|
1
|
Warsop Z, Anand N, Al Maliki H, De Souza S, Kamyab A, Al Hadad A, Alrubaiy L. Up-to-Date Snapshot of Current and Emerging Medical Therapies in Primary Biliary Cholangitis. J Pers Med 2024; 14:1133. [PMID: 39728045 DOI: 10.3390/jpm14121133] [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: 07/09/2024] [Revised: 09/06/2024] [Accepted: 11/21/2024] [Indexed: 12/28/2024] Open
Abstract
Background/Objectives: Primary biliary cholangitis (PBC) is an autoimmune chronic cholestatic disease of the liver that symptomatically can present with pruritus and fatigue. Its established first- and second-line therapies are ursodeoxycholic acid (UDCA) and obeticholic acid (OCA) although they provide limited symptom management. Liver transplantation offers a potentially curative therapeutic option in refractory cases progressing to cirrhosis. Novel research published after the current guidelines highlights the importance of providing an up-to-date analysis of treatment options available. Methods: In this study, we conducted a literature search using Pubmed, Ovid Medline, and SCOPUS to provide a narrative review of first-line, second-line, and emerging therapies in PBC. Results: UDCA has been well established as a long-term, safe therapy within the literature although it is possible that treatment dosage can be further optimised in refractory patients. It has a favourable side effect profile. Despite improving biochemical markers, histopathological profile, and overall outcomes, up to 30-40% of patients are refractory to it. Age and sex are highlighted as independent indicators of non-responsiveness. This necessitates effective second-line therapies. Future trials could aim to investigate UDCA as a co-first-line therapy. Further supporting results for OCA were found in the interim extension trial of the seminal POISE study. The long-term phase 4 COBOLT trial is still awaiting results to further assess the complications, adherence, and potential adverse effects. It is a viable option in UDCA-refractory patients. The high incidence rate of dose-related pruritis indicates that alternative second-line options are needed. Bezafibrate is an off-label antilipemic agent that shows promise as a prospective second-line therapy option. The landmark BEZURSO trial alleviated some efficacy and safety concerns, but it remains associated with elevated serum creatinine; thus, it should be considered with caution. Other prospective second-line therapies are budesonide, triple therapy, and novel agents such as seladelpar and elafibranor. Conclusions: UDCA should remain the treatment of choice for PBC, though perhaps not as monotherapy. With further investigation, BF shows promise as a new second-line therapy alongside OCA, which it may outperform.
Collapse
Affiliation(s)
- Zakary Warsop
- Gastroenterology and Hepatology Department, Imperial College London, London SW7 2AZ, UK
| | - Nikhil Anand
- Gastroenterology and Hepatology Department, Imperial College London, London SW7 2AZ, UK
| | - Husam Al Maliki
- Gastroenterology and Hepatology Department, Imperial College London, London SW7 2AZ, UK
| | - Shuell De Souza
- Gastroenterology and Hepatology Department, Imperial College London, London SW7 2AZ, UK
| | - Arya Kamyab
- Gastroenterology and Hepatology Department, Imperial College London, London SW7 2AZ, UK
| | - Amin Al Hadad
- Healthpoint Hospital, Abu Dhabi 112308, United Arab Emirates
| | - Laith Alrubaiy
- Healthpoint Hospital, Abu Dhabi 112308, United Arab Emirates
- Department of Medicine Health and Life Sciences, Singleton Bay Campus, Swansea University School of Medicine, Swansea SA2 8PP, UK
| |
Collapse
|
|
2
|
Costello RE, Waller KMJ, Smith R, Mells GF, Wong AYS, Schultze A, Mahalingasivam V, Herrett E, Zheng B, Lin LY, MacKenna B, Mehrkar A, Bacon SCJ, Goldacre B, Tomlinson LA, Tazare J, Rentsch CT. Ursodeoxycholic acid and severe COVID-19 outcomes in a cohort study using the OpenSAFELY platform. COMMUNICATIONS MEDICINE 2024; 4:238. [PMID: 39562612 PMCID: PMC11576861 DOI: 10.1038/s43856-024-00664-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2024] [Accepted: 11/05/2024] [Indexed: 11/21/2024] Open
Abstract
BACKGROUND Biological evidence suggests ursodeoxycholic acid (UDCA)-a common treatment of cholestatic liver disease-may prevent severe COVID-19 outcomes. We aimed to compare the hazard of COVID-19 hospitalisation or death between UDCA users versus non-users in a population with primary biliary cholangitis (PBC) or primary sclerosing cholangitis (PSC). METHODS With the approval of NHS England, we conducted a population-based cohort study using primary care records between 1 March 2020 and 31 December 2022, linked to death registration data and hospital records through the OpenSAFELY-TPP platform. Cox proportional hazards regression was used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for the association between time-varying UDCA exposure and COVID-19 related hospitalisation or death, stratified by geographical region and considering models unadjusted and fully adjusted for pre-specified confounders. RESULTS We identify 11,305 eligible individuals, 640 were hospitalised or died with COVID-19 during follow-up, 400 (63%) events among UDCA users. After confounder adjustment, UDCA is associated with a 21% relative reduction in the hazard of COVID-19 hospitalisation or death (HR 0.79, 95% CI 0.67-0.93), consistent with an absolute risk reduction of 1.35% (95% CI 1.07%-1.69%). CONCLUSIONS We found evidence that UDCA is associated with a lower hazard of COVID-19 related hospitalisation and death, support calls for clinical trials investigating UDCA as a preventative measure for severe COVID-19 outcomes.
Collapse
Affiliation(s)
| | - Karen M J Waller
- Collaborative Centre for Organ Donation Evidence, Sydney School of Public Health, Faculty of Medicine and Health, University of Sydney, Camperdown, NSW, Australia
- NHMRC Clinical Trials Centre, University of Sydney, Camperdown, NSW, Australia
- Department of Gastroenterology & Hepatology, Concord Repatriation General Hospital, Concord, NSW, Australia
| | - Rachel Smith
- Cambridge Liver Unit, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | - George F Mells
- Cambridge Liver Unit, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
- Academic Department of Medical Genetics, University of Cambridge, Cambridge, UK
| | - Angel Y S Wong
- London School of Hygiene and Tropical Medicine, London, UK
| | - Anna Schultze
- London School of Hygiene and Tropical Medicine, London, UK
| | | | - Emily Herrett
- London School of Hygiene and Tropical Medicine, London, UK
| | - Bang Zheng
- London School of Hygiene and Tropical Medicine, London, UK
| | - Liang-Yu Lin
- London School of Hygiene and Tropical Medicine, London, UK
| | - Brian MacKenna
- Bennett Institute for Applied Data Science, Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, UK
| | - Amir Mehrkar
- Bennett Institute for Applied Data Science, Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, UK
| | - Sebastian C J Bacon
- Bennett Institute for Applied Data Science, Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, UK
| | - Ben Goldacre
- Bennett Institute for Applied Data Science, Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, UK
| | | | - John Tazare
- London School of Hygiene and Tropical Medicine, London, UK
| | - Christopher T Rentsch
- London School of Hygiene and Tropical Medicine, London, UK
- Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA
| |
Collapse
|
|
3
|
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.
Collapse
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
| |
Collapse
|
|
4
|
van Hooff MC, de Veer RC, Karam V, Adam R, Taimr P, Polak WG, Pashtoun H, Murad SD, Corpechot C, Mirza D, Heneghan M, Lodge P, Oniscu GC, Thorburn D, Allison M, Metselaar HJ, den Hoed CM, van der Meer AJ. Type of calcineurin inhibitor and long-term outcomes following liver transplantation in patients with primary biliary cholangitis - an ELTR study. JHEP Rep 2024; 6:101100. [PMID: 39045337 PMCID: PMC11263784 DOI: 10.1016/j.jhepr.2024.101100] [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: 12/12/2023] [Revised: 04/09/2024] [Accepted: 04/16/2024] [Indexed: 07/25/2024] Open
Abstract
BACKGROUND & AIMS Tacrolimus has been associated with recurrence of primary biliary cholangitis (PBC) after liver transplantation (LT), which in turn may reduce survival. This study aimed to assess the association between the type of calcineurin inhibitor used and long-term outcomes following LT in patients with PBC. METHODS Survival analyses were used to assess the association between immunosuppressive drugs and graft or patient survival among adult patients with PBC in the European Liver Transplant Registry. Patients who received a donation after brain death graft between 1990 and 2021 with at least 1 year of event-free follow-up were included. RESULTS In total, 3,175 patients with PBC were followed for a median duration of 11.4 years (IQR 5.9-17.9) after LT. Tacrolimus (Tac) was registered in 2,056 (64.8%) and cyclosporin in 819 (25.8%) patients. Following adjustment for recipient age, recipient sex, donor age, and year of LT, Tac was not associated with higher risk of graft loss (adjusted hazard ratio [aHR] 1.07, 95% CI 0.92-1.25, p = 0.402) or death (aHR 1.06, 95% CI 0.90-1.24, p = 0.473) over cyclosporin. In this model, maintenance mycophenolate mofetil (MMF) was associated with a lower risk of graft loss (aHR 0.72, 95% CI 0.60-0.87, p <0.001) or death (aHR 0.72, 95% CI 0.59-0.87, p <0.001), while these risks were higher with use of steroids (aHR 1.31, 95% CI 1.13-1.52, p <0.001, and aHR 1.34, 95% CI 1.15-1.56, p <0.001, respectively). CONCLUSIONS In this large LT registry, type of calcineurin inhibitor was not associated with long-term graft or recipient survival, providing reassurance regarding the use of Tac post LT in the population with PBC. Patients using MMF had a lower risk of graft loss and death, indicating that the threshold for combination treatment with Tac and MMF should be low. IMPACT AND IMPLICATIONS This study investigated the association between immunosuppressive drugs and the long-term survival of patients with primary biliary cholangitis (PBC) following donation after brain death liver transplantation. While tacrolimus has previously been related to a higher risk of PBC recurrence, the type of calcineurin inhibitor was not related to graft or patient survival among patients transplanted for PBC in the European Liver Transplant Registry. Additionally, maintenance use of mycophenolate was linked to lower risks of graft loss and death, while these risks were higher with maintenance use of steroids. Our findings should provide reassurance for physicians regarding the continued use of Tac after liver transplantation in the population with PBC, and suggest potential benefit from combination therapy with mycophenolate.
Collapse
Affiliation(s)
- Maria C. van Hooff
- Department of Gastroenterology and Hepatology, Erasmus MC Transplant Institute, University Medical Center Rotterdam, The Netherlands
| | - Rozanne C. de Veer
- Department of Gastroenterology and Hepatology, Erasmus MC Transplant Institute, University Medical Center Rotterdam, The Netherlands
| | - Vincent Karam
- European Society for Organ Transplantation, Amsterdam, The Netherlands
| | - Rene Adam
- European Liver Transplant Registry, Department of Hepatobiliary and Pancreatic Surgery and Liver Transplantation AP-HP Hôpital Paul Brousse, Université Paris-Saclay Villejuif, France
| | - Pavel Taimr
- Department of Hepatology and Gastroenterology, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | - Wojciech G. Polak
- Department of Surgery, Division of HPB & Transplant Surgery, Erasmus MC Transplant Institute, University Medical Center Rotterdam, The Netherlands
| | - Hasina Pashtoun
- Department of Gastroenterology and Hepatology, Erasmus MC Transplant Institute, University Medical Center Rotterdam, The Netherlands
| | - Sarwa Darwish Murad
- Department of Gastroenterology and Hepatology, Erasmus MC Transplant Institute, University Medical Center Rotterdam, The 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 University, Paris, France
| | - Darius Mirza
- Department of HPB Surgery, Liver Unit, Queen Elizabeth Hospital, Birmingham, United Kingdom
| | - Michael Heneghan
- Institute of Liver Studies, King’s College Hospital, London, United Kingdom
| | - Peter Lodge
- The Leeds Teaching Hospitals NHS Trust, Leeds, United Kingdom
| | - Gabriel C. Oniscu
- Edinburgh Transplant Centre, Royal Infirmary of Edinburgh, Edinburg, United Kingdom
- Division of Transplantation, CLINTEC, Karolinska Institutet, Stockholm, Sweden
| | - Douglas Thorburn
- Department of Hepatology and Liver Transplantation, Royal Free Hospital, London, United Kingdom
| | - Michael Allison
- Liver Unit, Cambridge University Hospitals NHS Foundation Trust, Cambridge NIHR Biomedical Research Centre, Cambridge, United Kingdom
| | - Herold J. Metselaar
- Department of Gastroenterology and Hepatology, Erasmus MC Transplant Institute, University Medical Center Rotterdam, The Netherlands
| | - Caroline M. den Hoed
- Department of Gastroenterology and Hepatology, Erasmus MC Transplant Institute, University Medical Center Rotterdam, The Netherlands
| | - Adriaan J. van der Meer
- Department of Gastroenterology and Hepatology, Erasmus MC Transplant Institute, University Medical Center Rotterdam, The Netherlands
| |
Collapse
|
|
5
|
Akepati PR, Gochanour EM. Investigational farnesoid X receptor agonists for the treatment of primary biliary cholangitis. Expert Opin Investig Drugs 2024; 33:627-638. [PMID: 38676426 DOI: 10.1080/13543784.2024.2348743] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2024] [Accepted: 04/24/2024] [Indexed: 04/28/2024]
Abstract
INTRODUCTION Up to 40% of Primary biliary cholangitis (PBC) patients have a suboptimal response to Ursodeoxycholic acid (UDCA). Close to half of such patients show a remarkable improvement when additionally treated with Obeticholic acid (OCA) but have a dose-dependent increase of pruritus. This relative success of OCA, a first-in-class Farnesoid receptor (FXR) agonist, has positioned FXR as an attractive target for drug development. Novel candidates have since emerged, providing hope for this subgroup of patients who lack effective and safe treatments. AREAS COVERED We discussed the role of bile acids in PBC pathogenesis and how the FXR agonists provide therapeutic value by affecting bile acid synthesis and transport. Novel FXR agonists undergoing pre-clinical and clinical trials for PBC were enlisted via literature search by including the terms 'FXR agonists,' 'FXR PBC,' 'PBC clinical trials' on PubMed, MEDLINE via Ovid, and Clinicaltrials.gov. EXPERT OPINION Novel FXR agonists currently under investigation for PBC improve the disease surrogate markers in early trials. However, as with OCA, pruritus remains a concern with the newer drugs despite targeted chemical modifications to increase FXR specificity. Directing future resources toward studying the molecular mechanisms behind pruritus may lead to better drug design and efficacious yet safer drugs.
Collapse
Affiliation(s)
- Prithvi Reddy Akepati
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of New Mexico, Albuquerque, NM, USA
| | - Eric M Gochanour
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of New Mexico, Albuquerque, NM, USA
- The Gastroenterology Center, Valley View Hospital, Glenwood Springs, CO, USA
| |
Collapse
|
|
6
|
Ellez HI, Danis N, Akarca US. Evaluation of patients with positive anti-mitochondiral antibody and normal alkaline phosphatase levels for primary biliary cholangitis. Acta Gastroenterol Belg 2024; 87:282-286. [PMID: 39210760 DOI: 10.51821/87.2.12041] [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] [Indexed: 09/04/2024]
Abstract
Primary Biliary Cholangitis (PBC) is a chronic cholestatic liver disease typically diagnosed by elevated cholestatic liver enzymes and a positive anti-mitochondrial antibody (AMA) test. The clinical importance of AMA positivity in patients with normal cholestatic liver enzymes is unclear. The aim of this study was to determine the relationship between PBC and AMA positivity detected in individuals with normal cholestatic enzyme levels. The files of patients with AMA and/or AMA-M2 positivity between 2009 and 2018 and whose alkaline phosphatase (ALP) levels were below upper limit of normal (ULN) at initial admission were retrospectively analyzed. The ALP levels were normal in all patients. All patients had AMA positivity demonstrated by indirect immunofluorescence (IIF) or AMA-M2 positivity demonstrated by ELISA. A total of 16 patients underwent liver biopsy and seven (43.75%) showed changes consistent with those with PBC. A total of 12 patients were diagnosed with PBC and were treated and followed up with this diagnosis. People with AMA positivity and normal cholestasis enzyme levels are closely associated with PBC. Some of these patients were diagnosed with PBC as a result of biopsy and some were diagnosed by clinical and laboratory findings during follow-up.. The patients with an AMA titration of 1/20 were not associated with PBC. In our study, results similar to the studies confirmed by biopsies were obtained. In this regard, there is a need for prospective and retrospective studies with longer follow-up periods.
Collapse
Affiliation(s)
- Halil Ibrahim Ellez
- Department of Internal Medicine, Division of Medical Oncology, Dokuz Eylul University, Izmir, Turkey
| | - Nilay Danis
- Department of Internal Medicine, Division of Gastroenterology, Dokuz Eylul University, Izmir, Turkey
| | - Ulus Salih Akarca
- Department of Internal Medicine, Division of Gastroenterology, Ege University, Izmir, Turkey
| |
Collapse
|
|
7
|
Yu S, Vidal B, Peric M, Rosenbaum MW, Cates JMM, Gonzalez RS. Comparative histologic features among liver biopsies with biliary-pattern injury and confirmed clinical diagnoses. Hum Pathol 2024; 146:8-14. [PMID: 38479481 DOI: 10.1016/j.humpath.2024.03.003] [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: 12/21/2023] [Revised: 03/05/2024] [Accepted: 03/08/2024] [Indexed: 03/22/2024]
Abstract
Biliary-pattern injury in the liver (eg, duct injury, ductular reaction, cholestasis) can occur in several conditions, including primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), large duct obstruction (LDO), and drug-induced liver injury (DILI). While the histologic changes in these conditions have been individually well described, distinguishing among them remains often challenging, particularly when biopsy samples are limited in size, robust clinical information is unavailable, and/or the pathologist does not feel confident in evaluating liver disease. This study evaluated histologic features that could aid the diagnosis of biliary-pattern injury on biopsy. We reviewed 121 liver biopsies from clinically confirmed cases of PBC, PSC, chronic LDO, or DILI for multiple clinical and histologic parameters. The rates of these histologic findings were then compared among different entities. Onion-skin fibrosis was seen in 14% of PSC in comparison to 0%, 5%, and 0% of PBC, DILI, and chronic LDO (P = 0.031). Florid duct lesions were identified in 21% of PBC compared to 2% of PSC and 0% of DILI and LDO (P = 0.0065). Similarly, 42% of PBC showed lobular granulomas, compared to 7% of PSC, 11% of DILI, and 33% of chronic LDO (P = 0.0001). Cholestasis was more commonly seen in DILI (42%) and chronic LDO (83%) than in PBC (4%) and PSC (16%) (P < 0.0001). Lobular chronic inflammation was found in a significantly higher percentage of PBC and LDO than of PSC and DILI (P = 0.0009). There were significantly fewer cases of PBC showing neutrophils in ductular reaction than PSC, DILI, and LDO (P = 0.0063). Histologic findings that can help suggest a diagnosis in liver biopsies with biliary-pattern injury include florid duct lesions, lobular granulomas, lack of neutrophils in ductular reaction, and lobular chronic inflammation in PBC; onion-skin fibrosis in PSC; cholestasis and feathery degeneration in DILI; and lobular granulomas, lobular chronic inflammation, cholestasis, and feathery degeneration in chronic LDO. These findings are likely most helpful when complicating factors interfere with biopsy interpretation.
Collapse
Affiliation(s)
- Sanhong Yu
- Department of Pathology, Yale School of Medicine, New Heaven, CT, USA
| | - Barbara Vidal
- Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA, USA
| | - Masa Peric
- Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA, USA
| | - Matthew W Rosenbaum
- Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA, USA
| | | | - Raul S Gonzalez
- Department of Pathology and Laboratory Medicine, Emory University Hospital, Atlanta, GA, USA.
| |
Collapse
|
|
8
|
Chang JI, Kim JH, Sinn DH, Cho JY, Kim KM, Oh JH, Park Y, Sohn W, Goh MJ, Kang W, Gwak GY, Paik YH, Choi MS, Lee JH, Koh KC, Paik SW. Clinical Outcomes and Validation of Ursodeoxycholic Acid Response Scores in Patients with Korean Primary Biliary Cholangitis: A Multicenter Cohort Study. Gut Liver 2023; 17:620-628. [PMID: 36999383 PMCID: PMC10352064 DOI: 10.5009/gnl220420] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2022] [Revised: 12/01/2022] [Accepted: 12/08/2022] [Indexed: 04/01/2023] Open
Abstract
Background/Aims The ursodeoxycholic acid (UDCA) response score (URS) was developed to identify poor responders to UDCA before treatment, in order to offer timely and proactive intervention. However, validation of the URS in Asian population is warranted. Methods A total of 173 Asian patients diagnosed with primary biliary cholangitis (PBC) between 2007 and 2016 at seven academic institutions in Korea who started UDCA treatment were analyzed to validate the performance of URS. UDCA response was defined as an alkaline phosphatase level less than 1.67 times the upper limit of normal after 1-year of UDCA treatment. In addition, prognostic performance of URS for liver-related events, defined as newly developed hepatic decompensation or hepatocellular carcinoma was evaluated. Results After 1 year of UDCA treatment, 133 patients (76.9%) achieved UDCA response. UDCA response rate was 98.7% for those with URS ≥1.41 (n=76) and 58.8% for those with URS <1.41 (n=97). The area under the receiver operating characteristic curve of URS in predicting UDCA response was 0.84 (95% confidence interval, 0.78 to 0.88). During a median follow-up of 6.5 years, liver-related events developed in 18 patients (10.4%). Among 117 patients with PBC stage I-III by histological evaluation, the 5-year liver-related event-free survival rate differed according to the URS; 100% for URS ≥1.41 and 86.5% for URS <1.41 (p=0.005). Conclusions URS demonstrated good performance in predicting a UDCA treatment response in Asian PBC patients. In addition, the risk of liver-related events differed according to the URS for the PBC stage. Thus, URS can be used to predict the response and clinical outcome in patients with PBC.
Collapse
Affiliation(s)
- Jong-In Chang
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
- Department of Medicine, Chung-Ang University Gwangmyeong Hospital, Gwangmyeong, Korea
| | - Jung Hee Kim
- Division of Gastroenterology, Department of Internal Medicine, Hallym University Dongtan Sacred Heart Hospital, Hwaseong, Korea
| | - Dong Hyun Sinn
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Ju-Yeon Cho
- Department of Internal Medicine, Chosun University College of Medicine, Gwangju, Korea
| | - Kwang Min Kim
- Department of Medicine, Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, Changwon, Korea
| | - Joo Hyun Oh
- Department of Medicine, Nowon Eulji Medical Center, Eulji University School of Medicine, Seoul, Korea
| | - Yewan Park
- Department of Internal Medicine, College of Medicine, Kyung Hee University, Seoul, Korea
| | - Won Sohn
- Division of Gastroenterology, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Myung Ji Goh
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Wonseok Kang
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Geum-Youn Gwak
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Yong-Han Paik
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Moon Seok Choi
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Joon Hyeok Lee
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Kwang Cheol Koh
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Seung-Woon Paik
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| |
Collapse
|
|
9
|
Primary biliary cholangitis: review for radiologists. ABDOMINAL RADIOLOGY (NEW YORK) 2023; 48:127-135. [PMID: 34743232 DOI: 10.1007/s00261-021-03335-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/28/2021] [Revised: 10/19/2021] [Accepted: 10/22/2021] [Indexed: 01/21/2023]
Abstract
Primary biliary cholangitis is a rare progressive chronic inflammation of the medium and small bile ducts that abdominal radiologists may encounter, particularly if working in a tertiary setting or at a transplant center. This brief review covers current thinking about the pathophysiology and presentation of the disease, as well as the current diagnostic criteria in use by hepatologists. Imaging strategies for diagnosis will be reviewed as well as current treatment strategies and the use of imaging in monitoring response to treatment, including image-guided elastography.
Collapse
|
|
10
|
Corpechot C. Noninvasive Evaluation of Fibrosis and Portal Hypertension in Primary Biliary Cholangitis. Clin Liver Dis 2022; 26:681-689. [PMID: 36270723 DOI: 10.1016/j.cld.2022.06.010] [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
Primary biliary cholangitis (PBC) is a chronic cholestatic liver disease that, if left untreated or insufficiently treated, inexorably progresses toward cirrhosis and its potentially fatal complications. Alongside with the biochemical response to ursodeoxycholic acid therapy, advanced liver fibrosis and portal hypertension (PH) were shown to be major prognostic determinants in PBC. Therefore, one of the goals of noninvasive PBC evaluation should be to early diagnose compensated advanced disease and/or clinically significant PH. In this article, the main methods of noninvasive assessment of liver fibrosis and PH in PBC, and their clinical relevance, will be reviewed.
Collapse
Affiliation(s)
- Christophe Corpechot
- Reference Center for Inflammatory Biliary Diseases and Autoimmune Hepatitis, French network for rare liver diseases FILFOIE, European Reference Network ERN RARE-LIVER, Saint-Antoine Hospital, Assistance Publique - Hôpitaux de Paris, Inserm UMR_S938, Saint-Antoine Research Center (CRSA), Sorbonne University, 184 rue du Faubourg Saint-Antoine, Paris 75571 Cedex 12, France.
| |
Collapse
|
|
11
|
Liu CH, Bowlus CL. Treatment of Primary Biliary Cholangitis: First-Line and Second-Line Therapies. Clin Liver Dis 2022; 26:705-726. [PMID: 36270725 DOI: 10.1016/j.cld.2022.06.012] [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
Primary biliary cholangitis (PBC) is an autoimmune disease of the interlobular bile ducts leading to secondary damage of hepatocytes and may progress to cirrhosis and liver failure. The first-line treatment is ursodeoxycholic acid; up to 40% of patients do not have an adequate response and remain at risk of disease progression. Obeticholic acid has been conditionally approved for the treatment of PBC as add-on therapy and bezafibrate has shown similar efficacy in this group of patients. Several new therapies are in development and may further add to the treatment options available to patients with PBC.
Collapse
Affiliation(s)
- Chung-Heng Liu
- Drexel University College of Medicine, 2900 W Queen Ln, Philadelphia, PA 19129 USA
| | - Christopher L Bowlus
- Division of Gastroenterology and Hepatology, University of California Davis School of Medicine, 4150 V Street, PSSB 3500, Sacramento, CA 95817, USA.
| |
Collapse
|
|
12
|
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.
Collapse
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.
| |
Collapse
|
|
13
|
Yoshida EM, Swain MG, Tsien C, Tam E, Bailey RJ, Grbic D, Hin Ko H, Ramji A, Hilzenrat N, Elkhashab M, Kim E, O’Brien M, Amedeo Puglia M, Peltekian KM. Clinical characterization of patients with primary biliary cholangitis: A report from multiple Canadian centres. CANADIAN LIVER JOURNAL 2022; 5:372-387. [PMID: 36133904 PMCID: PMC9473559 DOI: 10.3138/canlivj-2021-0038] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Accepted: 01/15/2022] [Indexed: 08/30/2023]
Abstract
BACKGROUND Primary biliary cholangitis (PBC) is a rare, chronic autoimmune, cholestatic liver disease affecting approximately 318 per million Canadians. There is limited information regarding the characterization of this patient population in Canada. Consequently, we aim to describe a cohort of PBC patients managed across liver centres serving this type of population. METHODS A cross-sectional examination of 1,125 PBC patient charts at 15 liver centres across Canada was conducted between January 2016 and September 2017. RESULTS Data from 1,125 eligible patients were collected from 7 Canadian provinces. The patient population was largely female (90.2%), had a median overall age of 61.3 years, and a median overall time since diagnosis of 6.4 years. Of the patients included in the study, 89% were on ursodeoxycholic acid (UDCA) therapy at a median dose of 14.0 mg/kg/day and 4.4% were previously treated with UDCA, whereas 6.6% were never treated with UDCA. Of the patients with available data (n = 1067), 289 (27.1%) presented with alkaline phosphatase (ALP) levels ≥200 IU/L and/or total bilirubin levels ≥21 µmol/L. Assessment of UDCA treatment response revealed that 26.6% and 38.3% of patients were inadequate responders according to the Toronto and Paris-II criteria, respectively. Mortality occurred in 1.2% (14) of patients, with liver-related adverse outcomes being more commonly observed in patients who discontinued UDCA compared to those who are currently on treatment (36.3% and 19.6%, respectively). CONCLUSION This study showed that Canadian PBC patients present with demographics and features commonly reported in the literature for this disease. Over one third of PBC patients had inadequate response to UDCA treatment or were not currently being treated with UDCA. Consequently, there is a significant unmet therapeutic need in this Canadian PBC population.
Collapse
Affiliation(s)
- Eric M Yoshida
- Department of Medicine, Division of Gastroenterology, University of British Columbia, Vancouver, British Columbia, Canada
| | - Mark Gordon Swain
- Division of Gastroenterology and Hepatology, University of Calgary, Calgary, Alberta, Canada
| | - Cynthia Tsien
- Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
| | - Edward Tam
- Pacific Gastroenterology Associates, Vancouver, British Columbia, Canada
| | | | - Dusanka Grbic
- CIUSSS de l’Estrie CHUS, Université de Sherbrooke, Sherbrooke, Quebec, Canada
| | - Hin Hin Ko
- Liver Diseases Clinic, Jewish General Hospital, McGill University, Montreal, Quebec, Canada
| | | | - Nir Hilzenrat
- Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada
| | - Magdy Elkhashab
- Department of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada
| | - Euiseok Kim
- Hepatology and Gastroenterology, McMaster University, Hamilton, Ontario, Canada
| | - Meaghan O’Brien
- Division of Digestive Care and Endoscopy, QEII, Nova Scotia Health, Halifax, Nova Scotia, Canada
| | - Marco Amedeo Puglia
- Division of Digestive Care and Endoscopy, QEII, Nova Scotia Health, Halifax, Nova Scotia, Canada
| | - Kevork M Peltekian
- Division of Digestive Care and Endoscopy, QEII, Nova Scotia Health, Halifax, Nova Scotia, Canada
| |
Collapse
|
|
14
|
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: 63] [Impact Index Per Article: 21.0] [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
| |
Collapse
|
|
15
|
Sorda JA, González Ballerga E, Barreyro FJ, Avagnina A, Carballo P, Paes de Lima A, Daruich J. Bezafibrate therapy in primary biliary cholangitis refractory to ursodeoxycholic acid: a longitudinal study of paired liver biopsies at 5 years of follow up. Aliment Pharmacol Ther 2021; 54:1202-1212. [PMID: 34587309 DOI: 10.1111/apt.16618] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Revised: 07/16/2020] [Accepted: 09/10/2021] [Indexed: 12/19/2022]
Abstract
BACKGROUND Ursodeoxycholic acid (UDCA) is the first-line therapy for primary biliary cholangitis (PBC). However, nearly 40% of patients have an incomplete response to UDCA. The addition of bezafibrate has shown biochemical benefit in this group of patients. AIM To evaluate the long-term effects of UDCA in combination with bezafibrate on histological outcomes in patients with UDCA-refractory PBC. METHODS Fifty-nine patients refractory to UDCA were included. Clinical parameters were monitored and paired liver biopsy (PLB) was performed after 5 years of follow-up. RESULTS Of the total cohort, 49 subjects were analysed and 31 had PLB at 5 years. Values for serum ALP, AST, ALT and GGT significantly improved with UDCA-bezafibrate. This beneficial effect was observed at 12 months where 86% achieved ALP at normal levels. Analyses of PLB showed a significant decrease in liver damage as reflected by Ludwig (baseline 2.29 ± 1.2, to 1.84 ± 1 at year 5, P = 0.0242) and Ishak (baseline 6.19 ± 2.2 to 4.77 ± 2.2 at year 5, P = 0.0008) scores. Overall, regression of fibrosis was attained in 48% of patients. Furthermore, we observed a significant reduction in the proportion with cirrhosis from 19% at baseline to 3% at 5 years (P < 0.001). These beneficial effects were associated with better predictive risk scores using the GLOBE and UK-PBC prognosis models. CONCLUSIONS Adding bezafibrate to UDCA in patients with UDCA-refractory PBC showed a significant decrease in fibrosis and inflammatory histological scores at 5 years. These beneficial effects warrant further evaluation in long-term cohort studies and controlled trials.
Collapse
Affiliation(s)
- Juan Antonio Sorda
- Department of Gastroenterology and Hepatology, University Hospital "José de San Martín", Faculty of Medicine, University of Buenos Aires, Buenos Aires, Argentina
| | - Esteban González Ballerga
- Department of Gastroenterology and Hepatology, University Hospital "José de San Martín", Faculty of Medicine, University of Buenos Aires, Buenos Aires, Argentina
| | - Fernando Javier Barreyro
- Biotechnology Institute of Misiones (INBIOMIS), National University of Misiones, National Scientific and Technical Research Council (CONICET), Posadas, Argentina
| | - Alejandra Avagnina
- Department of Pathology, University Hospital "José de San Martín", Faculty of Medicine, University of Buenos Aires, Buenos Aires, Argentina
| | - Pilar Carballo
- Department of Pathology, University Hospital "José de San Martín", Faculty of Medicine, University of Buenos Aires, Buenos Aires, Argentina
| | - Andrea Paes de Lima
- Department of Pathology, University Hospital "José de San Martín", Faculty of Medicine, University of Buenos Aires, Buenos Aires, Argentina
| | - Jorge Daruich
- Department of Gastroenterology and Hepatology, University Hospital "José de San Martín", Faculty of Medicine, University of Buenos Aires, Buenos Aires, Argentina
| |
Collapse
|
|
16
|
John BV, Khakoo NS, Schwartz KB, Aitchenson G, Levy C, Dahman B, Deng Y, Goldberg DS, Martin P, Kaplan DE, Taddei TH. Ursodeoxycholic Acid Response Is Associated With Reduced Mortality in Primary Biliary Cholangitis With Compensated Cirrhosis. Am J Gastroenterol 2021; 116:1913-1923. [PMID: 33989225 PMCID: PMC8410631 DOI: 10.14309/ajg.0000000000001280] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2020] [Accepted: 03/12/2021] [Indexed: 12/11/2022]
Abstract
INTRODUCTION Patients with cirrhosis and men have been under-represented in most studies examining the clinical benefit of response to ursodeoxycholic acid (UDCA) in primary biliary cholangitis (PBC). The aim of this study was to study the association of UDCA response and liver-related death or transplantation, hepatic decompensation, and hepatocellular carcinoma (HCC) in patients with PBC cirrhosis. METHODS We conducted a retrospective cohort study of veterans, predominantly men, with PBC and compensated cirrhosis to assess the association of UDCA response with the development of all-cause and liver-related mortality or transplantation, hepatic decompensation, and HCC using competing risk time-updating Cox proportional hazards models. RESULTS We identified 501 subjects with PBC and compensated cirrhosis, including 287 UDCA responders (1,692.8 patient-years [PY] of follow-up) and 214 partial responders (838.9 PY of follow-up). The unadjusted rates of hepatic decompensation (3.8 vs 7.9 per 100 PY, P < 0.0001) and liver-related death or transplantation (3.7 vs 6.2 per 100 PY, P < 0.0001) were lower in UDCA responders compared with partial responders. UDCA response was associated with a lower risk of hepatic decompensation (subhazard ratio [sHR] 0.54, 95% confidence interval [CI] 0.31-0.95, P = 0.03), death from any cause or transplantation (adjusted hazard ratio 0.49, 95% CI 0.33-0.72, P = 0.0002), and liver-related death or transplantation (sHR 0.40, 95% CI 0.24-0.67, P = 0.0004), but not HCC (sHR 0.39, 95% CI 0.60-2.55, P = 0.32). In a sensitivity analysis, the presence of portal hypertension was associated with the highest UDCA-associated effect. DISCUSSION UDCA response is associated with a reduction in decompensation, all-cause, and liver-related death or transplantation in a cohort of predominantly male patients with cirrhosis, with the highest benefit in patients with portal hypertension.
Collapse
Affiliation(s)
- Binu V John
- Division of Hepatology, Bruce W Carter VA Medical Center, Miami, FL
| | | | - Kaley B Schwartz
- Division of Hepatology, Bruce W Carter VA Medical Center, Miami, FL
| | | | - Cynthia Levy
- 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
| | - Yangyang Deng
- Department of Health Behavior and Policy, Virginia Commonwealth University, Richmond, VA
| | - David S. Goldberg
- Division of Digestive Health and Liver Diseases, University of Miami Miller School of Medicine, Miami, FL
| | - Paul Martin
- 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
| | - Tamar H. Taddei
- Section of Digestive Diseases, Yale School of Medicine, New Haven, CT
- Division of Gastroenterology and Hepatology, VA Connecticut Healthcare System, West Haven, CT
| |
Collapse
|
|
17
|
Shimoyama S, Kawata K, Ohta K, Chida T, Suzuki T, Tsuneyama K, Shimoda S, Kurono N, Leung PSC, Gershwin ME, Suda T, Kobayashi Y. Ursodeoxycholic acid impairs liver-infiltrating T-cell chemotaxis through IFN-γ and CX3CL1 production in primary biliary cholangitis. Eur J Immunol 2021; 51:1519-1530. [PMID: 33710617 DOI: 10.1002/eji.202048589] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2020] [Revised: 02/05/2021] [Accepted: 03/09/2021] [Indexed: 11/05/2022]
Abstract
Ursodeoxycholic acid (UDCA) is the primary treatment for primary biliary cholangitis (PBC), but its mechanism of action remains unclear. Studies suggest that UDCA enhances NF erythroid 2-related factor 2 (NFE2L2) expression and that the interaction between IFN-γ and C-X3-C motif chemokine ligand 1 (CX3CL1) facilitates biliary inflammation in PBC. Therefore, we examined the effects of UDCA on the expression of IFN-γ and CX3CL1 in in vitro and in vivo PBC models such as human liver tissue, a murine model, cell lines, and isolated human intrahepatic biliary epithelial cells (IHBECs). We observed a significant decrease in IFN-γ mRNA levels and positive correlations between IFN-γ and CX3CL1 mRNA levels post-UDCA treatment in PBC livers. NFE2L2-mediated transcriptional activation was significantly enhanced in UDCA-treated Jurkat cells. In 2-octynoic acid-immunized mice, IFN-γ production by liver-infiltrating T cells was dependent on NFE2L2 activation. IFN-γ significantly and dose-dependentlyinduced CX3CL1 expression, which was significantly decreased in HuCC-T1 cells and IHBECs upon UDCA treatment. These results suggest that UDCA-induced suppression of IFN-γ and CX3CL1 production attenuates the chemotactic and adhesive abilities of liver-infiltrating T cells in PBC.
Collapse
Affiliation(s)
- Shin Shimoyama
- Hepatology Division, Department of Internal Medicine II, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
| | - Kazuhito Kawata
- Hepatology Division, Department of Internal Medicine II, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
| | - Kazuyoshi Ohta
- Hepatology Division, Department of Internal Medicine II, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan.,Department of Virology and Parasitology, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
| | - Takeshi Chida
- Hepatology Division, Department of Internal Medicine II, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan.,Department of Virology and Parasitology, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
| | - Tetsuro Suzuki
- Department of Virology and Parasitology, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
| | - Koichi Tsuneyama
- Department of Pathology and Laboratory Medicine, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Tokushima, Japan
| | - Shinji Shimoda
- Department of Medicine and Biosystemic Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Fukuoka, Japan
| | - Nobuhito Kurono
- Department of Chemistry, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
| | - Patrick S C Leung
- Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis School of Medicine, Davis, CA, USA
| | - M Eric Gershwin
- Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis School of Medicine, Davis, CA, USA
| | - Takafumi Suda
- Hepatology Division, Department of Internal Medicine II, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
| | - Yoshimasa Kobayashi
- Hepatology Division, Department of Internal Medicine II, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
| |
Collapse
|
|
18
|
Li X, Peng J, Ouyang R, Yang Y, Yu C, Lin H. Risk factors for recurrent primary biliary cirrhosis after liver transplantation: A systematic review and meta-analysis. Dig Liver Dis 2021; 53:309-317. [PMID: 33380381 DOI: 10.1016/j.dld.2020.12.005] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2020] [Revised: 11/03/2020] [Accepted: 12/04/2020] [Indexed: 12/11/2022]
Abstract
BACKGROUND Recurrent primary biliary cirrhosis (PBC) is frequently observed in patients with PBC after liver transplantation (LT). We performed a meta-analysis to evaluate the risk factors for PBC recurrence. METHODS We searched the EMBASE, PubMed and the Cochrane Library databases for studies published before August 2020. Studies that identified the risk factors of PBC recurrence were eligible for inclusion. We extracted the hazard ratio (HR) data with 95% confidence intervals (CI) for the risk factors. RESULTS Our meta-analysis included 6 studies, which comprised 3184 patients (88.5% females) who underwent liver transplantation from 1982 to 2017, and of these patients, 935 (29.4%) developed PBC recurrence. The use of tacrolimus (HR = 2.62, 95% CI = 1.35, 5.09) and preventive ursodeoxycholic acid (UDCA) (HR = 0.40, 95% CI = 0.28, 0.57) were significantly associated with the risk of PBC recurrence based on the pooled analysis of the results obtained from the multivariate analysis. CONCLUSIONS The use of tacrolimus is associated with an increased risk of PBC recurrence. Preventive UDCA after LT for PBC can help to prevent disease recurrence.
Collapse
Affiliation(s)
- Xiaocheng Li
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Hunan University of Medicine, Huaihua, Hunan, PR China
| | - Jing Peng
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Hunan University of Medicine, Huaihua, Hunan, PR China
| | - Renbin Ouyang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Hunan University of Medicine, Huaihua, Hunan, PR China
| | - Yaowei Yang
- Department of General Surgery, University-Town Hospital of Chongqing Medical University, Chongqing, PR China
| | - Chengdong Yu
- Department of Epidemiology & Medical Statistics, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, PR China
| | - Huapeng Lin
- Department of Intensive Care Unit, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, PR China.
| |
Collapse
|
|
19
|
Dong X, Luo Y, Lu S, Ma H, Zhang W, Zhu Y, Sun G, Sun X. Ursodesoxycholic acid alleviates liver fibrosis via proregeneration by activation of the ID1-WNT2/HGF signaling pathway. Clin Transl Med 2021; 11:e296. [PMID: 33635004 PMCID: PMC7828260 DOI: 10.1002/ctm2.296] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2020] [Revised: 01/07/2021] [Accepted: 01/10/2021] [Indexed: 01/15/2023] Open
Abstract
BACKGROUND The human liver possesses a remarkable capacity for self-repair. However, liver fibrosis remains a serious medical concern, potentially progressing to end-stage liver cirrhosis and even death. Liver fibrosis is characterized by excess accumulation of extracellular matrix in response to chronic injury. Liver regenerative ability, a strong indicator of liver health, is important in resisting fibrosis. In this study, we provide evidence that ursodesoxycholic acid (UDCA) can alleviate liver fibrosis by promoting liver regeneration via activation of the ID1-WNT2/hepatocyte growth factor (HGF) pathway. METHODS Bile duct ligation (BDL) and partial hepatectomy (PH) mouse models were used to verify the effects of UDCA on liver fibrosis, regeneration, and the ID1-WNT2/HGF pathway. An Id1 knockdown mouse model was also used to assess the role of Id1 in UDCA alleviation of liver fibrosis. RESULTS Our results demonstrate that UDCA can alleviate liver fibrosis in the BDL mice and promote liver regeneration via the ID1-WNT2/HGF pathway in PH mice. In addition, Id1 knockdown abolished the protection afforded by UDCA in BDL mice. CONCLUSIONS We conclude that UDCA protects against liver fibrosis by proregeneration via activation of the ID1-WNT2/HGF pathway.
Collapse
Affiliation(s)
- Xi Dong
- Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational MedicineInstitute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical SciencesBeijing100193P. R. China
- Key Laboratory of New Drug Discovery Based on Classic Chinese Medicine PrescriptionChinese Academy of Medical SciencesBeijing100193P. R. China
- Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education, Institute of Medicinal Plant DevelopmentChinese Academy of Medical Sciences & Peking Union Medical CollegeBeijing100193P. R. China
- Key Laboratory of Efficacy Evaluation of Chinese Medicine against Glycolipid Metabolic Disorders, State Administration of Traditional Chinese Medicine, Institute of Medicinal Plant DevelopmentPeking Union Medical College and Chinese Academy of Medical SciencesBeijing100193P. R. China
| | - Yun Luo
- Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational MedicineInstitute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical SciencesBeijing100193P. R. China
- Key Laboratory of New Drug Discovery Based on Classic Chinese Medicine PrescriptionChinese Academy of Medical SciencesBeijing100193P. R. China
- Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education, Institute of Medicinal Plant DevelopmentChinese Academy of Medical Sciences & Peking Union Medical CollegeBeijing100193P. R. China
- Key Laboratory of Efficacy Evaluation of Chinese Medicine against Glycolipid Metabolic Disorders, State Administration of Traditional Chinese Medicine, Institute of Medicinal Plant DevelopmentPeking Union Medical College and Chinese Academy of Medical SciencesBeijing100193P. R. China
| | - Shan Lu
- Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational MedicineInstitute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical SciencesBeijing100193P. R. China
- Key Laboratory of New Drug Discovery Based on Classic Chinese Medicine PrescriptionChinese Academy of Medical SciencesBeijing100193P. R. China
- Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education, Institute of Medicinal Plant DevelopmentChinese Academy of Medical Sciences & Peking Union Medical CollegeBeijing100193P. R. China
- Key Laboratory of Efficacy Evaluation of Chinese Medicine against Glycolipid Metabolic Disorders, State Administration of Traditional Chinese Medicine, Institute of Medicinal Plant DevelopmentPeking Union Medical College and Chinese Academy of Medical SciencesBeijing100193P. R. China
| | - Han Ma
- School of Traditional Chinese MedicineCapital Medical UniversityBeijingP. R. China
| | - Wenchao Zhang
- College of Life Science and TechnologyBeijing University of Chemical TechnologyBeijingP. R. China
| | - Yue Zhu
- Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational MedicineInstitute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical SciencesBeijing100193P. R. China
- Key Laboratory of New Drug Discovery Based on Classic Chinese Medicine PrescriptionChinese Academy of Medical SciencesBeijing100193P. R. China
- Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education, Institute of Medicinal Plant DevelopmentChinese Academy of Medical Sciences & Peking Union Medical CollegeBeijing100193P. R. China
- Key Laboratory of Efficacy Evaluation of Chinese Medicine against Glycolipid Metabolic Disorders, State Administration of Traditional Chinese Medicine, Institute of Medicinal Plant DevelopmentPeking Union Medical College and Chinese Academy of Medical SciencesBeijing100193P. R. China
| | - Guibo Sun
- Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational MedicineInstitute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical SciencesBeijing100193P. R. China
- Key Laboratory of New Drug Discovery Based on Classic Chinese Medicine PrescriptionChinese Academy of Medical SciencesBeijing100193P. R. China
- Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education, Institute of Medicinal Plant DevelopmentChinese Academy of Medical Sciences & Peking Union Medical CollegeBeijing100193P. R. China
- Key Laboratory of Efficacy Evaluation of Chinese Medicine against Glycolipid Metabolic Disorders, State Administration of Traditional Chinese Medicine, Institute of Medicinal Plant DevelopmentPeking Union Medical College and Chinese Academy of Medical SciencesBeijing100193P. R. China
| | - Xiaobo Sun
- Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational MedicineInstitute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical SciencesBeijing100193P. R. China
- Key Laboratory of New Drug Discovery Based on Classic Chinese Medicine PrescriptionChinese Academy of Medical SciencesBeijing100193P. R. China
- Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education, Institute of Medicinal Plant DevelopmentChinese Academy of Medical Sciences & Peking Union Medical CollegeBeijing100193P. R. China
- Key Laboratory of Efficacy Evaluation of Chinese Medicine against Glycolipid Metabolic Disorders, State Administration of Traditional Chinese Medicine, Institute of Medicinal Plant DevelopmentPeking Union Medical College and Chinese Academy of Medical SciencesBeijing100193P. R. China
| |
Collapse
|
|
20
|
Kawata K, Joshita S, Shimoda S, Yamashita Y, Yamashita M, Kitsugi K, Takatori S, Ohta K, Ito J, Shimoyama S, Noritake H, Suda T, Harada K. The ursodeoxycholic acid response score predicts pathological features in primary biliary cholangitis. Hepatol Res 2021; 51:80-89. [PMID: 33080094 DOI: 10.1111/hepr.13584] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/20/2020] [Revised: 09/30/2020] [Accepted: 10/13/2020] [Indexed: 12/12/2022]
Abstract
AIM The ursodeoxycholic acid response score (URS) can predict the biochemical response to 12 months of ursodeoxycholic acid (UDCA) treatment in patients with primary biliary cholangitis (PBC). We investigated the relationship between the URS and the histopathological features before and after UDCA treatment. METHODS Patients with PBC (n = 126) were examined for the association between the probability of response (POR) to UDCA based on the URS formulas and clinicopathological features. Furthermore, 30 patients were examined for the association between the POR and pathological changes. RESULTS The POR area under the receiver operating characteristic curve (AUROC) for predicting the biochemical response to UDCA was 0.861. The PORs of stage 1 in the Nakanuma system and grade 0 in the CK7 grading in hepatocytes were significantly higher than those of stage 3 and grade 3, respectively. The AUROCs for the prediction of stage ≥2, stage ≥3 and stage 4 in the Nakanuma system at pretreatment were 0.592, 0.710 and 0.817, respectively. The AUROCs for the prediction of grade ≥1, grade ≥2 and grade 3 in the CK7 hepatocyte grading were 0.741, 0.824 and 0.970, respectively. Furthermore, the AUROC for predicting the histological stage progression after UDCA treatment in the Scheuer classification and the Nakanuma system were 0.712 and 0.799, respectively. CONCLUSIONS The URS not only predicts the biochemical response, but also reflects the Nakanuma system and the CK7 hepatocyte grading at pretreatment. This scoring system can identify an inadequate histological response to UDCA treatment in the Scheuer classification and the Nakanuma system.
Collapse
Affiliation(s)
- Kazuhito Kawata
- Department of Internal Medicine II, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
| | - Satoru Joshita
- Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, Japan
| | - Shinji Shimoda
- Department of Medicine and Biosystemic Science Graduate School of Medical Sciences, Kyushu University, Japan
| | - Yuki Yamashita
- Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, Japan
| | - Maho Yamashita
- Department of Internal Medicine II, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
| | - Kensuke Kitsugi
- Department of Internal Medicine II, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
| | - Shingo Takatori
- Department of Internal Medicine II, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
| | - Kazuyoshi Ohta
- Department of Internal Medicine II, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
| | - Jun Ito
- Department of Internal Medicine II, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
| | - Shin Shimoyama
- Department of Internal Medicine II, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
| | - Hidenao Noritake
- Department of Internal Medicine II, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
| | - Takafumi Suda
- Department of Internal Medicine II, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
| | - Kenichi Harada
- Department of Human Pathology, Kanazawa University Graduate School of Medicine, Kanazawa
| |
Collapse
|
|
21
|
Corpechot C, Chazouillères O, Belnou P, Montano-Loza AJ, Mason A, Ebadi M, Eurich D, Chopra S, Jacob D, Schramm C, Sterneck M, Bruns T, Reuken P, Rauchfuss F, Roccarina D, Thorburn D, Gerussi A, Trivedi P, Hirschfield G, McDowell P, Nevens F, Boillot O, Bosch A, Giostra E, Conti F, Poupon R, Parés A, Reig A, Donato MF, Malinverno F, Floreani A, Russo FP, Cazzagon N, Verhelst X, Goet J, Harms M, van Buuren H, Hansen B, Carrat F, Dumortier J. Long-term impact of preventive UDCA therapy after transplantation for primary biliary cholangitis. J Hepatol 2020; 73:559-565. [PMID: 32275981 DOI: 10.1016/j.jhep.2020.03.043] [Citation(s) in RCA: 49] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2019] [Revised: 03/06/2020] [Accepted: 03/23/2020] [Indexed: 12/11/2022]
Abstract
BACKGROUND & AIMS Recurrence of primary biliary cholangitis (PBC) after liver transplantation (LT) is frequent and can impair graft and patient survival. Ursodeoxycholic acid (UDCA) is the current standard therapy for PBC. We investigated the effect of preventive exposure to UDCA on the incidence and long-term consequences of PBC recurrence after LT. METHODS We performed a retrospective cohort study in 780 patients transplanted for PBC, between 1983-2017 in 16 centers (9 countries), and followed-up for a median of 11 years. Among them, 190 received preventive UDCA (10-15 mg/kg/day). The primary outcome was histological evidence of PBC recurrence. The secondary outcomes were graft loss, liver-related death, and all-cause death. The association between preventive UDCA and outcomes was quantified using multivariable-adjusted Cox and restricted mean survival time (RMST) models. RESULTS While recurrence of PBC significantly shortened graft and patient survival, preventive exposure to UDCA was associated with reduced risk of PBC recurrence (adjusted hazard ratio [aHR] 0.41; 95% CI 0.28-0.61; p <0.0001), graft loss (aHR 0.33; 95% CI 0.13-0.82; p <0.05), liver-related death (aHR 0.46; 95% CI 0.22-0.98; p <0.05), and all-cause death (aHR 0.69; 95% CI 0.49-0.96; p <0.05). On RMST analysis, preventive UDCA led to a survival gain of 2.26 years (95% CI 1.28-3.25) over a period of 20 years. Exposure to cyclosporine rather than tacrolimus had a complementary protective effect alongside preventive UDCA, reducing the cumulative incidence of PBC recurrence and all-cause death. CONCLUSIONS Preventive UDCA after LT for PBC is associated with a reduced risk of disease recurrence, graft loss, and death. A regimen combining cyclosporine and preventive UDCA is associated with the lowest risk of PBC recurrence and mortality. LAY SUMMARY Recurrence of primary biliary cholangitis after liver transplantation is frequent and can impair graft and patient survival. We performed the largest international study of transplanted patients with primary biliary cholangitis to date. Preventive administration of ursodeoxycholic acid after liver transplantation was associated with reduced risk of disease recurrence, graft loss, liver-related and all-cause mortality. A regimen combining cyclosporine and preventive ursodeoxycholic acid was associated with the best outcomes.
Collapse
Affiliation(s)
- Christophe Corpechot
- Reference Center for Inflammatory Biliary Diseases and Autoimmune Hepatitis, ERN Rare-Liver, Saint-Antoine Hospital, Assistance Publique - Hôpitaux de Paris; Inserm UMR_S938, Saint-Antoine Research Center, Sorbonne University, Paris, France.
| | - Olivier Chazouillères
- Reference Center for Inflammatory Biliary Diseases and Autoimmune Hepatitis, ERN Rare-Liver, Saint-Antoine Hospital, Assistance Publique - Hôpitaux de Paris; Inserm UMR_S938, Saint-Antoine Research Center, Sorbonne University, Paris, France
| | - Pierre Belnou
- Public Health Unit, Saint-Antoine Hospital, Assistance Publique-Hôpitaux de Paris; Pierre Louis Institute of Epidemiology and Public Health, Sorbonne University, Paris, France
| | - Aldo J Montano-Loza
- Division of Gastroenterology and Liver Unit, University of Alberta, Edmonton, Canada
| | - Andrew Mason
- Division of Gastroenterology and Liver Unit, University of Alberta, Edmonton, Canada
| | - Maryam Ebadi
- Division of Gastroenterology and Liver Unit, University of Alberta, Edmonton, Canada
| | - Dennis Eurich
- Department of General, Visceral and Transplantation Surgery, Charité University Hospital, Berlin, Germany
| | - Sascha Chopra
- Department of General, Visceral and Transplantation Surgery, Charité University Hospital, Berlin, Germany
| | - Dietmar Jacob
- Department of General, Visceral and Transplantation Surgery, Charité University Hospital, Berlin, Germany
| | - Christoph Schramm
- Department of Medicine I and Martin Zeitz Center for Rare Diseases, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Martina Sterneck
- Department of Medicine I and Martin Zeitz Center for Rare Diseases, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Tony Bruns
- Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany; Department of Internal Medicine IV, Integrated Research and Treatment Center for Sepsis Control and Care, University Hospital, Jena, Germany
| | - Philipp Reuken
- Department of Internal Medicine IV, Integrated Research and Treatment Center for Sepsis Control and Care, University Hospital, Jena, Germany
| | - Falk Rauchfuss
- Department of General, Visceral and Vascular Surgery, University Hospital Jena, Jena, Germany
| | - Davide Roccarina
- University College London Institute for Liver and Digestive Health, Royal Free Hospital, London, United Kingdom
| | - Douglas Thorburn
- University College London Institute for Liver and Digestive Health, Royal Free Hospital, London, United Kingdom
| | - Alessio Gerussi
- University College London Institute for Liver and Digestive Health, Royal Free Hospital, London, United Kingdom
| | - Palak Trivedi
- National Institute for Health Research, Centre for Liver Research, University Hospitals Birmingham, Institute of Immunology and Immunotherapy, University of Birmingham, United Kingdom
| | - Gideon Hirschfield
- National Institute for Health Research, Centre for Liver Research, University Hospitals Birmingham, Institute of Immunology and Immunotherapy, University of Birmingham, United Kingdom; Department of Gastroenterology, University Hospitals Birmingham National Health Service Foundation Trust, Queen Elizabeth Hospital, Birmingham, United Kingdom; Toronto Centre for Liver Disease, University Health Network, University of Toronto, Toronto, Canada
| | - Patrick McDowell
- Department of Gastroenterology, University Hospitals Birmingham National Health Service Foundation Trust, Queen Elizabeth Hospital, Birmingham, United Kingdom
| | - Frederik Nevens
- Division Liver and Biliopancreatic Disorders, University Hospitals KU, Leuven, Belgium
| | - Olivier Boillot
- Transplant Hepatology Unit, Edouard Herriot Hospital, Hospices Civils de Lyon, Claude Bernard University, Lyon, France
| | - Alexie Bosch
- Transplant Hepatology Unit, Croix Rousse Hospital, Hospices Civils de Lyon, Claude Bernard University, Lyon, France
| | - Emiliano Giostra
- Hepatology and Gastroenterology Department, Geneva University Hospitals, Geneva, Switzerland
| | - Filomena Conti
- Transplant Hepatology Unit, Pitié-Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris, Sorbonne University, Paris, France
| | - Raoul Poupon
- Reference Center for Inflammatory Biliary Diseases and Autoimmune Hepatitis, ERN Rare-Liver, Saint-Antoine Hospital, Assistance Publique - Hôpitaux de Paris; Inserm UMR_S938, Saint-Antoine Research Center, Sorbonne University, Paris, France
| | - Albert Parés
- Liver Unit, Hospital Clínic, University of Barcelona, The August Pi i Sunyer Biomedical Research Institute, Biomedical Research Networking Center in Hepatic and Digestive Diseases, Barcelona, Spain
| | - Anna Reig
- Liver Unit, Hospital Clínic, University of Barcelona, The August Pi i Sunyer Biomedical Research Institute, Biomedical Research Networking Center in Hepatic and Digestive Diseases, Barcelona, Spain
| | - Maria Francesca Donato
- Transplant Hepatology Unit, Division of Gastroenterology and Hepatology, Maggiore Hospital Policlinico, Milan, Italy
| | - Federica Malinverno
- Transplant Hepatology Unit, Division of Gastroenterology and Hepatology, Maggiore Hospital Policlinico, Milan, Italy
| | - Annarosa Floreani
- Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy
| | - Francesco Paolo Russo
- Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy
| | - Nora Cazzagon
- Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy
| | - Xavier Verhelst
- Department of Gastroenterology and Hepatology, Ghent University Hospital, Ghent, Belgium
| | - Jorn Goet
- Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Maren Harms
- Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Henk van Buuren
- Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Bettina Hansen
- Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, The Netherlands; Toronto Centre for Liver Disease, University Health Network, University of Toronto, Toronto, Canada
| | - Fabrice Carrat
- Public Health Unit, Saint-Antoine Hospital, Assistance Publique-Hôpitaux de Paris; Pierre Louis Institute of Epidemiology and Public Health, Sorbonne University, Paris, France
| | - Jérôme Dumortier
- Transplant Hepatology Unit, Edouard Herriot Hospital, Hospices Civils de Lyon, Claude Bernard University, Lyon, France
| |
Collapse
|
|
22
|
Mané F, Cardoso H, Liberal R, Lopes S, Pereira P, Gonçalves R, Macedo G. Treatment response in primary biliary cholangitis: The role of autoimmune hepatitis features. Ann Hepatol 2020; 18:488-493. [PMID: 31036497 DOI: 10.1016/j.aohep.2018.11.006] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2018] [Revised: 11/14/2018] [Accepted: 11/23/2018] [Indexed: 02/04/2023]
Abstract
INTRODUCTION AND AIM Primary biliary cholangitis is a rare disease with scarce epidemiological data in Southern Europe. The authors aimed to evaluate treatment response in a cohort of patients. MATERIALS AND METHODS This retrospective observational single-centre study included patients with diagnostic criteria of primary biliary cholangitis. Data on disease presentation, laboratory results, treatment and clinical endpoints were collected and analyzed. RESULTS Fifty-three patients were included, 89% women, with mean age of 62±15 years at diagnosis. The majority was asymptomatic (49%), tested positive for antimitochondrial antibodies (96%) and had increased alkaline phosphatase (median=214U/L). 75% of the patients had liver histology and the majority were in Ludwig's stage I (42%). Autoimmune hepatitis (AIH) features were found in seven patients (13%). All were treated with ursodeoxycholic acid (UDCA) and 56% achieved biochemical response at one year; patients with AIH features exhibited steeper decreases in alkaline phosphatase (p=0.007) and reached the endpoint of 40% decrease in alkaline phosphatase more frequently (p=0.017). CONCLUSION In conclusion a significant proportion of patients failed to achieve an adequate response to UDCA treatment. The response rate of patients with AIH features was better, which could be related to a different phenotype or to the potential impact of immunosuppressive agents.
Collapse
Affiliation(s)
- Fernando Mané
- Gastroenterology Department, Faculty of Medicine, University of Porto, Porto, Portugal
| | - Hélder Cardoso
- Gastroenterology Department, Faculty of Medicine, University of Porto, Porto, Portugal; Gastroenterology Department, Hospitalar Center of São João, Porto, Portugal.
| | - Rodrigo Liberal
- Gastroenterology Department, Faculty of Medicine, University of Porto, Porto, Portugal; Gastroenterology Department, Hospitalar Center of São João, Porto, Portugal
| | - Susana Lopes
- Gastroenterology Department, Faculty of Medicine, University of Porto, Porto, Portugal; Gastroenterology Department, Hospitalar Center of São João, Porto, Portugal
| | - Pedro Pereira
- Gastroenterology Department, Faculty of Medicine, University of Porto, Porto, Portugal; Gastroenterology Department, Hospitalar Center of São João, Porto, Portugal
| | - Regina Gonçalves
- Gastroenterology Department, Faculty of Medicine, University of Porto, Porto, Portugal; Gastroenterology Department, Hospitalar Center of São João, Porto, Portugal
| | - Guilherme Macedo
- Gastroenterology Department, Faculty of Medicine, University of Porto, Porto, Portugal; Gastroenterology Department, Hospitalar Center of São João, Porto, Portugal
| |
Collapse
|
|
23
|
Yoon S, Lee H, Ji SC, Yoon SH, Cho JY, Chung JY. Pharmacokinetics and Pharmacodynamics of Ursodeoxycholic Acid in an Overweight Population With Abnormal Liver Function. Clin Pharmacol Drug Dev 2020; 10:68-77. [PMID: 32191400 DOI: 10.1002/cpdd.790] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2019] [Accepted: 02/12/2020] [Indexed: 01/01/2023]
Abstract
Ursodeoxycholic acid (UDCA) is a secondary bile acid that is used to treat primary biliary cholangitis. Although UDCA has a hepatoprotective effect in some diseases, its benefit in nonalcoholic fatty liver disease (NAFLD) remains controversial. We aimed to evaluate the pharmacokinetics (PK) and pharmacodynamics (PD) of UDCA in overweight subjects with elevated liver enzymes after multiple administrations of UDCA and compare these changes with vitamin E treatment. Overweight subjects (body mass index, 25-30 kg/m2 ) with elevated alanine aminotransferase (ALT) level (40-200 IU/L) were enrolled. Subjects received one of the following three 8-week treatments: UDCA 300 mg twice daily UDCA 300 mg twice daily for 4 weeks followed by UDCA 300 mg twice daily and metformin 500 mg twice daily for 4 weeks, and vitamin E 400 IU twice daily. PK and PD (liver function, lipid profiles, insulin sensitivity, and miR-122) analyses were performed. Thirty subjects were enrolled; 1 subject withdrew his consent during the study. The PK characteristics were similar to those of healthy volunteers. The ALT and miR-122 levels decreased in the UDCA groups, whereas the ALT and aspartate aminotransferase levels decreased in the vitamin E group. The lipid profiles and insulin sensitivity did not show significant changes among the groups. There was no serious adverse event, and the safety profiles were similar among the treatment groups. The liver enzyme and miR-122 levels were decreased by UDCA. Considering UDCA and vitamin E have a hepatoprotective effect and different mechanisms of action, combination therapy could be an option for NAFLD.
Collapse
Affiliation(s)
- Seonghae Yoon
- Clinical Trials Center, Seoul National University Bundang Hospital, Seongnam, Republic of Korea
| | - Heechan Lee
- Department of Clinical Pharmacology and Therapeutics, Seoul National University Hospital, Seoul, Republic of Korea.,Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Sang-Chun Ji
- Department of Clinical Pharmacology and Therapeutics, Seoul National University Hospital, Seoul, Republic of Korea.,Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Seo Hyun Yoon
- Department of Clinical Pharmacology and Therapeutics, Seoul National University Hospital, Seoul, Republic of Korea.,Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Joo-Youn Cho
- Department of Clinical Pharmacology and Therapeutics, Seoul National University Hospital, Seoul, Republic of Korea.,Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Jae-Yong Chung
- Clinical Trials Center, Seoul National University Bundang Hospital, Seongnam, Republic of Korea.,Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine, Seoul, Republic of Korea
| |
Collapse
|
|
24
|
Abstract
Primary biliary cholangitis is an uncommon cholestatic liver disease predominantly affecting middle-aged women. Left untreated, there is a high risk of progression to end-stage liver disease. Few treatment options exist. To date, ursodeoxycholic acid (UDCA) and obeticholic acid (OCA) are the only medical therapies approved for use, other than symptomatic treatments and liver transplantation, the latter of which is reserved for those developing complications of cirrhosis or with intractable pruritus. UDCA improves outcomes, but many patients do not adequately respond. OCA therapy may improve response, but long-term data are limited. New therapies are desperately needed, but evaluation has been limited by the fact that the disease is heterogeneous, hard end points take years to develop, and there are different criteria in use for determining therapeutic response based on surrogate biomarkers. Fibrates appear to be the most promising new therapy and have beneficially affected surrogate end points and are beginning to show improvement in clinical end points.
Collapse
|
|
25
|
Badman MK, Chen J, Desai S, Vaidya S, Neelakantham S, Zhang J, Gan L, Danis K, Laffitte B, Klickstein LB. Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of the Novel Non-Bile Acid FXR Agonist Tropifexor (LJN452) in Healthy Volunteers. Clin Pharmacol Drug Dev 2019; 9:395-410. [PMID: 31823525 PMCID: PMC7187203 DOI: 10.1002/cpdd.762] [Citation(s) in RCA: 63] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2019] [Accepted: 11/12/2019] [Indexed: 01/08/2023]
Abstract
Tropifexor (LJN452) is a potent, orally available, non–bile acid farnesoid X receptor agonist under clinical development for chronic liver diseases. Here, we present results from a first‐in‐human study of tropifexor following single‐ and multiple‐ascending doses (SAD/MAD) and food effect substudy in healthy volunteers. The SAD study included 6 fasted cohorts receiving 10‐ to 3000‐µg tropifexor or placebo and 1 cohort receiving 300‐µg tropifexor with a high‐fat meal. The MAD study included 4 lean cohorts receiving 10 to 100 µg and 1 obese cohort receiving 30‐µg once‐daily doses or placebo for 14 days. Pharmacodynamic assessment of fibroblast growth factor 19 and fasting plasma lipids was performed after dosing. Overall, 95 volunteers received at least 1 tropifexor or placebo dose. Tropifexor was well tolerated up to 3000 µg and 100 µg in the SAD and MAD studies, respectively; however, 2 subjects discontinued the MAD study due to asymptomatic elevation of liver transaminases. At single doses, tropifexor showed a moderate rate of absorption (median time to maximum concentration, 4 hours), dose‐proportional increases in exposure, and elimination half‐life of 13.5 to 21.9 hours. When taken with food, tropifexor exposure increased by ∼60%. With multiple dosing, steady state was reached on day 4 with <2‐fold accumulation. Single and multiple doses showed dose‐dependent increases in fibroblast growth factor 19. No changes in serum lipids were observed in tropifexor‐ vs placebo‐treated obese subjects. In conclusion, tropifexor was well tolerated, had a pharmacokinetic profile suitable for once‐daily dosing and showed dose‐dependent target engagement without altering plasma lipids in healthy volunteers.
Collapse
Affiliation(s)
- Michael K Badman
- Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, USA
| | - Jin Chen
- Novartis Institutes for BioMedical Research, East Hanover, New Jersey, USA
| | - Sachin Desai
- Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, USA
| | - Soniya Vaidya
- Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, USA
| | | | - Jie Zhang
- Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, USA
| | - Lu Gan
- Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, USA.,Current affiliation: X4 Pharmaceutical Inc., Cambridge, Massachusetts, USA
| | - Kate Danis
- Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, USA.,Current affiliation: Takeda Pharmaceutical Company Ltd., Lexington, Massachusetts, USA
| | - Bryan Laffitte
- Genonics Institute of the Novartis Research Foundation, San Diego, California, USA.,Current affiliation: Inception Sciences Inc., San Diego, California, USA
| | - Lloyd B Klickstein
- Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, USA
| |
Collapse
|
|
26
|
Murillo Perez CF, Hirschfield GM, Corpechot C, Floreani A, Mayo MJ, van der Meer A, Ponsioen CY, Lammers WJ, Parés A, Invernizzi P, Carbone M, Maria Battezzati P, Nevens F, Kowdley KV, Thorburn D, Mason AL, Trivedi PJ, Lindor KD, Bruns T, Dalekos GN, Gatselis NK, Verhelst X, Janssen HLA, Hansen BE, Gulamhusein A. Fibrosis stage is an independent predictor of outcome in primary biliary cholangitis despite biochemical treatment response. Aliment Pharmacol Ther 2019; 50:1127-1136. [PMID: 31621931 DOI: 10.1111/apt.15533] [Citation(s) in RCA: 68] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2019] [Revised: 07/10/2019] [Accepted: 09/18/2019] [Indexed: 12/12/2022]
Abstract
BACKGROUND Fibrosis stage predicts prognosis in patients with chronic liver disease independent of aetiology, although its precise role in risk stratification in patients with primary biliary cholangitis (PBC) remains undefined. AIM To assess the utility of baseline fibrosis stage in predicting long-term outcomes in the context of biochemical risk stratification METHODS: In a large and globally representative cohort of patients with PBC, liver biopsies performed from 1980 to 2014 were evaluated. The predictive ability of histologic fibrosis stage in addition to treatment response at 1 year (Toronto/Paris-II criteria), as well as non-invasive markers of fibrosis (AST/ALT ratio [AAR], AST to platelet ratio index [APRI], FIB-4), for transplant-free survival was assessed with Cox proportional-hazards models. RESULTS There were 1828 patients with baseline liver biopsy. Advanced histologic fibrosis (stage 3/4) was an independent predictor of survival in addition to non-invasive measures of fibrosis with the hazard ratios ranging from 1.59 to 2.73 (P < .001). Patients with advanced histologic fibrosis stage had worse survival despite biochemical treatment response, with a 10-year survival of 76.0%-86.6% compared to 94.5%-95.1% depending on the treatment response criteria used. Poor correlations were observed between non-invasive measures of fibrosis and histologic fibrosis stage. CONCLUSION Assessment of fibrosis stage grants prognostic value beyond biochemical treatment response at 1 year. This highlights the need to incorporate fibrosis stage in individual risk stratification in patients with PBC, partly to identify those that may derive benefit from novel therapies.
Collapse
|
|
27
|
Vespasiani-Gentilucci U, Rosina F, Pace-Palitti V, Sacco R, Pellicelli A, Chessa L, De Vincentis A, Barlattani M, Barlattani A, Feletti V, Mussetto A, Zolfino T, Russello M, Cozzolongo R, Garrucciu G, Niro G, Bacca D, Bertino G, Claar E, Ascione A, D'Adamo G, Adinolfi LE, Scifo G, Izzi A. Rate of non-response to ursodeoxycholic acid in a large real-world cohort of primary biliary cholangitis patients in Italy. Scand J Gastroenterol 2019; 54:1274-1282. [PMID: 31564176 DOI: 10.1080/00365521.2019.1669702] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2019] [Revised: 09/06/2019] [Accepted: 09/08/2019] [Indexed: 02/04/2023]
Abstract
Background and aim: Response to ursodeoxycholic acid (UDCA) is crucial for the prediction of primary biliary cholangitis (PBC) prognosis, and different response criteria were validated and proposed by reference centers for PBC. To date, rates of non-response to UDCA from real-world series are lacking.Methods: Hepatology/Gastroenterology centers belonging to 'Club Epatologi Ospedalieri' (CLEO) and 'Associazione Italiana Gastroenterologi Ospedalieri' (AIGO) were invited to participate in the study, and asked to extract all patients followed for PBC, without any selection or exclusion, and fill in the database provided.Results: Thirty-four centers were enrolled throughout Italy, for a total of 713 patients. None of these centers, except one, had a hepatology outpatient clinic devoted to the care of patients with autoimmune liver diseases. After excluding 79 cases of PBC/autoimmune hepatitis overlaps, 634 patients were analyzed: mean age, 64.4 ± 12.0 years; 91.2% females; F/M 10.3/1. For patients with at least 1 year of UDCA treatment (583), rates of non-response to UDCA were evaluated according to the Paris-I/-II, Toronto and GLOBE criteria, and compared with those in the original cohorts: 27% vs 39% in Paris-I cohort; 39.6% vs 52% in Paris-II; 20.1% vs 43.5% in Toronto; 15.7% vs 30% in GLOBE (age-specific cutoffs). Mean alkaline phosphatase levels on UDCA treatment, and the age-adjusted prevalence of F3/F4 fibrosis, appeared lower in this PBC population than in reference cohorts.Conclusions: A mean ∼15% better response to UDCA is observed in a real-world PBC population, probably due to migration of some of most severe/advanced cases to PBC referral centers.
Collapse
Affiliation(s)
| | | | | | - Rodolfo Sacco
- Department of Gastroenterology, University Hospital, Pisa, Italy
| | | | - Luchino Chessa
- Liver Unit, University Hospital of Cagliari, Cagliari, Italy
| | - Antonio De Vincentis
- Internal Medicine and Hepatology, University Campus Bio-Medico of Rome, Rome, Italy
| | | | | | - Valentina Feletti
- Gastroenterology Unit, Santa Maria Delle Croci Hospital, Ravenna, Italy
| | | | - Teresa Zolfino
- Department of Gastroenterology, Brotzu Hospital, Cagliari, Italy
| | | | - Raffaele Cozzolongo
- Gastroenterology Unit, National Institute of Gastroenterology "S de Bellis" Reseach Hospital, Castellana Grotte (Bari), Italy
| | - Giovanni Garrucciu
- General Medicine and Medical Pathology, Sassari University Hospital, Sassari, Italy
| | - Grazia Niro
- Department of Gastroenterology, Casa Sollievo Della Sofferenza Institute, San Giovanni Rotondo (Foggia), Italy
| | - Donato Bacca
- Internal Medicine Unit, Casarano Hospital, Lecce, Italy
| | - Gaetano Bertino
- Department of Hepatology, University Hospital Policlinico Vittorio Emanuele, Catania, Italy
| | - Ernesto Claar
- Department of Hepatology, Betania Hospital, Napoli, Italy
| | - Antonio Ascione
- Department of Hepatology, Fatebenefratelli Hospital, Napoli, Italy
| | - Giuseppe D'Adamo
- Department of General Medicine, Umberto I Hospital ASL Salerno, Nocera Inferiore, Italy
| | - Luigi Elio Adinolfi
- Department of Internal Medicine, Luigi Vanvitelli University of Campania, Napoli, Italy
| | - Gaetano Scifo
- Department of Infectious Diseases, Umberto I Hospital, Siracusa, Italy
| | - Antonio Izzi
- Department of Infectious Diseases, D. Cotugno Hospital, Napoli, Italy
| |
Collapse
|
|
28
|
Corpechot C, Poupon R, Chazouillères O. New treatments/targets for primary biliary cholangitis. JHEP Rep 2019; 1:203-213. [PMID: 32039371 PMCID: PMC7001536 DOI: 10.1016/j.jhepr.2019.05.005] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2019] [Revised: 05/11/2019] [Accepted: 05/14/2019] [Indexed: 02/06/2023] Open
Abstract
Primary biliary cholangitis (PBC) is an autoimmune, cholestatic, chronic liver disease that ultimately progresses towards cirrhosis and liver failure if untreated. While ursodeoxycholic acid has been established as standard of care for PBC in the last few decades, significant advances in second-line treatment options have recently been made and new therapeutic developments are currently under evaluation. The purpose of this article is to provide the clinician with an overview of the current treatment options and future opportunities for patients with PBC.
Collapse
Affiliation(s)
- Christophe Corpechot
- Reference Center for Inflammatory Biliary Diseases and Autoimmune Hepatitis, Hepatology Department, Saint-Antoine Hospital, Assistance Publique – Hôpitaux de Paris (APHP); INSERM UMR_S938, Saint-Antoine Research Center, Sorbonne University, Paris, France
- Corresponding author. Address: Hepatology Department, Saint Antoine Hospital, 184 rue du Faubourg Saint Antoine, 75571 Paris Cedex 12, France.
| | - Raoul Poupon
- Reference Center for Inflammatory Biliary Diseases and Autoimmune Hepatitis, Hepatology Department, Saint-Antoine Hospital, Assistance Publique – Hôpitaux de Paris (APHP); INSERM UMR_S938, Saint-Antoine Research Center, Sorbonne University, Paris, France
| | - Olivier Chazouillères
- Reference Center for Inflammatory Biliary Diseases and Autoimmune Hepatitis, Hepatology Department, Saint-Antoine Hospital, Assistance Publique – Hôpitaux de Paris (APHP); INSERM UMR_S938, Saint-Antoine Research Center, Sorbonne University, Paris, France
| |
Collapse
|
|
29
|
Zipprich A. Rheumatologie und Hepatologie: Diagnostik und Therapie von
autoimmunen Lebererkrankungen. AKTUEL RHEUMATOL 2019. [DOI: 10.1055/a-0885-9314] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Abstract
ZusammenfassungUnter autoimmunen Lebererkrankungen werden im klassischen Sinne 3 verschiedene
Entitäten, die Autoimmune Hepatitis (AIH), die Primär biliäre Cholangitis (PBC)
und die Primär sklerosierende Cholangitis (PSC) verstanden. Der nachfolgende
Übersichtartikel fokusiert auf die Diagnostik und die Therapie dieser 3
autoimmunen Lebererkrankungen und gibt eine Übersicht zu möglichen zusätzlich
assoziierten Autoimmunerkrankungen.
Collapse
|
|
30
|
Tanaka A. Emerging novel treatments for autoimmune liver diseases. Hepatol Res 2019; 49:489-499. [PMID: 30969002 DOI: 10.1111/hepr.13347] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2019] [Revised: 03/26/2019] [Accepted: 04/07/2019] [Indexed: 12/17/2022]
Abstract
The etiology of autoimmune liver diseases, such as autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), and primary sclerosing cholangitis (PSC), still remains largely unknown and no therapeutic agents that are able to "cure" these diseases have been developed. Although corticosteroids for AIH and ursodeoxycholic acid for PBC have been shown to significantly improve liver transplantation (LT)-free survival and are recommended as first-line drugs, treatment strategies for patients who show incomplete response to these drugs have not yet been fully established. No drug is significantly associated with long LT-free survival in PSC patients. Nevertheless, with progress in genetics, immunology, and cellular biology, several new compounds or antibodies are expected to have an effect on autoimmune liver diseases and several drugs are under consideration for clinical use. Although most clinical trials have been carried out in the USA or Europe, some are, or will be, undertaken in Japan in the future. In this review, the current standard-of-care of autoimmune liver diseases will be summarized, together with emerging novel treatments relevant to clinical practice in Japan.
Collapse
|
|
31
|
Lindor KD, Bowlus CL, Boyer J, Levy C, Mayo M. Primary Biliary Cholangitis: 2018 Practice Guidance from the American Association for the Study of Liver Diseases. Hepatology 2019; 69:394-419. [PMID: 30070375 DOI: 10.1002/hep.30145] [Citation(s) in RCA: 403] [Impact Index Per Article: 67.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2018] [Accepted: 05/30/2018] [Indexed: 02/06/2023]
Affiliation(s)
- Keith D Lindor
- Arizona State University, Division of Gastroenterology and Hepatology, Mayo Clinic, Phoenix, AZ
| | | | | | | | - Marlyn Mayo
- University of Texas Southwestern Medical Center, Dallas, TX
| |
Collapse
|
|
32
|
Bivalent Ligand UDCA-LPE Inhibits Pro-Fibrogenic Integrin Signalling by Inducing Lipid Raft-Mediated Internalization. Int J Mol Sci 2018; 19:ijms19103254. [PMID: 30347788 PMCID: PMC6214129 DOI: 10.3390/ijms19103254] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2018] [Revised: 10/08/2018] [Accepted: 10/10/2018] [Indexed: 01/07/2023] Open
Abstract
Ursodeoxycholyl lysophosphatidylethanolamide (UDCA-LPE) is a synthetic bile acid-phospholipid conjugate with profound hepatoprotective and anti-fibrogenic functions in vitro and in vivo. Herein, we aimed to demonstrate the inhibitory effects of UDCA-LPE on pro-fibrogenic integrin signalling. UDCA-LPE treatment of human embryonic liver cell line CL48 and primary human hepatic stellate cells induced a non-classical internalization of integrin β1 resulting in dephosphorylation and inhibition of SRC and focal adhesion kinase (FAK). Signalling analyses suggested that UDCA-LPE may act as a heterobivalent ligand for integrins and lysophospholipid receptor1 (LPAR1) and co-immunoprecipitation demonstrated the bridging effect of UDCA-LPE on integrin β1 and LPAR1. The disruption of either the UDCA-moiety binding to integrins by RGD-containing peptide GRGDSP or the LPE-moiety binding to LPAR1 by LPAR1 antagonist Ki16425 reversed inhibitory functions of UDCA-LPE. The lack of inhibitory functions of UDCA-PE and UDCA-LPE derivatives (14:0 and 12:0, LPE-moiety containing shorter fatty acid chain) as well as the consistency of the translocation of UDCA-LPE and integrins, which co-fractionated with LPE but not UDCA, suggested that the observed UDCA-LPE-induced translocation of integrins was mediated by LPE endocytic transport pathway.
Collapse
|
|
33
|
Martínez J, Aguilera L, Albillos A. Risk stratification and treatment of primary biliary cholangitis. REVISTA ESPANOLA DE ENFERMEDADES DIGESTIVAS 2018; 111:63-70. [PMID: 30338693 DOI: 10.17235/reed.2018.5662/2018] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
Primary biliary cholangitis is a chronic liver disorder characterized by progressive cholestasis that may evolve to liver cirrhosis. While ursodeoxycholic acid is the treatment of choice, around 30% of patients do not respond to this therapy. These patients have a poorer prognosis, hence should be identified early in order to be offered therapy options. Along these lines, improved understanding of the condition's pathophysiology has allowed the development of newer drugs, including obeticholic acid and fibrates. This review offers a perspective on risk stratification and treatment for these patients, from ursodeoxycholic acid to second-line treatments.
Collapse
Affiliation(s)
- Javier Martínez
- Servicio de Gastroenterología, Hospital Universitario Ramón y Cajal, España
| | | | - Agustín Albillos
- Servicio de Gastroenterología, Hospital Universitario Ramón y Cajal, España
| |
Collapse
|
|
34
|
Aguilar MT, Carey EJ. Current Status of Liver Transplantation for Primary Biliary Cholangitis. Clin Liver Dis 2018; 22:613-624. [PMID: 30259857 DOI: 10.1016/j.cld.2018.03.011] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [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 autoimmune cholestatic liver disease diagnosed with elevated alkaline phosphatase in the presence of antimitochondrial antibody. With the introduction and widespread use of ursodeoxycholic acid the proportion of PBC patients undergoing liver transplant (LT) has decreased. However, up to 40% of patients are ursodeoxycholic acid nonresponders and require second-line treatment or progress to end-stage liver disease requiring LT. Several scoring systems have been developed and validated to assess treatment response and transplant-free survival in patients. Although PBC is a favorable indication for LT, recurrence of PBC may occur and requires biopsy for diagnosis.
Collapse
Affiliation(s)
- Maria T Aguilar
- Division of Gastroenterology and Hepatology, Mayo Clinic, 13400 East Shea Boulevard, Scottsdale, AZ 85259, USA
| | - Elizabeth J Carey
- Division of Gastroenterology and Hepatology, Mayo Clinic, 5777 East Mayo Boulevard, Phoenix, AZ 85054, USA.
| |
Collapse
|
|
35
|
Natural History of Primary Biliary Cholangitis in the Ursodeoxycholic Acid Era: Role of Scoring Systems. Clin Liver Dis 2018; 22:563-578. [PMID: 30259853 DOI: 10.1016/j.cld.2018.03.007] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Primary biliary cholangitis (PBC) is a chronic disease that progresses to end-stage liver disease. Ursodeoxycholic acid (UDCA), the standard treatment for PBC for several decades, is associated with improved survival without liver transplantation. Approximately 40% of patients do not respond to UDCA. Because of disease variability, several prognostic models exist that incorporate various factors including biochemical response to UDCA. Useful for patient care and counseling as well as risk stratification for research and clinical trials, the role of these models in the pre-UDCA and UDCA eras is discussed.
Collapse
|
|
36
|
Abstract
Primary biliary cholangitis is a progressive, autoimmune disease of the interlobular bile ducts, leading to secondary damage of hepatocytes that may progress to cirrhosis and liver failure. Until recently, the only approved treatment was ursodeoxycholic acid. However, 40% of patients do not have an adequate response. Obeticholic acid was approved for treatment as add-on therapy in this group of patients. Off-label use of fibrates has also been reported to be effective. Several new therapies are in development and may further add to the treatment options available to patients with primary biliary cholangitis.
Collapse
Affiliation(s)
- Kimberly A Wong
- Department of Internal Medicine, UC Davis School of Medicine, 4150 V Street, PSSB 3000, Sacramento, CA 95817, USA
| | - Runalia Bahar
- Department of Internal Medicine, UC Davis School of Medicine, 4150 V Street, PSSB 3000, Sacramento, CA 95817, USA
| | - Chung H Liu
- Division of Gastroenterology and Hepatology, UC Davis School of Medicine, 4150 V Street, PSSB 3500, Sacramento, CA 95817, USA
| | - Christopher L Bowlus
- Division of Gastroenterology and Hepatology, UC Davis School of Medicine, 4150 V Street, PSSB 3500, Sacramento, CA 95817, USA.
| |
Collapse
|
|
37
|
Abstract
Primary biliary cholangitis is an archetypal autoimmune disease that causes cholestasis, fibrosis, and liver failure. Ursodeoxycholic acid and obeticholic acid are approved for its treatment. Not all patients respond, some are intolerant, many have ongoing symptoms, and new therapies are required. Herein we describe drugs in development and potential future biological targets. We consider compounds acting on the farnesoid X receptor/fibroblast growth factor 19 pathway, fibrates and other agonists of the peroxisome proliferator-activated receptor family, transmembrane-G-protein-receptor-5 agonists, and several immunological agents. We also consider the roles of bile acid reuptake inhibitors, nalfurafine, and fibrates in pruritus management.
Collapse
Affiliation(s)
- Gwilym J Webb
- National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham B15 2TT, UK
| | - Gideon M Hirschfield
- National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham B15 2TT, UK.
| |
Collapse
|
|
38
|
Goet JC, Harms MH, Carbone M, Hansen BE. Risk stratification and prognostic modelling in primary biliary cholangitis. Best Pract Res Clin Gastroenterol 2018; 34-35:95-106. [PMID: 30343715 DOI: 10.1016/j.bpg.2018.06.006] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2018] [Accepted: 06/08/2018] [Indexed: 01/31/2023]
Abstract
Primary biliary cholangitis (PBC) is a slowly progressive chronic cholestatic liver disease that, in a subgroup of patients, may result in liver failure or death. The definition of specific risk profiles, i.e. risk stratification, is of critical importance for the identification of these subgroups and thereby the targeting of care. Over the last few years large multicentre cohort studies have improved our knowledge regarding factors associated with progressive disease. Stratification based on biochemical response to ursodoxycholic acid provides a readily available measure to identify groups that might benefit from additional therapies to further improve prognosis. In addition, serum total bilirubin and alkaline phosphatase are now considered the most robustly validated biomarkers of long-term outcome in PBC and are used as endpoints in clinical trials. The GLOBE score and UK-PBC risk score enable us to quantify the risk of future events for the individual patient, allowing more individualized risk prediction. In this review, we discuss both established prognostic factors and newly developed tools to estimate prognosis in PBC, highlighting their strengths, limitations and applicability in clinical practice.
Collapse
Affiliation(s)
- Jorn C Goet
- Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, The Netherlands.
| | - Maren H Harms
- Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, The Netherlands.
| | - Marco Carbone
- Division of Gastroenterology and Program for Autoimmune Liver Diseases, International Center for Digestive Health, Department of Medicine and Surgery, University of Milan-Bicocca, Milan, Italy.
| | - Bettina E Hansen
- Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, The Netherlands; Toronto Centre for Liver Disease, Toronto General Hospital, Toronto, Canada; Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Canada.
| |
Collapse
|
|
39
|
Patterns of disease progression and incidence of complications in primary biliary cholangitis (PBC). Best Pract Res Clin Gastroenterol 2018; 34-35:71-83. [PMID: 30343713 DOI: 10.1016/j.bpg.2018.06.002] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2018] [Accepted: 06/08/2018] [Indexed: 02/07/2023]
Abstract
Clinical outcome for patients with primary biliary cholangitis (PBC) is dictated by development of cirrhosis, portal hypertension and its associated complications; including for some, a predisposition toward hepatocellular carcinoma. However rates of clinical progression vary, and accurately identifying disease course is of critical importance to patients, clinicians, as well as industry, who are committed to developing new effective and life-prolonging therapy as well as treating symptoms that appear disproportionate to underlying disease severity. Patients seek reassurance and guidance as to their own prognosis, and clinicians wish to confidently recognise those at highest risk of poor outcomes as equally as they strive to reassure individuals with a more favourable disease trajectory. International registries have facilitated a much greater knowledge of disease incidence and heterogeneity of presenting phenotypes. In so doing they highlight the opportunity to provide a more individualized estimate of the clinical course that patients experience, and have led to a renewed approach to risk stratification; both in terms of 'hard outcomes' and also disease-associated complications in PBC specifically.
Collapse
|
|
40
|
Setsu T, Yamagiwa S, Tominaga K, Kimura N, Honda H, Kamimura H, Tsuchiya A, Takamura M, Terai S. Persistent reduction of mucosal-associated invariant T cells in primary biliary cholangitis. J Gastroenterol Hepatol 2018; 33:1286-1294. [PMID: 29266628 DOI: 10.1111/jgh.14076] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2017] [Revised: 11/16/2017] [Accepted: 12/13/2017] [Indexed: 12/11/2022]
Abstract
BACKGROUND AND AIM Mucosal-associated invariant T (MAIT) cells constitute a novel subset of innate-like T lymphocytes characterized by a semi-invariant T-cell receptor repertoire capable of recognizing bacterial products. Considering the abundance of MAIT cells in the liver and the possible association between bacterial infections and primary biliary cholangitis (PBC), we aimed to analyze the involvement of MAIT cells in the immunopathogenesis of PBC. METHODS Peripheral blood and liver biopsy specimens were collected from 25 patients with PBC and 19 patients with chronic viral hepatitis. Surgically removed liver tissues distant from tumors in patients with metastatic liver tumors were used as controls. Mononuclear cells were separated using Ficoll gradient, and the expression of various markers was investigated by flow cytometry. Cytokine production was investigated using blood MAIT cells after stimulation by anti-CD3/CD28-coupled beads with/without interleukin-7 (IL-7). RESULTS Mucosal-associated invariant T cells were significantly reduced in both the blood and liver of PBC patients compared with those in controls. MAIT cells in the blood of PBC patients expressed significantly lower levels of activation markers and IL-7 receptor. Moreover, MAIT cells in the blood of PBC patients showed impaired production of cytokines, especially tumor necrosis factor alpha, after in vitro stimulation with IL-7. Interestingly, even after biochemical responses were achieved by ursodeoxycholic acid treatment, the frequencies of MAIT cells did not fully recover to normal levels. CONCLUSIONS These findings suggested that MAIT cells were activated, exhausted, and persistently depleted in PBC patients even after ursodeoxycholic acid treatment, possibly as a consequence of persistent liver inflammation.
Collapse
Affiliation(s)
- Toru Setsu
- Division of Gastroenterology and Hepatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Satoshi Yamagiwa
- Division of Gastroenterology and Hepatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Kentaro Tominaga
- Division of Gastroenterology and Hepatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Naruhiro Kimura
- Division of Gastroenterology and Hepatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Hiroki Honda
- 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
| | - Atsunori Tsuchiya
- Division of Gastroenterology and Hepatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Masaaki Takamura
- Division of Gastroenterology and Hepatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Shuji Terai
- Division of Gastroenterology and Hepatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| |
Collapse
|
|
41
|
Burman BE, Jhaveri MA, Kowdley KV. An Update on the Treatment and Follow-up of Patients with Primary Biliary Cholangitis. Clin Liver Dis 2017; 21:709-723. [PMID: 28987258 DOI: 10.1016/j.cld.2017.06.005] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Primary biliary cholangitis (PBC) is an autoimmune liver disease characterized by chronic granulomatous lymphocytic cholangitis of the small bile ducts. PBC was a leading indication for liver transplant in the United States; with early diagnosis and treatment, the majority of patients with PBC have a normal life expectancy. Pathogenesis involves inflammatory damage of bile duct epithelium secondary to innate and adaptive immune responses, and toxicity from accumulated bile acids. Cholestasis and disease progression can lead to cirrhosis. Extrahepatic complications include dyslipidemia, metabolic bone disease, and fat-soluble vitamin deficiency. Ursodeoxycholic acid is a well-established therapy. Novel targeted therapeutics are being developed.
Collapse
Affiliation(s)
- Blaire E Burman
- Division of Gastroenterology and Hepatology, Virginia Mason Medical Center, 1100 Ninth Avenue, Seattle, WA 98101, USA
| | - Manan A Jhaveri
- Department of Organ Transplant & Liver Center, Liver Care Network and Organ Care Research, Swedish Medical Center, Seattle, 1124 Columbia Street, WA 98101, USA
| | - Kris V Kowdley
- Department of Organ Transplant & Liver Center, Liver Care Network and Organ Care Research, Swedish Medical Center, Seattle, 1124 Columbia Street, WA 98101, USA.
| |
Collapse
|
|
42
|
Parés A. Advances in treatment options for patients with primary biliary cholangitis. Expert Opin Orphan Drugs 2017. [DOI: 10.1080/21678707.2017.1394840] [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: 10/18/2022]
Affiliation(s)
- Albert Parés
- Liver Unit, University of Barcelona, Hospital Clínic, Institut d’Investigacions Biomèdiques August Pi Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBEREHD), Barcelona, Spain
| |
Collapse
|
|
43
|
A brief review on prognostic models of primary biliary cholangitis. Hepatol Int 2017; 11:412-418. [DOI: 10.1007/s12072-017-9819-9] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2017] [Accepted: 08/29/2017] [Indexed: 12/12/2022]
|
|
44
|
Fan X, Wang T, Shen Y, Xi X, Yang L. Underestimated Male Prevalence of Primary Biliary Cholangitis in China: Results of a 16-yr cohort study involving 769 patients. Sci Rep 2017; 7:6560. [PMID: 28747696 PMCID: PMC5529550 DOI: 10.1038/s41598-017-06807-7] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2017] [Accepted: 06/16/2017] [Indexed: 02/05/2023] Open
Abstract
For primary biliary cholangitis (PBC), a sex ratio was reported to be significantly lower than previously cited in the West; we sought to evaluate sex ratio and long-term outcomes in PBC by studying a PBC cohort at a high-volume hospital from January 2001 to July 2016. A retrospective analysis including 769 PBC patients was conducted. The gender ratio was 6.1:1. Of the patients, 30.6% had one or more extrahepatic autoimmune (EHA) conditions. The proportion of patients with decompensated PBC at diagnosis increased from 25.0% in period 1 to 47.0% in period 4 (p < 0.05). Of the 420 patients without complications on presentation, the Kaplan-Meier estimate revealed distinct outcomes between non-cirrhotic PBC and cirrhotic PBC, with estimated mean survival times of 145.1 months and 104.5 months, respectively (p < 0.001). According to a subgroup analysis, gender and anti-mitochondrial antibody (AMA) status did not affect long-term prognosis, whereas patients with EHA conditions showed better prognoses. This study reveals evolving trends in male prevalence similar to their Western counterparts. Cirrhotic PBC patients were distinct from those with non-cirrhotic PBC at diagnosis based on difference in long-term outcome.
Collapse
Affiliation(s)
- Xiaoli Fan
- Division of Gastroenterology & Hepatology, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Tingting Wang
- Division of Gastroenterology & Hepatology, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Yi Shen
- Division of Gastroenterology & Hepatology, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Xiaotan Xi
- Division of Gastroenterology & Hepatology, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Li Yang
- Division of Gastroenterology & Hepatology, West China Hospital, Sichuan University, Chengdu, 610041, China.
| |
Collapse
|
|
45
|
Berdichevski T, Cohen-Ezra O, Pappo O, Ben-Ari Z. Positive antimitochondrial antibody but normal serum alkaline phosphatase levels: Could it be primary biliary cholangitis? Hepatol Res 2017; 47:742-746. [PMID: 27572231 DOI: 10.1111/hepr.12809] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2016] [Revised: 08/04/2016] [Accepted: 08/23/2016] [Indexed: 01/03/2023]
Abstract
AIM Primary biliary cholangitis (PBC) is a chronic cholestatic liver disease, typically diagnosed by elevated cholestatic liver enzymes and a positive antimitochondrial antibody (AMA) test. The clinical significance of AMA positivity in patients with normal cholestatic liver enzymes is uncertain. METHODS Charts of patients with normal cholestatic liver enzymes and AMA positivity who underwent liver biopsy between 2012 and 2015 were retrospectively analyzed. RESULTS Six AMA-positive patients with normal cholestatic liver enzymes who underwent a liver biopsy were identified. Four (67%) showed florid bile duct lesion compatible with early-stage PBC, whereas the other two showed mild and non-specific histological findings. The patients with histological findings compatible with PBC had higher enzyme-linked immunosorbent assay-determined AMA titers and significantly elevated immunoglobulin M (IgM) level. Patients with non-specific histological findings (33%) had low-titer AMA and a borderline elevated IgM level. CONCLUSIONS Antimitochondrial antibody-positive patients with normal cholestatic liver enzymes should be meticulously evaluated for PBC including a liver biopsy, mainly in patients with high-titer seropositivity for AMA and a significantly elevated IgM level. More studies are required to clarify the role of liver biopsy in these patients and further follow-up may elucidate the relationship of these patients to those with more classical forms of PBC.
Collapse
Affiliation(s)
- Tania Berdichevski
- Liver Disease Center, Sheba Medical Center, Ramat Gan, Israel.,The Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Oranit Cohen-Ezra
- Liver Disease Center, Sheba Medical Center, Ramat Gan, Israel.,The Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Orit Pappo
- Institute of Pathology, Sheba Medical Center, Ramat Gan, Israel
| | - Ziv Ben-Ari
- Liver Disease Center, Sheba Medical Center, Ramat Gan, Israel.,The Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
| |
Collapse
|
|
46
|
Olson JC. Acute-on-chronic and Decompensated Chronic Liver Failure: Definitions, Epidemiology, and Prognostication. Crit Care Clin 2017; 32:301-9. [PMID: 27339672 DOI: 10.1016/j.ccc.2016.02.001] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Chronic liver disease is the fifth leading cause of death worldwide and represents a major burden for the health care community. Cirrhosis is a progressive disease resulting in end-stage liver failure, which in the absence of liver transplantation is fatal. Acute-on-chronic liver failure carries high short-term mortality but is potentially reversible. Viral hepatitis, alcohol, and nonalcoholic fatty liver disease remain the principal causes of liver disease. Though treatments exist for hepatitis B and C, they remain unavailable to many with these diseases. This article reviews the epidemiology of advanced liver disease and the concept of acute-on-chronic liver failure.
Collapse
Affiliation(s)
- Jody C Olson
- Hepatology and Critical Care Medicine, University of Kansas Medical Center, 3901 Rainbow Boulevard, MS 1023, Kansas City, KS 66160, USA.
| |
Collapse
|
|
47
|
Mells GF, Jones DEJ. Stratified medicine and primary biliary cholangitis. Lancet Gastroenterol Hepatol 2017; 2:319-321. [PMID: 28397694 DOI: 10.1016/s2468-1253(17)30047-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2017] [Accepted: 02/03/2017] [Indexed: 10/19/2022]
Affiliation(s)
- George F Mells
- Academic Department of Medical Genetics, University of Cambridge, Cambridge, UK
| | - David E J Jones
- Institute of Cellular Medicine, Newcastle University, Newcastle NE2 4HH, UK.
| |
Collapse
|
|
48
|
Levy C. Primary biliary cholangitis: Treatment options finally expand. Hepatology 2017; 65:1405-1407. [PMID: 28093785 DOI: 10.1002/hep.29053] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2016] [Revised: 12/19/2016] [Accepted: 01/06/2017] [Indexed: 12/07/2022]
Affiliation(s)
- Cynthia Levy
- Division of Hepatology, University of Miami Miller School of Medicine, Miami, FL
| |
Collapse
|
|
49
|
Chascsa D, Carey EJ, Lindor KD. Old and new treatments for primary biliary cholangitis. Liver Int 2017; 37:490-499. [PMID: 28371104 DOI: 10.1111/liv.13294] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2016] [Accepted: 10/27/2016] [Indexed: 02/13/2023]
Abstract
Primary biliary cholangitis (formerly primary biliary cirrhosis) is a rare progressive cholestatic liver disease, whose hallmark features include a persistently elevated alkaline phosphatase level, presence of anti-mitochondrial antibodies and characteristic histology. Since 1998, ursodeoxycholic acid (UDCA), a bile acid, has been the only available therapeutic agent. Primary biliary cholangitis is associated with the development of end-stage liver disease, increased morbidity and mortality. UDCA has been shown to improve serum biochemistries, histology and delay the need for liver transplantation. The clinical issue is that approximately 25%-40% of patients do not respond to this standard therapy. In recent years, many trials have investigated alternative and adjunctive treatments, leading to the recent approval of obeticholic acid, an analogue of chenodeoxycholic acid, which has shown significant and sustained reductions in alkaline phosphatase levels in combination with UDCA. Obeticholic acid has rapidly been embraced as a new agent to improve the biochemical profile in refractory patients, in addition to being approved for use as monotherapy in patients who cannot tolerate UDCA. There are several other studies and targets which are being investigated. This review is intended to highlight the benefits of UDCA, educate the reader on the newly available obeticholic acid, and to summarize the many ongoing trials and therapeutic targets being investigated in attempts to control and cure primary biliary cholangitis.
Collapse
Affiliation(s)
- David Chascsa
- Division of Gastroenterology and Hepatology, Mayo Clinic, Phoenix, AZ, USA
| | - Elizabeth J Carey
- Division of Gastroenterology and Hepatology, Mayo Clinic, Phoenix, AZ, USA
| | - Keith D Lindor
- Division of Gastroenterology and Hepatology, Mayo Clinic, Phoenix, AZ, USA.,College of Health Solutions, Arizona State University, Phoenix, AZ, USA
| |
Collapse
|
|
50
|
Saffioti F, Gurusamy KS, Eusebi LH, Tsochatzis E, Davidson BR, Thorburn D, Cochrane Hepato‐Biliary Group. Pharmacological interventions for primary biliary cholangitis: an attempted network meta-analysis. Cochrane Database Syst Rev 2017; 3:CD011648. [PMID: 28350426 PMCID: PMC6464661 DOI: 10.1002/14651858.cd011648.pub2] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
BACKGROUND Primary biliary cholangitis (previously primary biliary cirrhosis) is a chronic liver disease caused by the destruction of small intra-hepatic bile ducts resulting in stasis of bile (cholestasis), liver fibrosis, and liver cirrhosis. The optimal pharmacological treatment of primary biliary cholangitis remains uncertain. OBJECTIVES To assess the comparative benefits and harms of different pharmacological interventions in the treatment of primary biliary cholangitis through a network meta-analysis and to generate rankings of the available pharmacological interventions according to their safety and efficacy. However, it was not possible to assess whether the potential effect modifiers were similar across different comparisons. Therefore, we did not perform the network meta-analysis, and instead, assessed the comparative benefits and harms of different interventions using standard Cochrane methodology. SEARCH METHODS We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2017, Issue 2), MEDLINE, Embase, Science Citation Index Expanded, World Health Organization International Clinical Trials Registry Platform, and randomised controlled trials registers to February 2017 to identify randomised clinical trials on pharmacological interventions for primary biliary cholangitis. SELECTION CRITERIA We included only randomised clinical trials (irrespective of language, blinding, or publication status) in participants with primary biliary cholangitis. We excluded trials which included participants who had previously undergone liver transplantation. We considered any of the various pharmacological interventions compared with each other or with placebo or no intervention. DATA COLLECTION AND ANALYSIS We used standard methodological procedures expected by Cochrane. We calculated the odds ratio (OR) and rate ratio with 95% confidence intervals (CI) using both fixed-effect and random-effects models based on available-participant analysis with Review Manager 5. We assessed risk of bias according to Cochrane, controlled risk of random errors with Trial Sequential Analysis, and assessed the quality of the evidence using GRADE. MAIN RESULTS We identified 74 trials including 5902 participants that met the inclusion criteria of this review. A total of 46 trials (4274 participants) provided information for one or more outcomes. All the trials were at high risk of bias in one or more domains. Overall, all the evidence was low or very low quality. The proportion of participants with symptoms varied from 19.9% to 100% in the trials that reported this information. The proportion of participants who were antimitochondrial antibody (AMA) positive ranged from 80.8% to 100% in the trials that reported this information. It appeared that most trials included participants who had not received previous treatments or included participants regardless of the previous treatments received. The follow-up in the trials ranged from 1 to 96 months.The proportion of people with mortality (maximal follow-up) was higher in the methotrexate group versus the no intervention group (OR 8.83, 95% CI 1.01 to 76.96; 60 participants; 1 trial; low quality evidence). The proportion of people with mortality (maximal follow-up) was lower in the azathioprine group versus the no intervention group (OR 0.56, 95% CI 0.32 to 0.98; 224 participants; 2 trials; I2 = 0%; low quality evidence). However, it has to be noted that a large proportion of participants (25%) was excluded from the trial that contributed most participants to this analysis and the results were not reliable. There was no evidence of a difference in any of the remaining comparisons. The proportion of people with serious adverse events was higher in the D-penicillamine versus no intervention group (OR 28.77, 95% CI 1.57 to 526.67; 52 participants; 1 trial; low quality evidence). The proportion of people with serious adverse events was higher in the obeticholic acid plus ursodeoxycholic acid (UDCA) group versus the UDCA group (OR 3.58, 95% CI 1.02 to 12.51; 216 participants; 1 trial; low quality evidence). There was no evidence of a difference in any of the remaining comparisons for serious adverse events (proportion) or serious adverse events (number of events). None of the trials reported health-related quality of life at any time point. FUNDING nine trials had no special funding or were funded by hospital or charities; 31 trials were funded by pharmaceutical companies; and 34 trials provided no information on source of funding. AUTHORS' CONCLUSIONS Based on very low quality evidence, there is currently no evidence that any intervention is beneficial for primary biliary cholangitis. However, the follow-up periods in the trials were short and there is significant uncertainty in this issue. Further well-designed randomised clinical trials are necessary. Future randomised clinical trials ought to be adequately powered; performed in people who are generally seen in the clinic rather than in highly selected participants; employ blinding; avoid post-randomisation dropouts or planned cross-overs; should have sufficient follow-up period (e.g. five or 10 years or more); and use clinically important outcomes such as mortality, health-related quality of life, cirrhosis, decompensated cirrhosis, and liver transplantation. Alternatively, very large groups of participants should be randomised to facilitate shorter trial duration.
Collapse
Affiliation(s)
- Francesca Saffioti
- Royal Free Hospital and the UCL Institute of Liver and Digestive HealthSheila Sherlock Liver CentrePond StreetHampsteadLondonUKNW3 2QG
- University of MessinaDepartment of Clinical and Experimental Medicine, Division of Clinical and Molecular HepatologyVia Consolare Valeria, 1MessinaMessinaItaly98125
| | - Kurinchi Selvan Gurusamy
- Royal Free Campus, UCL Medical SchoolDepartment of SurgeryRoyal Free HospitalRowland Hill StreetLondonUKNW3 2PF
| | - Leonardo Henry Eusebi
- Royal Free Hampstead NHS Foundation Trust and UCL Institute of Liver and Digestive HealthThe Royal Free Sheila Sherlock Liver CentreLondonUK
- University of BolognaDepartment of Medical and Surgical Sciences (DIMEC)BolognaItaly
| | - Emmanuel Tsochatzis
- Royal Free Hospital and the UCL Institute of Liver and Digestive HealthSheila Sherlock Liver CentrePond StreetHampsteadLondonUKNW3 2QG
| | - Brian R Davidson
- Royal Free Campus, UCL Medical SchoolDepartment of SurgeryRoyal Free HospitalRowland Hill StreetLondonUKNW3 2PF
| | - Douglas Thorburn
- Royal Free Hospital and the UCL Institute of Liver and Digestive HealthSheila Sherlock Liver CentrePond StreetHampsteadLondonUKNW3 2QG
| | | |
Collapse
|