title: Levels of alkaline phosphatase and bilirubin are surrogate end points of outcomes of patients with primary biliary cirrhosis: an international follow-up study.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus University Medical Centre, Rotterdam, The Netherlands.
authors.forename: Willem J
authors.initials: WJ
authors.lastname: Lammers
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus University Medical Centre, Rotterdam, The Netherlands.
authors.forename: Henk R
authors.initials: HR
authors.lastname: van Buuren
authors.affiliation: NIHR Biomedical Research Unit and Centre for Liver Research, University of Birmingham, Birmingham, England.
authors.forename: Gideon M
authors.initials: GM
authors.lastname: Hirschfield
authors.affiliation: Liver Clinic, Toronto Western & General Hospital, University Health Network, Toronto, Ontario, Canada.
authors.forename: Harry L A
authors.initials: HL
authors.lastname: Janssen
authors.affiliation: Liver Unit and Center for Autoimmune Liver Diseases, Humanitas Clinical and Research Center, Rozzano, Italy.
authors.forename: Pietro
authors.initials: P
authors.lastname: Invernizzi
authors.affiliation: Divison of Gastroenterology and Hepatology, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Mason
authors.affiliation: Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Cyriel Y
authors.initials: CY
authors.lastname: Ponsioen
authors.affiliation: Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy.
authors.forename: Annarosa
authors.initials: A
authors.lastname: Floreani
authors.affiliation: Centre de Référence des Maladies Inflammatoires des VoiesBiliaires, Hôpital Saint-Antoine, APHP, Paris, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Corpechot
authors.affiliation: Digestive and Liver Diseases, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Marlyn J
authors.initials: MJ
authors.lastname: Mayo
authors.affiliation: Department of Health Sciences, Università degli Studi di Milano, Milan, Italy.
authors.forename: Pier M
authors.initials: PM
authors.lastname: Battezzati
authors.affiliation: Liver Unit, Hospital Clínic, CIBERehd, IDIBAPS, University of Barcelona, Barcelona, Spain.
authors.forename: Albert
authors.initials: A
authors.lastname: Parés
authors.affiliation: Department of Hepatology, University Hospitals Leuven, KU Leuven, Leuven, Belgium.
authors.forename: Frederik
authors.initials: F
authors.lastname: Nevens
authors.affiliation: The Sheila Sherlock Liver Centre, The Royal Free Hospital, London, England.
authors.forename: Andrew K
authors.initials: AK
authors.lastname: Burroughs
authors.affiliation: Liver Center of Excellence, Digestive Disease Institute, Virginia Mason Medical Center, Seattle, Washington.
authors.forename: Kris V
authors.initials: KV
authors.lastname: Kowdley
authors.affiliation: NIHR Biomedical Research Unit and Centre for Liver Research, University of Birmingham, Birmingham, England.
authors.forename: Palak J
authors.initials: PJ
authors.lastname: Trivedi
authors.affiliation: Liver Clinic, Toronto Western & General Hospital, University Health Network, Toronto, Ontario, Canada; Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Ehime, Japan.
authors.forename: Teru
authors.initials: T
authors.lastname: Kumagi
authors.affiliation: Liver Clinic, Toronto Western & General Hospital, University Health Network, Toronto, Ontario, Canada.
authors.forename: Angela
authors.initials: A
authors.lastname: Cheung
authors.affiliation: Liver Unit and Center for Autoimmune Liver Diseases, Humanitas Clinical and Research Center, Rozzano, Italy.
authors.forename: Ana
authors.initials: A
authors.lastname: Lleo
authors.affiliation: Department of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Mohamad H
authors.initials: MH
authors.lastname: Imam
authors.affiliation: Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Kirsten
authors.initials: K
authors.lastname: Boonstra
authors.affiliation: Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy.
authors.forename: Nora
authors.initials: N
authors.lastname: Cazzagon
authors.affiliation: Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy.
authors.forename: Irene
authors.initials: I
authors.lastname: Franceschet
authors.affiliation: Centre de Référence des Maladies Inflammatoires des VoiesBiliaires, Hôpital Saint-Antoine, APHP, Paris, France.
authors.forename: Raoul
authors.initials: R
authors.lastname: Poupon
authors.affiliation: Liver Unit, Hospital Clínic, CIBERehd, IDIBAPS, University of Barcelona, Barcelona, Spain.
authors.forename: Llorenç
authors.initials: L
authors.lastname: Caballeria
authors.affiliation: The Sheila Sherlock Liver Centre, The Royal Free Hospital, London, England.
authors.forename: Giulia
authors.initials: G
authors.lastname: Pieri
authors.affiliation: Liver Center of Excellence, Digestive Disease Institute, Virginia Mason Medical Center, Seattle, Washington.
authors.forename: Pushpjeet S
authors.initials: PS
authors.lastname: Kanwar
authors.affiliation: Department of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota; College of Health Solutions, Arizona State University, Phoenix, Arizona.
authors.forename: Keith D
authors.initials: KD
authors.lastname: Lindor
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus University Medical Centre, Rotterdam, The Netherlands. Electronic address: b.hansen@erasmusmc.nl.
authors.forename: Bettina E
authors.initials: BE
authors.lastname: Hansen
mesh_terms: D000328:Adult; D000368:Aged; D000469:Alkaline Phosphatase / Q000097:blood*; D001663:Bilirubin / Q000097:blood*; D015415:Biomarkers; D002756:Cholagogues and Choleretics / Q000627:therapeutic use; D004502:Education, Medical, Continuing; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008105:Liver Cirrhosis, Biliary / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality*; D016031:Liver Transplantation / Q000706:statistics & numerical data; D008297:Male; D008875:Middle Aged; D011237:Predictive Value of Tests; D011379:Prognosis; D012307:Risk Factors; D016019:Survival Analysis; D014580:Ursodeoxycholic Acid / Q000627:therapeutic use
chemical_list: D015415:Biomarkers; D002756:Cholagogues and Choleretics; D014580:Ursodeoxycholic Acid; D000469:Alkaline Phosphatase; D001663:Bilirubin
keywords: Autoimmune Liver Disease; Biomarker; New Therapies; Response To Treatment