Author information

¹Toronto Centre for Liver Disease, Toronto General Hospital, University Health Network, Toronto, Canada.

²Li Ka Shing Knowledge Institute, St Michael's Hospital, Unity Health Toronto, Toronto, Canada.

³Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Canada.

⁴Department of Medicine, University of Saskatchewan, Saskatoon, Canada.

⁵Département de Médecine, Université de Montréal, Montréal, Canada.

⁶Department of Medicine, Queen's University, Kingston, Canada.

⁷Department of Medicine, University of Ottawa, Ottawa, Canada.

⁸Department of Medicine, Western University, London, Canada.

⁹Department of Medicine, University of Calgary, Calgary, Canada.

¹⁰Départment de Médecine, Université de Sherbrooke, Sherbrooke, Canada.

¹¹Department of Medicine, University of British Columbia, Vancouver, Canada.

¹²Department of Medicine, Dalhousie University, Halifax, Canada.

¹³Royal Free London National Health Service Foundation Trust, London, United Kingdom.

¹⁴Department of Medicine, University of Alberta, Edmonton, Canada.

¹⁵European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy.

¹⁶Division of Gastroenterology, Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy.

¹⁷Faculty of Medicine, University of Amsterdam, Amsterdam, the Netherlands.

¹⁸Department of Gastroenterology and Hepatology, University Hospital Rheinisch-Westfälische Technische Hochschule Aachen University, Aachen, Germany.

¹⁹University of Padova, Padova, Italy.

²⁰Mayo Clinic, Scottsdale, Arizona, USA.

²¹European Reference Network on Hepatological Diseases, Barcelona, Spain.

²²Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, Larissa, Greece.

²³Department of Hepatology, Ghent University Hospital, Ghent, Belgium.

²⁴Scientific Institute for Research, Hospitalization and Healthcare, Negrar, Verona, Italy.

²⁵Reference 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.

²⁶Department of Medicine, Division of Digestive and Liver Disease, University of Texas, Southwestern Medical Center, Dallas, Texas, USA.

²⁷Schiff Center for Liver Diseases, University of Miami Miller School of Medicine, Miami, FL, USA.

²⁸Liver 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.

²⁹Università degli Studi di Milano, Milan, Italy.

³⁰Department 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.

³¹University Hospital Katholieke Universiteit Leuven, Leuven, Belgium.

³²Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam, Rotterdam, the Netherlands.

³³Liver Institute Northwest, Seattle, Washington, USA.

³⁴Liver Unit, University Hospitals Birmingham National Health Service Foundation Trust Queen Elizabeth, Birmingham, UK.

³⁵National Institute for Health and Care Research (NIHR) Birmingham Liver Biomedical Research Centre, University of Birmingham, College of Medical and Dental Sciences, Birmingham, Birmingham, UK.

³⁶Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK.

³⁷Institute of Applied Health Research, University of Birmingham, Birmingham, UK.

³⁸Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy; IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy.

³⁹Toronto General Hospital Research Institute, University Health Network, Toronto, Canada.

⁴⁰Department of Epidemiology & Biostatistics, Erasmus MC, Rotterdam, the Netherlands.

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.