Carla F Murillo Perez1,2, Maren H Harms2, Keith D Lindor3, Henk R van Buuren2, Gideon M Hirschfield1, Christophe Corpechot4, Adriaan J van der Meer2, Jordan J Feld1, Aliya Gulamhusein1, Willem J Lammers2, Cyriel Y Ponsioen5, Marco Carbone6, Andrew L Mason7, Marlyn J Mayo8, Pietro Invernizzi6, Pier Maria Battezzati9, Annarosa Floreani10, Ana Lleo11, Frederik Nevens12, Kris V Kowdley13, Tony Bruns14,15, George N Dalekos16, Nikolaos K Gatselis16, Douglas Thorburn17, Palak J Trivedi18, Xavier Verhelst19, Albert Parés20, Harry L A Janssen1, Bettina E Hansen1,21. 1. Toronto Centre for Liver Disease, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada. 2. Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, Netherlands. 3. College of Health Solutions, Arizona State University, Phoenix, Arizona. 4. Centre de Re[Combining Acute Accent]fe[Combining Acute Accent]rence des Maladies Inflammatoires des VoiesBiliaires, Ho[Combining Circumflex Accent]pital Saint-Antoine, Paris, France. 5. Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, Netherlands. 6. Division of Gastroenterology and Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milan-Bicocca, Milan, Italy. 7. Divison of Gastroenterology and Hepatology, University of Alberta, Edmonton, Alberta, Canada. 8. Digestive and Liver Diseases, UT Southwestern Medical Center, Dallas, Texas. 9. Department of Health Sciences, Universita[Combining Grave Accent] degli Studi di Milano, Milan, Italy. 10. Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy. 11. Division of Internal Medicine and Hepatology, Humanitas Clinical Research Center IRCSS, Humanitas University, Rozzano (Milan), Italy. 12. Department of Hepatology, University Hospitals Leuven, KU Leuven, Leuven, Belgium. 13. Liver Care Network, Swedish Medical Center, Seattle, Washington. 14. Department of Internal Medicine IV, Jena University Hospital, Friedrich Schiller University, Jena, Germany. 15. Department of Internal Medicine III, University Hospital RWTH Aachen, Aachen, Germany. 16. Department of Medicine and Research Laboratory of Internal Medicine, University of Thessaly, Larissa, Greece. 17. The Sheila Sherlock Liver Centre, The Royal Free Hospital, London, United Kingdom. 18. National Institute for Health Research Birmingham Biomedical Research Centre and Centre for Liver Research, University of Birmingham, Birmingham, United Kingdom. 19. Department of Gastroenterology and Hepatology, Ghent University Hospital, Ghent, Belgium. 20. Liver Unit, Hospital Clínic, CIBERehd, IDIBAPS, University of Barcelona, Barcelona, Spain. 21. Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Ontario, Canada.
Abstract
INTRODUCTION: In primary biliary cholangitis (PBC), bilirubin and alkaline phosphatase (ALP) are widely established as independent predictors of prognosis. Current treatment goals do not aim for normalization of surrogate markers because their association with survival has not been defined. METHODS: The patient cohort from the GLOBAL PBC Study Group was used, comprising of long-term follow-up data from European and North American centers. Ursodeoxycholic acid-treated and untreated patients with bilirubin levels ≤1 × upper limit of normal (ULN) at baseline or 1 year were included. The association of normal ALP with transplant-free survival was assessed in a subgroup with ALP ≤1.67 × ULN at 1 year. Optimal thresholds of bilirubin and ALP to predict liver transplantation (LT) or death were evaluated. RESULTS: There were 2,281 patients included in the time zero cohort and 2,555 patients in the 1-year cohort. The bilirubin threshold with the highest ability to predict LT or death at 1 year was 0.6 × ULN (hazard ratio 2.12, 95% CI 1.69-2.66, P < 0.001). The 10-year survival rates of patients with bilirubin ≤0.6 × ULN and >0.6 × ULN were 91.3% and 79.2%, respectively (P < 0.001). The risk for LT or death was stable below the bilirubin levels of 0.6 × ULN, yet increased beyond this threshold. Ursodeoxycholic acid-induced reduction in bilirubin below this threshold was associated with an 11% improvement in 10-year survival. Furthermore, ALP normalization was optimal, with 10-year survival rates of 93.2% in patients with ALP ≤ 1 × ULN and 86.1% in those with ALP 1.0-1.67 × ULN. DISCUSSION: Attaining bilirubin levels ≤0.6 × ULN or normal ALP are associated with the lowest risk for LT or death in patients with PBC. This has important implications for treatment targets.
INTRODUCTION: In primary biliary cholangitis (PBC), bilirubin and alkaline phosphatase (ALP) are widely established as independent predictors of prognosis. Current treatment goals do not aim for normalization of surrogate markers because their association with survival has not been defined. METHODS: The patient cohort from the GLOBAL PBC Study Group was used, comprising of long-term follow-up data from European and North American centers. Ursodeoxycholic acid-treated and untreated patients with bilirubin levels ≤1 × upper limit of normal (ULN) at baseline or 1 year were included. The association of normal ALP with transplant-free survival was assessed in a subgroup with ALP ≤1.67 × ULN at 1 year. Optimal thresholds of bilirubin and ALP to predict liver transplantation (LT) or death were evaluated. RESULTS: There were 2,281 patients included in the time zero cohort and 2,555 patients in the 1-year cohort. The bilirubin threshold with the highest ability to predict LT or death at 1 year was 0.6 × ULN (hazard ratio 2.12, 95% CI 1.69-2.66, P < 0.001). The 10-year survival rates of patients with bilirubin ≤0.6 × ULN and >0.6 × ULN were 91.3% and 79.2%, respectively (P < 0.001). The risk for LT or death was stable below the bilirubin levels of 0.6 × ULN, yet increased beyond this threshold. Ursodeoxycholic acid-induced reduction in bilirubin below this threshold was associated with an 11% improvement in 10-year survival. Furthermore, ALP normalization was optimal, with 10-year survival rates of 93.2% in patients with ALP ≤ 1 × ULN and 86.1% in those with ALP 1.0-1.67 × ULN. DISCUSSION: Attaining bilirubin levels ≤0.6 × ULN or normal ALP are associated with the lowest risk for LT or death in patients with PBC. This has important implications for treatment targets.
Authors: Alena Laschtowitz; Rozanne C de Veer; Adriaan J Van der Meer; Christoph Schramm Journal: United European Gastroenterol J Date: 2020-04-16 Impact factor: 4.623
Authors: Eric M Yoshida; Mark Gordon Swain; Cynthia Tsien; Edward Tam; Robert James Bailey; Dusanka Grbic; Hin Hin Ko; Alnoor Ramji; Nir Hilzenrat; Magdy Elkhashab; Euiseok Kim; Meaghan O'Brien; Marco Amedeo Puglia; Kevork M Peltekian Journal: Can Liver J Date: 2022-08-16
Authors: David E J Jones; Aaron Wetten; Ben Barron-Millar; Laura Ogle; George Mells; Steven Flack; Richard Sandford; John Kirby; Jeremy Palmer; Sophie Brotherston; Laura Jopson; John Brain; Graham R Smith; Steve Rushton; Rebecca Jones; Simon Rushbrook; Douglas Thorburn; Stephen D Ryder; Gideon Hirschfield; Jessica K Dyson Journal: EBioMedicine Date: 2022-05-21 Impact factor: 11.205