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Goals of Treatment for Improved Survival in Primary Biliary Cholangitis: Treatment Target Should Be Bilirubin Within the Normal Range and Normalization of Alkaline Phosphatase
Open accessAbstract
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.
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“This retrospective study of more than 2000 patients in the Global PBC Group database who received ursodeoxycholic acid monotherapy found the 10-year liver transplant-free survival rates of patients with bilirubin less than 0•6 times ULN were 91•3% compared with 79•2% for patients with bilirubin levels of 0•6 times ULN (p<0•001).111”
From Primary biliary cholangitis. (2024) · cites this paper as [111]
In the citing paper
“Similarly, liver transplant-free survival rates were superior for patients with alkaline phosphatase less than ULN (93•2%) and for those with reductions to less than 1•67 times ULN (86•1%) after 1 year (p<0•001).111”
From Primary biliary cholangitis. (2024) · cites this paper as [111]
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“While normalisation of alkaline phosphatase levels has been associated with improved long-term outcomes in patients receiving ursodeoxycholic acid alone, 111,113 it remains unclear whether this association holds true for combination therapy, warranting further investigation.”
From Primary biliary cholangitis. (2024) · cites this paper as [111]
In the citing paper
“It has been shown that bilirubin within the normal range and normalization of ALP should be the goals of treatment for improved survival in PBC.21”
From Combination of fibrates with obeticholic acid is able to normalise biochemical liver tests in patients with difficult‐to‐treat primary biliary cholangitis (2021) · cites this paper as [21]
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References 33 · Cited by 188
Research works printed but not linked: 22
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Metadata
- Authors
- Murillo Perez, C. F., Harms, M. H., Lindor, K. D., van Buuren, H. R., Hirschfield, G. M., Corpechot, C., van der Meer, A. J., Feld, J. J., Gulamhusein, A., Lammers, W. J., Ponsioen, C. Y., Carbone, M., Mason, A. L., Mayo, M. J., Invernizzi, P., Battezzati, P. M., Floreani, A., Lleo, A., Nevens, F., Kowdley, K. V., Bruns, T., Dalekos, G. N., Gatselis, N. K., Thorburn, D., Trivedi, P. J., Verhelst, X., Parés, A., Janssen, H. L. A., Hansen, B. E., & on behalf of the GLOBAL PBC Study Group
- Affiliations
- Toronto Centre for Liver Disease, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada;
- Erasmus MC (NL)
- Arizona State University (US)
- Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, Netherlands;
- University Health Network (CA)
- Hôpital Saint-Antoine (FR)
- Amsterdam UMC Location University of Amsterdam (NL)
- University of Milano-Bicocca (IT)
- University of Alberta (CA)
- The University of Texas Southwestern Medical Center (US)
- University of Milan (IT)
- University of Padua (IT)
- Division of Internal Medicine and Hepatology, Humanitas Clinical Research Center IRCSS, Humanitas University, Rozzano (Milan), Italy;
- KU Leuven (BE)
- Swedish Medical Center (US)
- Universitätsklinikum Aachen (DE)
- University of Thessaly (GR)
- The Royal Free Hospital (GB)
- National Institute for Health and Care Research (GB)
- Ghent University Hospital (BE)
- Hospital Clínic de Barcelona (ES)
- Corresponding author
- Hansen, Bettina E.
- ORCID
- Harms, Maren H.
- Lindor, Keith D.
- Hirschfield, Gideon M.
- Corpechot, Christophe
- Feld, Jordan J.
- Gulamhusein, Aliya
- Lammers, Willem J.
- Ponsioen, Cyriel Y.
- Carbone, Marco
- Mason, Andrew L.
- Mayo, Marlyn J.
- Invernizzi, Pietro
- Battezzati, Pier Maria
- Floreani, Annarosa
- Nevens, Frederik
- Kowdley, Kris V.
- Bruns, Tony
- Gatselis, Nikolaos K.
- Thorburn, Douglas
- Trivedi, Palak J.
- Verhelst, Xavier
- Parés, Albert
- Janssen, Harry L.A.
- Hansen, Bettina E.
- Venue
- American Journal of Gastroenterology
- Published
- 2020-02-20
- Volume
- 115
- Issue
- 7
- Pages
- 1066-1074
- ISSN
- 0002-9270 (ISSN-L)
- 1572-0241
- OpenAlex
- W3007762014
- Semantic Scholar
- 453e575feb0dcd5558d87b04a679d12858c87ce2
- Cited by
- 188
- References
- 33
- Citations by year
- 2026: 41 · 2025: 43 · 2024: 30 · 2023: 19 · 2022: 27 · 2021: 18 · 2020: 10
- FWCI
- 10.88
- Type
- journal article
- Language
- en
- Open access
- green
- pure.amsterdamumc.nl
- Licence
- other-oa
- Locations
- The American Journal of Gastroenterology (publishedVersion)
- PubMed (publishedVersion)
- Ghent University Academic Bibliography (Ghent University) (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion)
- Lirias (KU Leuven) (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
- Ghent University Academic Bibliography (Ghent University) (submittedVersion)
- BOA (University of Milano-Bicocca) (submittedVersion)
- University of Thessaly Institutional Repository (University of Thessaly) (submittedVersion)
- Lirias (submittedVersion)
- Pure Amsterdam UMC (submittedVersion, other-oa)
- University of Birmingham Research Portal (University of Birmingham) (submittedVersion)
- Funders
- Falk Foundation
- Gilead Sciences
- Arizona State University
- University of Texas Southwestern Medical Center
- Università degli Studi di Milano
- Friedrich-Schiller-Universität Jena
- Intercept Pharmaceuticals
- University of Alberta
- National Institute for Health and Care Research
- Universitair Ziekenhuis Gent
- Università degli Studi di Padova
- Universiteit Gent
- Astellas Pharma
- Universitat de Barcelona
- Humanitas University
- University of Thessaly
- Dr. Falk Pharma
- Norgine
- Novartis Pharma
- Erasmus Universitair Medisch Centrum Rotterdam
- Cilag
- Topics
- Health Sciences › Medicine › Hepatology › Liver Diseases and Immunity
- Health Sciences › Medicine › Surgery › Pediatric Hepatobiliary Diseases and Treatments
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Keywords
- primary biliary cirrhosis, treatment goals, bilirubin, alkaline phosphatase, ursodeoxycholic acid, transplant-free survival, liver transplantation, mortality, surrogate markers, treatment thresholds, prognosis
- MeSH terms
- Alkaline Phosphatase, Bilirubin, Cholagogues and Choleretics, Cholangitis, Female, Humans, Male, Middle Aged, Prognosis, Reference Values, Ursodeoxycholic Acid, Biomarkers, Survival Rate
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