title: Optimising risk stratification in primary biliary cirrhosis: AST/platelet ratio index predicts outcome independent of ursodeoxycholic acid response.
abstract: OBJECTIVE
  Outcomes in primary biliary cirrhosis (PBC) can be predicted by biochemical response to ursodeoxycholic acid (UDCA). Such stratification inadequately captures cirrhosis/portal hypertension, recognised factors associated with adverse events.
  
  
  METHODS
  We evaluated a cohort of PBC patients (n=386) attending the Liver Unit in Birmingham (derivation cohort), seeking to identify risk-variables associated with transplant-free survival independent of UDCA-response. A validation cohort was provided through well-characterised patients attending the Toronto Center for Liver Diseases (n=479) and Jena University Hospital (n=150).
  
  
  RESULTS
  On multivariate analysis, factors at diagnosis associated with liver transplant (LT)/death were patient age (HR:1.06; p<0.001), elevated bilirubin (HR:1.27; p<0.001), early-onset cirrhosis (HR:2.40; p<0.001) and baseline AST/platelet ratio index (APRI) (HR:1.95; p<0.001). At 1-year, UDCA biochemical non-response predicted poorer transplant-free survival, and additional factors (multivariate) associated with adverse outcome were age (HR:1.02; p<0.05) and 1-year APRI (HR:1.15; p<0.001). Obtaining a cut-point from our derivation cohort, APRI >0.54 at baseline was predictive of LT/death (adjusted HR: 2.40; p<0.001), and retained statistical significance when applied at 1-year (APRI-r1, adjusted HR:2.75; p<0.001) despite controlling for UDCA-response. Across both cohorts, transplant-free survival was poorer for biochemical-responders with an APRI-r1 >0.54 vs. biochemical-responders with a lower APRI-r1 (p<0.01 and p<0.001, respectively); non-responders with high APRI-r1 had the poorest outcomes (p<0.001 and p<0.001).
  
  
  CONCLUSIONS
  In PBC, elevated APRI is associated with future risk of adverse events, independently and additively of UDCA-response. This cross-centre, robustly validated observation will contribute to ongoing efforts to refine existing risk-stratification tools, as well as direct focus for new therapies in patients with PBC.
authors.affiliation: National Institute for Health Research (NIHR) Birmingham Liver Biomedical Research Unit (BRU) and Centre for Liver Research, University of Birmingham, Birmingham, UK; Liver Unit, Queen Elizabeth Hospital, Edgbaston, Birmingham, UK.
authors.forename: Palak J
authors.initials: PJ
authors.lastname: Trivedi
authors.affiliation: National Institute for Health Research (NIHR) Birmingham Liver Biomedical Research Unit (BRU) and Centre for Liver Research, University of Birmingham, Birmingham, UK; Department of Internal Medicine IV, Jena University Hospital, Friedrich Schiller University Jena, Jena, Germany; Center for Sepsis Control and Care (CSCC), Jena University Hospital, Friedrich Schiller University Jena, Germany.
authors.forename: Tony
authors.initials: T
authors.lastname: Bruns
authors.affiliation: Toronto Center for Liver Diseases, Toronto Western Hospital, University Health Network, Toronto, Ontario, Canada.
authors.forename: Angela
authors.initials: A
authors.lastname: Cheung
authors.affiliation: National Institute for Health Research (NIHR) Birmingham Liver Biomedical Research Unit (BRU) and Centre for Liver Research, University of Birmingham, Birmingham, UK; Liver Unit, Queen Elizabeth Hospital, Edgbaston, Birmingham, UK.
authors.forename: Ka-Kit
authors.initials: KK
authors.lastname: Li
authors.affiliation: Department of Internal Medicine IV, Jena University Hospital, Friedrich Schiller University Jena, Jena, Germany.
authors.forename: Clemens
authors.initials: C
authors.lastname: Kittler
authors.affiliation: Toronto Center for Liver Diseases, Toronto Western Hospital, University Health Network, Toronto, Ontario, Canada; Gastroenterology and Metabology, Ehime University, Graduate School of Medicine, Shitsukawa To-on, Ehime, Japan.
authors.forename: Teru
authors.initials: T
authors.lastname: Kumagi
authors.affiliation: National Institute for Health Research (NIHR) Birmingham Liver Biomedical Research Unit (BRU) and Centre for Liver Research, University of Birmingham, Birmingham, UK; Liver Unit, Queen Elizabeth Hospital, Edgbaston, Birmingham, UK.
authors.forename: Husnain
authors.initials: H
authors.lastname: Shah
authors.affiliation: National Institute for Health Research (NIHR) Birmingham Liver Biomedical Research Unit (BRU) and Centre for Liver Research, University of Birmingham, Birmingham, UK; Liver Unit, Queen Elizabeth Hospital, Edgbaston, Birmingham, UK.
authors.forename: Christopher
authors.initials: C
authors.lastname: Corbett
authors.affiliation: Toronto Center for Liver Diseases, Toronto Western Hospital, University Health Network, Toronto, Ontario, Canada; Royal Hospital, Sultanate of Oman, Oman.
authors.forename: Nadya
authors.initials: N
authors.lastname: Al-Harthy
authors.affiliation: Toronto Center for Liver Diseases, Toronto Western Hospital, University Health Network, Toronto, Ontario, Canada.
authors.forename: Unsal
authors.initials: U
authors.lastname: Acarsu
authors.affiliation: Toronto Center for Liver Diseases, Toronto Western Hospital, University Health Network, Toronto, Ontario, Canada.
authors.forename: Catalina
authors.initials: C
authors.lastname: Coltescu
authors.affiliation: Liver Unit, Queen Elizabeth Hospital, Edgbaston, Birmingham, UK.
authors.forename: Dhiraj
authors.initials: D
authors.lastname: Tripathi
authors.affiliation: Department of Internal Medicine IV, Jena University Hospital, Friedrich Schiller University Jena, Jena, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Stallmach
authors.affiliation: Liver Unit, Queen Elizabeth Hospital, Edgbaston, Birmingham, UK; Organ Donation and Transplant, NHS Blood and Transplant, Bristol, UK.
authors.forename: James
authors.initials: J
authors.lastname: Neuberger
authors.affiliation: Toronto Center for Liver Diseases, Toronto Western Hospital, University Health Network, Toronto, Ontario, Canada; Division of Gastroenterology & Hepatology, Erasmus MC University Hospital, Rotterdam, The Netherlands.
authors.forename: Harry L A
authors.initials: HL
authors.lastname: Janssen
authors.affiliation: National Institute for Health Research (NIHR) Birmingham Liver Biomedical Research Unit (BRU) and Centre for Liver Research, University of Birmingham, Birmingham, UK; Liver Unit, Queen Elizabeth Hospital, Edgbaston, Birmingham, UK. Electronic address: g.hirschfield@bham.ac.uk.
authors.forename: Gideon M
authors.initials: GM
authors.lastname: Hirschfield
mesh_terms: D000328:Adult; D001219:Aspartate Aminotransferases / Q000097:blood*; D002756:Cholagogues and Choleretics / Q000627:therapeutic use*; D016208:Databases, Factual; D018572:Disease-Free Survival; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D053208:Kaplan-Meier Estimate; D008105:Liver Cirrhosis, Biliary / Q000188:drug therapy / Q000401:mortality / Q000601:surgery; D016031:Liver Transplantation; D008297:Male; D008875:Middle Aged; D010976:Platelet Count; D011237:Predictive Value of Tests; D016016:Proportional Hazards Models; D012307:Risk Factors; D014580:Ursodeoxycholic Acid / Q000627:therapeutic use*
chemical_list: D002756:Cholagogues and Choleretics; D014580:Ursodeoxycholic Acid; D001219:Aspartate Aminotransferases
keywords: Autoimmune liver disease; Cholestasis; Liver transplantation; Outcome prediction; Survival; Ursodeoxycholic acid