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Levy C, Buchanan-Peart KA, MacEwan JP, Levine A, Nair R, Wheeler D, Bessonova L, Goel A, Gish RG, Bonder A. A nationwide study of primary biliary cholangitis prevalence, geographic distribution, and health care providers. Hepatol Commun 2025; 9:e0677. [PMID: 40227093 PMCID: PMC11999412 DOI: 10.1097/hc9.0000000000000677] [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: 08/01/2024] [Accepted: 01/08/2025] [Indexed: 04/15/2025] Open
Abstract
BACKGROUND Prevalence estimates of primary biliary cholangitis (PBC) in the United States have evolved with the introduction of newer real-world data capture approaches. Little is known about the geographic distribution of PBC in the United States and the health care provider (HCP) landscape for patients with PBC. This real-world study aimed to estimate the prevalence of PBC in the United States, assess regional variability in its prevalence, and describe HCPs for patients with PBC. METHODS Patients with PBC were identified using Komodo's Healthcare Map, a large national administrative claims database. PBC prevalence per 100,000 adults was adjusted by age and gender at the 3-digit ZIP Code tabulation area level. Patients' PBC-related medical or pharmacy claims were used to determine HCP specialties and affiliations (academic vs. nonacademic); the latest claim and all claims were examined. RESULTS The adjusted 2021 PBC prevalence was 40.9 per 100,000 adults. The highest absolute number of patients with PBC in the United States was in heavily populated urban areas, but prevalence adjusted for population size was highest in some rural areas. Among all claims, most (83.2%) patients received care from a specialist (gastroenterologist/hepatologist) at one time. However, only approximately half (53.5%) of patients with PBC, irrespective of therapy use, were most recently treated for PBC by a specialist. CONCLUSIONS This is the most comprehensive and contemporary estimation of PBC prevalence in the United States to date. The pockets of high prevalence of PBC located in some rural areas highlight the need to better evaluate PBC risk factors and potential barriers in access to specialist care once patients are diagnosed. Greater awareness of PBC and its management are needed.
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Affiliation(s)
- Cynthia Levy
- Schiff Center for Liver Diseases, University of Miami, Miami, Florida, USA
- Division of Digestive Health and Liver Diseases, University of Miami, Miami, Florida, USA
| | | | | | - Alina Levine
- Genesis Research Group, Hoboken, New Jersey, USA
| | - Radhika Nair
- Intercept Pharmaceuticals, Inc., Morristown, New Jersey, USA
| | - Darren Wheeler
- Intercept Pharmaceuticals, Inc., Morristown, New Jersey, USA
- At the time of study
| | - Leona Bessonova
- Intercept Pharmaceuticals, Inc., Morristown, New Jersey, USA
| | - Aparna Goel
- Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University, Stanford, California, USA
| | - Robert G. Gish
- Robert G. Gish Consultants, LLC, San Diego, California, USA
| | - Alan Bonder
- Division of Gastroenterology and Hepatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
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Arroyave E, Saldarriaga OA, Bhatti S, Bergman I, Graham R, Tana M, Balitzer D, Khan KJ, Kueht M, Stevenson HL. Integrating Molecular Testing With Clinical Criteria and Histopathology Improves Diagnostic Precision in Immune-Mediated Liver Diseases. Mod Pathol 2025; 38:100728. [PMID: 39914772 DOI: 10.1016/j.modpat.2025.100728] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2024] [Revised: 01/17/2025] [Accepted: 01/28/2025] [Indexed: 03/06/2025]
Abstract
Autoimmune hepatitis (AIH) and primary biliary cholangitis (PBC) are immune-mediated liver diseases (IMLDs) that are diagnosed by a combination of clinical, serologic, and histologic features. Diagnosis may be challenging, particularly when patients have mixed features of both AIH and PBC, a disease often called overlap syndrome (OS). In addition, many patients have refractory disease. We hypothesized that adding molecular testing to the current diagnostic criteria would provide an additional tool that could assist in correctly classifying patients. RNA was isolated from liver biopsies from patients with AIH (n = 16), PBC (n = 13), OS (n = 8), drug-induced/serology-negative AIH (AIH DI/Ser-neg, n = 6), or controls (n = 10). Gene expression was determined using an nCounter Sprint Profiler, and principal component analysis delineated distinct clusters for patients with an inflammatory profile due to AIH, PBC, and AIH DI/Ser-neg. Two patients with minimal histologic features of PBC clustered with the control group, and 2 patients with predominantly AIH and minimal PBC features clustered with the PBC group. A patient with OS who received treatment for both conditions showed no disease progression, whereas a patient with OS treated solely for AIH failed to respond. Conversely, one of the gene signatures from a patient diagnosed with PBC fell within the AIH group. This patient did not respond to treatment with ursodiol and ultimately required liver replacement. These findings suggest that the IMLD initially diagnosed in these patients may have been incorrectly classified. As expected, molecular analysis could not identify a distinct cluster for patients diagnosed with OS, and these had variable gene signatures that fell throughout the identified AIH or PBC groups. Cluster analysis was also able to distinguish patients with disease progression from non-progressors with mild disease who responded to treatment. In summary, gene expression analysis may assist in confirming the type of IMLD, especially when the diagnosis is unclear. Combining molecular testing with existing criteria could provide an additional diagnostic tool, improving patient care and response to treatment.
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Affiliation(s)
- Esteban Arroyave
- Department of Pathology, University of Texas Medical Branch, Galveston, Texas
| | - Omar A Saldarriaga
- Department of Pathology, University of Texas Medical Branch, Galveston, Texas.
| | - Sundus Bhatti
- Department of Internal Medicine, University of Texas Medical Branch, Galveston, Texas
| | - Isabelle Bergman
- Department of Pathology, John Sealy School of Medicine, University of Texas Medical Branch, Galveston, Texas
| | - Rondell Graham
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
| | - Michele Tana
- Department of Medicine, University of California at San Francisco, San Francisco, California; Division of Gastroenterology and Hepatology, Zuckerberg San Francisco General Hospital and Trauma Center, San Francisco, California
| | - Dana Balitzer
- Department of Pathology, University of California at San Francisco, San Francisco, California
| | - Kashif J Khan
- Department of Internal Medicine, University of Texas Medical Branch, Galveston, Texas
| | - Michael Kueht
- Department of Surgery, University of Texas Medical Branch, Galveston, Texas
| | - Heather L Stevenson
- Department of Pathology, University of Texas Medical Branch, Galveston, Texas
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Chang ML, Le PH, Chen WT, Chen TD, Su CW, Chen CJ, Lin CY, Wu CH, Kuo CJ, Sung KF, Chien RN. Distinct characteristics of various autoimmune liver diseases: A 22-year hospital-based study in Taiwan. J Gastroenterol Hepatol 2024; 39:2835-2844. [PMID: 39307997 DOI: 10.1111/jgh.16736] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2024] [Revised: 08/13/2024] [Accepted: 08/27/2024] [Indexed: 12/21/2024]
Abstract
BACKGROUND AND AIM The characteristics of autoimmune liver diseases (AILDs), including primary biliary cholangitis (PBC), autoimmune hepatitis (AIH), and PBC-AIH overlap syndrome (OS), have rarely been investigated and compared in Asia. METHODS At the Taiwan tertiary referral center, 330 PBC patients (87% treated with ursodeoxycholic acid [UDCA]), 143 AIH patients (94.4% treated with immunosuppressive therapy [IST]) and 21 PBC-AIH OS patients (85.7% treated with UDCA and IST) were enrolled. RESULTS Compared with AIH patients, PBC patients were older at baseline and had greater female-to-male sex ratios, alkaline phosphatase (ALP) and γ-glutamyl transferase (γ-GT) levels, and liver cirrhosis (LC), dyslipidemia, and hepatic and cardiometabolic complication rates. PBC patients had the lowest transaminase levels, whereas AIH patients had the highest transaminase levels. PBC patients had greater 22-year all-cause mortality and liver transplantation (ACMaLT) (43.5 vs 25.4%, P = 0.004), LC (75 vs 58.5%, P < 0.01), dyslipidemia (54.4 vs 45.9%, P = 0.001), and cerebrovascular accident (11.3 vs 0.8%, P = 0.019) cumulative incidences (CIs) than did AIH patients; PBC-AIH OS patients had greater systemic lupus erythematosus (28.9 vs 8.9%, P = 0.009) CI than did PBC patients. Baseline ALP (hazard ratio: 1.001), albumin (0.514), platelet count (0.997), and LC (3.438) were associated with ACMaLT; age (1.110), albumin (0.350), cirrhosis (46.219), and hepatitis C virus antibody positivity (5.068) were associated with hepatocellular carcinoma (HCC); and female sex (2.183) and body mass index (1.054) were associated with autoimmune diseases. CONCLUSIONS Compared with AIH patients, PBC patients had greater cardiometabolic CI, and ACMaLT CI, which was associated with cholestasis, liver functional reserve and LC. Older AILD patients with LC and females with obesity demand special caution for the development of HCC and extrahepatic autoimmune diseases, respectively.
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Affiliation(s)
- Ming-Ling Chang
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, New Taipei City, Taiwan
- Department of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Puo-Hsien Le
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, New Taipei City, Taiwan
- Department of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Wei-Ting Chen
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, New Taipei City, Taiwan
- Department of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Tai-Di Chen
- Department of Anatomic Pathology, Chang Gung Memorial Hospital Linkou Main Branch, Taoyuan, Taiwan
- School of Medicine, National Tsing Hua University, Hsinchu, Taiwan
| | - Chung-Wei Su
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, New Taipei City, Taiwan
- Department of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Cheng-Jen Chen
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, New Taipei City, Taiwan
- Department of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Cheng-Yu Lin
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, New Taipei City, Taiwan
- Department of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Chi-Huan Wu
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, New Taipei City, Taiwan
- Department of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Chia-Jung Kuo
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, New Taipei City, Taiwan
- Department of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Kei-Feng Sung
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, New Taipei City, Taiwan
- Department of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Rong-Nan Chien
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, New Taipei City, Taiwan
- Department of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
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Younossi ZM, Kremer AE, Swain MG, Jones D, Bowlus C, Trauner M, Henry L, Gerber L. Assessment of fatigue and its impact in chronic liver disease. J Hepatol 2024; 81:726-742. [PMID: 38670320 DOI: 10.1016/j.jhep.2024.04.008] [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: 01/23/2024] [Revised: 03/19/2024] [Accepted: 04/12/2024] [Indexed: 04/28/2024]
Abstract
Patient-reported outcomes (PROs), such as health-related quality of life (HRQL), are important outcome measures for patients with chronic liver diseases (CLDs). Presence of cirrhosis and advanced liver disease have been associated with worsened HRQL and fatigue. On the other hand, some patients with earlier stages of CLD also experience fatigue, causing PRO impairment. Treatment for some CLDs may improve HRQL and, sometimes, levels of fatigue. We aimed to provide an in-depth expert review of concepts related to fatigue and HRQL in patients with primary biliary cholangitis, hepatitis C virus and MASLD (metabolic dysfunction-associated steatotic liver disease). A panel of experts in fatigue and CLD reviewed and discussed the literature and collaborated to provide this expert review of fatigue in CLD. Herein, we review and report on the complexity of fatigue, highlighting that it is comprised of peripheral (neuromuscular failure, often in conjunction with submaximal cardiorespiratory function) and central (central nervous system dysfunction) causes. Fatigue and HRQL are measured using validated self-report instruments. Additionally, fatigue can be measured through objective tests (e.g. grip strength). Fatigue has deleterious effects on HRQL and one's ability to be physically active and socially engaged but does not always correlate with CLD severity. Treatments for hepatitis C virus and MASLD can improve levels of fatigue and HRQL, but current treatments for primary biliary cholangitis do not seem to affect levels of fatigue. We conclude that obtaining PRO data, including on HRQL and fatigue, is essential for determining the comprehensive burden of CLD and its potential treatments.
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Affiliation(s)
- Zobair M Younossi
- Beatty Liver and Obesity Research Program, Inova Health System, Falls Church, VA, USA; The Global Liver Council, Washington DC, USA.
| | - Andreas E Kremer
- Department of Gastroenterology and Hepatology, University Hospital Zürich, University of Zürich, Zürich, Switzerland
| | - Mark G Swain
- Professor of Medicine, Cal Wenzel Family Foundation Chair in Hepatology, University of Calgary Liver Unit, Calgary, Canada
| | - David Jones
- Professor of Liver Immunology, Newcastle University, Newcastle upon Tyne, UK
| | - Christopher Bowlus
- Lena Valente Professor and Chief, Division of Gastroenterology and Hepatology, University of California Davis, United States
| | - Michael Trauner
- Div. of Gastroenterology & Hepatology, Dept. of Internal Medicine III, MedUni Wien, Medical University of Vienna, Austria
| | - Linda Henry
- Beatty Liver and Obesity Research Program, Inova Health System, Falls Church, VA, USA; The Global Liver Council, Washington DC, USA; Center for Outcomes Research in Liver Diseases, Washington DC, USA
| | - Lynn Gerber
- Beatty Liver and Obesity Research Program, Inova Health System, Falls Church, VA, USA; The Global Liver Council, Washington DC, USA
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Dong S, Zhou S, Liu J, Chen N, Li J, Han Z, Liu R, Xuan C, Wang W, Guo L, Zhou L. Associations between sleep disorders and clinical outcomes of patients with primary biliary cholangitis. Adv Med Sci 2024; 69:385-390. [PMID: 39209159 DOI: 10.1016/j.advms.2024.08.002] [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: 12/10/2023] [Revised: 03/16/2024] [Accepted: 08/26/2024] [Indexed: 09/04/2024]
Abstract
PURPOSE Primary biliary cholangitis (PBC) is a chronic autoimmune liver disease characterized by a range of symptoms, including sleep disturbances. The present study aimed to investigate the prevalence of sleep disorders and the associations between sleep disorders and clinical outcomes in PBC. PATIENTS AND METHODS We enrolled 177 patients with PBC and 165 healthy controls (age- and sex-matched). Sleep quality was assessed by the Pittsburgh Sleep Quality Index (PSQI). Demographic and clinical data were collected from comprehensive clinical records to investigate whether sleep disorder was correlated with disease severity, therapeutic response and liver cirrhosis. RESULTS The prevalence of sleep disorders in patients with PBC (50.8 %) was significantly higher than healthy controls (18.2 %). Patients with sleep disorders presented with higher levels of laboratory parameters including globulin (GLO), aspartate aminotransferase (AST), alkaline phosphatase (ALP), glutamyl transpeptidase (GGT), total bilirubin (TBIL), direct bilirubin (DBIL) and immunoglobulin M (IgM), as well as higher ratio of poor therapeutic response and liver cirrhosis (p < 0.05). There was a positive correlation between global PSQI score and AST, ALP, GGT, TBIL, DBIL and IgM in patients with PBC. Patients with poor therapeutic response and liver cirrhosis in PBC had a higher proportion of sleep disorders and more chaotic sleep patterns, whereas a stronger correlation between sleep quality and laboratory parameters was found in patients with liver cirrhosis. CONCLUSIONS Sleep disorders were prevalent and manifested as adverse effects in PBC. Assessment of sleep quality and intervention were essential to the overall clinical management of patients with PBC.
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Affiliation(s)
- Shijing Dong
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin, China
| | - Simin Zhou
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin, China
| | - Jiangpeng Liu
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin, China
| | - Nian Chen
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin, China
| | - Jiwen Li
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin, China
| | - Zongze Han
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin, China
| | - Ruiyun Liu
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin, China
| | - Chenyang Xuan
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin, China
| | - Weirong Wang
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin, China
| | - Liping Guo
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin, China.
| | - Lu Zhou
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin, China.
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Abdelhamed W, El-Kassas M. Rare liver diseases in Egypt: Clinical and epidemiological characterization. Arab J Gastroenterol 2024; 25:75-83. [PMID: 38228442 DOI: 10.1016/j.ajg.2023.12.002] [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: 09/23/2022] [Revised: 12/04/2023] [Accepted: 12/16/2023] [Indexed: 01/18/2024]
Abstract
Illnesses that afflict a tiny number of individuals are referred to as rare diseases (RDs), sometimes called orphan diseases. The local healthcare systems are constantly under financial, psychological, and medical strain due to low incidence rates, unusual presentations, flawed diagnostic standards, and a lack of treatment alternatives for these RDs. The effective management of the once widely spread viral hepatitis B and C has altered the spectrum of liver diseases in Egypt during the last several years. The detection of uncommon disorders such as autoimmune, cholestatic, and hereditary liver diseases has also been made easier by the increasing knowledge and greater accessibility of specific laboratory testing. Finally, despite Egypt's large population, there are more uncommon liver disorders than previously thought. This review article discusses the clinical and epidemiological characteristics of a few uncommon liver disorders and the information currently accessible concerning these illnesses in Egypt.
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Affiliation(s)
- Walaa Abdelhamed
- Endemic Medicine Department, Faculty of Medicine, Sohag University, Sohag, Egypt
| | - Mohamed El-Kassas
- Endemic Medicine Department, Faculty of Medicine, Helwan University, Cairo, Egypt.
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SORRENTINO MC, CARBONE T, CINQUANTA L, ALESSIO MG, INFANTINO M, DELEONARDI G, TREVISAN MT, PORCELLI B, TERZUOLI L, PLATZGUMMER S, BRUSCA I, ANTICO A, TAMPOIA M, PESCE G, VILLALTA D, BIZZARO N. Linee guida SIPMeL per la determinazione degli autoanticorpi nella diagnosi delle malattie autoimmuni del fegato. LA RIVISTA ITALIANA DELLA MEDICINA DI LABORATORIO 2024; 20. [DOI: 10.23736/s1825-859x.24.00226-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Xu F, Zhang H, Chen J, Zhan J, Liu P, Liu W, Qi S, Mu Y. Recent progress on the application of compound formulas of traditional Chinese medicine in clinical trials and basic research in vivo for chronic liver disease. JOURNAL OF ETHNOPHARMACOLOGY 2024; 321:117514. [PMID: 38042388 DOI: 10.1016/j.jep.2023.117514] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/19/2023] [Revised: 11/23/2023] [Accepted: 11/24/2023] [Indexed: 12/04/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Chronic liver diseases mainly include chronic viral liver disease, metabolic liver disease, cholestatic liver disease (CLD), autoimmune liver disease, and liver fibrosis or cirrhosis. Notably, the compound formulas of traditional Chinese medicine (TCM) is effective for chronic liver diseases in clinical trials and basic research in vivo, which provide evidence of chronic liver disease treatment with integrated TCM and traditional Western medicine. AIM OF THE REVIEW This paper aims to provide a comprehensive review of the compound formulas of TCM for treating different chronic liver diseases to elucidate the composition, main curative effects, and mechanisms of these formulas and research methods. MATERIALS AND METHODS Different keywords related to chronic liver diseases and keywords related to the compound formulas of TCM were used to search the literature. PubMed, Scopus, Web of Science, and CNKI were searched to screen out original articles about the compound formulas of TCM related to the treatment of chronic liver diseases, mainly including clinical trials and basic in vivo research related to Chinese patent drugs, classic prescriptions, proven prescriptions, and hospital preparations. We excluded review articles, meta-analysis articles, in vitro experiments, articles about TCM monomers, articles about single-medicine extracts, and articles with incomplete or uncertain description of prescription composition. Plant names were checked with MPNS (http://mpns.kew.org). RESULTS In this review, the clinical efficacy and mechanism of compound formulas of TCM were summarized for the treatment of chronic viral hepatitis, nonalcoholic fatty liver disease, CLD, and liver fibrosis or cirrhosis developed from these diseases and other chronic liver diseases. For each clinical trial and basic research in vivo, this review provides a detailed record of the specific composition of the compound formulas of TCM, type of clinical research, modeling method of animal experiments, grouping methods, medication administration, main efficacy, and mechanisms. CONCLUSION The general development process of chronic liver disease can be summarized as chronic hepatitis, liver fibrosis or cirrhosis, and hepatocellular carcinoma. The compound formulas of TCM have some applications in these stages of chronic liver diseases. Owing to the continuous progress of medical technology, the benefits of the compound formulas of TCM in the treatment of chronic liver diseases are constantly changing and developing.
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Affiliation(s)
- Feipeng Xu
- Institute of Liver Diseases, Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, 528 Zhangheng Road, Shanghai, 201203, China
| | - Hua Zhang
- Institute of Liver Diseases, Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, 528 Zhangheng Road, Shanghai, 201203, China
| | - Jiamei Chen
- Institute of Liver Diseases, Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, 528 Zhangheng Road, Shanghai, 201203, China
| | - Junyi Zhan
- Institute of Liver Diseases, Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, 528 Zhangheng Road, Shanghai, 201203, China
| | - Ping Liu
- Institute of Liver Diseases, Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, 528 Zhangheng Road, Shanghai, 201203, China; Institute of Interdisciplinary Complex Research, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Wei Liu
- Institute of Liver Diseases, Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, 528 Zhangheng Road, Shanghai, 201203, China; Department of pharmacy, The SATCM Third Grade Laboratory of Traditional Chinese Medicine Preparations, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
| | - Shenglan Qi
- Institute of Liver Diseases, Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, 528 Zhangheng Road, Shanghai, 201203, China; Department of pharmacy, The SATCM Third Grade Laboratory of Traditional Chinese Medicine Preparations, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China; Institute of Interdisciplinary Complex Research, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
| | - Yongping Mu
- Institute of Liver Diseases, Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, 528 Zhangheng Road, Shanghai, 201203, China.
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Abstract
Primary biliary cholangitis (PBC) is a chronic cholestatic liver disease that can progress to cirrhosis and hepatic failure if left untreated. Ursodeoxycholic acid (UDCA) was introduced as a first-line drug for PBC around 1990; it remarkably improved patient outcomes, leading to the nomenclature change of PBC in 2015, from primary biliary "cirrhosis" to primary biliary "cholangitis." Nevertheless, 20-30% of patients exhibit an incomplete response to UDCA, resulting in significantly worse outcomes compared to those with a complete response. Therefore, improving the long-term outcomes of patients with an incomplete response to UDCA has been recognized as an unmet need. In addition, patients with PBC often suffer from a variety of debilitating symptoms, such as pruritus, fatigue and sicca syndrome, which significantly impair their health-related quality of life. Thus, appropriate management of these symptoms is currently regarded as another unmet need for PBC treatment. In this review, several compounds and drugs under clinical trials that can potentially solve these unmet needs are comprehensively discussed, and future directions of treatment policy of PBC are proposed for significantly improving long-term outcome as well as health-related quality of life of patients.
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Affiliation(s)
- Atsushi Tanaka
- Department of Medicine, Teikyo University School of Medicine, 2-11-1, Kaga, Itabashi-ku, Tokyo, 173-8605, Japan.
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Dias B, Aguiar A, Morais CI, Nery FG. Correlation between individual autoantibodies and clinical features in primary biliary cholangitis: results of a retrospective longitudinal study. Eur J Gastroenterol Hepatol 2023; 35:682-689. [PMID: 37116005 DOI: 10.1097/meg.0000000000002565] [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: 04/30/2023]
Abstract
BACKGROUND AND AIMS Primary biliary cholangitis (PBC) is an immune-mediated liver disease. The immunological profile seems to relate to clinical prognosis. This study aims to determine the role of autoantibodies in the course of liver disease and in the response to ursodeoxycholic acid. METHODS Between January 2016 and December 2020, 143 patients with PBC who underwent immunological liver profile evaluation were enrolled. All data were extracted retrospectively from electronic clinical records. Chi-square test, Fisher's exact test and Mann-Whitney test were used to evaluate the relationship between autoantibodies and biochemical parameters, clinical outcomes and therapeutic response scores. A significance level of 0.05 was used. RESULTS Antimitochondrial antibodies were present in 91.6%, antiglycoprotein-210 antibody (anti-gp210) in 18.2% and anti-Sp100 in 19.6% of patients. The incidence of liver-related death was higher in patients with autoimmune hepatitis variants. The occurrence of cirrhosis or portal hypertension was not linked to the presence of any of the autoantibodies tested. No relationship was found with the probability of dying or being transplanted. Patients with anti-Sp100 antibodies had higher baseline levels of aspartate aminotransferase and alanine aminotransferase and lower immunoglobulin M levels. Patients with anti-gp210 were more likely to have a lower median transplant-free survival rate and higher median risk of liver transplant or liver-related death using the GLOBE and UK-PBC scores. CONCLUSION Our findings confirm a strong association between anti-gp210 antibodies and a worse outcome. The association between anti-Sp100 and hepatic lesions requires further elucidation.
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Affiliation(s)
- Beatriz Dias
- Instituto de Ciências Biomédicas de Abel Salazar
| | - Ana Aguiar
- Instituto de Ciências Biomédicas de Abel Salazar
- EPIUnit - Instituto De Saúde Pública, Universidade do Porto
- Laboratório para a Investigação Integrativa e Translacional em Saúde Populacional (ITR)
| | - Cátia Iracema Morais
- Instituto de Ciências Biomédicas de Abel Salazar
- Serviço de Imunologia, Departamento de Patologia, Centro Hospitalar e Universitário de Santo António
| | - Filipe Gaio Nery
- Instituto de Ciências Biomédicas de Abel Salazar
- EPIUnit - Instituto De Saúde Pública, Universidade do Porto
- Laboratório para a Investigação Integrativa e Translacional em Saúde Populacional (ITR)
- Unidade de Cuidados Intermédios Médicos, Serviço de Cuidados Intensivos, Centro Hospitalar e Universitário de Santo António, Porto, Portugal
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11
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Huang L, Wei W, Huang X, Li X, Liu H, Gui L, Jiang J, Wan L, Zhou X, Ding J, Jiang X, Zhang B, Lan K. High-fat diets enhance and delay ursodeoxycholic acid absorption but elevate circulating hydrophobic bile salts. Front Pharmacol 2023; 14:1168144. [PMID: 37138846 PMCID: PMC10149867 DOI: 10.3389/fphar.2023.1168144] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2023] [Accepted: 03/20/2023] [Indexed: 05/05/2023] Open
Abstract
Background: Ursodeoxycholic acid (UDCA) is a natural drug essential for the treatment of cholestatic liver diseases. The food effects on the absorption of UDCA and the disposition of circulating bile salts remain unclear despite its widespread global uses. This study aims to investigate the effects of high-fat (HF) diets on the pharmacokinetics of UDCA and disclose how the circulated bile salts were simultaneously perturbed. Methods: After an overnight fast, a cohort of 36 healthy subjects received a single oral dose (500 mg) of UDCA capsules, and another cohort of 31 healthy subjects received the same dose after consuming a 900 kcal HF meal. Blood samples were collected from 48 h pre-dose up to 72 h post-dose for pharmacokinetic assessment and bile acid profiling analysis. Results: The HF diets significantly delayed the absorption of UDCA, with the Tmax of UDCA and its major metabolite, glycoursodeoxycholic acid (GUDCA), changing from 3.3 h and 8.0 h in the fasting study to 4.5 h and 10.0 h in the fed study, respectively. The HF diets did not alter the Cmax of UDCA and GUDCA but immediately led to a sharp increase in the plasma levels of endogenous bile salts including those hydrophobic ones. The AUC0-72h of UDCA significantly increased from 25.4 μg h/mL in the fasting study to 30.8 μg h/mL in the fed study, while the AUC0-72h of GUDCA showed no difference in both studies. As a result, the Cmax of total UDCA (the sum of UDCA, GUDCA, and TUDCA) showed a significant elevation, while the AUC0-72h of total UDCA showed a slight increase without significance in the fed study compared to the fasting study. Conclusion: The HF diets delay UDCA absorption due to the extension of gastric empty time. Although UDCA absorption was slightly enhanced by the HF diets, the beneficial effect may be limited in consideration of the simultaneous elevation of circulating hydrophobic bile salts.
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Affiliation(s)
- Liang Huang
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, China
- West China Second University Hospital, Sichuan University, Chengdu, China
| | - Wei Wei
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, China
| | - Xiaomei Huang
- Department of Phase1 Clinical Trial Research Center, Xiangya Boai Rehabilitation Hospital, Changsha, China
| | - Xuejing Li
- Chengdu Cynogen Bio-pharmaceutical Tech Co, Ltd., Chengdu, China
| | - Haisha Liu
- Department of Phase1 Clinical Trial Research Center, Xiangya Boai Rehabilitation Hospital, Changsha, China
| | - Lanlan Gui
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, China
- Chengdu Cynogen Bio-pharmaceutical Tech Co, Ltd., Chengdu, China
| | - Jinping Jiang
- Chengdu Cynogen Bio-pharmaceutical Tech Co, Ltd., Chengdu, China
| | - Linfei Wan
- Chengdu Cynogen Bio-pharmaceutical Tech Co, Ltd., Chengdu, China
| | - Xiangxiang Zhou
- Chengdu Cynogen Bio-pharmaceutical Tech Co, Ltd., Chengdu, China
| | - Jingsong Ding
- Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, China
| | - Xuehua Jiang
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, China
| | - Bikui Zhang
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China
- *Correspondence: Ke Lan, ; Bikui Zhang,
| | - Ke Lan
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, China
- Chengdu Cynogen Bio-pharmaceutical Tech Co, Ltd., Chengdu, China
- *Correspondence: Ke Lan, ; Bikui Zhang,
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12
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Abstract
Hepatocellular carcinoma (HCC) is potentially fatal complication affecting patients with primary biliary cholangitis (PBC). The incidence of HCC is 13 per 1000 person-years in patients with PBC cirrhosis, but much lower at 2.7 per 1000 person-years among patients with PBC without cirrhosis. Risk factors for the development of HCC in PBC include the presence of advanced fibrosis or cirrhosis and male sex, with some studies suggesting that treatment with ursodeoxycholic acid (UDCA) and UDCA response may reduce risk.
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13
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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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14
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Colapietro F, Lleo A, Generali E. Antimitochondrial Antibodies: from Bench to Bedside. Clin Rev Allergy Immunol 2022; 63:166-177. [PMID: 34586589 PMCID: PMC8480115 DOI: 10.1007/s12016-021-08904-y] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/13/2021] [Indexed: 01/13/2023]
Abstract
Anti-mitochondrial antibodies (AMA) are directed against the E2 subunits of the 2-oxo acid dehydrogenase complexes (PDC-E2) and are the typical biomarkers of primary biliary cholangitis (PBC), being present in 90-95% of patients, with increasing sensitivity at increasing titers. Albeit being highly specific for PBC diagnosis, AMA can be detected in less than 1% of healthy subjects, and thus the management subjects with no sign or symptom of liver disease is still a challenge and data concerning clinical risk of developing PBC in this subgroup of patients are controversial. Moreover, AMA can also be detected in patients affected by overlap syndrome, as well as hepatic diseases (i.e., NASH and viral hepatitis), while the association with autoimmune diseases, in particular Sjögren's syndrome, systemic sclerosis, and systemic lupus erythematosus, is well established. Furthermore, new associations are being identified with inflammatory myositis and heart disease. AMA are directed towards the pyruvate dehydrogenase multi enzyme complex (PDC-E2) subunit, which represents an epithelial specific autoantigen for PBC. This review focuses on the main characteristics of AMA, their association with autoimmune diseases and liver diseases.
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Affiliation(s)
- Francesca Colapietro
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy
- Division of Internal Medicine and Hepatology, Department of Gastroenterology, Humanitas Research Hospital IRCCS, Rozzano, Milan, Italy
| | - Ana Lleo
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy.
- Division of Internal Medicine and Hepatology, Department of Gastroenterology, Humanitas Research Hospital IRCCS, Rozzano, Milan, Italy.
| | - Elena Generali
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy
- Division of Internal Medicine and Hepatology, Department of Gastroenterology, Humanitas Research Hospital IRCCS, Rozzano, Milan, Italy
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15
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Primary biliary cholangitis: perception and expectation of illness. Dig Liver Dis 2022; 54:1230-1233. [PMID: 35277351 DOI: 10.1016/j.dld.2022.02.006] [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: 11/23/2021] [Revised: 02/02/2022] [Accepted: 02/16/2022] [Indexed: 12/14/2022]
Abstract
An important tool to explore personal experience of symptoms, treatment and clinical outcome is stratification of illness perception in patients affected by PBC. AIM To assess the perception of illness in a cohort of Italian patients with PBC. METHODS Between June and December 2019, a specific questionnaire was administered to a pool of 210 patients from 7 tertiary Italian centers, in order to identify and assess the patient's past history, symptoms and their impact on the quality of life, follow-up, treatment and perceived satisfaction of patients toward the provided care. RESULTS Fatigue, pruritus, and abdominal discomfort and sicca syndrome were present in 50.4%, 45%, 30.4% and 28.5% of patients, fatigue having the most impacting the daily-life. After a consultation with a specialist, the diagnosis of PBC was met within 18 months for 143 patients. Patients were mostly concerned about possible health problems that occur and in 25% of cases, symptoms had a negative impact on their life. Eighty percent of patients said they were satisfied with efficacy and tolerability of treatment, while 26% requested an improvement in the relationship with the specialist. CONCLUSIONS The results highlight the importance of both promoting timely referral to the specialist and facilitating communication between healthcare professionals and patients.
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16
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Gungabissoon U, Gibbons DC, Requena G, Ribeiro de Souza A, Smith H. Disease burden of primary biliary cholangitis and associated pruritus based on a cross-sectional US claims analysis. BMJ Open Gastroenterol 2022; 9:bmjgast-2021-000857. [PMID: 35973742 PMCID: PMC9386220 DOI: 10.1136/bmjgast-2021-000857] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2021] [Accepted: 07/07/2022] [Indexed: 11/25/2022] Open
Abstract
Objective In order to identify areas of unmet need in patients with primary biliary cholangitis (PBC), this study sought to use real-world observational healthcare data to characterise the burden in patients with PBC and in PBC patients with a recorded diagnosis of pruritus. Design This retrospective, cross-sectional database study compared prevalence of prespecified comorbidities and medications in the PBC population and PBC-pruritus subpopulation with non-cases using an indirect standardisation approach. The PBC population was identified from the US IBM MarketScan Commercial Claims and Medicare Supplemental Database during 2016 using International Classification of Diseases 10th Revision, Clinical Modification codes (≥2 claims for PBC); the PBC-pruritus subpopulation additionally had ≥1 claim for pruritus during this period. Non-cases had no claims for PBC. Indirect age-sex standardised prevalence ratios (iSPR) and 95% confidence intervals (CIs) were calculated for prespecified comorbidities and medications recorded during 2017. Results The PBC population (N=1963) and PBC-pruritus subpopulation (N=139) had significantly higher prevalence of fatigue (19.9%, iSPR (95% CI): 1.51 (1.36 to 1.66); 26.6%, 2.10 (1.48 to 2.90)), depression/anxiety (21.3%, 1.09 (0.99 to 1.20); 28.1%, 1.46 (1.04 to 2.00)) and sleep-related issues (6.9%, 1.18 (0.99 to 1.40); 14.4%, 2.58 (1.58 to 3.99)) compared with non-cases. Bile acid sequestrants were prescribed in 5.8% and 18.0% of the PBC and PBC-pruritus populations, respectively. In general, a higher prevalence of comorbidities and medication use was observed in the PBC-pruritus subpopulation compared with the PBC population and non-cases. Conclusion Despite availability of treatments for PBC, the PBC population had a higher burden of comorbidities than non-cases. This burden was even greater among the PBC-pruritus subpopulation, with a particularly high prevalence of sleep disorders and depression/anxiety. Despite this, pruritus remains undertreated highlighting a need for treatments specifically indicated for cholestatic pruritus.
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Affiliation(s)
- Usha Gungabissoon
- Value Evidence and Outcomes (Epidemiology), Global Medical R&D, GSK, Brentford, UK
| | - Daniel C Gibbons
- Value Evidence and Outcomes (Real World Analytics), GSK, Brentford, UK
| | - Gema Requena
- Value Evidence and Outcomes (Epidemiology), Global Medical R&D, GSK, Brentford, UK
| | | | - Helen Smith
- Value Evidence and Outcomes (Specialty), GSK, Brentford, UK
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17
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Yang Y, Zhao RC, Zhang F. Potential mesenchymal stem cell therapeutics for treating primary biliary cholangitis: advances, challenges, and perspectives. Front Cell Dev Biol 2022; 10:933565. [PMID: 35923849 PMCID: PMC9339990 DOI: 10.3389/fcell.2022.933565] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2022] [Accepted: 06/27/2022] [Indexed: 11/24/2022] Open
Abstract
Primary biliary cholangitis (PBC) is a cholestatic autoimmune liver disease characterized by the gradual destruction of small intrahepatic bile ducts that eventually leads to liver cirrhosis, failure, and even carcinoma. The treatment options for PBC are limited, and the main treatment choices are the US Food and Drug Administration–approved ursodeoxycholic acid and obeticholic acid. However, many patients fail to respond adequately to these drugs and the adverse effects frequently lead to low life quality. For patients with end-stage PBC, liver transplantation remains the only effective treatment. Given their low immunogenicity, prominent immunomodulation property, differentiation potential, and tissue maintenance capacity, mesenchymal stem cells (MSCs) are emerging as new options for treating liver diseases, including PBC. Accumulating evidence from basic research to clinical studies supports the positive effects of MSC-based therapy for treating PBC. In this review, we characterized the underlying roles and mechanisms of MSCs for treating liver diseases and highlight recent basic and clinical advances in MSC-based therapy for treating PBC. Finally, the current challenges and perspectives for MSC-based therapy in clinical application are discussed, which could help accelerate the application of MSCs in clinical practice, especially for refractory diseases such as PBC.
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Affiliation(s)
- Yanlei Yang
- Clinical Biobank, National Science and Technology Key Infrastructure on Translational Medicine in Peking Union Medical College Hospital, Medical Science Research Centre, Medical Science Research Centre, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- The Ministry of Education Key Laboratory, Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Clinical Immunology Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Robert Chunhua Zhao
- Beijing Key Laboratory, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Peking Union Medical College Hospital, Center of Excellence in Tissue Engineering, Chinese Academy of Medical Sciences, Beijing, China
- School of Life Sciences, Shanghai University, Shanghai, China
- *Correspondence: Fengchun Zhang, ; Robert Chunhua Zhao,
| | - Fengchun Zhang
- The Ministry of Education Key Laboratory, Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Clinical Immunology Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- *Correspondence: Fengchun Zhang, ; Robert Chunhua Zhao,
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18
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Zhang Y, Jiao Z, Chen M, Shen B, Shuai Z. Roles of Non-Coding RNAs in Primary Biliary Cholangitis. Front Mol Biosci 2022; 9:915993. [PMID: 35874606 PMCID: PMC9305664 DOI: 10.3389/fmolb.2022.915993] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2022] [Accepted: 06/20/2022] [Indexed: 11/13/2022] Open
Abstract
Primary biliary cholangitis (PBC) is an autoimmune-mediated chronic cholestatic liver disease, fatigue, and skin itching are the most common clinical symptoms. Its main pathological feature is the progressive damage and destruction of bile duct epithelial cells. Non-coding RNA (NcRNA, mainly including microRNA, long non-coding RNA and circular RNA) plays a role in the pathological and biological processes of various diseases, especially autoimmune diseases. Many validated ncRNAs are expected to be biomarkers for the diagnosis or treatment of PBC. This review will elucidate the pathogenesis of PBC and help to identify potential ncRNA biomarkers for PBC.
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Affiliation(s)
- Yaqin Zhang
- Department of Rheumatology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Ziying Jiao
- Department of Physiology, School of Basic Medicine of Anhui Medical University, Hefei, China
| | - Mingwei Chen
- Department of Endocrinology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Bing Shen
- Department of Physiology, School of Basic Medicine of Anhui Medical University, Hefei, China
| | - Zongwen Shuai
- Department of Rheumatology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
- *Correspondence: Zongwen Shuai,
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19
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Wang CR, Tsai HW. Autoimmune liver diseases in systemic rheumatic diseases. World J Gastroenterol 2022; 28:2527-2545. [PMID: 35949355 PMCID: PMC9254143 DOI: 10.3748/wjg.v28.i23.2527] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Revised: 03/11/2022] [Accepted: 05/14/2022] [Indexed: 02/06/2023] Open
Abstract
Systemic rheumatic diseases (SRDs) are chronic, inflammatory, autoimmune disorders with the presence of autoantibodies that may affect any organ or system. Liver dysfunction in SRDs can be associated with prescribed drugs, viral hepatitis, alternative hepatic comorbidities and coexisting autoimmune liver diseases (AILDs), requiring an exclusion of secondary conditions before considering liver involvement. The patterns of overlap diseases depend predominantly on genetic determinants with common susceptible loci widely distributing in both disorders. In AILDs, it is important to identify the overlapping SRDs at an early stage since such a coexistence may influence the disease course and prognosis. Commonly co-occurring SRDs in AILDs are Sjögren syndrome (SS), rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE) in autoimmune hepatitis (AIH), and SS, RA or systemic sclerosis in primary biliary cholangitis. Owing to different disease complications and therapies, it is imperative to differentiate between SLE liver involvement and SLE-AIH overlap disease. Therapeutic options can be personalized to control coexisting conditions of liver autoimmunity and rheumatic manifestations in AILD-SRD overlap diseases. The collaboration between hepatologists and rheumatologists can lead to significant advances in managing such a complex scenario. In this review, we provide a comprehensive overview on coexisting AILDs in different SRDs and the therapeutic approach in managing these overlap diseases.
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Affiliation(s)
- Chrong-Reen Wang
- Department of Internal Medicine, National Cheng Kung University Hospital, Tainan 70403, Taiwan
| | - Hung-Wen Tsai
- Department of Pathology, National Cheng Kung University Hospital, Tainan 70403, Taiwan
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20
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Jiang P, Feng Z, Sheng L, Hu C, Ma X, Zhang S, Wu L, Xiao X, Wang Q, Guo C, Qiu D, Fang J, Xu J, Gershwin ME, Jiang M, Ma X, Pu J. Morphological, Functional, and Tissue Characterization of Silent Myocardial Involvement in Patients With Primary Biliary Cholangitis. Clin Gastroenterol Hepatol 2022; 20:1112-1121.e4. [PMID: 34461299 DOI: 10.1016/j.cgh.2021.08.035] [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: 01/03/2021] [Revised: 08/15/2021] [Accepted: 08/23/2021] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Cirrhotic cardiomyopathy is a major complication and cause of morbidity in end-stage primary biliary cholangitis (PBC). However, it is unclear whether there is clinically silent myocardial involvement at the early stage of PBC before cirrhosis and cardiac manifestations. This prospective, three-center, multi-modality cardiac imaging study on the early identification of myocardial impairment in PBC (EARLY-MYO-PBC) was designed to identify silent myocardial impairment in PBC patients without cardiac manifestations. METHODS A total of 112 subjects (56 with PBC and 56 age- and sex-matched controls) undergoing cardiovascular magnetic resonance (CMR) were enrolled. Demographic, serologic, and cardiac imaging data were prospectively collected. All participants had no cardiac discomfort or previous heart disease and had normal electrocardiographic findings. RESULTS Subclinical myocardial involvement, as evidenced by cardiac morphologic, functional, and tissue characterization changes on CMR, including hyperdynamic left ventricular (LV) ejection fraction (median, 75% in PBC patients vs 69% in controls, P = .029), subclinical myocardial edema by T2-short tau inversion recovery (21% vs 2% in controls, P = .001), elevated extracellular matrix indices (30% vs 26% in controls, P < .001), and impaired myocardial viability by positive late gadolinium enhancement (LGE) (36%), was detected in PBC patients. Importantly, a mid-wall "stripe" at the LV septum was identified as a PBC-specific LGE pattern that differs from other known cardiomyopathies. In multivariate analysis, gp210 positivity (odds ratio [OR] = 9.909, P = .010), lower hemoglobin (OR = 0.919, P = .004), and body mass index (OR = 0.638, P = .005) were independent predictors of cardiac abnormalities in PBC. CONCLUSIONS This study demonstrates clinically silent cardiac impairment with specific CMR patterns in PBC, allowing optimal screening for early myocardial impairment and potentially timely therapies. (Trial registration no.: NCT03545672).
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Affiliation(s)
- Pan Jiang
- State Key Laboratory for Oncogenes and Related Genes, Shanghai Cancer Institute; Division of Gastroenterology and Hepatology, Division of Cardiology, Key Laboratory of Coronary Heart Disease, Shanghai Municipal Education Commission; Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Zehao Feng
- State Key Laboratory for Oncogenes and Related Genes, Shanghai Cancer Institute; Division of Gastroenterology and Hepatology, Division of Cardiology, Key Laboratory of Coronary Heart Disease, Shanghai Municipal Education Commission; Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Li Sheng
- State Key Laboratory for Oncogenes and Related Genes, Shanghai Cancer Institute; Division of Gastroenterology and Hepatology, Division of Cardiology, Key Laboratory of Coronary Heart Disease, Shanghai Municipal Education Commission; Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Chenxi Hu
- Institute of Medical Imaging Technology, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China
| | - Xiang Ma
- Department of Cardiology, First Affiliated Hospital of Xinjiang Medical University, Xinjiang, China
| | - Shouyan Zhang
- Department of Cardiology, Luoyang Central Hospital Affiliated to Zhengzhou University, Luoyang, China
| | - Lianming Wu
- Department of Radiology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Xiao Xiao
- State Key Laboratory for Oncogenes and Related Genes, Shanghai Cancer Institute; Division of Gastroenterology and Hepatology, Division of Cardiology, Key Laboratory of Coronary Heart Disease, Shanghai Municipal Education Commission; Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Qixia Wang
- State Key Laboratory for Oncogenes and Related Genes, Shanghai Cancer Institute; Division of Gastroenterology and Hepatology, Division of Cardiology, Key Laboratory of Coronary Heart Disease, Shanghai Municipal Education Commission; Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Canjie Guo
- State Key Laboratory for Oncogenes and Related Genes, Shanghai Cancer Institute; Division of Gastroenterology and Hepatology, Division of Cardiology, Key Laboratory of Coronary Heart Disease, Shanghai Municipal Education Commission; Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Dekai Qiu
- State Key Laboratory for Oncogenes and Related Genes, Shanghai Cancer Institute; Division of Gastroenterology and Hepatology, Division of Cardiology, Key Laboratory of Coronary Heart Disease, Shanghai Municipal Education Commission; Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Jingyuan Fang
- State Key Laboratory for Oncogenes and Related Genes, Shanghai Cancer Institute; Division of Gastroenterology and Hepatology, Division of Cardiology, Key Laboratory of Coronary Heart Disease, Shanghai Municipal Education Commission; Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Jianrong Xu
- Department of Radiology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Merrill Eric Gershwin
- Division of Rheumatology, Allergy and Clinical Immunology, Department of Internal Medicine, University of California at Davis, Davis, California
| | - Meng Jiang
- State Key Laboratory for Oncogenes and Related Genes, Shanghai Cancer Institute; Division of Gastroenterology and Hepatology, Division of Cardiology, Key Laboratory of Coronary Heart Disease, Shanghai Municipal Education Commission; Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
| | - Xiong Ma
- State Key Laboratory for Oncogenes and Related Genes, Shanghai Cancer Institute; Division of Gastroenterology and Hepatology, Division of Cardiology, Key Laboratory of Coronary Heart Disease, Shanghai Municipal Education Commission; Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
| | - Jun Pu
- State Key Laboratory for Oncogenes and Related Genes, Shanghai Cancer Institute; Division of Gastroenterology and Hepatology, Division of Cardiology, Key Laboratory of Coronary Heart Disease, Shanghai Municipal Education Commission; Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
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21
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Smith A, Giles B, Aspinall RJ. Primary biliary cholangitis: advances in understanding and management. Br J Hosp Med (Lond) 2022; 83:1-9. [DOI: 10.12968/hmed.2021.0450] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
Recent years have seen major advances in our understanding of primary biliary cholangitis, with the condition now renamed to reflect the majority of patients who do not have cirrhosis. Data from large multicentre studies have greatly increased our knowledge of the natural history of primary biliary cholangitis, making the identification of higher risk patients clearer and facilitating the development of new medications. Recent guidelines have emphasised the importance of risk stratification, targeted treatment of symptoms and early prioritisation for second line therapies. The review summarises recent major developments in our understanding of primary biliary cholangitis and its management.
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Affiliation(s)
- Alex Smith
- Portsmouth Liver Centre, Portsmouth Hospitals University NHS Trust, Queen Alexandra Hospital, Portsmouth, UK
| | - Benjamin Giles
- Portsmouth Liver Centre, Portsmouth Hospitals University NHS Trust, Queen Alexandra Hospital, Portsmouth, UK
| | - Richard J Aspinall
- Portsmouth Liver Centre, Portsmouth Hospitals University NHS Trust, Queen Alexandra Hospital, Portsmouth, UK
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22
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Lei W, Zhao C, Sun J, Jin Y, Duan Z. Electroacupuncture Ameliorates Intestinal Barrier Destruction in Mice With Bile Duct Ligation-Induced Liver Injury by Activating the Cholinergic Anti-Inflammatory Pathway. Neuromodulation 2022; 25:1122-1133. [PMID: 35300921 DOI: 10.1016/j.neurom.2022.02.001] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Revised: 01/19/2022] [Accepted: 01/31/2022] [Indexed: 02/07/2023]
Abstract
OBJECTIVES Electroacupuncture (EA) at Zusanli (ST36) can attenuate inflammation in different rodent models. However, the therapeutic mechanisms underlying its action in inhibiting intestinal barrier destruction and liver injury in cholestasis mice have not been clarified. This study aimed at investigating whether EA at ST36 could activate the cholinergic anti-inflammatory pathway to inhibit intestinal barrier destruction and liver injury in cholestasis mice. MATERIALS AND METHODS Male Hmox1floxp/floxp C57BL/6 mice were randomized and subjected to a sham or bile duct ligation (BDL) surgery. The BDL mice were randomized and treated with, or without (BDL group), sham EA at ST36 (BDL+sham-ST36) or EA at ST36 (BDL+ST36), or received α-bungarotoxin (α-BGT), a specific inhibitor of nicotinic acetylcholine receptor α7 subunit (α7nAChR), before stimulation (BDL+ST36+α-BGT). These mice, together with a group of intestine-specific heme oxygenase-1 (HO-1) knockout (KO) Villin-Cre-HO-1-/- mice, were monitored for their body weights before and 14 days after BDL. The levels of plasma cytokines and liver injury-related alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were measured by enzyme-linked immunoassay, and pathological changes in the intestinal mucosa and liver fibrosis as well as intestinal barrier permeability in individual mice were examined by histology and immunohistochemistry. The levels of α7nAChR, HO-1, ZO-1, Occludin, Claudin-1, and NF-κBp65 expression and NF-κBp65 phosphorylation in intestinal tissues were quantified. RESULTS Compared with the sham group, BDL significantly increased the levels of plasma interleukin (IL)-1β, IL-6, IL-10, tumor necrosis factor α, ALT, and AST and caused intestinal mucosal damages, high permeability, and liver fibrosis in mice, which were remarkably mitigated, except for further increased levels of plasma IL-10 in the BDL+ST36 group of mice. Similarly, EA at ST36 significantly up-regulated α7nAChR and HO-1 expression; mitigated the BDL-decreased ZO-1, Occludin, and Claudin-1 expression; and attenuated the BDL-increased NF-κBp65 phosphorylation in intestinal tissues of mice. The therapeutic effects of EA at ST36 were significantly abrogated by pretreatment with α-BGT or HO-1 KO. CONCLUSION EA at ST36 inhibits the BDL-induced intestinal mucosal damage and liver fibrosis by activating the HO-1 cholinergic anti-inflammatory pathway in intestinal tissues of mice.
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Affiliation(s)
- Wei Lei
- Second Department of Gastroenterology, the First Affiliated Hospital of Dalian Medical University, Dalian, China; Laboratory of Integrated Chinese and Western Medicine, the First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Changcheng Zhao
- Second Department of Gastroenterology, the First Affiliated Hospital of Dalian Medical University, Dalian, China; Laboratory of Integrated Chinese and Western Medicine, the First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Jiasen Sun
- Second Department of Gastroenterology, the First Affiliated Hospital of Dalian Medical University, Dalian, China; Laboratory of Integrated Chinese and Western Medicine, the First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Yanling Jin
- Pathology Department, the First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Zhijun Duan
- Second Department of Gastroenterology, the First Affiliated Hospital of Dalian Medical University, Dalian, China; Laboratory of Integrated Chinese and Western Medicine, the First Affiliated Hospital of Dalian Medical University, Dalian, China.
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23
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Li C, Zheng K, Chen Y, He C, Liu S, Yang Y, Li M, Zeng X, Wang L, Zhang F. A randomized, controlled trial on fenofibrate in primary biliary cholangitis patients with incomplete response to ursodeoxycholic acid. Ther Adv Chronic Dis 2022; 13:20406223221114198. [PMID: 35924008 PMCID: PMC9340330 DOI: 10.1177/20406223221114198] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2022] [Accepted: 06/30/2022] [Indexed: 12/11/2022] Open
Abstract
Introduction: About one-third of primary biliary cholangitis (PBC) patients do not exhibit
complete response to ursodeoxycholic acid (UDCA). Some of these patients
were reported to benefit from the combination therapy of fibrates and UDCA,
but more clinical evidence is required. In this study, we conducted a
randomized, controlled trial on the safety and efficacy of fenofibrate in
the treatment of patients with PBC. Methods: Forty-eight PBC patients with incomplete response to UDCA were enrolled and
randomly assigned to two groups (24 in the experiment group and 24 in the
control group). For the experimental group, the patients were administered
13–15 mg/kg/day UDCA in combination with 200 mg/day fenofibrate. For the
control group, the patients continued to receive UDCA at 13–15 mg/kg/day.
The patients were followed up for at least 12 months. The serum levels of
alkaline phosphatase (ALP), gamma-glutamyl transferase (γ-GT), aspartate
aminotransferase (AST), and other biochemical parameters were measured at 3,
6, and 12 months during the trial to assess patient conditions. Results: At 12 months, 20.8% of the patients in the experimental group had all three
indexes of serum ALP, γ-GT, and total bilirubin normalized, while 0% of
patients in the control group reached the primary outcome (difference,
20.8 percentage points; 95% CI, 4.6–37.0). 54.2% of the patients had normal
ALP levels in the experimental group and 4.2% in the control group
(difference, 50 percentage points; 95% CI, 28.5–71.5). The experimental
group had greater improvement of ALP (p < 0.001) and IgG
(p = 0.026) than the control group. The biochemical
indexes of the patients in the experimental group also significantly
improved during the treatment of fenofibrate. Conclusion: Addition of fenofibrate can improve biochemical indexes of PBC patients who
had an incomplete response to UDCA. Reversible elevation of serum creatine
and transaminases is observed in some patients. The trial was registered in the Chinese Clinical Trial Registry (ChiCTR) as
ChiCTR1800020160 (protocol available online: http://www.chictr.org.cn/showproj.aspx?proj=32443).
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Affiliation(s)
- Chunlei Li
- Department of Internal Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Kunyu Zheng
- Department of Internal Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
- Department of Rheumatology and Clinical Immunology, Chinese Academy of Medical Sciences & Peking Union Medical College, National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), Ministry of Science & Technology, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital (PUMCH), Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing, China
| | - Yiran Chen
- Department of Internal Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
- Department of Rheumatology and Clinical Immunology, Chinese Academy of Medical Sciences & Peking Union Medical College, National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), Ministry of Science & Technology, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital (PUMCH), Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing, China
| | - Chengmei He
- Department of Internal Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
- Department of Rheumatology and Clinical Immunology, Chinese Academy of Medical Sciences & Peking Union Medical College, National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), Ministry of Science & Technology, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital (PUMCH), Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing, China
| | - Suying Liu
- Department of Internal Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
- Department of Rheumatology and Clinical Immunology, Chinese Academy of Medical Sciences & Peking Union Medical College, National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), Ministry of Science & Technology, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital (PUMCH), Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing, China
| | - Yunjiao Yang
- Department of Internal Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
- Department of Rheumatology and Clinical Immunology, Chinese Academy of Medical Sciences & Peking Union Medical College, National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), Ministry of Science & Technology, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital (PUMCH), Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing, China
| | - Mengtao Li
- Department of Internal Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
- Department of Rheumatology and Clinical Immunology, Chinese Academy of Medical Sciences & Peking Union Medical College, National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), Ministry of Science & Technology, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital (PUMCH), Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing, China
| | - Xiaofeng Zeng
- Department of Internal Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
- Department of Rheumatology and Clinical Immunology, Chinese Academy of Medical Sciences & Peking Union Medical College, National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), Ministry of Science & Technology, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital (PUMCH), Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing, China
| | - Li Wang
- Department of Internal Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
- Department of Rheumatology and Clinical Immunology, Chinese Academy of Medical Sciences & Peking Union Medical College, National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), Ministry of Science & Technology, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital (PUMCH), Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, No.1 Shuaifuyuan, Dongcheng District, Beijing 100730, China
| | - Fengchun Zhang
- Department of Internal Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
- Department of Rheumatology and Clinical Immunology, Chinese Academy of Medical Sciences & Peking Union Medical College, National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), Ministry of Science & Technology, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital (PUMCH), Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing, China
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24
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Karlsen TH, Sheron N, Zelber-Sagi S, Carrieri P, Dusheiko G, Bugianesi E, Pryke R, Hutchinson SJ, Sangro B, Martin NK, Cecchini M, Dirac MA, Belloni A, Serra-Burriel M, Ponsioen CY, Sheena B, Lerouge A, Devaux M, Scott N, Hellard M, Verkade HJ, Sturm E, Marchesini G, Yki-Järvinen H, Byrne CD, Targher G, Tur-Sinai A, Barrett D, Ninburg M, Reic T, Taylor A, Rhodes T, Treloar C, Petersen C, Schramm C, Flisiak R, Simonova MY, Pares A, Johnson P, Cucchetti A, Graupera I, Lionis C, Pose E, Fabrellas N, Ma AT, Mendive JM, Mazzaferro V, Rutter H, Cortez-Pinto H, Kelly D, Burton R, Lazarus JV, Ginès P, Buti M, Newsome PN, Burra P, Manns MP. The EASL-Lancet Liver Commission: protecting the next generation of Europeans against liver disease complications and premature mortality. Lancet 2022; 399:61-116. [PMID: 34863359 DOI: 10.1016/s0140-6736(21)01701-3] [Citation(s) in RCA: 351] [Impact Index Per Article: 117.0] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2021] [Revised: 07/10/2021] [Accepted: 07/15/2021] [Indexed: 02/07/2023]
Affiliation(s)
- Tom H Karlsen
- Department of Transplantation Medicine and Research Institute for Internal Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital Rikshospitalet and University of Oslo, Oslo, Norway.
| | - Nick Sheron
- Institute of Hepatology, Foundation for Liver Research, Kings College London, London, UK
| | - Shira Zelber-Sagi
- School of Public Health, Faculty of Social Welfare and Health Sciences, University of Haifa, Haifa, Israel; Department of Gastroenterology, Tel Aviv Medical Center, Tel Aviv, Israel
| | - Patrizia Carrieri
- Aix-Marseille University, Inserm, Institut de recherche pour le développement, Sciences Economiques et Sociales de la Santé et Traitement de l'Information Médicale (SESSTIM), ISSPAM, Marseille, France
| | - Geoffrey Dusheiko
- School of Medicine, University College London, London, UK; Kings College Hospital, London, UK
| | - Elisabetta Bugianesi
- Department of Medical Sciences, Division of Gastroenterology, University of Torino, Torino, Italy
| | | | - Sharon J Hutchinson
- School of Health and Life Sciences, Glasgow Caledonian University, Glasgow, UK; Clinical and Protecting Health Directorate, Public Health Scotland, Glasgow, UK
| | - Bruno Sangro
- Liver Unit, Clinica Universidad de Navarra-IDISNA and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Pamplona, Spain
| | - Natasha K Martin
- Division of Infectious Diseases and Global Public Health, University of California San Diego, San Diego, CA, USA; Population Health Sciences, University of Bristol, Bristol, UK
| | - Michele Cecchini
- Health Division, Organisation for Economic Co-operation and Development, Paris, France
| | - Mae Ashworth Dirac
- Department of Health Metrics Sciences, University of Washington, Seattle, WA, USA; Department of Family Medicine, University of Washington, Seattle, WA, USA; Institute for Health Metrics and Evaluation, University of Washington, Seattle, WA, USA
| | - Annalisa Belloni
- Health Economics and Modelling Division, Public Health England, London, UK
| | - Miquel Serra-Burriel
- Epidemiology, Biostatistics and Prevention Institute, University of Zurich, Zurich, Switzerland
| | - Cyriel Y Ponsioen
- Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam University Medical Centers, Amsterdam, Netherlands
| | - Brittney Sheena
- Institute for Health Metrics and Evaluation, University of Washington, Seattle, WA, USA
| | - Alienor Lerouge
- Health Division, Organisation for Economic Co-operation and Development, Paris, France
| | - Marion Devaux
- Health Division, Organisation for Economic Co-operation and Development, Paris, France
| | - Nick Scott
- Disease Elimination Program, Burnet Institute, Melbourne, VIC, Australia
| | - Margaret Hellard
- Disease Elimination Program, Burnet Institute, Melbourne, VIC, Australia; Department of Infectious Diseases, Alfred Hospital, Melbourne, VIC, Australia; Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, VIC, Australia; Doherty Institute and School of Population and Global Health, University of Melbourne, Melbourne, VIC, Australia
| | - Henkjan J Verkade
- Paediatric Gastroenterology and Hepatology, Department of Paediatrics, University Medical Centre Groningen, University of Groningen, Netherlands; European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Hamburg, Germany
| | - Ekkehard Sturm
- Division of Paediatric Gastroenterology and Hepatology, University Children's Hospital Tübingen, Tübingen, Germany; European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Hamburg, Germany
| | | | | | - Chris D Byrne
- Department of Nutrition and Metabolism, Faculty of Medicine, University of Southampton, Southampton, UK; Southampton National Institute for Health Research, Biomedical Research Centre, University Hospital Southampton and Southampton General Hospital, Southampton, UK
| | - Giovanni Targher
- Department of Medicine, Section of Endocrinology, Diabetes, and Metabolism, University of Verona, Verona, Italy
| | - Aviad Tur-Sinai
- Department of Health Systems Management, The Max Stern Yezreel Valley College, Yezreel Valley, Israel
| | - Damon Barrett
- School of Public Health and Community Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | | | - Tatjana Reic
- European Liver Patients Organization, Brussels, Belgium; Croatian Society for Liver Diseases-Hepatos, Split, Croatia
| | | | - Tim Rhodes
- London School of Hygiene & Tropical Medicine, London, UK
| | - Carla Treloar
- Centre for Social Research in Health, University of New South Wales, Sydney, NSW, Australia
| | - Claus Petersen
- Department of Pediatric Surgery, Hannover Medical School, Hannover, Germany
| | - Christoph Schramm
- Martin Zeitz Center for Rare Diseases, Hamburg Center for Translational Immunology (HCTI), and First Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Hamburg, Germany
| | - Robert Flisiak
- Department of Infectious Diseases and Hepatology, Medical University of Białystok, Poland
| | - Marieta Y Simonova
- Department of Gastroenterology, HPB Surgery and Transplantation, Clinic of Gastroentrology, Military Medical Academy, Sofia, Bulgaria
| | - Albert Pares
- Liver Unit, Hospital Clinic of Barcelona, Barcelona, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; CIBEREHD, Madrid, Spain
| | - Philip Johnson
- Department of Molecular and Clinical Cancer Medicine, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, UK
| | - Alessandro Cucchetti
- Department of Medical and Surgical Sciences-DIMEC, Alma Mater Studiorum, University of Bologna, Bologna, Italy
| | - Isabel Graupera
- Liver Unit, Hospital Clinic of Barcelona, Barcelona, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; CIBEREHD, Madrid, Spain; Faculty of Medicine and Health Sciences, University of Barcelona, Spain
| | - Christos Lionis
- Clinic of Social and Family Medicine, Medical School, University of Crete, Heraklion, Greece
| | - Elisa Pose
- Liver Unit, Hospital Clinic of Barcelona, Barcelona, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Faculty of Medicine and Health Sciences, University of Barcelona, Spain
| | - Núria Fabrellas
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; CIBEREHD, Madrid, Spain; Faculty of Medicine and Health Sciences, University of Barcelona, Spain
| | - Ann T Ma
- Liver Unit, Hospital Clinic of Barcelona, Barcelona, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Juan M Mendive
- Prevention and Health Promotion Research Network (redIAPP), Institute of Health Carlos III, Madrid, Spain; La Mina Health Centre, Catalan Institute of Health (ICS), Barcelona, Spain
| | - Vincenzo Mazzaferro
- HPB Surgery and Liver Transplantation, Istituto Nazionale Tumori IRCCS Foundation (INT), Milan, Italy; Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
| | - Harry Rutter
- Department of Social and Policy Sciences, University of Bath, Bath, UK
| | - Helena Cortez-Pinto
- Clínica Universitária de Gastrenterologia and Laboratório de Nutrição, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal
| | - Deirdre Kelly
- Liver Unit, Birmingham Women's and Children's Hospital and University of Birmingham, UK
| | - Robyn Burton
- Alcohol, Drugs, Tobacco and Justice Division, Public Health England, London, UK
| | - Jeffrey V Lazarus
- Barcelona Institute for Global Health (ISGlobal), Hospital Clínic, Barcelona, Spain
| | - Pere Ginès
- Liver Unit, Hospital Clinic of Barcelona, Barcelona, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; CIBEREHD, Madrid, Spain; Faculty of Medicine and Health Sciences, University of Barcelona, Spain
| | - Maria Buti
- CIBEREHD del Instituto de Salud Carlos III, Madrid, Spain; Liver Unit, Hospital Universitario Valle Hebron, Barcelona, Spain
| | - Philip N Newsome
- National Institute for Health Research Biomedical Research Centre, University Hospitals Birmingham NHS Foundation Trust, University of Birmingham, Birmingham, UK
| | - Patrizia Burra
- Multivisceral Transplant Unit, Gastroenterology, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, Padua, Italy
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25
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Xiang B, Deng C, Qiu F, Li J, Li S, Zhang H, Lin X, Huang Y, Zhou Y, Su J, Lu M, Ma Y. Single cell sequencing analysis identifies genetics-modulated ORMDL3 + cholangiocytes having higher metabolic effects on primary biliary cholangitis. J Nanobiotechnology 2021; 19:406. [PMID: 34872583 PMCID: PMC8647381 DOI: 10.1186/s12951-021-01154-2] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2021] [Accepted: 11/21/2021] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Primary biliary cholangitis (PBC) is a classical autoimmune disease, which is highly influenced by genetic determinants. Many genome-wide association studies (GWAS) have reported that numerous genetic loci were significantly associated with PBC susceptibility. However, the effects of genetic determinants on liver cells and its immune microenvironment for PBC remain unclear. RESULTS We constructed a powerful computational framework to integrate GWAS summary statistics with scRNA-seq data to uncover genetics-modulated liver cell subpopulations for PBC. Based on our multi-omics integrative analysis, 29 risk genes including ORMDL3, GSNK2B, and DDAH2 were significantly associated with PBC susceptibility. By combining GWAS summary statistics with scRNA-seq data, we found that cholangiocytes exhibited a notable enrichment by PBC-related genetic association signals (Permuted P < 0.05). The risk gene of ORMDL3 showed the highest expression proportion in cholangiocytes than other liver cells (22.38%). The ORMDL3+ cholangiocytes have prominently higher metabolism activity score than ORMDL3- cholangiocytes (P = 1.38 × 10-15). Compared with ORMDL3- cholangiocytes, there were 77 significantly differentially expressed genes among ORMDL3+ cholangiocytes (FDR < 0.05), and these significant genes were associated with autoimmune diseases-related functional terms or pathways. The ORMDL3+ cholangiocytes exhibited relatively high communications with macrophage and monocyte. Compared with ORMDL3- cholangiocytes, the VEGF signaling pathway is specific for ORMDL3+ cholangiocytes to interact with other cell populations. CONCLUSIONS To the best of our knowledge, this is the first study to integrate genetic information with single cell sequencing data for parsing genetics-influenced liver cells for PBC risk. We identified that ORMDL3+ cholangiocytes with higher metabolism activity play important immune-modulatory roles in the etiology of PBC.
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Affiliation(s)
- Bingyu Xiang
- Department of Infectious Diseases, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China
| | - Chunyu Deng
- School of Life Science and Technology, Harbin Institute of Technology, Harbin, 150080, China
| | - Fei Qiu
- Institute of Biomedical Big Data, School of Ophthalmology and Optometry and Eye Hospital, School of Biomedical Engineering, Wenzhou Medical University, Wenzhou, 325027, Zhejiang, China
| | - Jingjing Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University School of Medicine, Hangzhou, 310003, Zhejiang, China
| | - Shanshan Li
- Department of Infectious Diseases, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China
| | - Huifang Zhang
- Department of Infectious Diseases, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China
| | - Xiuli Lin
- Department of Infectious Diseases, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China
| | - Yukuan Huang
- Institute of Biomedical Big Data, School of Ophthalmology and Optometry and Eye Hospital, School of Biomedical Engineering, Wenzhou Medical University, Wenzhou, 325027, Zhejiang, China
| | - Yijun Zhou
- Institute of Biomedical Big Data, School of Ophthalmology and Optometry and Eye Hospital, School of Biomedical Engineering, Wenzhou Medical University, Wenzhou, 325027, Zhejiang, China
| | - Jianzhong Su
- Institute of Biomedical Big Data, School of Ophthalmology and Optometry and Eye Hospital, School of Biomedical Engineering, Wenzhou Medical University, Wenzhou, 325027, Zhejiang, China
- Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, 325011, Zhejiang, China
| | - Mingqin Lu
- Department of Infectious Diseases, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China.
| | - Yunlong Ma
- Institute of Biomedical Big Data, School of Ophthalmology and Optometry and Eye Hospital, School of Biomedical Engineering, Wenzhou Medical University, Wenzhou, 325027, Zhejiang, China.
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26
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Iwashita H, Shakado S, Yasuda H, Tanabe T, Yamaguchi M, Irie M, Hirai F. A case of episodic angioedema with eosinophilia in an elderly woman with primary biliary cholangitis. Clin J Gastroenterol 2021; 14:836-841. [PMID: 33751419 DOI: 10.1007/s12328-021-01375-w] [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: 10/20/2020] [Accepted: 02/22/2021] [Indexed: 10/21/2022]
Abstract
We present the case of a 56-year-old woman diagnosed with primary biliary cholangitis (PBC). She has continuously taken 600 mg/day of ursodeoxycholic acid. Edema of the lower limbs manifested on July 20, 20XX; after 2 weeks, she manifested rapid weight gain and nettle rash on the limbs and trunk. She was admitted to our hospital on August 22. She had marked eosinophilia, hypoalbuminemia, anemia, non-pitting lower limbs edema, and nettle rash of the limbs and the trunk. We ruled out other diseases that may have caused the edema and suspected her with episodic angioedema with eosinophilia (EAE). The peripheral blood eosinophil count rapidly decreased after the administration of 30 mg prednisolone. The edema and nettle rash improved on the 7th day of admission, and the hypoalbuminemia and anemia improved on the 14th day. Prednisolone was tapered and discontinued, and there was no relapse of edema. We revised our diagnosis to non-recurrent EAE. She was diagnosed with asymptomatic PBC; therefore, anemia and hypoalbuminemia were considered not PBC but chronic inflammation and decrease in appetite. In this case, elevation of serum IgG4 was observed at onset and at remission. This suggests that IgG4 may be involved in the development of EAE in patients with chronic liver disease.
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Affiliation(s)
- Hideyuki Iwashita
- Department of Gastroenterology and Medicine, Fukuoka University Nishijin Hospital, 15-7 Sohara, Sawara-ku, Fukuoka, 814-8522, Japan.
| | - Satoshi Shakado
- Department of Gastroenterology and Medicine, Faculty of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka, 814-0180, Japan
| | - Hideki Yasuda
- Department of Gastroenterology and Medicine, Fukuoka University Nishijin Hospital, 15-7 Sohara, Sawara-ku, Fukuoka, 814-8522, Japan
| | - Tarou Tanabe
- Department of Gastroenterology and Medicine, Fukuoka University Nishijin Hospital, 15-7 Sohara, Sawara-ku, Fukuoka, 814-8522, Japan
| | - Masashi Yamaguchi
- Department of Gastroenterology and Medicine, Fukuoka University Nishijin Hospital, 15-7 Sohara, Sawara-ku, Fukuoka, 814-8522, Japan
| | - Makoto Irie
- Department of Gastroenterology and Medicine, Fukuoka University Nishijin Hospital, 15-7 Sohara, Sawara-ku, Fukuoka, 814-8522, Japan
| | - Fumihito Hirai
- Department of Gastroenterology and Medicine, Faculty of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka, 814-0180, Japan
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Romero-Gómez M, Ampuero J. Looking for a new name for non-alcoholic fatty liver disease in Spanish: esteatosis hepática metabólica (EHmet). REVISTA ESPANOLA DE ENFERMEDADES DIGESTIVAS 2021; 113:161-163. [PMID: 33573385 DOI: 10.17235/reed.2021.7862/2021] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
The name of a disease does not follow any defined protocol and the scientific community's acceptance of several variants based on the customs of every location is usual. There are examples of prevalent entities with curious naming processes, such as diabetes mellitus. The first word, "diabetes", comes from the Greek dia (through), be (to go), and tes (factor), while the second word, "mellitus", comes from Latin melli (honey). As a consequence, diabetes mellitus literally means "the sweet factor that goes through…", pertaining to an excessive and sweet diuresis. Thus, we could deduce that a definition representing exactly the pathophysiology of the particular disease is not required.
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Affiliation(s)
- Manuel Romero-Gómez
- UGC Aparato Digestivo, Instituto de Biomedicina de Sevilla. Universidad de Sevilla, España
| | - Javier Ampuero
- UGC Aparato Digestivo, Instituto de Biomedicina de Sevilla. Universidad de Sevilla, España
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Sun K, Ma S, Tian S, Zhang M, Liu Y, Li B, Zhou X, Zheng X, Zhou X, Wang L, Han Y. An enhanced level of LAMP-2A participates in CD4 +T cell hyperactivity in patients with primary biliary cholangitis. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:101. [PMID: 33569403 PMCID: PMC7867869 DOI: 10.21037/atm-20-2427] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Background Primary biliary cholangitis (PBC) is an immune-mediated chronic cholestasis, in which T cell homeostasis plays an important role. Lysosomal-associated membrane protein 2 isoform A (LAMP-2A) has been implicated in the regulation of CD4+T cell responses. Methods We comprehensively evaluated the immunobiology of CD4+T cells in patients with PBC (PBC, n=42), chronic hepatitis B (CHB, n=20), and healthy control subjects (HC, n=20) by flow cytometry including activation status and LAMP-2A expression. Additionally, we investigated the activation responses of PBC-naïve CD4+T cells by stimulation in vitro and tested the changes caused by deleting the gene encoding LAMP-2A. Results Firstly, we found an increased activation status of circulating CD4+T cells from PBC patients compared to the HC subjects, and PBC-naïve CD4+T cells showed enhanced responses after stimulation in vitro. Secondly, PBC-naïve CD4+T cells expressed a significantly higher level of LAMP-2A compared to the HC and CHB groups [PBC vs. HC, 1,954.74 (1,254.28-3,057.14) vs. 1,542.12 (961.18-2,277.98), P=0.03; vs. CHB, 1,153.59 (726.87-1,275.48), P=0.02], and the overreactions of PBC-naïve CD4+T cells could be reversed by interfering with LAMP-2A expression in vitro. Thirdly, the LAMP-2A expression level of PBC-naïve CD4+T cells was related to disease severity and drug response. Conclusions An abnormally increased LAMP-2A expression of PBC-naïve CD4+T cells might be related to excessive activation responses. LAMP-2A could be a novel therapeutic target for the treatment of PBC by reversing excessive responses and consequently reducing biliary injury.
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Affiliation(s)
- Keshuai Sun
- State Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, The Fourth Military Medical University, Xi'an, China
| | - Shuoyi Ma
- State Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, The Fourth Military Medical University, Xi'an, China
| | - Siyuan Tian
- State Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, The Fourth Military Medical University, Xi'an, China
| | - Miao Zhang
- State Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, The Fourth Military Medical University, Xi'an, China
| | - Yansheng Liu
- State Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, The Fourth Military Medical University, Xi'an, China
| | - Bo Li
- State Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, The Fourth Military Medical University, Xi'an, China
| | - Xia Zhou
- State Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, The Fourth Military Medical University, Xi'an, China
| | - Xiaohong Zheng
- State Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, The Fourth Military Medical University, Xi'an, China
| | - Xinmin Zhou
- State Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, The Fourth Military Medical University, Xi'an, China
| | - Lu Wang
- State Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, The Fourth Military Medical University, Xi'an, China
| | - Ying Han
- State Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, The Fourth Military Medical University, Xi'an, China
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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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Ratziu V, Rinella M, Beuers U, Loomba R, Anstee QM, Harrison S, Francque S, Sanyal A, Newsome PN, Younossi Z. The times they are a-changin' (for NAFLD as well). J Hepatol 2020; 73:1307-1309. [PMID: 32890593 DOI: 10.1016/j.jhep.2020.08.028] [Citation(s) in RCA: 49] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/23/2020] [Accepted: 08/25/2020] [Indexed: 01/12/2023]
Affiliation(s)
- Vlad Ratziu
- Sorbonne Université, Hôpital Pitié-Salpêtrière, Institute for Cardiometabolism and Nutrition (ICAN) and INSERM UMRS 1138 CRC, Paris, France
| | - Mary Rinella
- Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
| | - Ulrich Beuers
- Department of Gastroenterology and Hepatology, Amsterdam University Medical Center, Amsterdam, the Netherlands
| | - Rohit Loomba
- NAFLD Research Center, University of California at San Diego, La Jolla, CA, USA
| | - Quentin M Anstee
- Translational & Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | | | - Sven Francque
- Department of Gastroenterology and Hepatology, Antwerp University Hospital and University of Antwerp, Edegem, Belgium
| | - Arun Sanyal
- Division of Gastroenterology, Virginia Commonwealth University, Richmond, VA, USA
| | - Philip N Newsome
- National Institute for Health Research Biomedical Research Centre at University Hospitals Birmingham NHS Foundation Trust and the University of Birmingham, UK.
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Ainosah RH, Hagras MM, Alharthi SE, Saadah OI. The effects of ursodeoxycholic acid on sepsis-induced cholestasis management in an animal model. J Taibah Univ Med Sci 2020; 15:312-320. [PMID: 32982635 PMCID: PMC7479157 DOI: 10.1016/j.jtumed.2020.04.007] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2020] [Revised: 04/22/2020] [Accepted: 04/29/2020] [Indexed: 12/16/2022] Open
Abstract
Objectives Cholestasis refers to a reduction in bile flow from the liver into the biliary system. Ursodeoxycholic acid (UDCA) is commonly used for the treatment of hepatic cholestasis. This study aimed to explore the role of UDCA in the treatment and prevention of lipopolysaccharide (LPS)-induced cholestasis. Methods Sixty male albino rats were randomly classified into five groups of 12 rats each: the control group (received saline and water), UDCA group (received UDCA), LPS group (received LPS), treatment group (received LPS followed by UDCA), and prevention group (received UDCA followed by LPS). Changes in gamma-glutamyl transferase (GGT), plasma aspartate transferase (AST), plasma alkaline transferase (ALT), plasma alkaline phosphatase (ALP), total bilirubin (TBIL), hepatocyte apoptosis, immunomodulatory activity, plasma pro-inflammatory cytokines (TNF-α, IL-1α, and IL-4), and liver histology were assessed. Results UDCA improved serum liver chemical markers (GGT, ALP, and AST) in both the prevention and treatment groups (p < 0.05 and p < 0.05, respectively). CD3 count was higher in the UDCA treatment group compared to the LPS group (p < 0.001). UDCA caused a reduction in plasma TNF-α in the prevention group (P < 0.05); however, it had no effect on the treatment group, as compared to the LPS group. Similarly, UDCA had no effect on IL-1α or IL-4. UDCA treatment resulted in improved liver histological features and a significant reduction in liver tissue apoptosis in both the treatment and prevention groups, as compared to the LPS group (p = 0.013 and p = 0.002, respectively). Conclusions This study provides evidence of the effectiveness of UDCA for the treatment and prevention of sepsis-induced cholestasis.
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Affiliation(s)
| | - Magda M Hagras
- Department of Clinical Pharmacology, Faculty of Medicine, Suez Canal University, Egypt
| | - Sameer E Alharthi
- Department of Pharmacology, Faculty of Medicine, King Abdulaziz University, Jeddah, KSA
| | - Omar I Saadah
- Department of Pediatrics, King Abdulaziz University, Jeddah, KSA
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Vetter M, Kremer AE. [Primary biliary cholangitis-established and novel therapies]. Internist (Berl) 2019; 59:544-550. [PMID: 29691599 DOI: 10.1007/s00108-018-0427-0] [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: 11/26/2022]
Abstract
BACKGROUND Patients with primary biliary cholangitis (PBC, formerly primary biliary cirrhosis) and insufficient treatment response or risk factors exhibit a remarkably increased risk for disease progression and associated complications. Furthermore, extrahepatic manifestations may considerably reduce quality of life in affected patients. OBJECTIVES This article presents an overview on standard therapy with ursodeoxycholic acid (UDCA) and further therapeutic options in patients with insufficient treatment response. In addition, symptom-orientated therapies will be presented in a practical and compact way. METHODS The current European and German guidelines from 2017 in addition to several research papers and expert opinions are the basis for this review. RESULTS Every PBC patient should be treated with UDCA life-long. In case of insufficient response to UDCA, obeticholic acid (OCA) has been approved as second line therapy since 2016. Fibrates and budesonide present off-label options for certain patient subpopulations. Pruritus should initially be treated with colestyramine. In case of insufficient efficacy or intolerance, rifampicin represents the most effective off-label option. If fatigue is present, differential diagnoses shall be excluded and coping strategies combined with regular physical activity can have a positive effect. CONCLUSION UDCA and OCA are effective and approved drugs for treating PBC. Patients with insufficient treatment response or risk factors have to be treated consequently. Due to the improved anti-cholestatic treatment options, therapies to reduce fatigue and pruritus are increasingly important.
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Affiliation(s)
- M Vetter
- Medizinische Klinik 1, Friedrich-Alexander-Universität Erlangen-Nürnberg, Ulmenweg 18, 91054, Erlangen, Deutschland
| | - A E Kremer
- Medizinische Klinik 1, Friedrich-Alexander-Universität Erlangen-Nürnberg, Ulmenweg 18, 91054, Erlangen, Deutschland.
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Liu X, Xu H, Zhan M, Niu J. The Potential Effects of Diabetes Mellitus on Liver Fibrosis in Patients with Primary Biliary Cholangitis. Med Sci Monit 2019; 25:6174-6180. [PMID: 31420961 PMCID: PMC6710003 DOI: 10.12659/msm.916107] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Background The impact of diabetes mellitus (DM) on the natural progression of primary biliary cholangitis (PBC) has not yet been determined. The objective of this study was to determine whether DM is associated with increased liver damage in PBC. Material/Methods There were 168 treatment-naïve PBC patients, including 37 patients with DM, enrolled in this study between 2012 and 2018. Patient demographics, clinical features, and biochemical and histopathological parameters were collected. Disease severity was assessed by pathological data, Child Pugh grade, and noninvasive indicators. Relevant risks for PBC-related cirrhosis were assessed by univariate and multivariate analyses. Results The noninvasive scores predicting fibrosis were all significantly higher in PBC-DM versus PBC-only patients (fibrosis-4 score: 4.08 versus 3.21, P=0.029; aminotransferase-to-platelet ratio index: 1.46 versus 1.09, P=0.036; red blood cell distribution width to platelet ratio: 0.12 versus 0.08, P=0.016; Mayo Risk Score: 1.52 versus 0.19, P=0.011; the Newcastle model: 2.85 versus 2.07, P=0.009; albumin-bilirubin score: −1.92 versus −2.10, P=0.023). Cirrhosis occurred at a higher rate (62.2% versus 42.0%, P=0.030) in PBC-DM patients, but Child Pugh grade and pathological differences could not be accurately determined. A multivariate analysis revealed DM increased the risk of PBC-related cirrhosis, with a resulting adjusted odds ratio of 2.351 (95% confidence interval, 1.022–5.409). Conclusions The results of this retrospective, single-center study suggest that DM is associated with more severe liver fibrosis in PBC. Consequently, improved management of DM might alter the prognosis of PBC patients.
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Affiliation(s)
- Xu Liu
- Department of Hepatology, The First Hospital of Jilin University, Changchun, Jilin, China (mainland)
| | - Hongqin Xu
- Department of Hepatology, The First Hospital of Jilin University, Changchun, Jilin, China (mainland)
| | - Mengru Zhan
- Department of Hepatology, The First Hospital of Jilin University, Changchun, Jilin, China (mainland)
| | - Junqi Niu
- Department of Hepatology, The First Hospital of Jilin University, Changchun, Jilin, China (mainland)
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Couto CA, Terrabuio DRB, Cançado ELR, Porta G, Levy C, Silva AEB, Bittencourt PL, Carvalho Filho RJD, Chaves DM, Miura IK, Codes L, Faria LC, Evangelista AS, Farias AQ, Gonçalves LL, Harriz M, Lopes EPDA, Luz GO, Oliveira PMC, Oliveira EMG, Schiavon JLN, Sevá-Pereira T. UPDATE OF THE BRAZILIAN SOCIETY OF HEPATOLOGY RECOMMENDATIONS FOR DIAGNOSIS AND MANAGEMENT OF AUTOIMMUNE DISEASES OF THE LIVER. ARQUIVOS DE GASTROENTEROLOGIA 2019; 56:232-241. [PMID: 31460591 DOI: 10.1590/s0004-2803.201900000-43] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/14/2019] [Accepted: 06/04/2019] [Indexed: 02/08/2023]
Abstract
New data concerning the management of autoimmune liver diseases have emerged since the last single-topic meeting sponsored by the Brazilian Society of Hepatology to draw recommendations about the diagnosis and treatment of autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), overlap syndromes of AIH, PBC and PSC and specific complications and topics concerning AIH and cholestatic liver diseases. This manuscript updates those previous recommendations according to the best evidence available in the literature up to now. The same panel of experts that took part in the first consensus document reviewed all recommendations, which were subsequently scrutinized by all members of the Brazilian Society of Hepatology using a web-based approach. The new recommendations are presented herein.
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Affiliation(s)
- Cláudia Alves Couto
- Universidade Federal de Minas Gerais, Faculdade de Medicina, Belo Horizonte, MG, Brasil
| | | | | | - Gilda Porta
- Hospital Menino Jesus, Hospital Sírio Libanês e Hospital A C Camargo Center, Grupo de Hepatologia e Transplante Hepático Pediátrico, São Paulo, SP, Brasil
| | - Cynthia Levy
- University of Miami, Schiff Center for Liver Diseases, USA
| | - Antônio Eduardo Benedito Silva
- Universidade Federal de São Paulo, Faculdade de Medicina, São Paulo, SP; Centro Universitário Lusíada (UNILUS), Santos, SP, Brasil
| | | | - Roberto José de Carvalho Filho
- Universidade Federal de São Paulo, Faculdade de Medicina, São Paulo, SP; Centro Universitário Lusíada (UNILUS), Santos, SP, Brasil
| | | | - Irene Kazue Miura
- Hospital Menino Jesus, Hospital Sírio Libanês e Hospital A C Camargo Center, Grupo de Hepatologia e Transplante Hepático Pediátrico, São Paulo, SP, Brasil
| | | | - Luciana Costa Faria
- Universidade Federal de Minas Gerais, Faculdade de Medicina, Belo Horizonte, MG, Brasil
| | | | | | | | - Michelle Harriz
- Universidade de São Paulo, Faculdade de Medicina, São Paulo, SP, Brasil
| | | | | | | | - Elze Maria Gomes Oliveira
- Universidade Federal de São Paulo, Faculdade de Medicina, São Paulo, SP; Centro Universitário Lusíada (UNILUS), Santos, SP, Brasil
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Marschall HU, Henriksson I, Lindberg S, Söderdahl F, Thuresson M, Wahlin S, Ludvigsson JF. Incidence, prevalence, and outcome of primary biliary cholangitis in a nationwide Swedish population-based cohort. Sci Rep 2019; 9:11525. [PMID: 31395896 PMCID: PMC6687809 DOI: 10.1038/s41598-019-47890-2] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2019] [Accepted: 06/28/2019] [Indexed: 02/08/2023] Open
Abstract
Available epidemiological data on primary biliary cholangitis (PBC) in Sweden originate from regional studies in the 1980s and may not reflect modern day PBC. We aimed to estimate incidence and prevalence, survival and death causes, and gender differences in PBC. We used international classification of disease (ICD) codes to identify patients with PBC in inpatient and outpatient registries 1987-2014 who were then linked to the Swedish cause of death, cancer and prescribed drug registries. Each PBC patient was matched with 10 reference individuals from the general population. In sensitivity analyses, we examined PBC patients identified through clinical patient records from Karolinska, Sahlgrenska and Örebro University Hospitals. We identified 5,350 adults with PBC. Prevalence of PBC increased steadily from 5.0 (1987) to 34.6 (2014) per 100,000 inhabitants whereas the yearly incidence rate was relatively constant with a median of 2.6 per 100,000 person-years, with a female:male gender ratio of 4:1. Compared to reference individuals, PBC individuals aged 15-39 years at diagnosis had a substantially higher risk of death (Hazard Ratio [HR] 12.7, 95% Confidence Interval [CI] 8.3-19.5) than those diagnosed between 40-59 (HR 4.1, 95% CI 3.7-4.5) and >60 (HR 3.7, 95% CI 3.5-3.9) years of age. Relative risks of mortality were highest in men. In conclusion, we found that recorded prevalence of PBC in Sweden has increased substantially during the last 30 years although incidence has been stable. Patients diagnosed in young adulthood were at a 12.7-fold increased risk of death, and male PBC patients had worse prognosis.
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Affiliation(s)
- Hanns-Ulrich Marschall
- Sahlgrenska Academy, Institute of Medicine, Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden.
| | - Ida Henriksson
- Department of Medicine, Örebro University Hospital, Örebro, Sweden
| | - Sara Lindberg
- Department of Internal Medicine, Skaraborg Hospital, Skövde, 54142, Sweden
| | | | | | - Staffan Wahlin
- Karolinska University Hospital Huddinge, Department of Gastroenterology and Hepatology, Stockholm, Sweden
| | - Jonas F Ludvigsson
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
- Department of Pediatrics, Örebro University Hospital, Örebro, Sweden
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Sultan K, Petkar M, Derbala M. Florid biliary duct lesions in an AMA -positive patient in absence of cholestatic liver biochemistry. J Autoimmun 2019; 101:153-155. [DOI: 10.1016/j.jaut.2019.04.004] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2019] [Revised: 03/31/2019] [Accepted: 04/04/2019] [Indexed: 02/08/2023]
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Arenas F, Hervías I, Sáez E, Melero S, Prieto J, Parés A, Medina JF. Promoter hypermethylation of the AE2/SLC4A2 gene in PBC. JHEP Rep 2019; 1:145-153. [PMID: 32039364 PMCID: PMC7001545 DOI: 10.1016/j.jhepr.2019.05.006] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2019] [Revised: 05/13/2019] [Accepted: 05/16/2019] [Indexed: 12/12/2022] Open
Abstract
Background & Aims Patients with primary biliary cholangitis (PBC) exhibit reduced AE2/SLC4A2 gene expression in the liver and peripheral blood mononuclear cells (PBMCs). AE2 encodes a Cl–/HCO3– exchanger involved in biliary bicarbonate secretion and intracellular pH regulation. Reduced AE2 expression in PBC may be pathogenic, as Ae2-knockout mice reproduce characteristic PBC features. Herein, we aimed to identify CpG-methylation abnormalities in AE2 promoter regions that might contribute to the reduced gene transcription in PBC livers and PBMCs. Methods CpG-cytosine methylation rates were interrogated at 1-base pair resolution in upstream and alternate AE2 promoter regions through pyrosequencing of bisulphite-modified genomic DNA from liver specimens and PBMCs. AE2a and alternative AE2b1 and AE2b2 mRNA levels were measured by real-time PCR. Human lymphoblastoid-T2 cells were treated with 5-aza-2´-deoxycytidine for demethylation assays. Results AE2 promoters were found to be hypermethylated in PBC livers compared to normal and diseased liver specimens. Receiver operating characteristic (ROC) curve analysis showed that minimal CpG-hypermethylation clusters of 3 AE2a-CpG sites and 4 alternate-AE2b2-CpG sites specifically differentiated PBC from normal and diseased controls, with mean methylation rates inversely correlating with respective transcript levels. Additionally, in PBMCs a minimal cluster of 3 hypermethylated AE2a-CpG sites distinguished PBC from controls, and mean methylation rates correlated negatively with AE2a mRNA levels in these immune cells. Alternate AE2b2/AE2b1 promoters in PBMCs were constitutively hypermethylated, in line with absent alternative mRNA expression in diseased and healthy PBMCs. Demethylation assays treating lymphoblastoid-T2 cells with 5-aza-2´-deoxycytidine triggered AE2b2/AE2b1 expression and upregulated AE2a-promoter expression. Conclusions Disease-specific hypermethylation of AE2 promoter regions and subsequent downregulation of AE2-gene expression in the liver and PBMCs of patients with PBC might be critically involved in the pathogenesis of this complex disease. Lay summary Primary biliary cholangitis (PBC) is a chronic immune-associated cholestatic liver disease with unclear complex/multifactorial etiopathogenesis affecting mostly middle-aged women. Patients with PBC exhibit reduced expression of the AE2/SLC4A2 gene. Herein, we found that AE2 promoter regions are hypermethylated in the liver and peripheral blood mononuclear cells of patients with PBC. This increased methylation is associated with downregulated AE2-gene expression, which might contribute to the pathogenesis of PBC. Therefore, novel epigenetic targets may improve treatment in patients with PBC who respond poorly to current pharmacological therapies.
Patients with PBC have higher AE2 CpG methylation in upstream AE2a and/or AE2b2/AE2b1 promoter regions in liver and PBMCs. Combined methylation rates of 2 minimal CpG-clusters in the liver and 1 minimal CpG-cluster in PBMCs specifically distinguished PBC from normal and diseased controls. Methylation rates of AE2 promoter regions inversely correlated with levels of respective AE2 mRNAs in liver and PBMCs. Alternate AE2b2/AE2b1 promoter regions were found to be densely methylated in both normal and diseased PBMC samples.
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Affiliation(s)
- Fabián Arenas
- Division of Gene Therapy and Hepatology, CIMA, School of Medicine and Clinic University of Navarra, and Ciberehd, Pamplona
| | - Isabel Hervías
- Division of Gene Therapy and Hepatology, CIMA, School of Medicine and Clinic University of Navarra, and Ciberehd, Pamplona
| | - Elena Sáez
- Division of Gene Therapy and Hepatology, CIMA, School of Medicine and Clinic University of Navarra, and Ciberehd, Pamplona
| | - Saida Melero
- Division of Gene Therapy and Hepatology, CIMA, School of Medicine and Clinic University of Navarra, and Ciberehd, Pamplona
| | - Jesús Prieto
- Division of Gene Therapy and Hepatology, CIMA, School of Medicine and Clinic University of Navarra, and Ciberehd, Pamplona
| | - Albert Parés
- Liver Unit, Hospital Clinic, IDIBAPS, University of Barcelona, and Ciberehd, Barcelona, Spain
| | - Juan F. Medina
- Division of Gene Therapy and Hepatology, CIMA, School of Medicine and Clinic University of Navarra, and Ciberehd, Pamplona
- Corresponding author. Address: Division of Gene Therapy and Hepatology, Center for Applied Medical Research (CIMA) University of Navarra School of Medicine, Pamplona, Spain.
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Abstract
For nearly 30 years ursodeoxycholic acid (UDCA) represented the only pharmacological treatment option available for primary biliary cholangitis (PBC). This changed at the end of 2016 when obeticholic acid was licensed in Europe for PBC patients not responding to UDCA. Novel treatment concepts involving the modulation of nuclear receptor signaling in cholestatic and other liver diseases have led to a host of new potential options, studies and drug candidates for the treatment of PBC. The analysis of large multinational cohorts has additionally confirmed the effectiveness of UDCA in slowing PBC progression, and has led to the development of new definitions for the risk assessment of PBC patients under therapy, which will be an asset for clinical decision making. One issue that remains unresolved is the therapeutic management of extrahepatic symptoms associated with PBC, namely fatigue and pruritus, which are the main factors influencing the quality of life of affected individuals. Their pathophysiological basis is poorly understood and treatment remains unsatisfactory.
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Affiliation(s)
- C P Strassburg
- Medizinische Klinik und Poliklinik I, Universitätsklinikum Bonn, Sigmund-Freud-Straße 25, 53127, Bonn, Deutschland.
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Mayo MJ, Pockros PJ, Jones D, Bowlus CL, Levy C, Patanwala I, Bacon B, Luketic V, Vuppalanchi R, Medendorp S, Dorenbaum A, Kennedy C, Novak P, Gu J, Apostol G, Hirschfield GM. A Randomized, Controlled, Phase 2 Study of Maralixibat in the Treatment of Itching Associated With Primary Biliary Cholangitis. Hepatol Commun 2019; 3:365-381. [PMID: 30859149 PMCID: PMC6396374 DOI: 10.1002/hep4.1305] [Citation(s) in RCA: 60] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2018] [Accepted: 11/14/2018] [Indexed: 12/19/2022] Open
Abstract
Primary biliary cholangitis (PBC) is typically associated with elevated serum bile acid levels and pruritus, but pruritus is often refractory to treatment with existing therapies. This phase 2 study assessed the efficacy and safety of maralixibat, a selective, ileal, apical, sodium‐dependent, bile acid transporter inhibitor, in adults with PBC and pruritus. Adults with PBC and pruritus who had received ursodeoxycholic acid (UDCA) for ≥6 months or were intolerant to UDCA were randomized 2:1 to maralixibat (10 or 20 mg/day) or placebo for 13 weeks in combination with UDCA (when tolerated). The primary outcome was change in Adult Itch Reported Outcome (ItchRO™) average weekly sum score (0, no itching; 70, maximum itching) from baseline to week 13/early termination (ET). The study enrolled 66 patients (maralixibat [both doses combined], n = 42; placebo, n = 24). Mean ItchRO™ weekly sum scores decreased from baseline to week 13/ET with maralixibat (–26.5; 95% confidence interval [CI], –31.8, –21.2) and placebo (–23.4; 95% CI, –30.3, –16.4). The difference between groups was not significant (P = 0.48). In the maralixibat and placebo groups, adverse events (AEs) were reported in 97.6% and 70.8% of patients, respectively. Gastrointestinal disorders were the most frequently reported AEs (maralixibat, 78.6%; placebo, 50.0%). Conclusion: Reductions in pruritus did not differ significantly between maralixibat and placebo. However, a large placebo effect may have confounded assessment of pruritus. Lessons learned from this rigorously designed and executed trial are indispensable for understanding how to approach trials assessing pruritus as the primary endpoint and the therapeutic window of bile acid uptake inhibition as a therapeutic strategy in PBC.
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Affiliation(s)
- Marlyn J Mayo
- Digestive and Liver Diseases University of Texas Southwestern Medical Center Dallas TX
| | - Paul J Pockros
- Scripps Clinic and Scripps Translational Science Institute La Jolla CA
| | - David Jones
- Institute of Cellular Medicine Newcastle University Newcastle upon Tyne United Kingdom
| | - Christopher L Bowlus
- Division of Gastroenterology and Hepatology University of California Davis School of Medicine Sacramento CA
| | - Cynthia Levy
- Division of Hepatology University of Miami Miller School of Medicine Miami FL
| | - Imran Patanwala
- Royal Liverpool University Hospital and University of Liverpool Liverpool United Kingdom
| | - Bruce Bacon
- Division of Gastroenterology and Hepatology Saint Louis University School of Medicine St. Louis MO
| | - Velimir Luketic
- Division of Gastroenterology, Hepatology and Nutrition Virginia Commonwealth University School of Medicine Richmond VA.,McGuire Research Institute, McGuire VA Medical Center Richmond VA
| | | | | | | | | | - Patricia Novak
- Lumena Pharmaceuticals San Diego CA (one of the Shire group of companies)
| | | | | | - Gideon M Hirschfield
- Toronto Centre for Liver Disease University Health Network, University of Toronto Toronto Canada
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Abstract
Primary biliary cholangitis (PBC) is a chronic, cholestatic, autoimmune disease with a variable progressive course. PBC can cause debilitating symptoms including fatigue and pruritus and, if left untreated, is associated with a high risk of cirrhosis and related complications, liver failure, and death. Recent changes to the PBC landscape include a name change, updated guidelines for diagnosis and treatment as well as new treatment options that have recently become available. Practicing clinicians face many unanswered questions when managing PBC. To assist these healthcare providers in managing patients with PBC, the American College of Gastroenterology (ACG) Institute for Clinical Research & Education, in collaboration with the Chronic Liver Disease Foundation (CLDF), organized a panel of experts to evaluate and summarize the most current and relevant peer-reviewed literature regarding PBC. This, combined with the extensive experience and clinical expertise of this expert panel, led to the formation of this clinical guidance on the diagnosis and management of PBC.
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Montano-Loza AJ, Hansen BE, Corpechot C, Roccarina D, Thorburn D, Trivedi P, Hirschfield G, McDowell P, Poupon R, Dumortier J, Bosch A, Giostria E, Conti F, Parés A, Reig A, Floreani A, Russo FP, Goet JC, Harms MH, van Buuren H, Van den Ende N, Nevens F, Verhelst X, Donato MF, Malinverno F, Ebadi M, Mason AL. Factors Associated With Recurrence of Primary Biliary Cholangitis After Liver Transplantation and Effects on Graft and Patient Survival. Gastroenterology 2019; 156:96-107.e1. [PMID: 30296431 DOI: 10.1053/j.gastro.2018.10.001] [Citation(s) in RCA: 70] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2018] [Revised: 09/18/2018] [Accepted: 10/02/2018] [Indexed: 01/05/2023]
Abstract
BACKGROUND & AIMS Primary biliary cholangitis (PBC) frequently recurs after liver transplantation. We evaluated risk factors associated with recurrence of PBC and its effects on patient and graft survival in a multicenter, international cohort (the Global PBC Study Group). METHODS We collected demographic and clinical data from 785 patients (89% female) with PBC who underwent liver transplantation (mean age, 54 ± 9 years) from February 1983 through June 2016, among 13 centers in North America and Europe. Results from biochemical tests performed within 12 months of liver transplantation were analyzed to determine whether markers of cholestasis could identify patients with recurrence of PBC (based on histologic analysis). Patients were followed for a median 6.9 years (interquartile range, 6.1-7.9 years). RESULTS PBC recurred in 22% of patients after 5 years and 36% after 10 years. Age at diagnosis <50 years (hazard ratio [HR], 1.79; 95% CI, 1.36-2.36; P < .001), age at liver transplantation <60 years (HR, 1.39; 95% CI, 1.02-1.90; P = .04), use of tacrolimus (HR, 2.31; 95% CI, 1.72-3.10; P < .001), and biochemical markers of severe cholestasis (bilirubin ≥100 μmol or alkaline phosphatase >3-fold the upper limit of normal) at 6 months after liver transplantation (HR, 1.79; 95% CI, 1.16-2.76; P = .008) were associated with higher risk of PBC recurrence, whereas use of cyclosporine reduced risk of PBC recurrence (HR, 0.62; 95% CI, 0.46-0.82; P = .001). In multivariable Cox regression with time-dependent covariate, recurrence of PBC significantly associated with graft loss (HR, 2.01; 95% CI, 1.16-3.51; P = .01) and death (HR, 1.72; 95% CI, 1.11-2.65; P = .02). CONCLUSIONS Younger age at the time of diagnosis with PBC or at liver transplantation, tacrolimus use, and biochemical markers of cholestasis after liver transplantation are associated with PBC recurrence. PBC recurrence reduces odds of graft and patient survival. Strategies are needed to prevent PBC recurrence or reduce its negative effects.
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Affiliation(s)
- Aldo J Montano-Loza
- Division of Gastroenterology and Liver Unit, University of Alberta, Edmonton, Alberta, Canada.
| | - Bettina E Hansen
- Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Christophe Corpechot
- Reference Center for Inflammatory Biliary Diseases, Saint-Antoine Hospital, Paris, France
| | - Davide Roccarina
- University College London Institute for Liver and Digestive Health, Royal Free Hospital, London, United Kingdom
| | - Douglas Thorburn
- University College London Institute for Liver and Digestive Health, Royal Free Hospital, London, United Kingdom
| | - Palak Trivedi
- National Institute for Health Research, Centre for Liver Research, University Hospitals Birmingham, Institute of Immunology and Immunotherapy, University of Birmingham, United Kingdom
| | - Gideon Hirschfield
- National Institute for Health Research, Centre for Liver Research, University Hospitals Birmingham, Institute of Immunology and Immunotherapy, University of Birmingham, United Kingdom; Department of Gastroenterology, University Hospitals Birmingham National Health Service Foundation Trust, Queen Elizabeth Hospital, Birmingham, United Kingdom; Toronto Centre for Liver Disease, University Health Network, University of Toronto, Toronto, Canada
| | - Patrick McDowell
- Department of Gastroenterology, University Hospitals Birmingham National Health Service Foundation Trust, Queen Elizabeth Hospital, Birmingham, United Kingdom
| | - Raoul Poupon
- Reference Center for Inflammatory Biliary Diseases, Saint-Antoine Hospital, Paris, France
| | - Jerome Dumortier
- Liver Transplant Unit, Edouard Herriot Hospital, Hospices Civils de Lyon, Lyon, France
| | - Alexie Bosch
- Liver Transplant Unit, Edouard Herriot Hospital, Hospices Civils de Lyon, Lyon, France
| | - Emiliano Giostria
- Hepatology and Gastroenterology Department, University Hospitals of Geneva, Geneva, Switzerland
| | - Filomena Conti
- Liver Transplant Unit, Pitié-Salpêtrière Hôpital, Paris France
| | - Albert Parés
- Liver Unit, Hospital Clínic, University of Barcelona, The August Pi i Sunyer Biomedical Research Institute, Biomedical Research Networking Center in Hepatic and Digestive Diseases, Barcelona Spain
| | - Anna Reig
- Liver Unit, Hospital Clínic, University of Barcelona, The August Pi i Sunyer Biomedical Research Institute, Biomedical Research Networking Center in Hepatic and Digestive Diseases, Barcelona Spain
| | - Annarosa Floreani
- Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy
| | - Francesco Paolo Russo
- Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy
| | - Jorn C Goet
- Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Maren H Harms
- Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Henk van Buuren
- Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, The Netherlands
| | | | - Frederik Nevens
- Division Liver and Biliopancreatic Disorders, Leuven, Belgium
| | - Xavier Verhelst
- Department of Gastroenterology and Hepatology, Ghent University Hospital, Ghent, Belgium
| | - Maria Francesca Donato
- Transplant Hepatology Unit, Division of Gastroenterology and Hepatology, Maggiore Hospital Policlinico, Milan, Italy
| | - Federica Malinverno
- Transplant Hepatology Unit, Division of Gastroenterology and Hepatology, Maggiore Hospital Policlinico, Milan, Italy
| | - Maryam Ebadi
- Division of Gastroenterology and Liver Unit, University of Alberta, Edmonton, Alberta, Canada
| | - Andrew L Mason
- Division of Gastroenterology and Liver Unit, University of Alberta, Edmonton, Alberta, Canada
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Influence factors and a predictive scoring model for measuring the biochemical response of primary biliary cholangitis to ursodeoxycholic acid treatment. Eur J Gastroenterol Hepatol 2018; 30:1352-1360. [PMID: 29889683 DOI: 10.1097/meg.0000000000001186] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
AIMS The biochemical response after ursodeoxycholic acid (UDCA) treatment contributes toward predicting the prognosis for primary biliary cholangitis (PBC) patients. This study aimed to establish a score model that can be used for predicting the biochemical response. PATIENTS AND METHODS A total of 218 patients in the derivation group and 66 patients in the verification group were enrolled. Response endpoints were based on the Barcelona criteria combined with the Paris I criteria. We determined independent factors of the biochemical response by univariate and multivariate analyses. Then, we established a predictive score model on the basis of regression coefficients after adjusted multivariate analyses. RESULTS The median follow-up duration in the derivation and the verification group was 12.9 and 12.2 months, respectively. Multivariate logistic regression analysis after adjusting for sex and age indicated that First-UDCA treatment [odds ratio (OR)=2.543, 95% confidence interval (CI): 1.234-5.240, P=0.011], baseline alanine aminotransferase level (OR=1.265, 95% CI: 1.089-1.471, P=0.002), and baseline total bilirubin level (OR=0.571, 95% CI: 0.420-0.776, P<0.001) were independent factors that influenced the biochemical response in PBC patients after 1 year of UDCA treatment. Therefore, the resulting biochemical response prediction score model represented the sum of the points corresponding to these three variables. The area under the receiver operating characteristic curve of the score model in the derivation group and the verification group was 0.763 (95% CI: 0.701-0.817, P<0.001) and 0.798 (95% CI: 0.681-0.887, P<0.001), respectively. CONCLUSION We developed and verified an easy-to-use scoring model for the first time, which showed excellent predictive value for the biochemical response in PBC patients.
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Martínez J, Aguilera L, Albillos A. Risk stratification and treatment of primary biliary cholangitis. REVISTA ESPANOLA DE ENFERMEDADES DIGESTIVAS 2018; 111:63-70. [PMID: 30338693 DOI: 10.17235/reed.2018.5662/2018] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
Primary biliary cholangitis is a chronic liver disorder characterized by progressive cholestasis that may evolve to liver cirrhosis. While ursodeoxycholic acid is the treatment of choice, around 30% of patients do not respond to this therapy. These patients have a poorer prognosis, hence should be identified early in order to be offered therapy options. Along these lines, improved understanding of the condition's pathophysiology has allowed the development of newer drugs, including obeticholic acid and fibrates. This review offers a perspective on risk stratification and treatment for these patients, from ursodeoxycholic acid to second-line treatments.
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Affiliation(s)
- Javier Martínez
- Servicio de Gastroenterología, Hospital Universitario Ramón y Cajal, España
| | | | - Agustín Albillos
- Servicio de Gastroenterología, Hospital Universitario Ramón y Cajal, España
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44
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Chapman RW. Cost effectiveness of using ursodeoxycholic acid to treat primary biliary cholangitis. Br J Hosp Med (Lond) 2018; 79:460-464. [DOI: 10.12968/hmed.2018.79.8.460] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Affiliation(s)
- Roger W Chapman
- Emeritus Consultant in Hepatology, Nuffield Department of Medicine, Oxford University and Translational Gastroenterology Unit, Oxford University Hospital, Oxford OX3 9DU
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45
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de Graaf KL, Lapeyre G, Guilhot F, Ferlin W, Curbishley SM, Carbone M, Richardson P, Moreea S, McCune CA, Ryder SD, Chapman RW, Floreani A, Jones DE, de Min C, Adams DH, Invernizzi P. NI-0801, an anti-chemokine (C-X-C motif) ligand 10 antibody, in patients with primary biliary cholangitis and an incomplete response to ursodeoxycholic acid. Hepatol Commun 2018; 2:492-503. [PMID: 29761166 PMCID: PMC5944576 DOI: 10.1002/hep4.1170] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2017] [Revised: 02/18/2018] [Accepted: 02/22/2018] [Indexed: 12/14/2022] Open
Abstract
NI-0801 is a fully human monoclonal antibody against chemokine (C-X-C motif) ligand 10 (CXCL10), which is involved in the recruitment of inflammatory T cells into the liver. The safety and efficacy of NI-0801 was assessed in patients with primary biliary cholangitis. In this open-label phase 2a study, patients with primary biliary cholangitis with an inadequate response to ursodeoxycholic acid received six consecutive intravenous administrations of NI-0801 (10 mg/kg) every 2 weeks. Patients were followed up for 3 months after the last infusion. Liver function tests, safety assessments, as well as pharmacokinetic and pharmacodynamic parameters were evaluated at different time points throughout the dosing period and the safety follow-up period. Twenty-nine patients were enrolled in the study and were treated with NI-0801. The most frequently reported adverse events included headaches (52%), pruritus (34%), fatigue (24%), and diarrhea (21%). No study drug-related serious adverse events were reported. NI-0801 administration did not lead to a significant reduction in any of the liver function tests assessed at the end of the treatment period (i.e., 2 weeks after final NI-0801 administration) compared to baseline. Conclusion: Despite clear pharmacologic responses in the blood, no therapeutic benefit of multiple administrations of NI-0801 could be demonstrated. The high production rate of CXCL10 makes it difficult to achieve drug levels that lead to sustained neutralization of the chemokine, thus limiting its targetability. (Hepatology Communications 2018;2:492-503).
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Affiliation(s)
| | | | | | | | - Stuart M. Curbishley
- Centre for Liver ResearchUniversity of BirminghamBirminghamUnited Kingdom
- National Institute for Health Research (NIHR) Biomedical Research CentreBirminghamUnited Kingdom
| | - Marco Carbone
- Division of Gastroenterology and Program for Autoimmune Liver Diseases, International Center for Digestive Health, Department of Medicine and SurgeryUniversity of Milan‐BicoccaMilanItaly
| | - Paul Richardson
- Royal Liverpool University National Health Service TrustLiverpoolUnited Kingdom
| | - Sulleman Moreea
- Department of GastroenterologyBradford Teaching Hospitals National Health Service Foundation TrustBradfordUnited Kingdom
| | - C. Anne McCune
- Department of HepatologyBristol Royal InfirmaryBristolUnited Kingdom
| | - Stephen D. Ryder
- NIHR Biomedical Research Unit in Gastrointestinal and Liver Diseases at Nottingham University Hospitals National Health Service Trust and The University of NottinghamNottinghamUnited Kingdom
| | - Roger W. Chapman
- Translational Gastroenterology UnitJohn Radcliffe HospitalOxfordUnited Kingdom
| | - Annarosa Floreani
- Department of Surgery, Oncology and GastroenterologyUniversity of PaduaPaduaItaly
| | - David E. Jones
- NIHR Newcastle Biomedical Research Centre and the Institute of Cellular MedicineNewcastle UniversityNewcastle upon TyneUnited Kingdom
| | | | - David H. Adams
- Centre for Liver ResearchUniversity of BirminghamBirminghamUnited Kingdom
- National Institute for Health Research (NIHR) Biomedical Research CentreBirminghamUnited Kingdom
| | - Pietro Invernizzi
- Division of Gastroenterology and Program for Autoimmune Liver Diseases, International Center for Digestive Health, Department of Medicine and SurgeryUniversity of Milan‐BicoccaMilanItaly
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The immunobiology of mucosal-associated invariant T cell (MAIT) function in primary biliary cholangitis: Regulation by cholic acid-induced Interleukin-7. J Autoimmun 2018; 90:64-75. [PMID: 29429758 DOI: 10.1016/j.jaut.2018.01.007] [Citation(s) in RCA: 44] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2017] [Revised: 01/27/2018] [Accepted: 01/30/2018] [Indexed: 12/11/2022]
Abstract
Mucosal-associated invariant T (MAIT) cells are novel innate-like T cells constituting a significant proportion of circulating and hepatic T cells. Herein, we extensively examine the phenotypical and functional alterations of MAIT cells and their regulation in a cohort of 56 patients with Primary Biliary Cholangitis (PBC) and 53 healthy controls (HC). Additionally alterations of MAIT cells were assessed before and after UDCA treatment. Finally the localization of MAIT cell in liver was examined using specific tetramer staining and the underlying mechanisms of these alterations in PBC were explored. Our data demonstrated that the frequency and number of circulating MAIT cells were decreased, whereas hepatic MAIT cells were increased in PBC compared to HC. Moreover, circulating MAIT cells were more activated in PBC than HC, reflected by elevated expression levels of granzyme B. Six months of UDCA treatment significantly attenuated the circulating MAIT cells differences in PBC. Of note, the expression levels of IL-7 were significantly increased in both plasma and liver from PBC as compared to HC, which promoted the production of inflammatory cytokines and granzyme B by inducing signal transduction and activation of transcription 5 (STAT5) phosphorylation in MAIT cells. Finally, cholic acid, one of the major bile acids in liver, upregulated IL-7 expression in hepatocyte cell line L02 by inducing Farnesoid X Receptor (FXR) binding to the IL-7 promoter. Hence MAIT cells are activated and enriched in the liver of PBC. Cholic acid-induced IL-7 production in hepatocytes plays a critical role in regulating MAIT cell function, highlighting that hepatocytes may bridge cholangiocyte injury and innate immunity through a bile acid signaling pathway.
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Genetics and epigenetics in the pathogenesis of primary biliary cholangitis. Clin J Gastroenterol 2017; 11:11-18. [PMID: 29159718 DOI: 10.1007/s12328-017-0799-z] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2017] [Accepted: 11/05/2017] [Indexed: 02/07/2023]
Abstract
Primary biliary cholangitis (PBC) is a chronic, slowly progressive cholestatic autoimmune liver disease predominantly afflicting women. PBC is characterized by the presence of disease-specific antimitochondrial antibodies and the histological destruction of intrahepatic bile ducts, which eventually lead to cirrhosis and hepatic failure. Fortunately, ursodeoxycholic acid therapy has improved the outcome of the vast majority of PBC cases. Although the etiology of PBC has not yet been elucidated, human leukocyte antigen (HLA) class II alleles have been consistently associated with disease onset for decades. PBC patients may also have genetically determined risk factors in non-HLA regions. Meanwhile, exposure to environmental factors, such as infectious diseases and harmful chemicals, can produce epigenetic alterations in some individuals and subsequent PBC onset. In this review, we describe the influence of HLA alleles and other gene polymorphisms on PBC along with the results of genome-wide association studies on this disease and its future prospects in terms of epigenetics.
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Terziroli Beretta-Piccoli B, Invernizzi P, Gershwin ME, Mainetti C. Skin Manifestations Associated with Autoimmune Liver Diseases: a Systematic Review. Clin Rev Allergy Immunol 2017; 53:394-412. [DOI: 10.1007/s12016-017-8649-9] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
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Fan X, Wang T, Shen Y, Xi X, Yang L. Underestimated Male Prevalence of Primary Biliary Cholangitis in China: Results of a 16-yr cohort study involving 769 patients. Sci Rep 2017; 7:6560. [PMID: 28747696 PMCID: PMC5529550 DOI: 10.1038/s41598-017-06807-7] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2017] [Accepted: 06/16/2017] [Indexed: 02/05/2023] Open
Abstract
For primary biliary cholangitis (PBC), a sex ratio was reported to be significantly lower than previously cited in the West; we sought to evaluate sex ratio and long-term outcomes in PBC by studying a PBC cohort at a high-volume hospital from January 2001 to July 2016. A retrospective analysis including 769 PBC patients was conducted. The gender ratio was 6.1:1. Of the patients, 30.6% had one or more extrahepatic autoimmune (EHA) conditions. The proportion of patients with decompensated PBC at diagnosis increased from 25.0% in period 1 to 47.0% in period 4 (p < 0.05). Of the 420 patients without complications on presentation, the Kaplan-Meier estimate revealed distinct outcomes between non-cirrhotic PBC and cirrhotic PBC, with estimated mean survival times of 145.1 months and 104.5 months, respectively (p < 0.001). According to a subgroup analysis, gender and anti-mitochondrial antibody (AMA) status did not affect long-term prognosis, whereas patients with EHA conditions showed better prognoses. This study reveals evolving trends in male prevalence similar to their Western counterparts. Cirrhotic PBC patients were distinct from those with non-cirrhotic PBC at diagnosis based on difference in long-term outcome.
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Affiliation(s)
- Xiaoli Fan
- Division of Gastroenterology & Hepatology, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Tingting Wang
- Division of Gastroenterology & Hepatology, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Yi Shen
- Division of Gastroenterology & Hepatology, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Xiaotan Xi
- Division of Gastroenterology & Hepatology, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Li Yang
- Division of Gastroenterology & Hepatology, West China Hospital, Sichuan University, Chengdu, 610041, China.
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[Chronic cholestatic liver diseases : Differential diagnosis, pathogenesis and current treatment in adults]. Internist (Berl) 2017; 58:805-825. [PMID: 28721532 DOI: 10.1007/s00108-017-0287-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
In the long-term course chronic cholestasis regularly leads to fibrotic restructuring and ultimately to functional failure of the liver, independent of the cause. Cholestatic diseases are often clinically asymptomatic. In order to avoid progression, early diagnosis of the underlying disease and a targeted therapy are therefore decisive. The differential diagnoses of chronic cholestasis are broad; therefore, algorithms are of assistance in the diagnostic work-up. A better understanding of the pathogenesis is now leading to the development of new therapeutic agents in addition to ursodeoxycholic acid, which has long been known for its anticholestatic effects. Obeticholic acid and, in the near future, bezafibrate are therapeutic options. The possibilities for genetic diagnostics of unclear cholestasis syndromes improve the understanding of the pathogenesis of many diseases and are being introduced increasingly earlier into the clinical routine.
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