospital, Seoul, Korea
| | - Woo Jin Chung
- Department of Internal Medicine, Keimyung University School of Medicine, Daegu, Korea
| | - Dae Hee Choi
- Department of Internal Medicine, Kangwon National University School of Medicine, Chuncheon, Korea
| | - Eun Sun Jang
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Sook-Hyang Jeong
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
- Correspondence to Sook-Hyang Jeong, M.D. Department of Internal Medicine, Seoul National University Bundang Hospital, 82 Gumi-ro 173 Beon-gil, Bundang-gu, Seongnam 13620, Korea Tel: +82-31-787-7034 Fax: +82-31-787-4052 E-mail:
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44
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Abstract
Pruritus is one of the most common and bothersome symptoms of skin disorders, and its clinical characteristics and related pathomechanisms have been well described in certain dermatologic conditions, such as atopic dermatitis and urticaria. Although pruritus is believed to be as common in cutaneous autoimmune connective tissue diseases (ACTDs) as in other inflammatory skin disorders, its true characteristics have not been elucidated either qualitatively or quantitatively. Pruritus is present in ACTDs with various prevalence rates, characteristics, and mechanisms depending on the disease types. Pruritus most frequently and severely affects the patients with dermatomyositis, in which itch is strongly correlated with disease activity and severity, thus increased itch could also indicate a disease flare. Patients with other ACTDs, including lupus erythematosus (LE), Sjögren syndrome (SS), morphea, and systemic sclerosis (SSc), also suffer from their fair share of pruritus. Unfortunately, the currently available treatments for ACTDs seem to have only limited and unsatisfactory effects to control pruritus. The extensive impact of pruritus on the patients’ quality of life (QOL) and functioning warrants more targeted and individualized approaches against pruritus in ACTDs. This review will address the prevalence, suggested pathogenesis based on currently available evidences, and potential treatment options of pruritus in various ACTDs of the skin.
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Affiliation(s)
- Hee Joo Kim
- Department of Dermatology, Gachon Gil Medical Center, Gachon University College of Medicine, Incheon, South Korea
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45
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Kato T, Akagawa S, Kusaka K, Kawashima M, Ohshima N, Kitani M, Hebisawa A, Matsui H. An autopsy case report of yellow nail syndrome coincided with primary biliary cholangitis. Respir Med Case Rep 2020; 32:101332. [PMID: 33511030 PMCID: PMC7817504 DOI: 10.1016/j.rmcr.2020.101332] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2020] [Revised: 12/19/2020] [Accepted: 12/27/2020] [Indexed: 12/19/2022] Open
Abstract
Yellow nail syndrome (YNS) is a rare entity characterized by thickened yellowish nails, lymphedema and respiratory manifestations such as pleural effusion. Lymphatic dysfunction is considered as a cause of YNS. However, evidence of systemic dilatation/hyperplasia of lymphatics based on autopsy in YNS is not available. In this report, autopsy revealed dilatation and hyperplasia of lymphatic vessels in lungs, visceral and parietal pleurae, and intestines. We identified the direct opening of lymphatic vessels of the visceral pleura to the pleural cavity, which indicated the pathophysiology of uncontrollable pleural effusion in YNS. The current case was compromised with primary biliary cholangitis (PBC). The onset of PBC seemed to be related with the progression of YNS.
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Affiliation(s)
- Takafumi Kato
- Center for Pulmonary Diseases, National Hospital Organization Tokyo National Hospital, Tokyo, Japan
| | - Shinobu Akagawa
- Center for Pulmonary Diseases, National Hospital Organization Tokyo National Hospital, Tokyo, Japan
| | - Kei Kusaka
- Center for Pulmonary Diseases, National Hospital Organization Tokyo National Hospital, Tokyo, Japan
| | - Masahiro Kawashima
- Center for Pulmonary Diseases, National Hospital Organization Tokyo National Hospital, Tokyo, Japan
| | - Nobuharu Ohshima
- Center for Pulmonary Diseases, National Hospital Organization Tokyo National Hospital, Tokyo, Japan
| | - Masashi Kitani
- Division of Pathology, National Hospital Organization Tokyo National Hospital, Tokyo, Japan
| | - Akira Hebisawa
- Division of Pathology, National Hospital Organization Tokyo National Hospital, Tokyo, Japan
| | - Hirotoshi Matsui
- Center for Pulmonary Diseases, National Hospital Organization Tokyo National Hospital, Tokyo, Japan
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46
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Rabiee A, Polanco NAP, Vara AFDL, Levy C. Hispanic Patients with Primary Biliary Cholangitis Have Decreased Access to Care Compared to Non-Hispanics. J Clin Transl Hepatol 2020; 8:391-396. [PMID: 33447522 PMCID: PMC7782121 DOI: 10.14218/jcth.2020.00006] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2020] [Revised: 07/21/2020] [Accepted: 09/18/2020] [Indexed: 12/30/2022] Open
Abstract
Background and Aims: Hispanic patients with primary biliary cholangitis (PBC) have reduced rates of biochemical response to ursodeoxycholic acid (UDCA) and increased risk of disease progression compared to non-Hispanic patients. In this study, we sought to identify differences in demographics, comorbidities, environmental risk factors and socioeconomic status between Hispanic and non-Hispanic patients with PBC. Methods: In a case control study, we analyzed data from Hispanic (n=37 females and 1 male) and non-Hispanic (n=54 females and 4 males) patients with PBC seen at the University of Miami/Jackson Memorial Hospital from January 1998 through January 2013. Data were obtained by filling out a questionnaire either via phone call, mail, or e-mail. Odds ratios were calculated to measure the association between exposure and outcomes. Results: Baseline demographics, environmental risk factors and comorbidities were similar between Hispanic and non-Hispanic patients with PBC. Hispanic patients were less likely to be married and fewer Hispanics had education beyond high school level compared to non-Hispanics. Sixty four percent of Hispanic patients had a household income of less than $50000, compared to 19.5% of non-Hispanics. Fewer Hispanic patients with PBC had health insurance coverage compared to non-Hispanics (86.5% vs. 98.1%; odds ratio: 0.1, 95% confidence interval: 0-0.9). Conclusions: Differences in disease severity and response to therapy observed in prior studies could not be explained by environmental exposures. In addition to genetic variation, socioeconomic discrepancies (access to care) may further explain these differences.
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Affiliation(s)
- Atoosa Rabiee
- Department of Gastroenterology and Hepatology, VA Medical Center, Washington DC, USA
- Correspondence to: Atoosa Rabiee, Department of Gastroenterology and Hepatology, VA Medical Center, 50 Irving St NW, Washington DC 20422, USA. Tel: +1-202-745-8456, E-mail:
| | - Nathalie A Pena Polanco
- Divison of Digestive Health and Liver Diseases Department of Medicine University of Miami Miller School of Medicine USA
| | | | - Cynthia Levy
- Divison of Digestive Health and Liver Diseases Department of Medicine University of Miami Miller School of Medicine USA
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47
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Lleo A, Wang GQ, Gershwin ME, Hirschfield GM. Primary biliary cholangitis. Lancet 2020; 396:1915-1926. [PMID: 33308474 DOI: 10.1016/s0140-6736(20)31607-x] [Citation(s) in RCA: 147] [Impact Index Per Article: 29.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/26/2019] [Revised: 06/27/2020] [Accepted: 07/10/2020] [Indexed: 12/14/2022]
Abstract
Primary biliary cholangitis is an autoimmune liver disease that predominantly affects women. It is characterised by a chronic and destructive, small bile duct, granulomatous lymphocytic cholangitis, with typical seroreactivity for antimitochondrial antibodies. Patients have variable risks of progressive ductopenia, cholestasis, and biliary fibrosis. Considerations for the cause of this disease emphasise an interaction of chronic immune damage with biliary epithelial cell responses and encompass complex, poorly understood genetic risks and environmental triggers. Licensed disease-modifying treatment focuses on amelioration of cholestasis, with weight-dosed oral ursodeoxycholic acid. For patients who do not respond sufficiently, or patients with ursodeoxycholic acid intolerance, conditionally licensed add-on therapy is with the FXR (NR1H4) agonist, obeticholic acid. Off-label therapy is recognised as an alternative, notably with the pan-PPAR agonist bezafibrate; clinical trial agents are also under development. Baseline characteristics, such as young age, male sex, and advanced disease, and serum markers of liver injury, particularly bilirubin and ALP, are used to stratify risk and assess treatment responsiveness. Parallel attention to the burden of patient symptoms is paramount, including pruritus and fatigue.
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Affiliation(s)
- Ana Lleo
- Department of Biomedical Sciences, Humanitas University, Milan, Italy; Division of Internal Medicine and Hepatology, Department of Gastroenterology, Humanitas Clinical and Research Center IRCCS, Rozzano, Italy
| | - Giu-Qiang Wang
- Department of Infectious Diseases and Center for Liver Diseases, Peking University First Hospital, Beijing, China; Department of Infectious Diseases and Liver Diseases, Peking University International Hospital, Beijing, China
| | - Merrill Eric Gershwin
- Division of Rheumatology, Allergy and Clinical Immunology, The University of California, Davis, CA, USA
| | - Gideon M Hirschfield
- Toronto Centre for Liver Disease, Division of Gastroenterology and Hepatology, University of Toronto, Toronto, ON, Canada.
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48
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Abstract
Primary biliary cholangitis (PBC) causes chronic and persistent cholestasis in the liver, eventually resulting in cirrhosis and hepatic failure without appropriate treatment. PBC mainly develops in middle-aged women, but it is also common in young women and men. PBC is considered a model of autoimmune disease because of the presence of disease-specific autoantibodies, that is, antimitochondrial antibodies (AMAs), intense infiltration of mononuclear cells into the bile ducts, and a high prevalence of autoimmune diseases such as comorbidities. Histologically, PBC is characterized by degeneration and necrosis of intrahepatic biliary epithelial cells surrounded by a dense infiltration of mononuclear cells, coined as chronic non-suppurative destructive cholangitis, which leads to destructive changes and the disappearance of small- or medium-sized bile ducts. Since 1990, early diagnosis with the detection of AMAs and introduction of ursodeoxycholic acid as first-line treatment has greatly altered the clinical course of PBC, and liver transplantation-free survival of patients with PBC is now comparable to that of the general population.
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Affiliation(s)
- Atsushi Tanaka
- Department of Medicine, Teikyo University School of Medicine, Tokyo, Japan
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49
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Dyson JK, Blain A, Foster Shirley MD, Hudson M, Rushton S, Jeffreys Jones DE. Geo-epidemiology and environmental co-variate mapping of primary biliary cholangitis and primary sclerosing cholangitis. JHEP Rep 2020; 3:100202. [PMID: 33474546 PMCID: PMC7803647 DOI: 10.1016/j.jhepr.2020.100202] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2020] [Revised: 09/14/2020] [Accepted: 10/09/2020] [Indexed: 02/07/2023] Open
Abstract
Background & Aims Autoimmune liver disease (AILD) is thought to result from a complex interplay between genetics and the environment. Studies to date have focussed on primary biliary cholangitis (PBC) and demonstrated higher disease prevalence in more urban, polluted, and socially deprived areas. This study utilises a large cohort of patients with PBC and primary sclerosing cholangitis (PSC) to investigate potential environmental contributors to disease and to explore whether the geo-epidemiology of PBC and PSC are disease-specific or pertain to cholestatic AILD in general. Methods All adult patients with PBC and PSC in a tightly defined geographical area within the UK were identified. Point- and area-based analyses and structural equation modelling (SEM) were used to investigate for disease clustering and examine for relationships between prevalence, distribution of environmental contaminants, and socio-economic status. Results We identified 2,150 patients with PBC and 472 with PSC. Significant spatial clustering was seen for each disease. A high prevalence of PBC was found in urban, post-industrial areas with a strong coal-mining heritage and increased environmental cadmium levels, whereas a high PSC prevalence was found in rural areas and inversely associated with social deprivation. Conclusions This study demonstrates spatial clustering of PBC and PSC and adds to our understanding of potential environmental co-variates for both diseases. Disease clustering, within the same geographical area but over different scales, is confirmed for each disease with distinct risk profiles identified and associations with separate putative environmental factors and socio-economic status. This suggests that different triggers and alternative pathways determine phenotypic expression of autoimmunity in the affected population. Co-variate analysis points towards the existence of specific disease triggers. Lay summary This study looked for potential environmental triggers in patients with primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) living in the north-east of England and north Cumbria. We found that PBC was more common in urban areas with a history of coal mining and high levels of cadmium whereas PSC was more common in rural areas with lower levels of social deprivation.
Clustering of PBC and PSC patients occurs with notable geographical differences. A high prevalence of PBC is seen in urban, post-industrial areas. PSC is more common in rural areas and inversely associated with social deprivation. PBC risk is associated with proximity to coal mines and environmental cadmium levels. Comprehensive epidemiological study can increase understanding of disease aetiology.
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Key Words
- AHSN NENC, Academic Health Science Network for the North East and North Cumbria
- AIH, autoimmune hepatitis
- AILD, autoimmune liver disease
- Autoimmune hepatitis
- BECs, biliary epithelial cells
- CFI, comparative fit index
- Cadmium
- DIC, deviance information criterion
- Geo-epidemiology
- IMD, Index of Multiple Deprivation
- PBC, primary biliary cholangitis
- PSC, primary sclerosing cholangitis
- Primary biliary cholangitis
- Primary sclerosing cholangitis
- RMSEA, root mean square error of association
- Rural
- SEM, structural equation modelling
- SFS, superfund toxic waste site
- Socio-economic status
- Urban
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Affiliation(s)
- Jessica Katharine Dyson
- Translational and Clinical Research Institute, Newcastle University, Newcastle-upon-Tyne, UK.,Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle-upon-Tyne, UK
| | - Alasdair Blain
- Wellcome Centre for Mitochondrial Research, Newcastle University, Newcastle-upon-Tyne, UK
| | | | - Mark Hudson
- Translational and Clinical Research Institute, Newcastle University, Newcastle-upon-Tyne, UK.,Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle-upon-Tyne, UK
| | - Steven Rushton
- School of Natural and Environmental Sciences, Newcastle University, Newcastle-upon-Tyne, UK
| | - David Emrys Jeffreys Jones
- Translational and Clinical Research Institute, Newcastle University, Newcastle-upon-Tyne, UK.,Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle-upon-Tyne, UK
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50
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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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