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Mol B, Werner E, Culver EL, van der Meer AJ, Bogaards JA, Ponsioen CY. Epidemiological and economical burden of cholestatic liver disease. Hepatology 2025:01515467-990000000-01224. [PMID: 40168457 DOI: 10.1097/hep.0000000000001341] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/02/2025] [Accepted: 03/24/2025] [Indexed: 04/03/2025]
Abstract
The main cholestatic liver diseases comprise primary sclerosing cholangitis, primary biliary cholangitis, and IgG4-related cholangitis. Despite being classified as rare diseases, these are becoming gradually more important in the field of hepatology since their incidence is slowly rising while the viral hepatitis burden is declining. Cholestatic liver diseases now rank among the 3 most frequent indications for liver transplantation in many Western countries. An accurate understanding of the epidemiology and burden of disease on both the individual and society of cholestatic diseases is of great importance. This review aims to provide a comprehensive overview of the current literature on the epidemiology, health-related quality of life, and economic burden of primary sclerosing cholangitis, primary biliary cholangitis, and IgG4-related cholangitis.
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Affiliation(s)
- Bregje Mol
- Department of Gastroenterology and Hepatology, Amsterdam University Medical Centre, Amsterdam, The Netherlands
- Endocrinology and Metabolism, Amsterdam Institute of Gastroenterology, Amsterdam, The Netherlands
| | - Ellen Werner
- Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center Rotterdam, The Netherlands
| | - Emma L Culver
- Oxford Liver Unit, John Radcliffe Hospital, Oxford, UK
| | - Adriaan J van der Meer
- Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center Rotterdam, The Netherlands
| | - Johannes A Bogaards
- Department of Epidemiology and Data Science, Amsterdam University Medical Centre, Amsterdam, The Netherlands
| | - Cyriel Y Ponsioen
- Department of Gastroenterology and Hepatology, Amsterdam University Medical Centre, Amsterdam, The Netherlands
- Endocrinology and Metabolism, Amsterdam Institute of Gastroenterology, Amsterdam, The Netherlands
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Burra P, Zanetto A, Schnabl B, Reiberger T, Montano-Loza AJ, Asselta R, Karlsen TH, Tacke F. Hepatic immune regulation and sex disparities. Nat Rev Gastroenterol Hepatol 2024; 21:869-884. [PMID: 39237606 DOI: 10.1038/s41575-024-00974-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/25/2024] [Indexed: 09/07/2024]
Abstract
Chronic liver disease is a major cause of morbidity and mortality worldwide. Epidemiology, clinical phenotype and response to therapies for gastrointestinal and liver diseases are commonly different between women and men due to sex-specific hormonal, genetic and immune-related factors. The hepatic immune system has unique regulatory functions that promote the induction of intrahepatic tolerance, which is key for maintaining liver health and homeostasis. In liver diseases, hepatic immune alterations are increasingly recognized as a main cofactor responsible for the development and progression of chronic liver injury and fibrosis. In this Review, we discuss the basic mechanisms of sex disparity in hepatic immune regulation and how these mechanisms influence and modify the development of autoimmune liver diseases, genetic liver diseases, portal hypertension and inflammation in chronic liver disease. Alterations in gut microbiota and their crosstalk with the hepatic immune system might affect the progression of liver disease in a sex-specific manner, creating potential opportunities for novel diagnostic and therapeutic approaches to be evaluated in clinical trials. Finally, we identify and propose areas for future basic, translational and clinical research that will advance our understanding of sex disparities in hepatic immunity and liver disease.
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Affiliation(s)
- Patrizia Burra
- Gastroenterology and Multivisceral Transplant Unit, Department of Surgery, Oncology, and Gastroenterology, Padua University Hospital, Padua, Italy.
| | - Alberto Zanetto
- Gastroenterology and Multivisceral Transplant Unit, Department of Surgery, Oncology, and Gastroenterology, Padua University Hospital, Padua, Italy
| | - Bernd Schnabl
- Department of Medicine, University of California San Diego, La Jolla, CA, USA
- Department of Medicine, VA San Diego Healthcare System, San Diego, CA, USA
| | - Thomas Reiberger
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Aldo J Montano-Loza
- Division of Gastroenterology and Liver Unit, Department of Medicine, University of Alberta Hospital, Edmonton, Alberta, Canada
| | - Rosanna Asselta
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy
- IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
| | - Tom Hemming Karlsen
- Department of Transplantation Medicine, Clinic of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital and University of Oslo, Oslo, Norway
- Research Institute of Internal Medicine, Clinic of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital and University of Oslo, Oslo, Norway
| | - Frank Tacke
- Department of Hepatology and Gastroenterology, Charité - Universitätsmedizin Berlin, Campus Virchow-Klinikum (CVK) and Campus Charité Mitte (CCM), Berlin, Germany
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Levy C, Bowlus CL. Primary biliary cholangitis: Personalizing second-line therapies. Hepatology 2024:01515467-990000000-01086. [PMID: 39707635 DOI: 10.1097/hep.0000000000001166] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2024] [Accepted: 11/04/2024] [Indexed: 12/23/2024]
Abstract
Primary biliary cholangitis (PBC) is an enigmatic, autoimmune disease targeting the small intralobular bile ducts resulting in cholestasis and potentially progression to biliary cirrhosis. Primarily affecting middle-aged women, the diagnosis of PBC is typically straightforward, with most patients presenting with cholestatic liver tests and the highly specific antimitochondrial antibody. For decades, the foundational treatment of PBC has been ursodeoxycholic acid, which delays disease progression in most patients but has no impact on PBC symptoms. Large cohort studies of patients with PBC have established the benefit of maximizing the reduction in serum alkaline phosphatase levels with ursodeoxycholic acid and the need to add second-line agents in patients who do not achieve an adequate response. Advances in the understanding of bile acid physiology have led to the development of new agents that improve cholestasis in patients with PBC and are predicted to reduce the risk of disease progression. Obeticholic acid, the first second-line therapy to be approved for PBC, significantly improves liver biochemistries and has been associated with improved long-term clinical outcomes but is limited by its propensity to induce pruritus. Elafibranor and seladelpar are peroxisome proliferator-activated receptor agonists recently approved for use in patients with PBC, whereas bezafibrate and fenofibrate are available as off-label therapies. They also have shown biochemical improvements among patients with an inadequate response to ursodeoxycholic acid but may improve symptoms of pruritus. Herein, we review the patient features to consider when deciding whether a second-line agent is indicated and which agent to consider for a truly personalized approach to PBC patient care.
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Affiliation(s)
- Cynthia Levy
- Schiff Center for Liver Diseases, University of Miami Miller School of Medicine, Miami, Florida, USA
- Department of Medicine, Division of Digestive Health and Liver Diseases, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - Christopher L Bowlus
- Department of Medicine, Division of Gastroenterology and Hepatology, University of California Davis School of Medicine, Sacramento, California, USA
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Roberts SB, Choi WJ, Worobetz L, Vincent C, Flemming JA, Cheung A, Qumosani K, Swain M, Grbic D, Ko HH, Peltekian KM, Abrahamyan L, Saini M, Tirona K, Aziz B, Lytvyak E, Invernizzi P, Ponsioen CY, Bruns T, Cazzagon N, Lindor K, Dalekos GN, Gatselis NK, Verhelst X, Floreani A, Corpechot C, Mayo MJ, Levy C, Londoño MC, Battezzati PM, Pares A, Nevens F, van der Meer A, Kowdley KV, Trivedi PJ, Lleo A, Thorburn D, Carbone M, Selzner N, Gulamhusein AF, Janssen HLA, Montano-Loza AJ, Mason AL, Hirschfield GM, Hansen BE, the Canadian Network for Autoimmune Liver disease (CaNAL). Loss of biochemical response at any time worsens outcomes in UDCA-treated patients with primary biliary cholangitis. JHEP Rep 2024; 6:101168. [PMID: 39380718 PMCID: PMC11460452 DOI: 10.1016/j.jhepr.2024.101168] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2024] [Revised: 06/28/2024] [Accepted: 07/04/2024] [Indexed: 10/10/2024] Open
Abstract
BACKGROUND & AIMS Biochemical response to ursodeoxycholic acid (UDCA) therapy is associated with good prognosis in people living with primary biliary cholangitis (PBC). Biochemical response is typically assessed early in disease and it is not known what proportion of patients lose previously attained biochemical response, nor whether this impacts long-term liver transplant (LT)-free survival. METHODS We identified all UDCA-treated patients with PBC from the Canadian Network for Autoimmune Liver disease with biochemical measurements at 1 year, and evaluated their liver biochemistry over time. Inadequate biochemical response was defined as serum alkaline phosphatase ≥1.67x the upper limit of normal or abnormal serum total bilirubin at 1 year of UDCA therapy and all time points thereafter. Multistate Markov models were used to estimate transition rates between biochemical response states and from each state to LT or death. Results were validated in an external cohort (GLOBAL PBC registry). RESULTS A total of 823 patients from eight centers were included. Mean age at diagnosis was 53 years, 91% were female, 33% had inadequate biochemical response to UDCA at 1 year (n = 269). Patients who retained initial adequate response had lower rates of LT or death compared to patients who subsequently lost response (relative rate 0.102, 95% CI 0.047-0.223). Patients who regained adequate response had lower rates than patients who did not (0.016, 95% CI 0.001-0.568), and patients who lost response once more (0.010, 95% CI 0.001-0.340). Patients who regained adequate response for a third time also had lower rates than patients who did not (0.151, 95% CI 0.040-0.566). Analyses in the GLOBAL PBC registry (n = 2,237) validated these results. CONCLUSION Loss of biochemical response at any time is associated with heightened risks of LT or death in people living with PBC. Achievement of biochemical response is an important goal throughout follow-up, regardless of biochemical response profile early in therapy. IMPACT AND IMPLICATIONS Early biochemical response to ursodeoxycholic acid is associated with good prognosis in patients with primary biliary cholangitis (PBC). Our work demonstrates that patients with PBC transition between biochemical response states over time, and that these transitions correspond with changes in risk of liver transplantation or death. Clinicians should re-evaluate risk and optimize treatment decisions for patients with PBC throughout follow-up, regardless of early biochemical response to therapy.
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Affiliation(s)
- Surain B. Roberts
- Toronto Centre for Liver Disease, Toronto General Hospital, University Health Network, Toronto, Canada
- Li Ka Shing Knowledge Institute, St Michael’s Hospital, Unity Health Toronto, Toronto, Canada
- Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Canada
| | - Woo Jin Choi
- Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Canada
| | - Lawrence Worobetz
- Department of Medicine, University of Saskatchewan, Saskatoon, Canada
| | | | | | - Angela Cheung
- Department of Medicine, University of Ottawa, Ottawa, Canada
| | - Karim Qumosani
- Department of Medicine, Western University, London, Canada
| | - Mark Swain
- Department of Medicine, University of Calgary, Calgary, Canada
| | - Dusanka Grbic
- Départment de Médecine, Université de Sherbrooke, Sherbrooke, Canada
| | - Hin Hin Ko
- Department of Medicine, University of British Columbia, Vancouver, Canada
| | | | - Lusine Abrahamyan
- Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Canada
- Royal Free London National Health Service Foundation Trust, London, United Kingdom
| | - Monika Saini
- Toronto Centre for Liver Disease, Toronto General Hospital, University Health Network, Toronto, Canada
| | - Kattleya Tirona
- Toronto Centre for Liver Disease, Toronto General Hospital, University Health Network, Toronto, Canada
| | - Bishoi Aziz
- Department of Medicine, University of Alberta, Edmonton, Canada
| | - Ellina Lytvyak
- Department of Medicine, University of Alberta, Edmonton, Canada
| | - Pietro Invernizzi
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy
- Division of Gastroenterology, Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
| | - Cyriel Y. Ponsioen
- Faculty of Medicine, University of Amsterdam, Amsterdam, the Netherlands
| | - Tony Bruns
- Department of Gastroenterology and Hepatology, University Hospital Rheinisch-Westfälische Technische Hochschule Aachen University, Aachen, Germany
| | | | | | - George N. Dalekos
- European Reference Network on Hepatological Diseases, Barcelona, Spain
| | - Nikolaos K. Gatselis
- Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, Larissa, Greece
| | - Xavier Verhelst
- Department of Hepatology, Ghent University Hospital, Ghent, Belgium
| | - Annarosa Floreani
- University of Padova, Padova, Italy
- Scientific Institute for Research, Hospitalization and Healthcare, Negrar, Verona, Italy
| | - Christophe Corpechot
- Reference center for inflammatory biliary diseases and autoimmune hepatitis, French network for rare liver diseases FILFOIE, European reference network RARE-LIVER, Saint-Antoine University Hospital, APHP & Sorbonne University, Paris, France
| | - Marlyn J. Mayo
- Department of Medicine, Division of Digestive and Liver Disease, University of Texas, Southwestern Medical Center, Dallas, Texas, USA
| | - Cynthia Levy
- Schiff Center for Liver Diseases, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Maria-Carlota Londoño
- Liver Unit, Hospital Clinic Barcelona, Fundació de Recerca Clínic Barcelona-Institut d’Investigació Pi i Sunyer (FRCB-IDIBAPS), CIBEREHD, European Reference Network on Hepatological Rare Diseases (ERN-Liver), University of Barcelona, Barcelona, Spain
| | | | - Albert Pares
- Department of Medicine, 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; European Reference Network on Hepatological Diseases, Barcelona, Spain
| | - Frederik Nevens
- University Hospital Katholieke Universiteit Leuven, Leuven, Belgium
| | - Adriaan van der Meer
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam, Rotterdam, the Netherlands
| | | | - Palak J. Trivedi
- Liver Unit, University Hospitals Birmingham National Health Service Foundation Trust Queen Elizabeth, Birmingham, UK
- National Institute for Health and Care Research (NIHR) Birmingham Liver Biomedical Research Centre, University of Birmingham, College of Medical and Dental Sciences, Birmingham, Birmingham, UK
- Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK
- Institute of Applied Health Research, University of Birmingham, Birmingham, UK
| | - Ana Lleo
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy; IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
| | - Douglas Thorburn
- Royal Free London National Health Service Foundation Trust, London, United Kingdom
| | - Marco Carbone
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy
- Division of Gastroenterology, Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
| | - Nazia Selzner
- Toronto General Hospital Research Institute, University Health Network, Toronto, Canada
| | - Aliya F. Gulamhusein
- Toronto Centre for Liver Disease, Toronto General Hospital, University Health Network, Toronto, Canada
- Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Canada
| | - Harry LA. Janssen
- Toronto Centre for Liver Disease, Toronto General Hospital, University Health Network, Toronto, Canada
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam, Rotterdam, the Netherlands
| | | | - Andrew L. Mason
- Department of Medicine, University of Alberta, Edmonton, Canada
| | - Gideon M. Hirschfield
- Toronto Centre for Liver Disease, Toronto General Hospital, University Health Network, Toronto, Canada
- Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Canada
| | - Bettina E. Hansen
- Toronto Centre for Liver Disease, Toronto General Hospital, University Health Network, Toronto, Canada
- Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Canada
- Department of Epidemiology & Biostatistics, Erasmus MC, Rotterdam, the Netherlands
| | - the Canadian Network for Autoimmune Liver disease (CaNAL)
- Toronto Centre for Liver Disease, Toronto General Hospital, University Health Network, Toronto, Canada
- Li Ka Shing Knowledge Institute, St Michael’s Hospital, Unity Health Toronto, Toronto, Canada
- Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Canada
- Department of Medicine, University of Saskatchewan, Saskatoon, Canada
- Département de Médecine, Université de Montréal, Montréal, Canada
- Department of Medicine, Queen’s University, Kingston, Canada
- Department of Medicine, University of Ottawa, Ottawa, Canada
- Department of Medicine, Western University, London, Canada
- Department of Medicine, University of Calgary, Calgary, Canada
- Départment de Médecine, Université de Sherbrooke, Sherbrooke, Canada
- Department of Medicine, University of British Columbia, Vancouver, Canada
- Department of Medicine, Dalhousie University, Halifax, Canada
- Department of Medicine, University of Alberta, Edmonton, Canada
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy
- Faculty of Medicine, University of Amsterdam, Amsterdam, the Netherlands
- Department of Gastroenterology and Hepatology, University Hospital Rheinisch-Westfälische Technische Hochschule Aachen University, Aachen, Germany
- University of Padova, Padova, Italy
- Mayo Clinic, Scottsdale, Arizona, USA
- European Reference Network on Hepatological Diseases, Barcelona, Spain
- Department of Hepatology, Ghent University Hospital, Ghent, Belgium
- Reference center for inflammatory biliary diseases and autoimmune hepatitis, French network for rare liver diseases FILFOIE, European reference network RARE-LIVER, Saint-Antoine University Hospital, APHP & Sorbonne University, Paris, France
- Department of Medicine, Division of Digestive and Liver Disease, University of Texas, Southwestern Medical Center, Dallas, Texas, USA
- Schiff Center for Liver Diseases, University of Miami Miller School of Medicine, Miami, FL, USA
- Liver Unit, Hospital Clinic Barcelona, Fundació de Recerca Clínic Barcelona-Institut d’Investigació Pi i Sunyer (FRCB-IDIBAPS), CIBEREHD, European Reference Network on Hepatological Rare Diseases (ERN-Liver), University of Barcelona, Barcelona, Spain
- Università degli Studi di Milano, Milan, Italy
- Department of Medicine, 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; European Reference Network on Hepatological Diseases, Barcelona, Spain
- University Hospital Katholieke Universiteit Leuven, Leuven, Belgium
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam, Rotterdam, the Netherlands
- Liver Institute Northwest, Seattle, Washington, USA
- Liver Unit, University Hospitals Birmingham National Health Service Foundation Trust Queen Elizabeth, Birmingham, UK
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy; IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
- Royal Free London National Health Service Foundation Trust, London, United Kingdom
- Division of Gastroenterology, Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
- Toronto General Hospital Research Institute, University Health Network, Toronto, Canada
- Department of Epidemiology & Biostatistics, Erasmus MC, Rotterdam, the Netherlands
- National Institute for Health and Care Research (NIHR) Birmingham Liver Biomedical Research Centre, University of Birmingham, College of Medical and Dental Sciences, Birmingham, Birmingham, UK
- Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK
- Institute of Applied Health Research, University of Birmingham, Birmingham, UK
- Scientific Institute for Research, Hospitalization and Healthcare, Negrar, Verona, Italy
- Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, Larissa, Greece
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Marenco-Flores A, Rojas Amaris N, Kahan T, Sierra L, Barba Bernal R, Medina-Morales E, Goyes D, Patwardhan V, Bonder A. The External Validation of GLOBE and UK-PBC Risk Scores for Predicting Ursodeoxycholic Acid Treatment Response in a Large U.S. Cohort of Primary Biliary Cholangitis Patients. J Clin Med 2024; 13:4497. [PMID: 39124763 PMCID: PMC11312962 DOI: 10.3390/jcm13154497] [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: 07/10/2024] [Revised: 07/29/2024] [Accepted: 07/30/2024] [Indexed: 08/12/2024] Open
Abstract
Background: The cornerstone treatment for primary biliary cholangitis (PBC) is ursodeoxycholic acid (UDCA), but many patients exhibit an incomplete response, leading to disease progression. Risk prediction models like the GLOBE and UK-PBC scores hold promise for patient stratification and management. We aimed to independently assess the predictive accuracy of these risk scores for UDCA response in a prospective U.S. cohort. Methods: We conducted a prospective cohort study at a U.S. liver center, monitoring UDCA-treated PBC patients over a one-year follow-up. We evaluated the predictive efficacy of the GLOBE and UK-PBC scores for UDCA treatment response, comparing them to the Paris II criteria. Efficacy was assessed using univariate and multivariate analyses, followed by prognostic performance evaluation via receiver operating characteristic (ROC) curve analysis. Results: We evaluated 136 PBC patients undergoing UDCA therapy. Based on the Paris II criteria, patients were categorized into UDCA full-response and non-response groups. The GLOBE score identified a non-responder rate of 18% (p = 0.205), compared to 20% (p = 0.014) with the Paris II criteria. Multivariate analysis, adjusted for age and biochemical markers, showed that both the GLOBE and UK-PBC scores were strongly associated with treatment response (p < 0.001). The area under the ROC curve was 0.87 (95% CI 0.83-0.95) for the GLOBE score and 0.94 (95% CI 0.86-0.99) for the UK-PBC risk score. Conclusions: Our study demonstrates that GLOBE and UK-PBC scores effectively predict UDCA treatment response in PBC patients. The early identification of patients at risk of an incomplete response could improve treatment strategies and identify patients who may need second-line therapies.
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Affiliation(s)
- Ana Marenco-Flores
- Division of Gastroenterology, Hepatology, and Nutrition, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; (A.M.-F.); (N.R.A.); (V.P.)
| | - Natalia Rojas Amaris
- Division of Gastroenterology, Hepatology, and Nutrition, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; (A.M.-F.); (N.R.A.); (V.P.)
| | - Tamara Kahan
- Division of Gastroenterology, Hepatology, and Nutrition, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; (A.M.-F.); (N.R.A.); (V.P.)
| | - Leandro Sierra
- Division of Gastroenterology, Hepatology, and Nutrition, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; (A.M.-F.); (N.R.A.); (V.P.)
| | - Romelia Barba Bernal
- Department of Internal Medicine, Texas Tech University System, Lubbock, TX 79430, USA
| | - Esli Medina-Morales
- Department of Medicine, Rutgers New Jersey Medical School, Newark, NJ 07103, USA
| | - Daniela Goyes
- Division of Digestive Diseases, Yale School of Medicine, New Haven, CT 06520, USA
| | - Vilas Patwardhan
- Division of Gastroenterology, Hepatology, and Nutrition, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; (A.M.-F.); (N.R.A.); (V.P.)
| | - Alan Bonder
- Division of Gastroenterology, Hepatology, and Nutrition, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; (A.M.-F.); (N.R.A.); (V.P.)
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Sun D, Xie C, Zhao Y, Liao J, Li S, Zhang Y, Wang D, Hua K, Gu Y, Du J, Huang G, Huang J. The gut microbiota-bile acid axis in cholestatic liver disease. Mol Med 2024; 30:104. [PMID: 39030473 PMCID: PMC11265038 DOI: 10.1186/s10020-024-00830-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2024] [Accepted: 05/07/2024] [Indexed: 07/21/2024] Open
Abstract
Cholestatic liver diseases (CLD) are characterized by impaired normal bile flow, culminating in excessive accumulation of toxic bile acids. The majority of patients with CLD ultimately progress to liver cirrhosis and hepatic failure, necessitating liver transplantation due to the lack of effective treatment. Recent investigations have underscored the pivotal role of the gut microbiota-bile acid axis in the progression of hepatic fibrosis via various pathways. The obstruction of bile drainage can induce gut microbiota dysbiosis and disrupt the intestinal mucosal barrier, leading to bacteria translocation. The microbial translocation activates the immune response and promotes liver fibrosis progression. The identification of therapeutic targets for modulating the gut microbiota-bile acid axis represents a promising strategy to ameliorate or perhaps reverse liver fibrosis in CLD. This review focuses on the mechanisms in the gut microbiota-bile acids axis in CLD and highlights potential therapeutic targets, aiming to lay a foundation for innovative treatment approaches.
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Affiliation(s)
- Dayan Sun
- Department of Neonatal Surgery, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, No. 56 Nalishi Road, Xicheng District, Beijing, 100045, China
| | - Chuanping Xie
- Department of Neonatal Surgery, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, No. 56 Nalishi Road, Xicheng District, Beijing, 100045, China
| | - Yong Zhao
- Department of Neonatal Surgery, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, No. 56 Nalishi Road, Xicheng District, Beijing, 100045, China
| | - Junmin Liao
- Department of Neonatal Surgery, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, No. 56 Nalishi Road, Xicheng District, Beijing, 100045, China
| | - Shuangshuang Li
- Department of Neonatal Surgery, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, No. 56 Nalishi Road, Xicheng District, Beijing, 100045, China
| | - Yanan Zhang
- Department of Neonatal Surgery, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, No. 56 Nalishi Road, Xicheng District, Beijing, 100045, China
| | - Dingding Wang
- Department of Neonatal Surgery, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, No. 56 Nalishi Road, Xicheng District, Beijing, 100045, China
| | - Kaiyun Hua
- Department of Neonatal Surgery, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, No. 56 Nalishi Road, Xicheng District, Beijing, 100045, China
| | - Yichao Gu
- Department of Neonatal Surgery, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, No. 56 Nalishi Road, Xicheng District, Beijing, 100045, China
| | - Jingbin Du
- Department of Neonatal Surgery, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, No. 56 Nalishi Road, Xicheng District, Beijing, 100045, China
| | - Guoxian Huang
- Department of Pediatric Surgery, Women and Children's Hospital, School of Medicine, Xiamen University, Xiamen, Fujian, 361000, China
| | - Jinshi Huang
- Department of Neonatal Surgery, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, No. 56 Nalishi Road, Xicheng District, Beijing, 100045, China.
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van Hooff MC, Werner E, van der Meer AJ. Treatment in primary biliary cholangitis: Beyond ursodeoxycholic acid. Eur J Intern Med 2024; 124:14-21. [PMID: 38307734 DOI: 10.1016/j.ejim.2024.01.030] [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: 10/10/2023] [Revised: 01/17/2024] [Accepted: 01/19/2024] [Indexed: 02/04/2024]
Abstract
Primary biliary cholangitis (PBC) is a rare cholestatic immune-mediated liver disease. The clinical course varies from mild to severe, with a substantial group of patients developing cirrhosis within a decade. These patients are at risk of hepatocellular carcinoma, decompensation and liver failure. First line Ursodeoxycholic acid (UDCA) treatment improves the cholestatic surrogate markers, and was recently associated with a favorable survival free of liver transplantation, even in case of an incomplete biochemical response. However, despite adequate UDCA therapy, patients remain at risk of liver disease progression. Therefore, on-treatment multifactor-based risk stratification is necessary to identify patients in need of additional therapy. This requires a personalized approach; especially as recent studies suggest that complete biochemical normalization as most stringent response criterion might be preferred in selected patients to optimize their outcome. Today, stricter biochemical goals might actually be reachable with the addition of farnesoid X receptor or peroxisome proliferator-activated receptor agonists, or, in highly-selected cases, use of corticosteroids. Randomized controlled trials showed improvements in the key biochemical surrogate markers with the addition of these drugs, which have also been associated with improved clinical outcome. Considering this evolving PBC landscape, with more versatile treatment options and treatment goals, this review recapitulates the recent insight in UDCA therapy, the selection of patients with a residual risk of liver disease progression and the results of the currently available second line treatment options.
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Affiliation(s)
- M C van Hooff
- Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center Rotterdam, Doctor Molewaterplein 40, NA building, Floor 6, Rotterdam 3015 GD, the Netherlands
| | - E Werner
- Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center Rotterdam, Doctor Molewaterplein 40, NA building, Floor 6, Rotterdam 3015 GD, the Netherlands
| | - A J van der Meer
- Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center Rotterdam, Doctor Molewaterplein 40, NA building, Floor 6, Rotterdam 3015 GD, the Netherlands.
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Cançado GGL, Gomes NMDF, Couto CA, Cançado ELR, Terrabuio DRB, Villela-Nogueira CA, Braga MH, Nardelli MJ, Faria LC, Oliveira EMG, Rotman V, Oliveira MB, Cunha SMCFD, Mazo DFDC, Mendes LSC, Ivantes CAP, Codes L, Borges VFDAE, Pace FHDL, Pessôa MG, Signorelli IV, Coral GP, Bittencourt PL, Fucuta P, Filho RJDC, Ferraz MLG. A new and simple score to predict adequate and deep response to ursodeoxycholic acid in patients with primary biliary cholangitis: the ALP-A score. Eur J Gastroenterol Hepatol 2024; 36:628-635. [PMID: 38555601 DOI: 10.1097/meg.0000000000002744] [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: 04/02/2024]
Abstract
BACKGROUND Ursodeoxycholic acid (UDCA) is the standard treatment for primary biliary cholangitis (PBC), but a significant proportion of patients do not respond adequately, leading to increased risk of adverse outcomes. This study aims to develop a new and straightforward predictive score to identify PBC patients likely to achieve a complete response to UDCA. METHODS A logistic regression analysis was conducted using a derivation cohort of PBC patients to identify pre-treatment variables associated with response to UDCA. This analysis led to the development of the ALP-A score, calculated as: Age at diagnosis divided by (alkaline phosphatase at diagnosis/upper limit of normal). ALP-A score accuracy was evaluated using the area under the ROC curve, validated with a large external cohort from Brazil. Additionally, the correlation between the ALP-A score and the previously validated UDCA response score (URS) was assessed. RESULTS ALP-A score had good predictive power for adequate (AUC 0.794; 95% CI, 0.737-0.852) and deep (0.76; 95% CI, 0.69-0.83) UDCA response at 1 year of treatment. A cutoff score of 17 and 23 points was determined to be the optimal threshold for distinguishing adequate and deep responders, respectively, from non-responders. ALP-A score demonstrated a sensitivity of 73%, specificity of 71%, positive predictive value of 65%, negative predictive value of 78%, and overall accuracy of 72% for biochemical response. The URS displayed similar discriminative ability (AUC 0.798; 95% CI, 0.741-0.855). CONCLUSION ALP-A score performs comparably to URS but offers the great advantage of simplicity for routine clinical use. It serves as a valuable tool to identify PBC patients less likely to respond to UDCA treatment, facilitating early consideration of alternative therapeutic approaches.
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Affiliation(s)
- Guilherme Grossi Lopes Cançado
- Instituto Alfa de Gastroenterologia, Hospital das Clínicas da Universidade Federal de Minas Gerais
- Hospital da Polícia Militar de Minas Gerais, Belo Horizonte, Minas Gerais
| | | | - Cláudia Alves Couto
- Instituto Alfa de Gastroenterologia, Hospital das Clínicas da Universidade Federal de Minas Gerais
| | | | | | - Cristiane Alves Villela-Nogueira
- Hospital Universitário Clementino Fraga Filho e Departamento de Clínica Médica da Faculdade de Medicina, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Rio de Janeiro
| | - Michelle Harriz Braga
- Departamento de Gastroenterologia, Faculdade de Medicina da Universidade de São Paulo, São Paulo, São Paulo
| | - Mateus Jorge Nardelli
- Instituto Alfa de Gastroenterologia, Hospital das Clínicas da Universidade Federal de Minas Gerais
| | - Luciana Costa Faria
- Instituto Alfa de Gastroenterologia, Hospital das Clínicas da Universidade Federal de Minas Gerais
| | | | - Vivian Rotman
- Hospital Universitário Clementino Fraga Filho e Departamento de Clínica Médica da Faculdade de Medicina, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Rio de Janeiro
| | - Maria Beatriz Oliveira
- Ambulatório Municipal de Hepatites Virais de São José dos Campos, São José dos Campos, São Paulo
| | | | - Daniel Ferraz de Campos Mazo
- Divisão de Gastroenterologia (Gastrocentro), Faculdade de Ciências Médicas, Universidade Estadual de Campinas, Campinas, São Paulo
| | | | | | - Liana Codes
- Escola Bahiana de Medicina e Saúde Pública
- Hospital Português, Salvador, Bahia
| | | | - Fabio Heleno de Lima Pace
- Serviço de Gastroenterologia e Hepatologia, Universidade Federal de Juiz de Fora, Juiz de Fora, Minas Gerais
| | - Mário Guimarães Pessôa
- Departamento de Gastroenterologia, Faculdade de Medicina da Universidade de São Paulo, São Paulo, São Paulo
| | | | - Gabriela Perdomo Coral
- Irmandade da Santa Casa de Misericórdia de Porto Alegre, Porto Alegre, Rio Grande do Sul, Brazil
| | | | - Patrícia Fucuta
- Disciplina de Gastroenterologia, Universidade Federal de São Paulo
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Feng SL, Li JY, Dong CL. Primary biliary cholangitis presenting with granulomatous lung disease misdiagnosed as lung cancer: A case report. World J Clin Cases 2024; 12:354-360. [PMID: 38313637 PMCID: PMC10835678 DOI: 10.12998/wjcc.v12.i2.354] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2023] [Revised: 12/06/2023] [Accepted: 12/25/2023] [Indexed: 01/11/2024] Open
Abstract
BACKGROUND There are few cases of pulmonary granulomatous changes secondary to primary biliary cirrhosis (PBC). No case of granulomatous lung disease secondary to PBC misdiagnosed as lung cancer had been reported. CASE SUMMARY A middle-aged woman presented with lung nodules and was misdiagnosed with lung cancer by positron emission tomography/computed tomography. She underwent left lobectomy, and the pathology of the nodules showed granulomatous inflammation, which was then treated with antibiotics. However, a new nodule appeared. Further investigation with lung biopsy and liver serology led to the diagnosis of PBC, and chest computed tomography indicated significant reduction in the pulmonary nodule by treatment with methylprednisolone and ursodeoxycholic acid. CONCLUSION Diagnosis of pulmonary nodules requires integrating various clinical data to avoid unnecessary pulmonary lobectomy.
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Affiliation(s)
- Shan-Li Feng
- Department of Respiratory and Critical Care Medicine, The Second Hospital of Jilin University, Changchun 130041, Jilin Province, China
| | - Jun-Yao Li
- Department of Respiratory and Critical Care Medicine, The Second Hospital of Jilin University, Changchun 130041, Jilin Province, China
| | - Chun-Ling Dong
- Department of Respiratory and Critical Care Medicine, The Second Hospital of Jilin University, Changchun 130041, Jilin Province, China
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Kimura N, Takahashi K, Setsu T, Horibata Y, Kaneko Y, Miyazaki H, Ogawa K, Kawata Y, Sakai N, Watanabe Y, Abe H, Kamimura H, Sakamaki A, Yokoo T, Kamimura K, Tsuchiya A, Terai S. Development and validation of machine learning model for predicting treatment responders in patients with primary biliary cholangitis. Hepatol Res 2024; 54:67-77. [PMID: 37691006 DOI: 10.1111/hepr.13966] [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: 05/27/2023] [Revised: 08/24/2023] [Accepted: 08/31/2023] [Indexed: 09/12/2023]
Abstract
AIMS Ursodeoxycholic acid is the first-line treatment for primary biliary cholangitis, and treatment response is one of the factors predicting the outcome. To prescribe alternative therapies, clinicians might need additional information before deciphering the treatment response to ursodeoxycholic acid, contributing to a better patient prognosis. In this study, we developed and validated machine learning (ML) algorithms to predict treatment responses using pretreatment data. METHODS This multicenter cohort study included collecting datasets from two data samples. Data 1 included 245 patients from 18 hospitals for ML development, and was divided into (i) training and (ii) development sets. Data 2 (iii: test set) included 51 patients from our hospital for validation. An extreme gradient boosted tree predicted the treatment response in the ML model. The area under the curve was used to evaluate the efficacy of the algorithm. RESULTS Data 1 showed that patients complying with the Paris II treatment response had significantly lower serum alkaline phosphatase and total bilirubin levels than those who did not respond. Three factors, total bilirubin, total protein, and alanine aminotransferase levels were selected as essential variables for prediction. Data 2 showed that patients complying with the Paris II criteria had significantly high prothrombin time and low total bilirubin levels. The area under the curve of extreme gradient boosted tree was good for (ii) (0.811) and (iii) (0.856). CONCLUSIONS We demonstrated the efficacy of ML in predicting the treatment response for patients with primary biliary cholangitis. Early identification of cases requiring additional treatment with our novel ML model may improve prognosis.
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Affiliation(s)
- Naruhiro Kimura
- Division of Gastroenterology and Hepatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Kazuya Takahashi
- Division of Gastroenterology and Hepatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Toru Setsu
- Division of Gastroenterology and Hepatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Yusuke Horibata
- Division of Gastroenterology and Hepatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Yusuke Kaneko
- Division of Gastroenterology and Hepatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Haruka Miyazaki
- Division of Gastroenterology and Hepatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Kohei Ogawa
- Division of Gastroenterology and Hepatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Yuzo Kawata
- Division of Gastroenterology and Hepatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Norihiro Sakai
- Division of Gastroenterology and Hepatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Yusuke Watanabe
- Division of Gastroenterology and Hepatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Hiroyuki Abe
- Division of Gastroenterology and Hepatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Hiroteru Kamimura
- Division of Gastroenterology and Hepatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Akira Sakamaki
- Division of Gastroenterology and Hepatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Takeshi Yokoo
- Division of Gastroenterology and Hepatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Kenya Kamimura
- Division of Gastroenterology and Hepatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Atsunori Tsuchiya
- Division of Gastroenterology and Hepatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Shuji Terai
- Division of Gastroenterology and Hepatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
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Bowlus CL, Levy C. Optimizing treatment of primary biliary cholangitis: Is good, good enough? Hepatology 2024; 79:3-5. [PMID: 37526603 DOI: 10.1097/hep.0000000000000556] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/20/2023] [Accepted: 07/24/2023] [Indexed: 08/02/2023]
Affiliation(s)
| | - Cynthia Levy
- Schiff Center for Liver Disease and Division of Gastroenterology and Hepatology, University of Miami, Miami, Florida, USA
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12
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Wang YW, Chao HC, Wang HS, Lin JL, Chang CC, Huang SF. Primary biliary cholangitis with features of autoimmune hepatitis in a 19-year-old adolescent with 14q24.1q24.2 deletion: a case report. Front Pediatr 2023; 11:1280409. [PMID: 38152650 PMCID: PMC10751923 DOI: 10.3389/fped.2023.1280409] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2023] [Accepted: 11/24/2023] [Indexed: 12/29/2023] Open
Abstract
Introduction Primary biliary cholangitis (PBC) is a rare and chronic autoimmune liver disease characterized by the progressive destruction of small intrahepatic bile ducts that may eventually lead to cirrhosis. PBC with features of autoimmune hepatitis (AIH) has rarely been reported in pediatric patients with genetic defects. We present the case of an adolescent with chromosome 14q24.1q24.2 deletion who was given the diagnosis of stage IV PBC with features of AIH. Case presentation A 19-year-old male adolescent with multiple congenital abnormalities and an intellectual disability presented with abnormal liver enzymes levels and pruritus for more than 5 years. Laboratory examinations revealed elevated levels of aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, and gamma-glutamyl transpeptidase. After the exclusion of viral hepatitis, alpha-1 antitrypsin deficiency, Wilson's disease, and other genetic cholestatic liver diseases by laboratory tests and whole exome sequencing, a liver biopsy was performed and stage IV PBC was diagnosed. Notably, features of AIH were also noted in the histopathological report, indicating the presence of PBC with AIH features. The patient responded well to a combination therapy of ursodeoxycholic acid and steroids. Array comparative genomic hybridization analysis performed to study the congenital abnormalities revealed a 3.89 Mb 14q24.1q24.2 deletion. Conclusion PBC with AIH features has rarely been reported in an adolescent with a chromosomal abnormality. The present case can increase awareness for early-onset PBC and its possible correlation with chromosomal defects.
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Affiliation(s)
- Yi-Wei Wang
- Division of Pediatric Gastroenterology, Department of Pediatrics, Chang Gung Children’s Medical Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Hsun-Chin Chao
- Division of Pediatric Gastroenterology, Department of Pediatrics, Chang Gung Children’s Medical Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Huei-Shyong Wang
- Division of Pediatric Neurology, Department of Pediatrics, Chang Gung Children’s Medical Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Ju-Li Lin
- Division of Endocrine & Medical Genetics, Department of Pediatrics, Chang Gung Children’s Medical Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Chih-Chen Chang
- Department of Medical Imaging and Intervention, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Shiu-Feng Huang
- Division of Molecular and Genomic Medicine, Department of Pathology, National Health Research Institute, Miaoli, Taiwan
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Cooper KM, Delk M, Devuni D, Sarkar M. Sex differences in chronic liver disease and benign liver lesions. JHEP Rep 2023; 5:100870. [PMID: 37791378 PMCID: PMC10542645 DOI: 10.1016/j.jhepr.2023.100870] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2023] [Revised: 06/23/2023] [Accepted: 07/01/2023] [Indexed: 10/05/2023] Open
Abstract
The epidemiology, natural history, and therapeutic responses of chronic liver diseases and liver lesions often vary by sex. In this review, we summarize available clinical and translational data on these aspects of the most common liver conditions encountered in clinical practice, including the potential contributions of sex hormones to the underlying pathophysiology of observed differences. We also highlight areas of notable knowledge gaps and discuss sex disparities in access to liver transplant and potential strategies to address these barriers. Given established sex differences in immune response, drug metabolism, and response to liver-related therapies, emerging clinical trials and epidemiological studies should prioritize dedicated analyses by sex to inform sex-specific approaches to liver-related care.
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Affiliation(s)
- Katherine M. Cooper
- UMass Chan Medical School, Department of Medicine, Division of Gastroenterology/Hepatology, Worcester, MA, United States
| | - Molly Delk
- University of California San Francisco, Department of Medicine, Division of Gastroenterology/Hepatology, San Francisco, CA, United States
| | - Deepika Devuni
- UMass Chan Medical School, Department of Medicine, Division of Gastroenterology/Hepatology, Worcester, MA, United States
| | - Monika Sarkar
- University of California San Francisco, Department of Medicine, Division of Gastroenterology/Hepatology, San Francisco, CA, United States
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Ismail A, Kennedy L, Francis H. Sex-Dependent Differences in Cholestasis: Why Estrogen Signaling May Be a Key Pathophysiological Driver. THE AMERICAN JOURNAL OF PATHOLOGY 2023; 193:1355-1362. [PMID: 37422150 PMCID: PMC10548272 DOI: 10.1016/j.ajpath.2023.06.010] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Revised: 05/30/2023] [Accepted: 06/15/2023] [Indexed: 07/10/2023]
Abstract
Primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) are cholestatic liver diseases that have significant clinical impact with debilitating symptoms and mortality. While PBC is predominantly seen in perimenopausal and postmenopausal women, men who are diagnosed with PBC have worse clinical outcomes and all-cause mortality. In contrast, 60% to 70% of patients with PSC are men; the data indicate that female sex may be an independent factor against PSC-related complications. These findings suggest a sex-dependent biological basis for these differences. Estrogen has been implicated in the pathogenesis of intrahepatic cholestasis of pregnancy and may induce cholestasis through a variety of interactions. However, it is unclear why some sexual dimorphic features may provide a protective effect despite known estrogen models that induce cholestasis. This article provides a brief introductory background and discusses the sexual dimorphism in clinical presentation in PSC and PBC. It also explores the role of estrogen signaling in pathogenesis and how it relates to intrahepatic cholestasis of pregnancy. Studies have already targeted certain molecules involved in estrogen signaling, and this review discusses these studies that identify estrogen-related receptor, estrogen receptor-α, estrogen receptor-β, farnesoid X receptor, and mast cells as possible targets, in addition to long noncoding RNA H19-induced cholestasis and sexual dimorphism. It also explores these interactions and their role in the pathogenesis of PBC and PSC.
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Affiliation(s)
- AbdiGhani Ismail
- Division of Internal Medicine, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana
| | - Lindsey Kennedy
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana; Department of Research, Richard L. Roudebush VA Medical Center, Indianapolis, Indiana.
| | - Heather Francis
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana; Department of Research, Richard L. Roudebush VA Medical Center, Indianapolis, Indiana.
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Martini F, Balducci D, Mancinelli M, Buzzanca V, Fracchia E, Tarantino G, Benedetti A, Marzioni M, Maroni L. Risk Stratification in Primary Biliary Cholangitis. J Clin Med 2023; 12:5713. [PMID: 37685780 PMCID: PMC10488776 DOI: 10.3390/jcm12175713] [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: 07/10/2023] [Revised: 08/25/2023] [Accepted: 08/30/2023] [Indexed: 09/10/2023] Open
Abstract
Primary Biliary Cholangitis (PBC) is a chronic cholestatic liver disease with a heterogeneous presentation, symptomatology, disease progression, and response to therapy. The current risk stratification assessment, aimed at identifying patients with a higher risk of disease progression, encompasses an in-depth analysis of demographic data, clinical and laboratory findings, antibody profiles, and the evaluation of liver fibrosis using both invasive and noninvasive techniques. Treatment response scores after one year of therapy remain to date a major factor influencing the prognosis of PBC patients. While the initial therapeutic approach with ursodeoxycholic acid (UDCA) is universally applied, new second-line treatment options have recently emerged, with many others under investigation. Consequently, the prevailing one-size-fits-all approach is poised to be supplanted by tailored strategies, ensuring high-risk patients receive the most appropriate treatment regimen from diagnosis. This will require the development of a risk prediction model to assess, at the time of diagnosis, the course, outcome, and response to first and additional treatments of PBC patients. This manuscript provides a comprehensive overview of the current and emerging tools used for risk stratification in PBC and speculates on how these developments might shape the disease landscape in the near future.
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Affiliation(s)
- Francesco Martini
- Clinic of Gastroenterology, Hepatology, and Emergency Digestive Endoscopy, Università Politecnica delle Marche, 60126 Ancona, Italy; (D.B.); (M.M.); (V.B.); (E.F.); (G.T.); (A.B.); (M.M.); (L.M.)
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Kim KA, Choi HY, Ki M, Jang ES, Jeong SH. Epidemiological trends and outcomes of primary biliary cholangitis in South Korea between 2009 and 2019. J Gastroenterol 2023; 58:682-692. [PMID: 37195516 DOI: 10.1007/s00535-023-01999-4] [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: 01/03/2023] [Accepted: 05/03/2023] [Indexed: 05/18/2023]
Abstract
BACKGROUND There are no longitudinal studies on the epidemiology of primary biliary cholangitis (PBC) in Korea. This study aimed to elucidate the temporal trends in the epidemiology and outcomes of PBC in South Korea between 2009 and 2019. METHODS The epidemiology and outcomes of PBC were estimated using data from the Korean National Health Service database. Temporal trends in the PBC incidence and prevalence were analyzed using join-point regression. Transplant-free survival was analyzed according to age, sex, and ursodeoxycholic acid (UDCA) treatment using Kaplan-Meier and Cox regression analyses. RESULTS The age and sex-standardized incidence between 2010 and 2019 (total patients, 4230) was 1.03 per 100,000 per year on average and increased from 0.71 to 1.14 per 100,000 with an annual percent change (APC) of 5.5. The age and sex-standardized prevalence between 2009 and 2019 was 8.21 per 100,000 on average and increased from 4.30 to 12.32 per 100,000 with an APC of 10.9. The increasing trend in prevalence was prominent in males and elderly individuals. Among patients with PBC, 98.2% received UDCA with 77.3% adherence. The 5-year transplant-free overall survival rate was 87.8%. Male sex and low adherence to UDCA were associated with all-cause death or transplantation (hazard ratios of 1.59 and 1.89, respectively), and liver-related death or transplantation (hazard ratios of 1.43 and 1.87, respectively). CONCLUSIONS The incidence and prevalence of PBC in Korea increased significantly between 2009 and 2019. Male sex and low adherence to UDCA were poor prognostic factors for PBC.
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Affiliation(s)
- Kyung-Ah Kim
- Department of Internal Medicine, Inje University Ilsan Paik Hospital, 170 Juhwa-ro, Ilsanseo-gu, Goyang-si, Gyeonggi-do, 10380, Republic of Korea.
| | - Hwa Young Choi
- Department of Cancer Control and Policy, Graduate School of Cancer Science and Policy, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang-si, Gyeonggi-do, 10408, Republic of Korea
| | - Moran Ki
- Department of Cancer Control and Policy, Graduate School of Cancer Science and Policy, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang-si, Gyeonggi-do, 10408, Republic of Korea
| | - Eun Sun Jang
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital, 82 Gumi-ro, 173 Beon-gil, Bundang-gu, Seongnam-si, Gyeonggi-do, 13620, Republic of Korea
| | - Sook-Hyang Jeong
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital, 82 Gumi-ro, 173 Beon-gil, Bundang-gu, Seongnam-si, Gyeonggi-do, 13620, Republic of Korea
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Levy C, Manns M, Hirschfield G. New Treatment Paradigms in Primary Biliary Cholangitis. Clin Gastroenterol Hepatol 2023; 21:2076-2087. [PMID: 36809835 DOI: 10.1016/j.cgh.2023.02.005] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2022] [Revised: 01/28/2023] [Accepted: 02/03/2023] [Indexed: 02/24/2023]
Abstract
Primary biliary cholangitis (PBC) is an archetypal autoimmune disease. Chronic lymphocytic cholangitis is associated with interface hepatitis, ductopenia, cholestasis, and progressive biliary fibrosis. People living with PBC are frequently symptomatic, experiencing a quality-of-life burden dominated by fatigue, itch, abdominal pain, and sicca complex. Although the female predominance, specific serum autoantibodies, immune-mediated cellular injury, as well as genetic (HLA and non-HLA) risk factors, identify PBC as autoimmune, to date treatment has focused on cholestatic consequences. Biliary epithelial homeostasis is abnormal and contributes to disease. The impact of cholangiocyte senescence, apoptosis, and impaired bicarbonate secretion enhances chronic inflammation and bile acid retention. First-line therapy is a non-specific anti-cholestatic agent, ursodeoxycholic acid. For those with residual cholestasis biochemically, obeticholic acid is introduced, and this semisynthetic farnesoid X receptor agonist adds choleretic, anti-fibrotic, and anti-inflammatory activity. Future PBC licensed therapy will likely include peroxisome proliferator activated receptor (PPAR) pathway agonists, including specific PPAR-delta agonism (seladelpar), as well as elafibrinor and saroglitazar (both with broader PPAR agonism). These agents dovetail the clinical and trial experience for off-label bezafibrate and fenofibrate use. Symptom management is essential, and encouragingly, PPAR agonists reduce itch; IBAT inhibition (eg, linerixibat) also appears promising for pruritus. For those where liver fibrosis is the target, NOX inhibition is being evaluated. Earlier stage therapies in development include therapy to impact immunoregulation in patients, as well other approaches to treating pruritus (eg, antagonists of MrgprX4). Collectively the PBC therapeutic landscape is exciting. Therapy goals are increasingly proactive and individualized and aspire to rapidly achieve normal serum tests and quality of life with prevention of end-stage liver disease.
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Affiliation(s)
- Cynthia Levy
- Division of Digestive Health and Liver Diseases, University of Miami School of Medicine, Miami, Florida.
| | | | - Gideon Hirschfield
- Toronto Centre for Liver Disease, Division of Gastroenterology and Hepatology, University of Toronto, Toronto, Canada
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You H, Duan W, Li S, Lv T, Chen S, Lu L, Ma X, Han Y, Nan Y, Xu X, Duan Z, Wei L, Jia J, Zhuang H, Chinese Society of Hepatology, Chinese Medical Association. Guidelines on the Diagnosis and Management of Primary Biliary Cholangitis (2021). J Clin Transl Hepatol 2023; 11:736-746. [PMID: 36969891 PMCID: PMC10037524 DOI: 10.14218/jcth.2022.00347] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2022] [Revised: 11/02/2022] [Accepted: 11/20/2022] [Indexed: 03/29/2023] Open
Abstract
In 2015, the Chinese Society of Hepatology and the Chinese Society of Gastroenterology published a consensus on primary biliary cholangitis (PBC). In the past years, numerous clinical studies have been published in the field of PBC. To guide the clinical diagnosis and management of PBC patients, the Chinese Society of Hepatology invited a panel of experts to assess the new clinical evidence and formulate the current guidelines.
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Affiliation(s)
- Hong You
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University & National Clinical Research Center for Digestive Diseases, Beijing, China
| | - Weijia Duan
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University & National Clinical Research Center for Digestive Diseases, Beijing, China
| | - Shuxiang Li
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University & National Clinical Research Center for Digestive Diseases, Beijing, China
| | - Tingting Lv
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University & National Clinical Research Center for Digestive Diseases, Beijing, China
| | - Sha Chen
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University & National Clinical Research Center for Digestive Diseases, Beijing, China
| | - Lungen Lu
- Department of Gastroenterology, First People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiong Ma
- Department of Gastroenterology and Hepatology, Renji Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Ying Han
- Department of Gastroenterology, Xijing Hospital, Fourth Military Medical University, Xi’an, Shaanxi, China
| | - Yuemin Nan
- Department of Traditional and Western Medical Hepatology, The Third Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Xiaoyuan Xu
- Department of Infectious Diseases and Center for Liver Diseases, Peking University First Hospital, Beijing, China
- Correspondence to: Jidong Jia, Liver Research Center, Beijing Friendship Hospital, Capital Medical University, 95 Yong-an Road, Beijing 100050, China. ORCID: https://orcid.org/0000-0002-4673-8890. Tel: +86-10-63139816, Fax: +86-10-63139246, E-mail: ; Xiaoyuan Xu, Department of Infectious Diseases, Peking University First Hospital, Beijing 100034, China. ORCID: https://orcid.org/0000-0002-1759-4330. Tel/Fax: +86-10-83575787, E-mail:
| | - Zhongping Duan
- Artificial Liver Center, Beijing You-An Hospital, Capital Medical University, Beijing, China
| | - Lai Wei
- Hepatobiliary Pancreatic Center, Tsinghua Changgung Hospital, Tsinghua University, Beijing, China
| | - Jidong Jia
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University & National Clinical Research Center for Digestive Diseases, Beijing, China
- Correspondence to: Jidong Jia, Liver Research Center, Beijing Friendship Hospital, Capital Medical University, 95 Yong-an Road, Beijing 100050, China. ORCID: https://orcid.org/0000-0002-4673-8890. Tel: +86-10-63139816, Fax: +86-10-63139246, E-mail: ; Xiaoyuan Xu, Department of Infectious Diseases, Peking University First Hospital, Beijing 100034, China. ORCID: https://orcid.org/0000-0002-1759-4330. Tel/Fax: +86-10-83575787, E-mail:
| | - Hui Zhuang
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
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Trivella J, John BV, Levy C. Primary biliary cholangitis: Epidemiology, prognosis, and treatment. Hepatol Commun 2023; 7:02009842-202306010-00027. [PMID: 37267215 DOI: 10.1097/hc9.0000000000000179] [Citation(s) in RCA: 30] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2023] [Accepted: 04/10/2023] [Indexed: 06/04/2023] Open
Abstract
Primary biliary cholangitis (PBC) is a chronic cholestatic autoimmune liver disease characterized by a destructive, small duct, and lymphocytic cholangitis, and marked by the presence of antimitochondrial antibodies. The incidence and prevalence of PBC vary widely in different regions and time periods, and although disproportionally more common among White non-Hispanic females, contemporary data show a higher prevalence in males and racial minorities than previously described. Outcomes largely depend on early recognition of the disease and prompt institution of treatment, which, in turn, are directly influenced by provider bias and socioeconomic factors. Ursodeoxycholic acid remains the initial treatment of choice for PBC, with obeticholic acid and fibrates (off-label therapy) reserved as add-on therapy for the management of inadequate responders or those with ursodeoxycholic acid intolerance. Novel and repurposed drugs are currently at different stages of clinical development not only for the treatment of PBC but also for its symptomatic management. Here, we summarize the most up-to-date data regarding the epidemiology, prognosis, and treatment of PBC, providing clinically useful information for its holistic management.
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Affiliation(s)
- Juan Trivella
- Department of Medicine, Division of Gastroenterology and Hepatology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| | - Binu V John
- Department of Medicine, Division of Gastroenterology and Hepatology, Miami VA Medical System, Miami, Florida, USA
- Department of Medicine, Division of Digestive Health and Liver Diseases, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - Cynthia Levy
- Department of Medicine, Division of Digestive Health and Liver Diseases, University of Miami Miller School of Medicine, Miami, Florida, USA
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Nevens F, Trauner M, Manns MP. Primary biliary cholangitis as a roadmap for the development of novel treatments for cholestatic liver diseases †. J Hepatol 2023; 78:430-441. [PMID: 36272496 DOI: 10.1016/j.jhep.2022.10.007] [Citation(s) in RCA: 27] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Revised: 10/07/2022] [Accepted: 10/07/2022] [Indexed: 11/16/2022]
Abstract
The discovery of nuclear receptors and transporters has contributed to the development of new drugs for the treatment of cholestatic liver diseases. Particular progress has been made in the development of second-line therapies for PBC. These new drugs can be separated into compounds primarily targeting cholestasis, molecules targeting fibrogenesis and molecules with immune-mediated action. Finally, drugs aimed at symptom relief (pruritus and fatigue) are also under investigation. Obeticholic acid is currently the only approved second-line therapy for PBC. Drugs in the late phase of clinical development include peroxisome proliferator-activated receptor agonists, norursodeoxycholic acid and NADPH oxidase 1/4 inhibitors.
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Affiliation(s)
- Frederik Nevens
- Department of Gastroenterology and Hepatology, University Hospital KU Leuven, Belgium; Centre of ERN RARE-LIVER.
| | - Michael Trauner
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Austria; Centre of ERN RARE-LIVER
| | - Michael P Manns
- Hannover Medical School, Hannover, Germany; Centre of ERN RARE-LIVER
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21
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Caspase-10 affects the pathogenesis of primary biliary cholangitis by regulating inflammatory cell death. J Autoimmun 2022; 133:102940. [PMID: 36323068 DOI: 10.1016/j.jaut.2022.102940] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2022] [Revised: 10/08/2022] [Accepted: 10/14/2022] [Indexed: 11/07/2022]
Abstract
Primary biliary cholangitis (PBC) is an autoimmune disease that involves chronic inflammation and injury to biliary epithelial cells. To identify critical genetic factor(s) in PBC patients, we performed whole-exome sequencing of five female siblings, including one unaffected and four affected sisters, in a multi-PBC family, and identified 61 rare heterozygote variants that segregated only within the affected sisters. Among them, we were particularly interested in caspase-10, for although several caspases are involved in cell death, inflammation and autoimmunity, caspase-10 is little known from this perspective. We generated caspase-10 knockout macrophages, and then investigated the obtained phenotypes in comparison to those of its structurally similar protein, caspase-8. Unlike caspase-8, caspase-10 does not play a role during differentiation into macrophages, but after differentiation, it regulates the process of inflammatory cell deaths such as necroptosis and pyroptosis more strongly. Interestingly, caspase-10 displays better protease activity than caspase-8 in the process of RIPK1 cleavage, and an enhanced ability to form a complex with RIPK1 and FADD in human macrophages. Higher inflammatory cell death affected the fibrotic response of hepatic stellate cells; this effect could be recovered by treatment with UDCA and OCA, which are currently approved for PBC patients. Our findings strongly indicate that the defective roles of caspase-10 in macrophages contribute to the pathogenesis of PBC, thereby suggesting a new therapeutic strategy for PBC treatment.
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22
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Hussain N, Trivedi PJ. The Inconvenient Truth of Primary Biliary Cholangitis/Autoimmune Hepatitis Overlap Syndrome. Clin Liver Dis 2022; 26:657-680. [PMID: 36270722 DOI: 10.1016/j.cld.2022.06.007] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
The term 'PBC/AIH-overlap' has been applied when features of autoimmune hepatitis (AIH), be they biochemical, serological or histological, coexist with primary biliary cholangitis (PBC), either at first presentation or sequentially during disease course. Several treatment paradigms have been proposed, extrapolated from those of the primary conditions. However, there are no randomised studies showing improved survival with combination therapy compared to bile acid monotherapy. In the absence of high-quality evidence, multidisciplinary patient-specific approaches must be used to individualise treatment pathways, with appreciation that disease phenotypes are not always static, differ in treatment responses, and have the potential to evolve over time.
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Affiliation(s)
- Nasir Hussain
- NIHR Birmingham BRC, Institute of Immunology and Immunotherapy, Centre for Liver and Gastrointestinal Research, University of Birmingham, Birmingham B15 2TT, United Kingdom; Liver Unit, University Hospitals Birmingham National Health Service Foundation Trust Queen Elizabeth, Birmingham, United Kingdom
| | - Palak J Trivedi
- NIHR Birmingham BRC, Institute of Immunology and Immunotherapy, Centre for Liver and Gastrointestinal Research, University of Birmingham, Birmingham B15 2TT, United Kingdom; Liver Unit, University Hospitals Birmingham National Health Service Foundation Trust Queen Elizabeth, Birmingham, United Kingdom; Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom; Institute of Applied Health Research, University of Birmingham, Birmingham, United Kingdom.
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Huang LX, Wang ZL, Jin R, Chen HS, Feng B. Incomplete response to ursodeoxycholic acid in primary biliary cholangitis: criteria, epidemiology, and possible mechanisms. Expert Rev Gastroenterol Hepatol 2022; 16:1065-1078. [PMID: 36469627 DOI: 10.1080/17474124.2022.2153672] [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] [Indexed: 12/10/2022]
Abstract
INTRODUCTION As a common autoimmune disease with the characteristic of early complication, primary biliary cholangitis (PBC) leads to an increasing number of mortalities among people with end-stage liver disease (ESLD) waiting for liver transplantation. Ursodeoxycholic acid (UDCA) is the only approved first-line medicine for PBC, and a good response to treatment could acquire an ideal prognosis. Patients with poor UDCA response usually have more adverse outcomes and worse survival, therefore, the management of this group become a major consideration. AREAS COVERED Due to the complexity of race and environment for PBC, different criteria for UDCA response exhibit various predictive performances. Factors affecting UDCA response conditions include gender, age, ethnicity, serum indicators, auto-antibodies, and autoimmune comorbidities, while no agreement has been reached. In this review, we mainly focus on cellular senescence, immune-mediated damage, and vitamin D deficiency as possible mechanisms for UDCA non-responders. EXPERT OPINION The pathogenesis of PBC has yet to be clarified. Immunology-related mechanisms and therapy targets ought to be the main effort made for further study. Irrespective of the response condition, UDCA is recommended for routine administration in all PBC patients without contraindication. Ongoing clinical trials of second-line and additional therapy exhibit promising prospects.
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Affiliation(s)
- Lin-Xiang Huang
- Peking University People's Hospital, Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Beijing, PR China
| | - Zi-Long Wang
- Peking University People's Hospital, Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Beijing, PR China
| | - Rui Jin
- Peking University People's Hospital, Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Beijing, PR China
| | - Hong-Song Chen
- Peking University People's Hospital, Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Beijing, PR China
| | - Bo Feng
- Peking University People's Hospital, Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Beijing, PR China
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de Veer RC, Harms MH, Corpechot C, Thorburn D, Invernizzi P, Janssen HLA, Battezzati PM, Nevens F, Lindor KD, Floreani A, Ponsioen CY, Mayo MJ, Parés A, Mason AL, Kowdley KV, Trivedi PJ, Hirschfield GM, Bruns T, Dalekos GN, Gatselis NK, Verhelst X, Lammers WJ, Hansen BE, van Buuren HR, van der Meer AJ, the Global PBC Study Group. Liver transplant-free survival according to alkaline phosphatase and GLOBE score in patients with primary biliary cholangitis treated with ursodeoxycholic acid. Aliment Pharmacol Ther 2022; 56:1408-1418. [PMID: 36138566 PMCID: PMC9826062 DOI: 10.1111/apt.17226] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Revised: 06/23/2022] [Accepted: 09/05/2022] [Indexed: 01/30/2023]
Abstract
BACKGROUND After 1 year of ursodeoxycholic acid (UDCA), patients with primary biliary cholangitis (PBC) may have a normal GLOBE score despite high alkaline phosphatase (ALP) levels. AIM To assess the association between ALP and liver transplantation (LT)-free survival according to the GLOBE score METHODS: Among patients with a normal or elevated GLOBE score in the Global PBC cohort, the association between ALP after 1 year of UDCA and the risk of LT/death was assessed. The LT-free survival was compared with that of a matched general population. RESULTS After 1 year of UDCA, ALP was associated with the risk of LT/death (aHR 1.31, 95% CI 1.003-1.72, p = 0.048) among 2729 patients with a normal GLOBE score. The 10-year LT-free survival among these patients with an ALP >2.0 × ULN was 94.0% (95% CI 90.1-97.9) for those <50 years, and 82.6% (95% CI 76.5-88.7) for those ≥50 years, which was significantly lower (p = 0.040) and similar (p = 0.736) to that of the matched population, respectively. The 10-year LT-free survival in patients ≥50 years with normal GLOBE score and normal ALP (90.8%, 95% CI 87.7-93.9) was significantly higher (p = 0.022) than the matched population. Among 1045 patients with an elevated GLOBE score, ALP was associated with LT/death only in those <50 years (aHR 1.38, 95% CI 1.06-1.81, p = 0.016). CONCLUSION The LT-free survival of patients with PBC with a normal GLOBE score is optimal in case of normal ALP levels, also in relation to the general population. Despite their generally favourable prognosis, an elevated ALP level may still indicate a need for add-on therapy.
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Affiliation(s)
- Rozanne C. de Veer
- Department of Gastroenterology and HepatologyErasmus University Medical CenterRotterdamThe Netherlands
| | - Maren H. Harms
- Department of Gastroenterology and HepatologyErasmus University Medical CenterRotterdamThe Netherlands
| | - Christophe Corpechot
- Reference Center for Inflammatory Biliary Diseases and Autoimmune Hepatitis, European Reference Network on Hepatological Diseases (ERN Rare‐Liver)Saint‐Antoine Hospital, Assistance Publique ‐ Hôpitaux de Paris; Inserm UMR_S938, Saint‐Antoine Research Center, Sorbonne UniversityParisFrance
| | - Douglas Thorburn
- The Sheila Sherlock Liver Centre, and UCL Institute of Liver and Digestive HealthThe Royal Free HospitalLondonUK
| | - Pietro Invernizzi
- Division of Gastroenterology and Center for Autoimmune Liver Diseases, Department of Medicine and SurgeryUniversity of Milano‐BicoccaMilanItaly
| | - Harry L. A. Janssen
- Toronto Centre for Liver disease, Toronto General HospitalUniversity Health NetworkTorontoCanada
| | | | - Frederik Nevens
- Department of HepatologyUniversity Hospitals LeuvenKU LeuvenLeuvenBelgium
| | - Keith D. Lindor
- Department of Gastroenterology and HepatologyMayo ClinicRochesterMinnesotaUSA,Arizona State UniversityCollege of Health SolutionsPhoenixArizonaUSA
| | - Annarosa Floreani
- Department of Surgery, Oncology and GastroenterologyUniversity of PaduaPaduaItaly,Scientific Institute for ResearchHospitalization and HealthcareNegrarVeronaItaly
| | - Cyriel Y. Ponsioen
- Department of Gastroenterology and Hepatology, Amsterdam University Medical Centreslocation Academic Medical CenterAmsterdamThe Netherlands
| | - Marlyn J. Mayo
- Digestive and Liver diseases, UT Southwestern Medical CenterDallasTexasUSA
| | - Albert Parés
- Liver UnitHospital Clínic, CIBERehd, IDIBAPS, University of BarcelonaBarcelonaSpain
| | - Andrew L. Mason
- Division of Gastroenterology and HepatologyUniversity of AlbertaEdmontonAlbertaCanada
| | - Kris V. Kowdley
- Liver Care Network and Organ Care ResearchSwedish Medical CenterSeattleWAUSA
| | - Palak J. Trivedi
- Birmingham NIHR Biomedical Research Centre, and Centre for Liver ResearchUniversity of BirminghamBirminghamUK
| | - Gideon M. Hirschfield
- Toronto Centre for Liver disease, Toronto General HospitalUniversity Health NetworkTorontoCanada,Birmingham NIHR Biomedical Research Centre, and Centre for Liver ResearchUniversity of BirminghamBirminghamUK
| | - Tony Bruns
- Department of Internal Medicine IVJena University Hospital, Friedrich Schiller UniversityJenaGermany,Department of Internal Medicine IIIUniversity Hospital RWTH AachenAachenGermany
| | - George N. Dalekos
- Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver DiseasesGeneral University Hospital of LarissaLarissaGreece,European Reference Network on Hepatological Diseases (ERN RARE‐LIVER)General University Hospital of LarissaLarissaGreece
| | - Nikolaos K. Gatselis
- Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver DiseasesGeneral University Hospital of LarissaLarissaGreece,European Reference Network on Hepatological Diseases (ERN RARE‐LIVER)General University Hospital of LarissaLarissaGreece
| | - Xavier Verhelst
- Department of Gastroenterology and HepatologyGhent University HospitalBelgium
| | - Willem J. Lammers
- Department of Gastroenterology and HepatologyErasmus University Medical CenterRotterdamThe Netherlands
| | - Bettina E. Hansen
- Toronto Centre for Liver disease, Toronto General HospitalUniversity Health NetworkTorontoCanada,Institute of Health Policy, Management and EvaluationUniversity of TorontoTorontoCanada
| | - Henk R. van Buuren
- Department of Gastroenterology and HepatologyErasmus University Medical CenterRotterdamThe Netherlands
| | - Adriaan J. van der Meer
- Department of Gastroenterology and HepatologyErasmus University Medical CenterRotterdamThe Netherlands
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Shaker M, Mansour N, John BV. Primary Biliary Cholangitis in Males: Pathogenesis, Clinical Presentation, and Prognosis. Clin Liver Dis 2022; 26:643-655. [PMID: 36270721 DOI: 10.1016/j.cld.2022.06.008] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Primary biliary cholangitis (PBC) is an immune-mediated chronic liver disease characterized by progressive cholestasis, bile duct destruction, biliary fibrosis, and cirrhosis. Patients who respond to ursodeoxycholic acid have an expected survival similar to the general population. Although PBC primarily affects females, the prevalence in males is higher than was previously believed, with contemporary studies suggesting a female-to-male ratio of 4-6:1. A diagnosis of PBC is often delayed among males because of the myth that PBC is rare in males.
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Affiliation(s)
- Mina Shaker
- Division of Hepatology, Miami VA Medical Center 1201 NW 16th Street, Miami, FL 33125 USA.
| | - Natalie Mansour
- Division of Hepatology, Miami VA Medical Center 1201 NW 16th Street, Miami, FL 33125 USA
| | - Binu V John
- Division of Hepatology, Miami VA Medical Center 1201 NW 16th Street, Miami, FL 33125 USA; Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, USA
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26
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Martin EF. Liver Transplantation for Primary Biliary Cholangitis. Clin Liver Dis 2022; 26:765-781. [PMID: 36270728 DOI: 10.1016/j.cld.2022.06.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Despite a significant increase in the total number of liver transplants (LTs) performed over the last 3 decades, primary biliary cholangitis (PBC) has become an uncommon indication for LT, which likely reflects the benefits of earlier diagnosis and available treatment, such as ursodeoxycholic acid (UDCA). Nonetheless, LT remains the only cure for patients with progressive PBC despite medical therapy with survival rates that are among the highest of all indications for LT. Post-LT PBC patients, however, are at increased risk of rejection and disease recurrence.
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Affiliation(s)
- Eric F Martin
- Division of Digestive Health and Liver Diseases, University of Miami Miller School of Medicine, Miami Transplant Institute, Highland Professional Building, 1801 Northwest 9(th) Avenue, Miami, FL 33136, USA.
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27
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Abstract
Primary biliary cholangitis (PBC) is a cholestatic liver disease with potential evolution to liver cirrhosis when left untreated. Despite being rare, PBC has a substantial impact on the quality of life and survival of affected patients. Women are the most diagnosed worldwide; however, male subjects seem to have more aggressive disease and worse prognosis. Changing epidemiologic trends are emerging in PBC, with increasing global prevalence and slight smoothing of sex differences. In this review we present available data on incidence rates and prevalence of PBC worldwide, highlighting geographic differences and factors impacting clinical outcomes.
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Affiliation(s)
- Francesca Colapietro
- Division of Internal Medicine and Hepatology, Department of Gastroenterology, IRCCS Humanitas Research Hospital, Via A. Manzoni 56, Rozzano 20089, Italy; Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy
| | - Arianna Bertazzoni
- Division of Internal Medicine and Hepatology, Department of Gastroenterology, IRCCS Humanitas Research Hospital, Via A. Manzoni 56, Rozzano 20089, Italy; Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy
| | - Ana Lleo
- Division of Internal Medicine and Hepatology, Department of Gastroenterology, IRCCS Humanitas Research Hospital, Via A. Manzoni 56, Rozzano 20089, Italy; Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy.
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28
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Obeticholic Acid for Primary Biliary Cholangitis. Biomedicines 2022; 10:biomedicines10102464. [PMID: 36289726 PMCID: PMC9599277 DOI: 10.3390/biomedicines10102464] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2022] [Revised: 09/09/2022] [Accepted: 09/28/2022] [Indexed: 11/25/2022] Open
Abstract
Primary biliary cholangitis (PBC) is a rare autoimmune cholestatic liver disease that may progress to fibrosis and/or cirrhosis. Treatment options are currently limited. The first-line therapy for this disease is the drug ursodeoxycholic acid (UDCA), which has been proven to normalize serum markers of liver dysfunction, halt histologic disease progression, and lead to a prolongation of transplant-free survival. However, 30–40% of patients unfortunately do not respond to this first-line therapy. Obeticholic acid (OCA) is the only registered agent for second-line treatment in UDCA-non responders. In this review, we focus on the pharmacological features of OCA, describing its mechanism of action of and its tolerability and efficacy in PBC patients. We also highlight current perspectives on future therapies for this condition.
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Li J, Lu M, Zhou Y, Bowlus CL, Lindor K, Rodriguez-Watson C, Romanelli RJ, Haller IV, Anderson H, VanWormer JJ, Boscarino JA, Schmidt MA, Daida YG, Sahota A, Vincent J, Wu KHH, Trudeau S, Rupp LB, Melkonian C, Gordon SC. Dynamic Risk Prediction of Response to Ursodeoxycholic Acid Among Patients with Primary Biliary Cholangitis in the USA. Dig Dis Sci 2022; 67:4170-4180. [PMID: 34499271 DOI: 10.1007/s10620-021-07219-4] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2021] [Accepted: 08/05/2021] [Indexed: 12/12/2022]
Abstract
BACKGROUND Ursodeoxycholic acid (UDCA) remains the first-line therapy for primary biliary cholangitis (PBC); however, inadequate treatment response (ITR) is common. The UK-PBC Consortium developed the modified UDCA Response Score (m-URS) to predict ITR (using alkaline phosphatase [ALP] > 1.67 times the upper limit of normal [*ULN]) at 12 months post-UDCA initiation). Using data from the US-based Fibrotic Liver Disease Consortium, we assessed the m-URS in our multi-racial cohort. We then used a dynamic modeling approach to improve prediction accuracy. METHODS Using data collected at the time of UDCA initiation, we assessed the m-URS using the original formula; then, by calibrating coefficients to our data, we also assessed whether it remained accurate when using Paris II criteria for ITR. Next, we developed and validated a dynamic risk prediction model that included post-UDCA initiation laboratory data. RESULTS Among 1578 patients (13% men; 8% African American, 9% Asian American/American Indian/Pacific Islander; 25% Hispanic), the rate of ITR was 27% using ALP > 1.67*ULN and 45% using Paris II criteria. M-URS accuracy was "very good" (AUROC = 0.87, sensitivity = 0.62, and specificity = 0.82) for ALP > 1.67*ULN and "moderate" (AUROC = 0.74, sensitivity = 0.57, and specificity = 0.70) for Paris II. Our dynamic model significantly improved accuracy for both definitions of ITR (ALP > 1.67*ULN: AUROC = 0.91; Paris II: AUROC = 0.81); specificity approached 100%. Roughly 9% of patients in our cohort were at the highest risk of ITR. CONCLUSIONS Early identification of patients who will not respond to UDCA treatment using a dynamic prediction model based on longitudinal, repeated risk factor measurements may facilitate earlier introduction of adjuvant treatment.
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Affiliation(s)
- Jia Li
- Department of Public Health Sciences, Henry Ford Health System, 3E One Ford Place, Detroit, MI, 48202, USA.
| | - Mei Lu
- Department of Public Health Sciences, Henry Ford Health System, 3E One Ford Place, Detroit, MI, 48202, USA
| | - Yueren Zhou
- Department of Public Health Sciences, Henry Ford Health System, 3E One Ford Place, Detroit, MI, 48202, USA
| | | | - Keith Lindor
- College of Health Solutions, Arizona State University, Phoenix, AZ, USA
| | - Carla Rodriguez-Watson
- Mid-Atlantic Permanente Research Institute, Kaiser Permanente Mid-Atlantic States, Rockville, MD, USA
- Innovation in Medical Evidence Development and Surveillance, The Reagan-Udall Foundation for the FDA, Washington, DC, USA
| | | | - Irina V Haller
- Essentia Institute of Rural Health, Essentia Health, Duluth, MN, USA
| | - Heather Anderson
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Aurora, CO, USA
| | | | - Joseph A Boscarino
- Department of Epidemiology and Health Services Research, Geisinger Clinic, Danville, PA, USA
| | - Mark A Schmidt
- Center for Health Research, Kaiser Permanente Northwest, Portland, OR, USA
| | - Yihe G Daida
- Center for Integrated Health Care Research, Kaiser Permanente Hawaii, Honolulu, HI, USA
| | - Amandeep Sahota
- Department of Research and Evaluation, Kaiser Permanente Southern California, Los Angeles, CA, USA
| | | | - Kuan-Han Hank Wu
- Department of Public Health Sciences, Henry Ford Health System, 3E One Ford Place, Detroit, MI, 48202, USA
| | - Sheri Trudeau
- Department of Public Health Sciences, Henry Ford Health System, 3E One Ford Place, Detroit, MI, 48202, USA
| | - Loralee B Rupp
- Center for Health Policy and Health Services Research, Henry Ford Health System, Detroit, MI, USA
| | - Christina Melkonian
- Department of Public Health Sciences, Henry Ford Health System, 3E One Ford Place, Detroit, MI, 48202, USA
| | - Stuart C Gordon
- Department of Gastroenterology and Hepatology, Henry Ford Health System, and Wayne State University School of Medicine, Detroit, MI, USA
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30
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Gender and Autoimmune Liver Diseases: Relevant Aspects in Clinical Practice. J Pers Med 2022; 12:jpm12060925. [PMID: 35743710 PMCID: PMC9225254 DOI: 10.3390/jpm12060925] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Revised: 05/25/2022] [Accepted: 05/28/2022] [Indexed: 12/12/2022] Open
Abstract
Autoimmune liver diseases (AILDs) include autoimmune hepatitis, primary biliary cholangitis and primary sclerosing cholangitis. The etiologies of AILD are not well understood but appear to involve a combination of genetic and environmental factors. AILDs commonly affect young individuals and are characterized by a highly variable clinical course. These diseases significantly influence quality of life and can progress toward liver decompensation or the onset of hepatocellular or cholangiocarcinoma; a significant number of patients eventually progress to end-stage liver disease, requiring liver transplantation. In this review, we focus on the sex characteristics and peculiarities of AILD patients and highlight the relevance of a sex-specific analysis in future studies. Understanding the sex differences underlying AILD immune dysregulation may be critical for developing more effective treatments.
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31
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John BV, Dahman B, Deng Y, Khakoo NS, Taddei TH, Kaplan DE, Levy C. Rates of decompensation, hepatocellular carcinoma and mortality in AMA-negative primary biliary cholangitis cirrhosis. Liver Int 2022; 42:384-393. [PMID: 34614294 PMCID: PMC8810619 DOI: 10.1111/liv.15079] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Revised: 09/21/2021] [Accepted: 09/30/2021] [Indexed: 02/03/2023]
Abstract
BACKGROUND The natural history of patients with anti-mitochondrial antibody (AMA)-negative Primary Biliary Cholangitis (PBC) cirrhosis has not been well defined, with prior studies showing discordant results. Furthermore, most studies of AMA-negative PBC have limited numbers of patients with cirrhosis and liver-related outcomes. METHODS We investigated the association of AMA-negative PBC and the development of death, liver-related death, decompensation and hepatocellular carcinoma (HCC), in a large cohort of predominantly male patients with PBC cirrhosis assembled from the Veterans Health Administration. RESULTS In a cohort of 521 patients with PBC cirrhosis (65 AMA-negative) with a total follow-up of 2504.3 person-years (PY) from cirrhosis diagnosis, patients with AMA-negative PBC were younger and more likely to be black but had similar rates of UDCA response. AMA-negative PBC cirrhosis was associated with similar unadjusted rates of liver-related death (4.6 vs 5.9 per 100 PY, P = .44), overall death (7.7 vs 9.6 per 100 PY, P = .31), decompensation (7.3 vs 5.1 per 100 PY, P = .12) and HCC (0.6 vs 1.0 per 100 PY, P = .63) to AMA-positive PBC. After adjusting for confounders, AMA-negative PBC cirrhosis was associated with similar rates of liver-related death (sub-Hazard Ratio [sHR] 1.27, 95% CI 0.71-2.28, P = .42, death [sHR] 1.24, 95% CI 0.81-1.90, P = .32), decompensation (sHR 1.05, 95% CI 0.56-1.98, P = .87) and HCC (sHR 0.48, 95% CI 0.11-2.10, P = .33) to AMA-positive patients. CONCLUSION In a cohort of predominantly male patients, AMA-negative PBC cirrhosis was associated with similar rates of overall or liver-related death, HCC or decompensation compared with AMA-positive disease.
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Affiliation(s)
- Binu V John
- Division of Hepatology, Bruce W Carter VA Medical Center, Miami, Florida, USA
- Division of Digestive Health and Liver Diseases, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - Bassam Dahman
- Department of Health Behavior and Policy, Virginia Commonwealth University, Richmond, Virginia, USA
| | - Yangyang Deng
- Department of Health Behavior and Policy, Virginia Commonwealth University, Richmond, Virginia, USA
| | - Nidah S Khakoo
- Department of Medicine, Jackson Memorial Hospital, Miami, Florida, USA
| | - Tamar H Taddei
- Section of Digestive Diseases, Yale School of Medicine, New Haven, Connecticut, USA
- VA Connecticut Healthcare System, West Haven, Connecticut, USA
| | - David E Kaplan
- Division of Gastroenterology and Hepatology, University of Pennsylvania, Philadelphia, Pennsylvania, USA
- Division of Gastroenterology and Hepatology, Corporal Michael J. Crescenz VA Medical Center, Philadelphia, Pennsylvania, USA
| | - Cynthia Levy
- Division of Digestive Health and Liver Diseases, University of Miami Miller School of Medicine, Miami, Florida, USA
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32
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You H, Ma X, Efe C, Wang G, Jeong SH, Abe K, Duan W, Chen S, Kong Y, Zhang D, Wei L, Wang FS, Lin HC, Yang JM, Tanwandee T, Gani RA, Payawal DA, Sharma BC, Hou J, Yokosuka O, Dokmeci AK, Crawford D, Kao JH, Piratvisuth T, Suh DJ, Lesmana LA, Sollano J, Lau G, Sarin SK, Omata M, Tanaka A, Jia J. APASL clinical practice guidance: the diagnosis and management of patients with primary biliary cholangitis. Hepatol Int 2022; 16:1-23. [PMID: 35119627 PMCID: PMC8843914 DOI: 10.1007/s12072-021-10276-6] [Citation(s) in RCA: 55] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Accepted: 11/08/2021] [Indexed: 12/14/2022]
Affiliation(s)
- Hong You
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, 95 Yong-an Road, Beijing, Mainland, China
| | - Xiong Ma
- Department of Gastroenterology and Hepatology, Renji Hospital, Shanghai Jiao Tong University, Shanghai, Mainland, China
| | - Cumali Efe
- Department of Gastroenterology, Gazi Yaşargil Education and Research Hospital, Diyarbakir, Turkey
| | - Guiqiang Wang
- Department of Infectious Diseases and Center for Liver Diseases, Peking University First Hospital, Beijing, Mainland, China
| | - Sook-Hyang Jeong
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seoul, South Korea
| | - Kazumichi Abe
- Department of Gastroenterology, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Weijia Duan
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, 95 Yong-an Road, Beijing, Mainland, China
| | - Sha Chen
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, 95 Yong-an Road, Beijing, Mainland, China
| | - Yuanyuan Kong
- Clinical Epidemiology and EBM Unit, Beijing Friendship Hospital, Capital Medical University, Beijing, Mainland, China
| | - Dong Zhang
- Experimental and Translational Research Center, Beijing Clinical Research Institute, Beijing, Mainland, China
| | - Lai Wei
- Hepatobiliary Pancreatic Center, Tsinghua Changgung Hospital, Tsinghua University, Beijing, Mainland, China
| | - Fu-Sheng Wang
- Treatment and Research Center for Infectious Diseases, The Fifth Medical Center of PLA General Hospial, Beijing, Mainland, China
| | - Han-Chieh Lin
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Jin Mo Yang
- Division of Hepatology, Department of Internal Medicine, College of Medicine, St. Vincent’s Hospital, The Catholic University of Korea, Suwon, South Korea
| | - Tawesak Tanwandee
- Division of Gastroenterology, Department of Medicine, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Rino A. Gani
- Department of Internal Medicine, Cipto Mangunkusumo Hospital, University of Indonesia, Jakarta, Indonesia
| | - Diana A. Payawal
- Department of Medicine, Fatima University Medical Center, Manila, Philippines
| | | | - Jinlin Hou
- Department of Infectious Disease and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, Mainland, China
| | - Osamu Yokosuka
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - A. Kadir Dokmeci
- Department of Medicine, Ankara University School of Medicine, Ankara, Turkey
| | - Darrell Crawford
- School of Medicine, University of Queensland, Brisbane, Australia
| | - Jia-Horng Kao
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Teerha Piratvisuth
- NKC Institute of Gastroenterology and Hepatology, Faculty of Medicine, Prince of Songkla University, Hatyai, Thailand
| | - Dong Jin Suh
- Department of Gastroenterology, University of Ulsan College of Medicine, Seoul, South Korea
| | | | - Jose Sollano
- Department of Medicine, University of Santo Tomas, Manila, Philippines
| | - George Lau
- Humanity and Health Clinical Trial Center, Humanity and Health Medical Group, Hong Kong SAR, China
| | - Shiv K. Sarin
- Department of Hepatology, Institute of Liver and Biliary Sciences, Vasant Kunj, New Delhi, India
| | - Masao Omata
- Department of Gastroenterology, Yamanashi Central Hospital, Yamanashi, Japan
- University of Tokyo, Tokyo, Japan
| | - Atsushi Tanaka
- Department of Medicine, Teikyo University School of Medicine, Tokyo, Japan
| | - Jidong Jia
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, 95 Yong-an Road, Beijing, Mainland, China
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33
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Murillo Perez CF, Gulamhusein A, Carbone M, Trivedi PJ, van der Meer AJ, Corpechot C, Battezzati PM, Lammers WJ, Cazzagon N, Floreani A, Parés A, Nevens F, Lleo A, Mayo MJ, Kowdley KV, Ponsioen CY, Dalekos GN, Gatselis NK, Thorburn D, Mason AL, Janssen H, Verhelst X, Bruns T, Lindor KD, Chazouillères O, Invernizzi P, Hansen BE, Hirschfield GM. Simplified care-pathway selection for nonspecialist practice: the GLOBAL Primary Biliary Cholangitis Study Group Age, Bilirubin, Alkaline phosphatase risk assessment tool. Eur J Gastroenterol Hepatol 2021; 33:e266-e273. [PMID: 33323757 DOI: 10.1097/meg.0000000000002029] [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: 12/10/2022]
Abstract
BACKGROUND Opportunity to redefine the care journeys for those living with primary biliary cholangitis (PBC) includes facilitating access to enhanced (PBC-dedicated) programmes by nonspecialist risk 'flagging' of patients. OBJECTIVE To develop a nonexpert PBC stratification tool to help care pathway choices (standard vs. enhanced) choices in PBC. METHODS We included ursodeoxycholic acid-treated patients with PBC from the Global PBC Study Group. The performance of baseline and 1-year clinical markers with transplant-free survival was assessed to develop the 'ABA' tool using Age (A), Bilirubin (B), and Alkaline phosphatase (A). Added value of fibrosis estimation was assessed. RESULTS 'ABA' classification mapped three risk groups (n = 2226): low [Age > 50 years, bilirubin ≤ 1 × ULN, alkaline phosphatase (ALP) ≤ 3 × ULN], high (Age ≤ 50 years, bilirubin > 1 × ULN, ALP > 3 × ULN), and intermediate (other). Transplant-free survival at 10 years in the low-, intermediate-, and high-risk groups were 89, 77, and 59% at baseline and 86, 76, and 40% at 1 year, respectively. We propose that high-risk patients at baseline be directly triaged to enhanced (PBC-dedicated) care and the remaining be reassessed at 1 year. Modelling showed after 1 year 46% patients were proposed to enhanced care and 54% to standard care. The 'ABA' mapped pathways facilitated identification of patients at risk based on a young age, as compared to traditional liver biochemical stratification. In patients proposed to standard care, estimated fibrosis stage had ongoing prognostic value. CONCLUSION Nonspecialist use of the 'ABA' risk tool could prioritize care journey choices for patients with PBC.
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Affiliation(s)
- Carla F Murillo Perez
- Toronto Centre for Liver Disease, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada
- Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - Aliya Gulamhusein
- Toronto Centre for Liver Disease, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada
| | - Marco Carbone
- Division of Gastroenterology and Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milano-Bicocca, San Gerardo Hospital, Monza, Italy
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER)
| | - Palak J Trivedi
- National Institute for Health Research Birmingham Biomedical Research Centre and Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK
| | - Adriaan J van der Meer
- Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - Christophe Corpechot
- Reference Center for Inflammatory Biliary Diseases and Autoimmune Hepatitis, Saint-Antoine Hospital, APHP, Sorbonne University, Paris, France
| | | | - Willem J Lammers
- Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - Nora Cazzagon
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER)
- Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy
| | - Annarosa Floreani
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER)
- Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy
| | - Albert Parés
- Liver Unit, Hospital Clínic, CIBERehd, IDIBAPS, University of Barcelona, Barcelona, Spain
| | - Frederik Nevens
- Department of Hepatology, University Hospitals Leuven, KU Leuven, Leuven, Belgium
| | - Ana Lleo
- Division of Internal Medicine and Hepatology, Humanitas Clinical Research Center IRCSS, Humanitas University, Rozzano, Milan, Italy
| | - Marlyn J Mayo
- Digestive and Liver Diseases Clinic, UT Southwestern Medical Center, Dallas, Texas
| | - Kris V Kowdley
- Liver Care Network and Organ Care Research, Swedish Medical Center, Seattle, Washington, USA
| | - Cyriel Y Ponsioen
- Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, the Netherlands
| | - George N Dalekos
- Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, Larissa, Greece
| | - Nikolaos K Gatselis
- Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, Larissa, Greece
| | - Douglas Thorburn
- The Sheila Sherlock Liver Centre, The Royal Free Hospital, London, UK
| | - Andrew L Mason
- Divison of Gastroenterology and Hepatology, University of Alberta, Edmonton, Alberta, Canada
| | - Harry Janssen
- Toronto Centre for Liver Disease, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada
| | - Xavier Verhelst
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER)
- Department of Gastroenterology and Hepatology, Ghent University Hospital, Ghent, Belgium
| | - Tony Bruns
- Department of Internal Medicine IV, Jena University Hospital, Friedrich Schiller University, Jena, Department of Internal Medicine III, University Hospital RWTH Aachen, Aachen, Germany
| | - Keith D Lindor
- College of Health Solutions, Arizona State University, Phoenix, Arizona, USA
| | - Olivier Chazouillères
- Reference Center for Inflammatory Biliary Diseases and Autoimmune Hepatitis, Saint-Antoine Hospital, APHP, Sorbonne University, Paris, France
| | - Pietro Invernizzi
- Division of Gastroenterology and Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milano-Bicocca, San Gerardo Hospital, Monza, Italy
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER)
| | - Bettina E Hansen
- Toronto Centre for Liver Disease, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada
- Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Ontario, Canada
| | - Gideon M Hirschfield
- Toronto Centre for Liver Disease, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada
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Involvement of Autophagy in Ageing and Chronic Cholestatic Diseases. Cells 2021; 10:cells10102772. [PMID: 34685751 PMCID: PMC8534511 DOI: 10.3390/cells10102772] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 10/05/2021] [Accepted: 10/13/2021] [Indexed: 01/18/2023] Open
Abstract
Autophagy is a “housekeeping” lysosomal degradation process involved in numerous physiological and pathological processes in all eukaryotic cells. The dysregulation of hepatic autophagy has been described in several conditions, from obesity to diabetes and cholestatic disease. We review the role of autophagy, focusing on age-related cholestatic diseases, and discuss its therapeutic potential and the molecular targets identified to date. The accumulation of toxic BAs is the main cause of cell damage in cholestasis patients. BAs and their receptor, FXR, have been implicated in the regulation of hepatic autophagy. The mechanisms by which cholestasis induces liver damage include mitochondrial dysfunction, oxidative stress and ER stress, which lead to cell death and ultimately to liver fibrosis as a compensatory mechanism to reduce the damage. The stimulation of autophagy seems to ameliorate the liver damage. Autophagic activity decreases with age in several species, whereas its basic extends lifespan in animals, suggesting that it is one of the convergent mechanisms of several longevity pathways. No strategies aimed at inducing autophagy have yet been tested in cholestasis patients. However, its stimulation can be viewed as a novel therapeutic strategy that may reduce ageing-dependent liver deterioration and also mitigate hepatic steatosis.
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35
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Lleo A, Hirschfield GM. Letter to the Editor: Are We Confident That Primary Biliary Cholangitis Liver-Related Mortality Is Higher in Males? Hepatology 2021; 74:2307. [PMID: 33942335 DOI: 10.1002/hep.31882] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/08/2022]
Affiliation(s)
- Ana Lleo
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy
- IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
| | - Gideon M Hirschfield
- Toronto Centre for Liver Disease, Division of Gastroenterology and Hepatology, University of Toronto, Toronto, Ontario, Canada
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36
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Trivedi PJ, Hirschfield GM. Recent advances in clinical practice: epidemiology of autoimmune liver diseases. Gut 2021; 70:1989-2003. [PMID: 34266966 DOI: 10.1136/gutjnl-2020-322362] [Citation(s) in RCA: 129] [Impact Index Per Article: 32.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2021] [Accepted: 06/24/2021] [Indexed: 12/13/2022]
Abstract
Autoimmune liver diseases are chronic inflammatory hepatobiliary disorders that when classically defined encompass three distinctive clinical presentations; primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC) and autoimmune hepatitis (AIH). Meaningful changes in disease epidemiology are reported, with increasing incidence and prevalence of AIH and PSC in Europe, and rising prevalence of PBC across Europe, North America and the Asia-Pacific region. However, there appears to be very significant global variation with contemporary incidence rates of disease per 100 000 ranging from 0.84 to 2.75 for PBC, 0.1 to 4.39 for PSC and 0.4 to 2.39 for AIH. Prevalence corresponds, and per 100 000 estimates for PBC range from 1.91 to 40.2, for PSC between 0.78 and 31.7 and for AIH from 4.8 to 42.9. Population-based studies and multicentre observational cohort series provide improved understanding of the clinical course that patients experience, highlighting variations in presenting phenotypes geographically and temporally. Collectively, while autoimmune liver diseases are rare, the clinical burden is disproportionately high relative to population incidence and prevalence. Age, sex and race also impact clinical outcomes, and patient morbidity and mortality are reflected by high need for gastroenterology, hepatology and organ transplant services.
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Affiliation(s)
- Palak J Trivedi
- National Institute for Health Research (NIHR) Birmingham Liver Biomedical Research Centre, University of Birmingham College of Medical and Dental Sciences, Birmingham, Birmingham, UK
- Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK
- Institute of Applied Health Research, University of Birmingham, Birmingham, UK
- Liver Unit, University Hospitals Birmingham National Health Service Foundation Trust Queen Elizabeth, Birmingham, UK
| | - Gideon M Hirschfield
- Toronto Centre for Liver Disease, Division of Gastroenterology and Hepatology, University of Toronto, Toronto, Ontario, Canada
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37
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John BV, Dahman B, Taddei TH, Levy C, Kaplan DE. REPLY. Hepatology 2021; 74:2308. [PMID: 33942361 PMCID: PMC8463416 DOI: 10.1002/hep.31876] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/08/2022]
Affiliation(s)
- Binu V. John
- Division of Hepatology, Bruce W Carter VA Medical Center,
Miami, FL,Division of Digestive Health and Liver Diseases,
University of Miami Miller School of Medicine, Miami, FL
| | - Bassam Dahman
- Department of Health Behavior and Policy, Virginia
Commonwealth University, Richmond, VA
| | - Tamar H. Taddei
- Section of Digestive Diseases, Yale School of Medicine,
New Haven, CT,VA Connecticut Healthcare System, West Haven, CT
| | - Cynthia Levy
- Division of Digestive Health and Liver Diseases,
University of Miami Miller School of Medicine, Miami, FL
| | - David E. Kaplan
- Division of Gastroenterology and Hepatology, University of
Pennsylvania, Philadelphia, PA,Division of Gastroenterology and Hepatology, Corporal
Michael J. Crescenz VA Medical Center, Philadelphia, PA
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38
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Yehezkel E, Israel I, Houri I, Leshno M, Shibolet O, Zigmond E. Real-World Management of Patients with Primary Biliary Cholangitis-A Retrospective Study from a Tertiary Medical Center in Israel. J Clin Med 2021; 10:jcm10194551. [PMID: 34640567 PMCID: PMC8509713 DOI: 10.3390/jcm10194551] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 09/22/2021] [Accepted: 09/27/2021] [Indexed: 11/16/2022] Open
Abstract
Background: Primary biliary cholangitis (PBC) is a rare autoimmune liver disease with variation in prevalence, phenotype and prognosis across different geographical regions. Little is known about PBC in Israel. Our aim was to characterize the demography, clinical presentation, treatment patterns and prognosis in a cohort of PBC patients followed in a referral center in central Israel. Methods: Clinical, demographic and laboratory data were collected from the medical records of PBC patients followed at Tel Aviv Medical Center in the years 2003–2020. Results: We have identified 189 patients with a confirmed diagnosis of PBC; 92.6% were female and the mean age at diagnosis was 54.7 years. Thirty-nine percent were diagnosed with another autoimmune disease and 5.9% were diagnosed with a PBC-AIH (autoimmune hepatitis) variant syndrome. Ninety-six percent were treated with ursodeoxycholic acid (UDCA) at a mean dose of 13.3 mg/kg. A total of 28.1% were found with inadequate response to UDCA according to the Toronto criteria, and 53% of the UDCA non-responders were treated with bezafibrate. Younger age at diagnosis, higher baseline levels of alkaline phosphatase (ALP) and gamma-glutamyltransferase (GGT), AIH-PBC variant and positive anti-smooth muscle antibodies (ASMA) were associated with an inadequate UDCA response. In a multivariable analysis, higher ALP at diagnosis (OR = 1.92 CI 1.11–3.20 per 50-unit change, p = 0.018) and ASMA (OR = 27.6 CI 2.58–295, p = 0.006) independently predicted inadequate UDCA response. Higher alanine transaminase (ALT), ALP and GGT, lower albumin, younger age at diagnosis and pruritus conferred an increased risk for disease progression. Conclusions: Disease characteristics, treatment patterns, response to therapy and prognosis of a PBC patient cohort in a tertiary center in central Israel were revealed. The results highlight the importance of risk stratification in PBC, specifically in younger patients, those presenting with a high level of liver enzymes and in ASMA-positive patients with an assumed diagnosis of the AIH-PBC variant.
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Affiliation(s)
- Eyal Yehezkel
- Center for Autoimmune Liver Diseases, Department of Gastroenterology, Tel Aviv Sourasky Medical Center, Tel Aviv 6423906, Israel; (E.Y.); (I.H.); (M.L.); (O.S.)
| | - Inbal Israel
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel;
| | - Inbal Houri
- Center for Autoimmune Liver Diseases, Department of Gastroenterology, Tel Aviv Sourasky Medical Center, Tel Aviv 6423906, Israel; (E.Y.); (I.H.); (M.L.); (O.S.)
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel;
| | - Moshe Leshno
- Center for Autoimmune Liver Diseases, Department of Gastroenterology, Tel Aviv Sourasky Medical Center, Tel Aviv 6423906, Israel; (E.Y.); (I.H.); (M.L.); (O.S.)
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel;
| | - Oren Shibolet
- Center for Autoimmune Liver Diseases, Department of Gastroenterology, Tel Aviv Sourasky Medical Center, Tel Aviv 6423906, Israel; (E.Y.); (I.H.); (M.L.); (O.S.)
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel;
| | - Ehud Zigmond
- Center for Autoimmune Liver Diseases, Department of Gastroenterology, Tel Aviv Sourasky Medical Center, Tel Aviv 6423906, Israel; (E.Y.); (I.H.); (M.L.); (O.S.)
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel;
- Correspondence:
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John BV, Aitcheson G, Schwartz KB, Khakoo NS, Dahman B, Deng Y, Goldberg D, Martin P, Taddei TH, Levy C, Kaplan DE. Male Sex Is Associated With Higher Rates of Liver-Related Mortality in Primary Biliary Cholangitis and Cirrhosis. Hepatology 2021; 74:879-891. [PMID: 33636012 DOI: 10.1002/hep.31776] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Revised: 01/10/2021] [Accepted: 02/01/2021] [Indexed: 12/18/2022]
Abstract
BACKGROUND AND AIMS The impact of sex on the postcirrhosis progression of primary biliary cholangitis (PBC) has not been well defined. Prior studies have suggested that men have worse outcomes but present at more advanced stages of fibrosis than women. This observation, however, has been limited by small numbers of men and even fewer patients with cirrhosis. APPROACH AND RESULTS We investigated the association of sex with the development of all-cause and liver-related mortality or transplantation, decompensation, and hepatocellular carcinoma (HCC), using competing-risk time-updating Cox proportional hazards models in a large cohort of predominantly male patients with PBC cirrhosis assembled from the Veterans Health Administration. In a cohort of 532 participants (418 male) with PBC-related cirrhosis with a total follow-up of 3,231.6 person-years (PY) from diagnosis of compensated cirrhosis, male participants had a higher unadjusted rates of death or transplantation (8.5 vs. 3.8 per 100 PY; P < 0.0001), liver-related death or transplantation (5.5 vs. 2.7 per 100 PY; P < 0.0001), decompensation (5.5 vs. 4.0 per 100 PY; P = 0.002), and HCC (0.9 vs. 0.3 per 100 PY; P < 0.0001). After adjusting for confounders, male sex was associated with a higher risk of death or transplantation (adjusted hazard ratio, 1.80; 95% CI, 1.01-3.19; P = 0.046), and liver-related death or transplantation (subhazard ratio, 2.17; 95% CI, 1.15-4.08; P = 0.02). A sensitivity analysis that defined ursodeoxycholic acid response as normalization of alkaline phosphatase and total bilirubin revealed similar findings. CONCLUSIONS In patients with PBC and well-compensated cirrhosis, male sex is associated with a higher risk of both death and liver-related death or transplantation.
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Affiliation(s)
- Binu V John
- Division of HepatologyBruce W Carter VA Medical CenterMiamiFLUSA
| | | | - Kaley B Schwartz
- Division of HepatologyBruce W Carter VA Medical CenterMiamiFLUSA
| | - Nidah S Khakoo
- Department of MedicineJackson Memorial HospitalMiamiFLUSA
| | - Bassam Dahman
- Department of Health Behavior and PolicyVirginia Commonwealth UniversityRichmondVAUSA
| | - Yangyang Deng
- Department of Health Behavior and PolicyVirginia Commonwealth UniversityRichmondVAUSA
| | - David Goldberg
- Division of Digestive Health and Liver DiseasesUniversity of Miami Miller School of MedicineMiamiFLUSA
| | - Paul Martin
- Division of Digestive Health and Liver DiseasesUniversity of Miami Miller School of MedicineMiamiFLUSA
| | - Tamar H Taddei
- Section of Digestive DiseasesYale School of MedicineNew HavenCTUSA.,Division of Gastroenterology and HepatologyVA Connecticut Healthcare SystemWest HavenCTUSA
| | - Cynthia Levy
- Division of Digestive Health and Liver DiseasesUniversity of Miami Miller School of MedicineMiamiFLUSA
| | - David E Kaplan
- Division of Gastroenterology and HepatologyUniversity of PennsylvaniaPhiladelphiaPAUSA.,Division of Gastroenterology and HepatologyCorporal Michael J. Crescenz VA Medical CenterPhiladelphiaPAUSA
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Cortez-Pinto H, Liberal R, Lopes S, Machado MV, Carvalho J, Dias T, Santos A, Agostinho C, Figueiredo P, Loureiro R, Martins A, Alexandrino G, Cotrim I, Leal C, Presa J, Mesquita M, Nunes J, Gouveia C, Vale AHE, Alves AL, Coelho M, Maia L, Pedroto I, Banhudo A, Pinto JS, Gomes MV, Oliveira J, Andreozzi V, Calinas F. Predictors for incomplete response to ursodeoxycholic acid in primary biliary cholangitis. Data from a national registry of liver disease. United European Gastroenterol J 2021; 9:699-706. [PMID: 34102008 PMCID: PMC8280809 DOI: 10.1002/ueg2.12095] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2020] [Accepted: 03/28/2021] [Indexed: 12/11/2022] Open
Abstract
Background The current standard of treatment in primary biliary cholangitis (PBC) is ursodeoxycholic acid (UDCA), although a considerable proportion of patients show incomplete response resulting in disease progression. Objective This study aimed to assess the prevalence of incomplete response to UDCA and determine associated patients' characteristics. Methods Patients with PBC as main diagnosis were included from a national multicentric patient registry—Liver.pt. Main endpoints included incomplete response to UDCA treatment according to Barcelona, Paris I and Paris II criteria, Globe and UK PBC scores and the association between baseline characteristics and incomplete response according to Paris II criteria. Results A total of 434 PBC patients were identified, with a mean age of 55 years and 89.2% females. Nearly half of patients were asymptomatic at diagnosis and 93.2% had positive anti‐mitochondrial antibodies. Almost all patients (95.6%) had been prescribed at least one drug for PBC treatment. At the last follow‐up visit, 93.3% were under treatment of which 99.8% received UDCA. Incomplete response to UDCA was observed in 30.7%, 35.3%, 53.7% and 36.4% of patients according to Barcelona, Paris I, Paris II criteria and Globe score, respectively. After adjusting for age and sex, and accordingly to Paris II criteria, the risk for incomplete biochemical response was 25% higher for patients with cirrhosis at diagnosis (odds ratio [OR] = 1.25; 95% confidence interval [95%CI]: 1.02–1.54; p = 0.033) and 35% (95%CI:1.06–1.72; p = 0.016) and 5% (OR = 1.05; 95%CI:1.01–1.10; p = 0.013) for those with elevated gamma‐glutamyl transferase (GGT) and alkaline phosphatase (ALP). Conclusion A considerable proportion of patients showed incomplete biochemical response to UDCA treatment according to Paris II criteria. Cirrhosis, elevated GGT and ALP at diagnosis were identified as associated risk factors for incomplete response. Early identification of patients at risk of incomplete response could improve treatment care and guide clinical decision to a more careful patient monitorization.
Summarise the established knowledge on this subject
Primary biliary cholangitis is a liver disease that can progress to end‐stage liver disease, with premature death or need for liver transplantation. Treatment with ursodeoxycholic acid (UDCA) significantly increases liver transplant‐free survival. However, incomplete response to UDCA reduces this beneficial effect.
What are the significant and/or new findings of this study?
By evaluating prevalence and risk factors for UDCA incomplete response through a large multicentric national registry it was found that 53.7% of patients were incomplete responders, according to Paris II criteria, with cirrhosis, elevated gamma‐glutamyl transferase and alkaline phosphatase at diagnosis as the main risk factors. These findings suggest that patients diagnosed at an advanced stage should be closely monitored and might benefit from novel therapies to improve outcomes if incomplete response is present.
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Affiliation(s)
- Helena Cortez-Pinto
- Clínica Universitária de Gastrenterologia, Departamento de Gastrenterologia, Faculdade de Medicina, Universidade de Lisboa, Centro Hospitalar Lisboa Norte, Lisboa, Portugal
| | - Rodrigo Liberal
- Gastroenterology Department, Centro Hospitalar e Universitário São João, Porto, Portugal.,Gastroenterology Department, Faculty of Medicine, University of Porto, Porto, Portugal
| | - Susana Lopes
- Gastroenterology Department, Centro Hospitalar e Universitário São João, Porto, Portugal.,Gastroenterology Department, Faculty of Medicine, University of Porto, Porto, Portugal
| | - Mariana V Machado
- Clínica Universitária de Gastrenterologia, Departamento de Gastrenterologia, Faculdade de Medicina, Universidade de Lisboa, Centro Hospitalar Lisboa Norte, Lisboa, Portugal.,Gastroenterology Department, Hospital Vila Franca de Xira, Vila Franca de Xira, Portugal
| | - Joana Carvalho
- Clínica Universitária de Gastrenterologia, Departamento de Gastrenterologia, Faculdade de Medicina, Universidade de Lisboa, Centro Hospitalar Lisboa Norte, Lisboa, Portugal
| | - Teresa Dias
- Department of Internal Medicine, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal
| | - Arsénio Santos
- Department of Internal Medicine, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal
| | - Cláudia Agostinho
- Gastroenterology Department, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal
| | - Pedro Figueiredo
- Gastroenterology Department, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal
| | - Rafaela Loureiro
- Gastroenterology Department, Central Lisbon Hospital Centre, Lisboa, Portugal
| | - Alexandra Martins
- Gastroenterology Department, Hospital Prof. Doutor Fernando da Fonseca, Lisboa, Portugal
| | - Gonçalo Alexandrino
- Gastroenterology Department, Hospital Prof. Doutor Fernando da Fonseca, Lisboa, Portugal
| | - Isabel Cotrim
- Gastroenterology Department, Centro Hospitalar de Leiria, Leiria, Portugal
| | - Carina Leal
- Gastroenterology Department, Centro Hospitalar de Leiria, Leiria, Portugal
| | - José Presa
- Internal Medicine Department, Liver Unit, Centro Hospitalar de Trás-os-Montes e Alto Douro, Vila Real, Portugal
| | - Mónica Mesquita
- Internal Medicine Department, Liver Unit, Centro Hospitalar de Trás-os-Montes e Alto Douro, Vila Real, Portugal
| | - Joana Nunes
- Gastroenterology Department, Hospital Beatriz Ângelo, Lisboa, Portugal
| | - Catarina Gouveia
- Gastroenterology Department, Hospital Beatriz Ângelo, Lisboa, Portugal
| | | | - Ana Luísa Alves
- Gastroenterology Department, Centro Hospitalar de Setúbal, Setúbal, Portugal
| | - Mariana Coelho
- Gastroenterology Department, Centro Hospitalar de Setúbal, Setúbal, Portugal
| | - Luís Maia
- Gastroenterology Department, Centro Hospitalar Universitário do Porto, Porto, Portugal
| | - Isabel Pedroto
- Gastroenterology Department, Centro Hospitalar Universitário do Porto, Porto, Portugal
| | - António Banhudo
- Gastroenterology Department, Unidade Local de Saúde Castelo Branco, Castelo Branco, Portugal
| | - João Sebastião Pinto
- Gastroenterology Department, Unidade Local de Saúde Castelo Branco, Castelo Branco, Portugal
| | | | | | | | - Filipe Calinas
- Gastroenterology Department, Central Lisbon Hospital Centre, Lisboa, Portugal
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Li H, Guan Y, Han C, Zhang Y, Liu Q, Wei W, Ma Y. The pathogenesis, models and therapeutic advances of primary biliary cholangitis. Biomed Pharmacother 2021; 140:111754. [PMID: 34044277 DOI: 10.1016/j.biopha.2021.111754] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Revised: 05/17/2021] [Accepted: 05/19/2021] [Indexed: 12/30/2022] Open
Abstract
Primary biliary cholangitis (PBC) is an autoimmune disease characterized by the destruction of intrahepatic small bile ducts and the presence of antimitochondrial antibody (AMA), eventually progresses to liver fibrosis and cirrhosis. Genetic predisposition and environmental factors are involved in the occurrence of PBC, and the epitopes exposure and the imbalance of autoimmune tolerance are the last straw. The apoptosis of biliary epithelial cell (BEC) leads to the release of autoantigen epitopes, which activate the immune system, and the disorder of innate and adaptive immunity eventually leads to the start of disease. Animal models have unique advantages in investigating the pathogenesis and drug exploitation of PBC. Multiple models have been reported, and spontaneous model and induced model have been widely used in relevant research of PBC in recent years. Currently, the only drugs licensed for PBC are ursodesoxycholic acid (UDCA) and obeticholic acid (OCA). In the last few years, as the learned more about the pathogenesis of PBC, more and more targets have been discovered, and multiple targeted drugs are being in developed. In this review, the pathogenesis, murine models and treatment strategies of PBC were summarized, and the current research status was discussed to provide insights for the further study of PBC.
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Affiliation(s)
- Hao Li
- Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, Hefei, China
| | - Yanling Guan
- Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, Hefei, China
| | - Chenchen Han
- Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, Hefei, China
| | - Yu Zhang
- Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, Hefei, China
| | - Qian Liu
- Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, Hefei, China
| | - Wei Wei
- Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, Hefei, China.
| | - Yang Ma
- Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, Hefei, China.
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42
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Mulinacci G, Palermo A, Invernizzi P, Carbone M. Old and novel prognostic biomarkers in primary biliary cholangitis. Expert Opin Orphan Drugs 2021. [DOI: 10.1080/21678707.2021.1927700] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Affiliation(s)
- G Mulinacci
- Division of Gastroenterology, Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milan Bicocca, Milan, Italy
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, Monza, Italy
| | - A Palermo
- Division of Gastroenterology, Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milan Bicocca, Milan, Italy
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, Monza, Italy
| | - Pietro Invernizzi
- Division of Gastroenterology, Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milan Bicocca, Milan, Italy
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, Monza, Italy
| | - Marco Carbone
- Division of Gastroenterology, Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milan Bicocca, Milan, Italy
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, Monza, Italy
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Takamura M, Matsuda Y, Kimura N, Takatsuna M, Setsu T, Tsuchiya A, Osaki A, Waguri N, Yanagi M, Takahashi T, Sugitani S, Kobayashi Y, Yoshikawa A, Ishikawa T, Yoshida T, Watanabe T, Bannai H, Kubota T, Funakoshi K, Wakabayashi H, Kurita S, Ogata N, Watanabe M, Mita Y, Mori S, Sugiyama M, Miyajima T, Takahashi S, Sato S, Ishizuka K, Ohta H, Aoyagi Y, Terai S. Changes in disease characteristics of primary biliary cholangitis: An observational retrospective study from 1982 to 2016. Hepatol Res 2021; 51:166-175. [PMID: 33126288 DOI: 10.1111/hepr.13586] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2020] [Revised: 10/14/2020] [Accepted: 10/23/2020] [Indexed: 12/13/2022]
Abstract
AIM Disease characteristics of primary biliary cholangitis have changed recently. However, detailed studies on the subject have been limited. Therefore, we aimed to clarify disease characteristics of patients with recent primary biliary cholangitis using the cohort from Niigata University and 21 affiliated hospitals. METHODS Overall, 508 patients were enrolled in this study from 1982 to 2016, divided into three cohorts according to their year of diagnosis: ≤1999, 2000-2009 and ≥2010. We compared differences in clinical characteristics, response to ursodeoxycholic acid and prognosis. RESULTS The male-to-female ratio increased incrementally from 1:16.4 (≤1999) to 1:3.8 (≥2010) (P < 0.001). In women, the median age at diagnosis increased incrementally from 54.0 years (≤1999) to 60.5 years (≥2010) (P < 0.001) and serum albumin decreased gradually (P = 0.001), which might have affected the increase in the Fibrosis-4 Index and albumin-bilirubin score. The ursodeoxycholic acid response rate according to the Barcelona criteria increased incrementally from 26.7% (≤1999) to 78.4% (≥2010) (P < 0.010), and those according to other criteria (Paris-I, Rotterdam and Toronto) were approximately ≥80% in all cohorts. Ten-year survival rate in the ≤1999 and 2000-2009 cohorts were 98.6% and 95.6%, respectively. These earlier cohorts were also characterized by a higher rate of asymptomatic state and mild histology (83.5% [≤1999] and 84.7% [2000-2009], and 93.6% [≤1999] and 91.1% [2000-2009]). CONCLUSIONS Patients with primary biliary cholangitis were characterized by older age at diagnosis and an increase in male to female ratio as well as higher response rates of ursodeoxycholic acid and longer survival, resulting from the early recognition of primary biliary cholangitis.
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Affiliation(s)
- Masaaki Takamura
- Division of Gastroenterology and Hepatology, Niigata University Graduate School of Medical and Dental Science, Niigata, Niigata, Japan
| | - Yasunobu Matsuda
- Department of Medical Technology, Niigata University Graduate School of Health Sciences, Niigata, Niigata, Japan
| | - Naruhiro Kimura
- Division of Gastroenterology and Hepatology, Niigata University Graduate School of Medical and Dental Science, Niigata, Niigata, Japan
| | - Masafumi Takatsuna
- Division of Gastroenterology and Hepatology, Niigata University Graduate School of Medical and Dental Science, Niigata, Niigata, Japan
| | - Toru Setsu
- Division of Gastroenterology and Hepatology, Niigata University Graduate School of Medical and Dental Science, Niigata, Niigata, Japan
| | - Atsunori Tsuchiya
- Division of Gastroenterology and Hepatology, Niigata University Graduate School of Medical and Dental Science, Niigata, Niigata, Japan
| | - Akihiko Osaki
- Niigata City General Hospital, Niigata, Niigata, Japan
| | - Nobuo Waguri
- Niigata City General Hospital, Niigata, Niigata, Japan
| | - Masahiko Yanagi
- JA Niigata Kouseiren Ojiya General Hospital, Ojiya, Niigata, Japan
| | - Toru Takahashi
- JA Niigata Kouseiren Ojiya General Hospital, Ojiya, Niigata, Japan
| | - Soichi Sugitani
- JA Niigata Kouseiren Murakami general Hospital, Murakami, Niigata, Japan
| | - Yuka Kobayashi
- JA Niigata Kouseiren Nagaoka Chuo General Hospital, Nagaoka, Niigata, Japan
| | - Akira Yoshikawa
- JA Niigata Kouseiren Nagaoka Chuo General Hospital, Nagaoka, Niigata, Japan
| | | | | | | | | | | | | | | | - So Kurita
- Niigata Cancer Center Hospital, Niigata, Niigata, Japan
| | - Norio Ogata
- Niigata Cancer Center Hospital, Niigata, Niigata, Japan
| | | | | | - Shigeki Mori
- Niitsu Medical Center Hospital, Niigata, Niigata, Japan
| | | | - Toru Miyajima
- JA Niigata Kouseiren Toyosaka Hospital, Niigata, Niigata, Japan
| | | | | | - Kisei Ishizuka
- Niigata Shirone General Hospital, Niigata, Niigata, Japan
| | - Hironobu Ohta
- Niigata Shirone General Hospital, Niigata, Niigata, Japan
| | | | - Shuji Terai
- Division of Gastroenterology and Hepatology, Niigata University Graduate School of Medical and Dental Science, Niigata, Niigata, Japan
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Gomez E, Garcia Buey L, Molina E, Casado M, Conde I, Berenguer M, Jorquera F, Simón MA, Olveira A, Hernández-Guerra M, Mesquita M, Presa J, Costa-Moreira P, Macedo G, Arenas JI, Manuel Sousa J, Ampuero J, Morillas RM, Santos A, De Carvalho A, Uriz J, Carrión JA, Luisa Gutiérrez M, Pérez-Fernández E, Fernández-Rodríguez CM. Effectiveness and safety of obeticholic acid in a Southern European multicentre cohort of patients with primary biliary cholangitis and suboptimal response to ursodeoxycholic acid. Aliment Pharmacol Ther 2021; 53:519-530. [PMID: 33314220 DOI: 10.1111/apt.16181] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2020] [Revised: 09/02/2020] [Accepted: 11/10/2020] [Indexed: 12/09/2022]
Abstract
BACKGROUND Obeticholic acid (OCA) was recently approved as the only on-label alternative for patients with primary biliary cholangitis (PBC) with intolerance or suboptimal response to ursodeoxycholic acid (UDCA). However, few data are available outside clinical trials. AIM To assess the effectiveness and safety of OCA in a real-world cohort of patients with non-effective UDCA therapy. METHODS Open-label, prospective, real-world, multicentre study, enrolling consecutive patients who did not meet Paris II criteria, from 18 institutions in Spain and Portugal. Effectiveness was assessed by the changes in GLOBE and UK-PBC scores from baseline. POISE and Paris II criteria were evaluated after 12 months of OCA . Liver fibrosis was evaluated by FIB-4 and AST to platelet ratio index (APRI). RESULTS One hundred and twenty patients were eligible, median time since PBC diagnosis 9.3 (4.0-13.8) years, 21.7% had cirrhosis, and 26.7% received had previous or concomitant treatment with fibrates. Seventy-eight patients completed at least 1 year of OCA. The Globe-PBC score decreased to 0.17 (95% CI 0.05 to 0.28; P = 0.005) and the UK-PBC score decreased to 0.81 (95% CI -0.19 to 1.80; P = 0.11). There was a significant decrease in alkaline phosphatase of 81.3 U/L (95% CI 42.5 to 120; P < 0.001), ALT 22.1 U/L (95% CI 10.4 to 33.8; P < 0.001) and bilirubin 0.12 mg/dL (95% CI 0 to 0.24; P = 0.044). FIB-4 and APRI remained stable. According to the POISE criteria, 29.5% (23 out of 78) achieved response. The adverse events rate was 35%; 11.67% discontinued (8.3% due to pruritus). CONCLUSIONS This study supports data from phase III trials with significant improvement of PBC-Globe continuous prognostic marker score among OCA-treated patients with good tolerability.
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Gochanour EM, Kowdley KV. Investigational drugs in early phase development for primary biliary cholangitis. Expert Opin Investig Drugs 2020; 30:131-141. [PMID: 33249947 DOI: 10.1080/13543784.2021.1857364] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Introduction: With a large percentage of patients having an incomplete response or intolerance to current FDA approved medications, new therapies for the treatment of primary biliary cholangitis are in great demand. Areas covered: In this review, we assess currently available drugs as well as promising new therapies for the treatment of primary biliary cholangitis. A literature search was performed with the following search terms: 'PBC treatment,' 'PBC therapeutics,' 'PBC clinical trials,' and included original articles, meta-analyses, and systematic reviews from 1 January 1981, to 1 January 2020. ClinicalTrials.gov was accessed for data from ongoing trials. Expert opinion: Targeted drug therapies offer an alternative for patients who are unable to meet their therapeutic goals with either of the two currently approved treatment options. Specifically, new drugs targeting bile-acid regulation, immune-modulation, and fibrogenic pathways are currently in development with multiple agents showing encouraging early results with the ultimate goal of developing therapies that will achieve high rates of biochemical remission, will be well tolerated, and improve symptoms and quality of life in patients with primary biliary cholangitis. Based on a review of the current literature, PPAR agonists appear to be promising agents, along with FGF19 analogs and FXR agonists.
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Kaps L, Grambihler A, Yemane B, Nagel M, Labenz C, Ploch P, Michel M, Galle PR, Wörns MA, Schattenberg JM. Symptom Burden and Treatment Response in Patients with Primary Biliary Cholangitis (PBC). Dig Dis Sci 2020; 65:3006-3013. [PMID: 31853781 DOI: 10.1007/s10620-019-06009-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2019] [Accepted: 12/10/2019] [Indexed: 12/27/2022]
Abstract
BACKGROUND Primary biliary cholangitis (PBC) is a chronic, cholestatic liver disease that can lead to end-stage liver disease and impairs the quality of life. At current, most data come from few large cohorts. AIM This cross-sectional study evaluated treatment response and symptom burden in patients with PBC in Germany to expand the available data. METHODS A total of 140 PBC patients were prospectively enrolled at the outpatient liver clinic of the University Medical Center in Mainz starting in June 2016. Historic and current response rates of UDCA treatment were determined using published binary models. Symptom burden was assessed using the PBC-40 questionnaire. RESULTS The primary treatment response ranged between 73 and 86% depending on the definition used. Importantly, this response rate was maintained over a median time of 5 years in follow-up. The highest symptom burden was observed for fatigue and emotional (2.4 ± 1; 2.3 ± 1.1 of 5), while pruritus (1.1 ± 1.1 of 5) had the lowest scores. IgG correlated with the PBC-40 domain social (r = 0.211, p = 0.032), while HDL inversely correlated with the symptom burden of pruritus (r = - 0.236; p = 0.018). CONCLUSION In this tertiary care cohort, 75% of the patients showed biochemical response after 1 year according to the acknowledged Paris II criteria. Patients reported a significant symptom burden, and the domain fatigue of the PBC-40 was most prominently impaired.
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Affiliation(s)
- Leonard Kaps
- I. Department of Medicine, University Medical Center of the Johannes Gutenberg-University, Langenbeckstrasse 1, 55131, Mainz, Germany.,Metabolic Liver Research Program, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany
| | - Annette Grambihler
- I. Department of Medicine, University Medical Center of the Johannes Gutenberg-University, Langenbeckstrasse 1, 55131, Mainz, Germany.,Metabolic Liver Research Program, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany
| | - Bethlehem Yemane
- Metabolic Liver Research Program, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany
| | - Michael Nagel
- I. Department of Medicine, University Medical Center of the Johannes Gutenberg-University, Langenbeckstrasse 1, 55131, Mainz, Germany.,Metabolic Liver Research Program, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany
| | - Christian Labenz
- I. Department of Medicine, University Medical Center of the Johannes Gutenberg-University, Langenbeckstrasse 1, 55131, Mainz, Germany.,Metabolic Liver Research Program, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany
| | - Pascal Ploch
- I. Department of Medicine, University Medical Center of the Johannes Gutenberg-University, Langenbeckstrasse 1, 55131, Mainz, Germany.,Metabolic Liver Research Program, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany
| | - Maurice Michel
- I. Department of Medicine, University Medical Center of the Johannes Gutenberg-University, Langenbeckstrasse 1, 55131, Mainz, Germany.,Metabolic Liver Research Program, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany
| | - Peter R Galle
- I. Department of Medicine, University Medical Center of the Johannes Gutenberg-University, Langenbeckstrasse 1, 55131, Mainz, Germany
| | - Marcus-Alexander Wörns
- I. Department of Medicine, University Medical Center of the Johannes Gutenberg-University, Langenbeckstrasse 1, 55131, Mainz, Germany
| | - Jörn M Schattenberg
- I. Department of Medicine, University Medical Center of the Johannes Gutenberg-University, Langenbeckstrasse 1, 55131, Mainz, Germany. .,Metabolic Liver Research Program, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany.
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Pinto C, Ninfole E, Gaggiano L, Benedetti A, Marzioni M, Maroni L. Aging and the Biological Response to Liver Injury. Semin Liver Dis 2020; 40:225-232. [PMID: 31887774 DOI: 10.1055/s-0039-3402033] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
Interest in understanding the aging process has recently risen in the scientific community. Aging, commonly defined as the functional decline in the function of organs and tissues, is indeed the major risk factor for the development of many chronic diseases, such as cardiovascular diseases, pathologies of nervous system, or cancer. To date, the influence of aging in the pathophysiology of liver and biliary diseases is not fully understood. Although liver cells have a high regenerative capacity, hepatocytes and cholangiocytes undergo extensive molecular changes in response to aging. Following time-dependent damage induced by aging, liver cells initially activate compensatory mechanisms that, if hyperstimulated, may lead to the decline of regenerative capacity and the development of pathologies. A deeper understanding of molecular aging has undoubtedly the potential to improve the clinical management of patients, possibly unveiling new pathways for selective drug treatment.
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Affiliation(s)
- Claudio Pinto
- Department of Gastroenterology and Hepatology, Università Politecnica delle Marche, Ancona, Italy
| | - Elisabetta Ninfole
- Department of Gastroenterology and Hepatology, Università Politecnica delle Marche, Ancona, Italy
| | - Laura Gaggiano
- Department of Gastroenterology and Hepatology, Università Politecnica delle Marche, Ancona, Italy
| | - Antonio Benedetti
- Department of Gastroenterology and Hepatology, Università Politecnica delle Marche, Ancona, Italy
| | - Marco Marzioni
- Department of Gastroenterology and Hepatology, Università Politecnica delle Marche, Ancona, Italy
| | - Luca Maroni
- Department of Gastroenterology and Hepatology, Università Politecnica delle Marche, Ancona, Italy
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Roberts SB, Ismail M, Kanagalingam G, Mason AL, Swain MG, Vincent C, Yoshida EM, Tsien C, Flemming JA, Janssen HLA, Hirschfield GM, Hansen BE, Gulamhusein AF. Real-World Effectiveness of Obeticholic Acid in Patients with Primary Biliary Cholangitis. Hepatol Commun 2020; 4:1332-1345. [PMID: 32923836 PMCID: PMC7471421 DOI: 10.1002/hep4.1518] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2019] [Revised: 02/07/2020] [Accepted: 03/26/2020] [Indexed: 12/30/2022] Open
Abstract
Patients with primary biliary cholangitis (PBC) with incomplete response to ursodeoxycholic acid are at risk of disease progression and need additional therapy. Obeticholic acid (OCA) was approved in Canada in May 2017, but its effectiveness in a real‐world setting has not been described. We sought to describe our experience with OCA in a Canadian cohort. OCA‐naive patients treated at two Canadian centers were included. Clinical and biochemical data were collected at OCA initiation and during follow‐up. Primary outcomes were changes in serum alkaline phosphatase (ALP), gamma‐glutamyl transferase (GGT), and total bilirubin (TB) over the duration of therapy. Secondary outcomes were changes in alanine aminotransferase (ALT), aspartate aminotransferase (AST), immunoglobulin M (IgM), platelets, and albumin; and achievement of the primary endpoint of the original phase 3 study that led to OCA approval (A Placebo‐Controlled Trial of Obeticholic Acid in Primary Biliary Cholangitis [POISE]), dose reductions, discontinuations, and tolerability. Repeated‐measures models were used to assess changes in biochemistry over time. Sixty‐four patients were included; 4 carried a diagnosis of overlap with autoimmune hepatitis. Mean age was 54.6 years, median ALP was 250 U/L, TB was 13 µmol/L, platelet count was 225 × 109/L, and 24% had liver stiffness measurements ≥16.9 kPa. There was a significant reduction in mean ALP of 55 U/L (P < 0.001), GGT of 138 U/L (P < 0.001), ALT of 11.9 U/L (P < 0.001), AST of 5.7 U/L (P < 0.05), and IgM of 0.70 g/L (P < 0.001) over 12 months; TB remained stable (P = 0.98). Forty‐four patients met POISE‐inclusion criteria, 39% (n = 17) of whom had 12‐month biochemical measurements. In this subset, 18% (n = 3/17) met the 12‐month POISE primary endpoint, but considering follow‐up to 19 months, 43% achieved this target (n = 9/21). Pruritus was the most commonly reported complaint. Conclusion: Use of OCA was associated with improvement in biochemical surrogates of outcome in PBC in a real‐world setting.
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Affiliation(s)
- Surain B Roberts
- Toronto Centre for Liver Disease Toronto General Hospital University Health Network Toronto ON Canada.,Institute of Health Policy, Management and Evaluation University of Toronto Toronto ON Canada
| | - Marwa Ismail
- Toronto Centre for Liver Disease Toronto General Hospital University Health Network Toronto ON Canada
| | - Gowthami Kanagalingam
- Toronto Centre for Liver Disease Toronto General Hospital University Health Network Toronto ON Canada
| | - Andrew L Mason
- Department of Medicine University of Alberta Edmonton AB Canada
| | - Mark G Swain
- Department of Medicine University of Calgary Calgary AB Canada
| | | | - Eric M Yoshida
- Department of Medicine University of British Columbia Vancouver BC Canada
| | - Cynthia Tsien
- Department of Medicine University of Ottawa Ottawa ON Canada
| | | | - Harry L A Janssen
- Toronto Centre for Liver Disease Toronto General Hospital University Health Network Toronto ON Canada
| | - Gideon M Hirschfield
- Toronto Centre for Liver Disease Toronto General Hospital University Health Network Toronto ON Canada
| | - Bettina E Hansen
- Toronto Centre for Liver Disease Toronto General Hospital University Health Network Toronto ON Canada.,Institute of Health Policy, Management and Evaluation University of Toronto Toronto ON Canada
| | - Aliya F Gulamhusein
- Toronto Centre for Liver Disease Toronto General Hospital University Health Network Toronto ON Canada.,Institute of Health Policy, Management and Evaluation University of Toronto Toronto ON Canada
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Phaw NA, Dyson JK, Jones D. Emerging drugs for the treatment of primary biliary cholangitis. Expert Opin Emerg Drugs 2020; 25:101-112. [PMID: 32253941 DOI: 10.1080/14728214.2020.1751814] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
INTRODUCTION Primary biliary cholangitis (PBC) is a progressive inflammatory autoimmune cholestatic liver disease. Without treatment, it may result in fibrosis and eventually end stage liver disease. In addition to the disease burden, the symptom impact on the quality of life for PBC patients is significant. Ursodeoxycholic acid, and the second-line therapy, Obeticholic acid, are the only available licensed treatments. Although there has been rapid development of novel therapies in recent years for the treatment of PBC, there are very few symptoms directed therapies. AREA COVERED This literature review aims to review the current treatment landscape in PBC and to explore how the next few years may unfold in the field. The current guidelines and emerging therapies in phase 2, 3 and 4 clinical trials have been included. EXPERT OPINION The currently available therapies are effective, but their use has limitations and challenges and there is still significant unmet need. Although there have been promising therapeutic interventions in recent years, further research into personalizing therapeutic strategies with available treatments and new agents is needed.
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Affiliation(s)
- Naw April Phaw
- Institute of Translational and Clinical Research, Newcastle University , Newcastle-upon-Tyne, UK.,Hepatology Department, Newcastle Hospital NHS Foundation Trust , Newcastle-upon-Tyne, UK
| | - Jessica Katharine Dyson
- Institute of Translational and Clinical Research, Newcastle University , Newcastle-upon-Tyne, UK.,Hepatology Department, Newcastle Hospital NHS Foundation Trust , Newcastle-upon-Tyne, UK
| | - David Jones
- Institute of Translational and Clinical Research, Newcastle University , Newcastle-upon-Tyne, UK.,Hepatology Department, Newcastle Hospital NHS Foundation Trust , Newcastle-upon-Tyne, UK.,NIHR Newcastle Biomedical Research Centre, Newcastle University , Newcastle-upon-Tyne, UK
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50
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Factors Associated With Progression and Outcomes of Early Stage Primary Biliary Cholangitis. Clin Gastroenterol Hepatol 2020; 18:684-692.e6. [PMID: 31419573 DOI: 10.1016/j.cgh.2019.08.013] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2018] [Revised: 07/26/2019] [Accepted: 08/02/2019] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS Patients usually receive a diagnosis of primary biliary cholangitis (PBC) at an early stage, based on biochemical analyses. We investigated the proportion of patients who progress to moderate or advanced PBC and factors associated with progression and patient survival. METHODS We obtained data from 1615 patients (mean age, 55.4 y) with early stage PBC (based on their normal levels of albumin and bilirubin), collected at the time of initial evaluation or treatment, from the Global PBC Study Group database (comprising patients at 19 liver centers in North American and European countries). We collected data from health care evaluations on progression to moderate PBC (abnormal level of bilirubin or albumin) or advanced-stage PBC (abnormal level of both). The median follow-up time was 7.9 years. The composite end point was decompensation, hepatocellular carcinoma, liver transplantation, or death. RESULTS Of the 1615 patients identified with early stage PBC, 904 developed moderate PBC and 201 developed advanced disease over the study period. The proportions of patients who transitioned to moderate PBC at 1, 3, and 5 years were 12.9%, 30.2%, and 45.8%. The proportions of these patients who then transitioned to advanced PBC at 1, 3, and 5 years later were 3.4%, 12.5%, and 16.0%, respectively. During the follow-up period, 236 patients had a clinical event. The proportions of patients with moderate PBC and event-free survival were 97.9%, 95.1%, and 91.5% at 1, 3, and 5 years, respectively, and the proportions of patients with advanced PBC and event-free survival were 90.6%, 71.2%, and 58.3% at 1, 3, and 5 years later, respectively. Variables associated with transition from early to moderate PBC included baseline levels of bilirubin, albumin, and alkaline phosphatase; aspartate to alanine aminotransferase ratio; platelet count; and treatment with ursodeoxycholic acid. Transitions from early to moderate PBC and from moderate to advanced PBC were associated with higher probabilities of a clinical event (time-dependent hazard ratios, 3.0; 95% CI, 2.0-4.5; and 4.6; 95% CI, 3.5-6.2). CONCLUSIONS Approximately half of patients with early stage PBC progress to a more severe stage within 5 years. Progression is associated with an increased risk of a clinical event, so surveillance is important for patients with early stage PBC.
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