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Levels of Alkaline Phosphatase and Bilirubin Are Surrogate End Points of Outcomes of Patients With Primary Biliary Cirrhosis: An International Follow-up Study
Open accessAbstract
Background & aims Noninvasive surrogate end points of long-term outcomes of patients with primary biliary cirrhosis (PBC) are needed to monitor disease progression and evaluate potential treatments. We performed a meta-analysis of individual patient data from cohort studies to evaluate whether patients' levels of alkaline phosphatase and bilirubin correlate with their outcomes and can be used as surrogate end points.Methods We performed a meta-analysis of data from 4845 patients included in 15 North American and European long-term follow-up cohort studies. Levels of alkaline phosphatase and bilirubin were analyzed in different settings and subpopulations at different time points relative to the clinical end point (liver transplantation or death).Results Of the 4845 patients, 1118 reached a clinical end point. The median follow-up period was 7.3 years; 77% survived for 10 years after study enrollment. Levels of alkaline phosphatase and bilirubin measured at study enrollment (baseline) and each year for 5 years were strongly associated with clinical outcomes (lower levels were associated with longer transplant-free survival). At 1 year after study enrollment, levels of alkaline phosphatase that were 2.0 times the upper limit of normal (ULN) best predicted patient outcome (C statistic, 0.71) but not significantly better than other thresholds. Of patients with alkaline phosphatase levels ≤ 2.0 times the ULN, 84% survived for 10 years compared with 62% of those with levels >2.0 times the ULN (P < .0001). Absolute levels of alkaline phosphatase 1 year after study enrollment predicted patient outcomes better than percentage change in level. One year after study enrollment, a bilirubin level 1.0 times the ULN best predicted patient transplant-free survival (C statistic, 0.79). Of patients with bilirubin levels ≤ 1.0 times the ULN, 86% survived for 10 years after study enrollment compared with 41% of those with levels >1.0 times the ULN (P < .0001). Combining levels of alkaline phosphatase and bilirubin increased the ability to predict patient survival times. We confirmed the predictive value of alkaline phosphatase and bilirubin levels in multiple subgroups, such as patients who had not received treatment with ursodeoxycholic acid, and at different time points after study enrollment.Conclusions Levels of alkaline phosphatase and bilirubin can predict outcomes (liver transplantation or death) of patients with PBC and might be used as surrogate end points in therapy trials.
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“In the current trial, bezafibrate was associated with a rapid and sustained decrease in alkaline phosphatase level and a parallel decrease in total bilirubin, the two most important prognostic indicators in primary biliary cholangitis.25”
From A Placebo-Controlled Trial of Bezafibrate in Primary Biliary Cholangitis (2018) · cites this paper as [25]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Serum bilirubin has been recognised since the 1970s as a major predictor of poor outcome in PBC [72,7].”
From EASL Clinical Practice Guidelines: The diagnosis and management of patients with primary biliary cholangitis. (2017) · cites this paper as [7]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Patients were selected on the basis of Paris 2 criteria, 15 which have been recognized as relevant predictors of clinical outcomes in several independent populations of patients with primary biliary cholangitis.24,25”
From A Placebo-Controlled Trial of Bezafibrate in Primary Biliary Cholangitis (2018) · cites this paper as [25]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“In a large, international cohort analysis involving patients with primary biliary cholangitis, elevations in the alkaline phosphatase level were independently associated with a risk of liver transplantation or death that was 2.0 to 2.5 times as high as the risk associated with normal levels. 10”
From A Placebo-Controlled Trial of Obeticholic Acid in Primary Biliary Cholangitis (2016) · cites this paper as [10]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“An abnormally elevated bilirubin level, which occurs later in disease progression, was a stronger predictor of outcomes, with a risk of liver transplantation or death that was 5.1 to 10.7 times the risk associated with normal levels; however, even increased values within the normal range were associated with a risk of disease progression. 10”
From A Placebo-Controlled Trial of Obeticholic Acid in Primary Biliary Cholangitis (2016) · cites this paper as [10]
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In the citing paper
“The disease is chronic and often progressive, resulting in end-stage liver disease and its associated complications [6][7][8].”
From EASL Clinical Practice Guidelines: The diagnosis and management of patients with primary biliary cholangitis. (2017) · cites this paper as [7]
The cited source says what the claim attributes to it.
In the citing paper
“Response to UDCA is variable, and incomplete response is associated with increased risk of death from PBC or need for liver transplantation.11–18”
From The British Society of Gastroenterology/UK-PBC primary biliary cholangitis treatment and management guidelines (2018) · cites this paper as [11]
The cited source says what the claim attributes to it.
In the citing paper
“Serum bilirubin has been recognised since the 1970s as a major predictor of poor outcome in PBC [72,7].”
From EASL Clinical Practice Guidelines: The diagnosis and management of patients with primary biliary cholangitis. (2017) · cites this paper as [7]
The cited source says what the claim attributes to it.
In the citing paper
“The disease is chronic and often progressive, resulting in end-stage liver disease and its associated complications [6][7][8].”
From EASL Clinical Practice Guidelines: The diagnosis and management of patients with primary biliary cholangitis. (2017) · cites this paper as [7]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“In a large, international meta-analysis including 4,845 patients, UDCAtreated individuals had significantly improved transplant-free survival at 5, 10, and 15 years compared with nontreated individuals (90%, 78%, and 66% versus 79%, 59%, and 32%, respectively).(77)”
From Primary Biliary Cholangitis: 2018 Practice Guidance from the American Association for the Study of Liver Diseases (2019) · cites this paper as [77]
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In the citing paper
“Specifically, serum ALP and total bilirubin predict outcomes in this context.(77)”
From Primary Biliary Cholangitis: 2018 Practice Guidance from the American Association for the Study of Liver Diseases (2019) · cites this paper as [77]
The cited source says what the claim attributes to it.
In the citing paper
“Higher levels of alkaline phosphatase and bilirubin levels correlate with disease progression, and lower levels are predictive of survival without the need for liver transplantation. 9,10”
From A Placebo-Controlled Trial of Obeticholic Acid in Primary Biliary Cholangitis (2016) · cites this paper as [10]
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In the citing paper
“The majority of patients diagnosed today are asymptomatic at diagnosis and one contemporary series showed that nearly 90% do not have fibrosis when first identified (although others have shown higher rates potentially reflecting case mix).11 12 26 27”
From The British Society of Gastroenterology/UK-PBC primary biliary cholangitis treatment and management guidelines (2018) · cites this paper as [11]
Experimental — accuracy not yet measuredIn the citing paper
“two of the main prognostic factors that predict long-term survival in PBC.20”
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 [20]
In the citing paper
“Higher levels of ALP correlate with disease progression, and are associated with higher risk of liver transplantation or death.4”
From NGM282 for Treatment of Patients With Primary Biliary Cholangitis: A Multicenter, Randomized, Double‐Blind, Placebo‐Controlled Trial (2018) · cites this paper as [4]
In the citing paper
“Reduction in ALP levels has been validated as a surrogate marker of slower disease progression as well as improved transplant‐free overall survival.4”
From NGM282 for Treatment of Patients With Primary Biliary Cholangitis: A Multicenter, Randomized, Double‐Blind, Placebo‐Controlled Trial (2018) · cites this paper as [4]
In the citing paper
“Recent data have revealed the importance of ALP as a surrogate of clinical outcomes in patients with PBC.4”
From NGM282 for Treatment of Patients With Primary Biliary Cholangitis: A Multicenter, Randomized, Double‐Blind, Placebo‐Controlled Trial (2018) · cites this paper as [4]
In the citing paper
“Elevated levels of ALP are prognostic of worse clinical outcomes in PBC, with lower levels of ALP associated with longer transplant‐free survival and improved overall survival.”
From NGM282 for Treatment of Patients With Primary Biliary Cholangitis: A Multicenter, Randomized, Double‐Blind, Placebo‐Controlled Trial (2018) · cites this paper as [4]
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Citations
Cites
Transection of the oesophagus for bleeding oesophageal varices
Pugh, R. N. H., Murray-Lyon, I. M., Dawson, J. L., Pietroni, M. C., & Williams, R. (1973) · Journal of British Surgery · doi:10.1002/bjs.1800600817 · Cited by 7,941
A Model to Predict Survival in Patients With End–Stage Liver Disease
Kamath, P. S., Wiesner, R. H., Malinchoc, M., Kremers, W. K., Therneau, T. M., Kosberg, C. L., D’Amico, G., Dickson, R. E., & Kim, W. R. (2001) · Hepatology · doi:10.1053/jhep.2001.22172 · Cited by 5,066
Kaplan, M. M. (1987) · New England Journal of Medicine · doi:10.1056/nejm198702263160907 · Cited by 2,016
Rockey, D. C., Caldwell, S. H., Goodman, Z. D., Nelson, R. C., & Smith, A. D. (2008) · Hepatology · doi:10.1002/hep.22742 · Cited by 2,004
Surgery and portal hypertension.
Child, C. G., & Turcotte, J. (1964) · PubMed · Cited by 1,933
EASL Clinical Practice Guidelines: management of cholestatic liver diseases
European Association for the Study of the Liver (2009) · Journal of Hepatology · doi:10.1016/j.jhep.2009.04.009 · Cited by 1,729
Schwab, M. (2011) · Springer eBooks · doi:10.1007/978-3-642-16483-5_4730 · Cited by 1,241
Kaplan, M. M., & Gershwin, M. E. (2005) · New England Journal of Medicine · doi:10.1056/nejmra043898 · Cited by 1,144
Lindor, K. D., Gershwin, E. M., Poupon, R., Kaplan, M., Bergasa, N. V., & Heathcote, J. E. (2009) · Hepatology · doi:10.1002/hep.22906 · Cited by 1,099
Self-citationPrognosis in primary biliary cirrhosis: Model for decision making
Dickson, R. E., Grambsch, P. M., Fleming, T. R., Fisher, L. D., & Langworthy, A. (1989) · Hepatology · doi:10.1002/hep.1840100102 · Cited by 816
(2015) · Elsevier eBooks · doi:10.1016/b978-0-323-37755-3.50202-6 · Cited by 808
Parés, A., Caballería, L., & Rodés, J. (2006) · Gastroenterology · doi:10.1053/j.gastro.2005.12.029 · Cited by 756
Self-citationStaging of chronic nonsuppurative destructive cholangitis (syndrome of primary biliary cirrhosis)
Ludwig, J., Dickson, E. R., & McDonald, G. S. A. (1978) · Virchows Archiv A Pathological Anatomy and Histology · doi:10.1007/bf00432479 · Cited by 753
Poupon, R., Lindor, K., Cauch-Dudek, K., Dickson, E., Poupon, R., & Heathcote, E. (1997) · Gastroenterology · doi:10.1016/s0016-5085(97)70183-5 · Cited by 648
Self-citationBiochemical response to ursodeoxycholic acid and long-term prognosis in primary biliary cirrhosis
Corpechot, C., Abenavoli, L., Rabahi, N., Chrétien, Y., Andréani, T., Johanet, C., Chazouillères, O., & Poupon, R. (2008) · Hepatology · doi:10.1002/hep.22428 · Cited by 646
Self-citationSymposium: Advances in Liver Pathology [ Abridged ]
Scheuer, P. J. (1967) · Proceedings of the Royal Society of Medicine · doi:10.1177/003591576706001205 · Cited by 559
Biomarkers and surrogate endpoints in clinical trials
Fleming, T. R., & Powers, J. H. (2012) · Statistics in Medicine · doi:10.1002/sim.5403 · Cited by 559
Celaya, F. B. (1989) · PubMed · Cited by 508
Ursodiol for the Long-Term Treatment of Primary Biliary Cirrhosis
Poupon, R. E., Poupon, R., & Balkau, B. (1994) · New England Journal of Medicine · doi:10.1056/nejm199405123301903 · Cited by 497
Self-citationCorpechot, C., Chazouillères, O., & Poupon, R. (2011) · Journal of Hepatology · doi:10.1016/j.jhep.2011.02.031 · Cited by 460
Self-citationKuiper, E. M. M., Hansen, B. E., de Vries, R. A., den Ouden–Muller, J. W., van Ditzhuijsen, T. J. M., Haagsma, E. B., Houben, M. H. M. G., Witteman, B. J. M., van Erpecum, K. J., & van Buuren, H. R. (2009) · Gastroenterology · doi:10.1053/j.gastro.2009.01.003 · Cited by 460
Self-citationThe effect of ursodeoxycholic acid therapy on the natural course of primary biliary cirrhosis
Corpechot, C., Carrat, F., Bahr, A., Chrétien, Y., Poupon, R., & Poupon, R. Y. (2005) · Gastroenterology · doi:10.1053/j.gastro.2004.11.009 · Cited by 392
Self-citationCarbone, M., Mells, G. F., Pells, G., Dawwas, M. F., Newton, J. L., Heneghan, M. A., Neuberger, J. M., Day, D. B., Ducker, S. J., Sandford, R. N., et al. (2013) · Gastroenterology · doi:10.1053/j.gastro.2012.12.005 · Cited by 386
Kumagi, T., Guindi, M., Fischer, S. E., Arenovich, T., Abdalian, R., Coltescu, C., Heathcote, J. E., & Hirschfield, G. M. (2010) · American Journal of Gastroenterology · doi:10.1038/ajg.2010.216 · Cited by 372
Self-citationCorpechot, C., Carrat, F., Poujol-Robert, A., Gaouar, F., Wendum, D., Chazouillères, O., & Poupon, R. (2012) · Hepatology · doi:10.1002/hep.25599 · Cited by 351
Self-citationSerum bilirubin: a prognostic factor in primary biliary cirrhosis
Shapiro, J. M., Smith, H., & Schaffner, F. (1979) · Gut · doi:10.1136/gut.20.2.137 · Cited by 319
Goulis, J., Leandro, G., & Burroughs, A. K. (1999) · The Lancet · doi:10.1016/s0140-6736(98)11293-x · Cited by 315
Self-citationUrsodeoxycholic acid for primary biliary cirrhosis
Rudić, J. S., Poropat, G., Krstic, M. N., Bjelaković, G., & Gluud, C. N. (2012) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd000551.pub3 · Cited by 277
Surrogate Endpoints And FDA’s Accelerated Approval Process
Fleming, T. R. (2005) · Health Affairs · doi:10.1377/hlthaff.24.1.67 · Cited by 252
Angulo, P., Lindor, K. D., Therneau, T. M., Jorgensen, R. A., Malinchoc, M., Kamath, P. S., & Dickson, E. R. (1999) · Liver International · doi:10.1111/j.1478-3231.1999.tb00020.x · Cited by 203
Self-citationter Borg, P. C. J., Schalm, S. W., Hansen, B. E., & van Buuren, H. R. (2006) · The American Journal of Gastroenterology · doi:10.1111/j.1572-0241.2006.00699.x · Cited by 160
Self-citationShi, J. Q., Wu, C., Lin, Y., Chen, Y.-X., Zhu, L., & Xie, W.-F. (2006) · The American Journal of Gastroenterology · doi:10.1111/j.1572-0241.2006.00634.x · Cited by 124
Bonnand, A.-M., Heathcote, J., Lindor, K. D., & Poupon, R. E. (1999) · Hepatology · doi:10.1002/hep.510290140 · Cited by 85
Self-citationWessler, S. (1968) · JAMA · doi:10.1001/jama.1968.03150060059013 · Cited by 84
Optimizing biochemical markers as endpoints for clinical trials in primary biliary cirrhosis
Momah, N., Silveira, M. G., Jorgensen, R., Sinakos, E., & Lindor, K. D. (2012) · Liver International · doi:10.1111/j.1478-3231.2011.02678.x · Cited by 77
Self-citationAzemoto, N., Kumagi, T., Abe, M., Konishi, I., Matsuura, B., Hiasa, Y., & Onji, M. (2011) · Hepatology Research · doi:10.1111/j.1872-034x.2011.00782.x · Cited by 54
Self-citationWarnes, T. W. (1972) · Gut · doi:10.1136/gut.13.11.926 · Cited by 54
Is serum bilirubin concentration the only valid prognostic marker in primary biliary cirrhosis?
Krzeski, P., Zych, W., Kraszewska, E., Milewski, B., Butruk, E., & Habior, A. (1999) · Hepatology · doi:10.1002/hep.510300415 · Cited by 42
Serum alkaline phosphatase isoenzymes in liver disease.
Tw, W., Hine, P., & Kay, G. H. (1972) · PubMed · Cited by 6
Cited by
Sorted by citations
Burden of liver diseases in the world
Asrani, S. K., Devarbhavi, H., Eaton, J., & Kamath, P. S. (2019) · Journal of Hepatology · doi:10.1016/j.jhep.2018.09.014 · Cited by 3,783
Hirschfield, G. M., Beuers, U., Corpechot, C., Invernizzi, P., Jones, D., Marzioni, M., & Schramm, C. (2017) · Journal of Hepatology · doi:10.1016/j.jhep.2017.03.022 · Cited by 1,480
Self-citationA Placebo-Controlled Trial of Obeticholic Acid in Primary Biliary Cholangitis
Nevens, F., Andreone, P., Mazzella, G., Strasser, S. I., Bowlus, C., Invernizzi, P., Drenth, J. P. H., Pockros, P. J., Regula, J., Beuers, U., et al. (2016) · New England Journal of Medicine · doi:10.1056/nejmoa1509840 · Cited by 1,131
Self-citationLindor, K. D., Bowlus, C. L., Boyer, J., Levy, C., & Mayo, M. (2019) · Hepatology · doi:10.1002/hep.30145 · Cited by 913
Self-citationPrimary sclerosing cholangitis – a comprehensive review
Karlsen, T. H., Folseraas, T., Thorburn, D., & Vesterhus, M. (2017) · Journal of Hepatology · doi:10.1016/j.jhep.2017.07.022 · Cited by 868
Metadata
- Authors
- Lammers, W. J., van Buuren, H. R., Hirschfield, G. M., Janssen, H. L. A., Invernizzi, P., Mason, A. L., Ponsioen, C. Y., Floreani, A., Corpechot, C., Mayo, M. J., Battezzati, P. M., Parés, A., Nevens, F., Burroughs, A. K., Kowdley, K. V., Trivedi, P. J., Kumagi, T., Cheung, A., Lleo, A., Imam, M. H., Boonstra, K., Cazzagon, N., Franceschet, I., Poupon, R., Caballeria, L., Pieri, G., Kanwar, P. S., Lindor, K. D., & Hansen, B. E.
- Affiliations
- Erasmus MC (NL)
- University of Birmingham (GB)
- University Health Network (CA)
- Fondazione Humanitas per la Ricerca (IT)
- University of Alberta (CA)
- Amsterdam UMC Location University of Amsterdam (NL)
- University of Padua (IT)
- Assistance Publique – Hôpitaux de Paris (FR)
- The University of Texas Southwestern Medical Center (US)
- University of Milan (IT)
- Hospital Clínic de Barcelona (ES)
- Universitair Ziekenhuis Leuven (BE)
- The Royal Free Hospital (GB)
- Virginia Mason Medical Center (US)
- Mayo Clinic (US)
- Corresponding author
- Hansen, Bettina E.
- ORCID
- Lammers, Willem J.
- Hirschfield, Gideon M.
- Janssen, Harry L.A.
- Invernizzi, Pietro
- Mason, Andrew L.
- Ponsioen, Cyriel Y.
- Floreani, Annarosa
- Corpechot, Christophe
- Mayo, Marlyn J.
- Battezzati, Pier M.
- Parés, Albert
- Nevens, Frederik
- Burroughs, Andrew K.
- Kowdley, Kris V.
- Trivedi, Palak J.
- Kumagi, Teru
- Cheung, Angela
- Imam, Mohamad H.
- Boonstra, Kirsten
- Cazzagon, Nora
- Poupon, Raoul
- Pieri, Giulia
- Lindor, Keith D.
- Hansen, Bettina E.
- Venue
- Gastroenterology
- Publisher
- Elsevier BV
- Published
- 2014-12
- Volume
- 147
- Issue
- 6
- Pages
- 1338-1349.e5
- ISSN
- 0016-5085 (ISSN-L)
- OpenAlex
- W1987523828
- Semantic Scholar
- 0d4f9630f12910194b9fbfed618c9a235f64faaf
- Cited by
- 498
- References
- 39
- Citations by year
- 2026: 47 · 2025: 41 · 2024: 40 · 2023: 43 · 2022: 47 · 2021: 53 · 2020: 40 · 2019: 46 · 2018: 49 · 2017: 30 · 2016: 28 · 2015: 30 · 2014: 3
- FWCI
- 3.95
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Gastroenterology (publishedVersion)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion)
- Padua Research Archive (University of Padova) (submittedVersion, other-oa)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
- BOA (University of Milano-Bicocca) (submittedVersion)
- CINECA IRIS Institutial Research Information System (University of Genoa) (submittedVersion)
- University of Birmingham Research Portal (University of Birmingham) (submittedVersion, other-oa)
- Funders
- Stichting voor Lever- en Maag-Darm Onderzoek
- Intercept Pharmaceuticals
- Topics
- Health Sciences › Medicine › Hepatology › Liver Diseases and Immunity
- Health Sciences › Medicine › Surgery › Pediatric Hepatobiliary Diseases and Treatments
- Health Sciences › Medicine › Hepatology › Liver Disease and Transplantation
- Keywords
- primary biliary cirrhosis, alkaline phosphatase, bilirubin, surrogate endpoints, transplant-free survival, liver transplantation, disease progression, prognostic factors, individual patient data meta-analysis, survival prediction, cholestatic liver disease, mortality risk stratification, treatment response monitoring, liver fibrosis markers
- MeSH terms
- Adult, Aged, Alkaline Phosphatase, Bilirubin, Cholagogues and Choleretics, Education, Medical, Continuing, Female, Follow-Up Studies, Humans, Liver Cirrhosis, Biliary, Male, Middle Aged, Predictive Value of Tests, Prognosis, Risk Factors, Ursodeoxycholic Acid, Biomarkers, Survival Analysis, Liver Transplantation
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