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Abstract Details
Goals of Treatment for Improved Survival in Primary Biliary Cholangitis: Treatment Target Should Be Bilirubin Within the Normal Range and Normalization of Alkaline Phosphatase
Am J Gastroenterol. 2020 Feb 20. doi: 10.14309/ajg.0000000000000557. Online ahead of print.
Carla F Murillo Perez12, 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 Bruns1415, George N Dalekos16, Nikolaos K Gatselis16, Douglas Thorburn17, Palak J Trivedi18, Xavier Verhelst19, Albert Parés20, Harry L A Janssen1, Bettina E Hansen121, GLOBAL PBC Study Group
Author information
1Toronto Centre for Liver Disease, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada.
2Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, Netherlands.
3College of Health Solutions, Arizona State University, Phoenix, Arizona.
4Centre de Re[Combining Acute Accent]fe[Combining Acute Accent]rence des Maladies Inflammatoires des VoiesBiliaires, Ho[Combining Circumflex Accent]pital Saint-Antoine, Paris, France.
5Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, Netherlands.
6Division of Gastroenterology and Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milan-Bicocca, Milan, Italy.
7Divison of Gastroenterology and Hepatology, University of Alberta, Edmonton, Alberta, Canada.
8Digestive and Liver Diseases, UT Southwestern Medical Center, Dallas, Texas.
9Department of Health Sciences, Universita[Combining Grave Accent] degli Studi di Milano, Milan, Italy.
10Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy.
11Division of Internal Medicine and Hepatology, Humanitas Clinical Research Center IRCSS, Humanitas University, Rozzano (Milan), Italy.
12Department of Hepatology, University Hospitals Leuven, KU Leuven, Leuven, Belgium.
13Liver Care Network, Swedish Medical Center, Seattle, Washington.
14Department of Internal Medicine IV, Jena University Hospital, Friedrich Schiller University, Jena, Germany.
15Department of Internal Medicine III, University Hospital RWTH Aachen, Aachen, Germany.
16Department of Medicine and Research Laboratory of Internal Medicine, University of Thessaly, Larissa, Greece.
17The Sheila Sherlock Liver Centre, The Royal Free Hospital, London, United Kingdom.
18National Institute for Health Research Birmingham Biomedical Research Centre and Centre for Liver Research, University of Birmingham, Birmingham, United Kingdom.
19Department of Gastroenterology and Hepatology, Ghent University Hospital, Ghent, Belgium.
20Liver Unit, Hospital Clínic, CIBERehd, IDIBAPS, University of Barcelona, Barcelona, Spain.
21Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Ontario, Canada.
Abstract
Objectives: 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.