title: Stratification of hepatocellular carcinoma risk in primary biliary cirrhosis: a multicentre international study.
abstract: OBJECTIVE
  Hepatocellular carcinoma (HCC) is an infrequent yet critical event in primary biliary cirrhosis (PBC); however, predictive tools remain ill-defined. Our objective was to identify candidate risk factors for HCC development in patients with PBC.
  
  
  METHODS
  Risk factor analysis was performed in over 15 centres from North America and Europe spanning >40 years observation period using Cox proportional hazards assumptions, logistic regression, and Kaplan-Meier estimates.
  
  
  RESULTS
  Of 4565 patients with PBC 123 developed HCC, yielding an incidence rate (IR) of 3.4 cases/1000 patient-years. HCC was significantly more common in men (p<0.0001), and on univariate analysis factors at PBC diagnosis associated with future HCC development were male sex (unadjusted HR 2.91, p<0.0001), elevated serum aspartate transaminase (HR 1.24, p<0.0001), advanced disease (HR 2.72, p=0.022), thrombocytopenia (HR 1.65, p<0.0001), and hepatic decompensation (HR 9.89, p<0.0001). As such, non-treatment with ursodeoxycholic acid itself was not associated with cancer development; however, 12-month stratification by biochemical non-response (Paris-I criteria) associated significantly with future risk of HCC (HR 4.52, p<0.0001; IR 6.6 vs 1.4, p<0.0001). Non-response predicted future risk in patients with early stage disease (IR 4.7 vs 1.2, p=0.005), advanced disease (HR 2.79, p=0.02; IR 11.2 vs 4.4, p=0.033), and when restricting the analysis to only male patients (HR 4.44, p<0.001; IR 18.2 vs 5.4, p<0.001). On multivariable analysis biochemical non-response remained the most significant factor predictive of future HCC risk (adjusted HR 3.44, p<0.0001).
  
  
  CONCLUSIONS
  This uniquely powered, internationally representative cohort robustly demonstrates that 12-month biochemical non-response is associated with increased future risk of developing HCC in PBC. Such risk stratification is relevant to patient care and development of new therapies.
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, Birmingham, UK.
authors.forename: Palak J
authors.initials: PJ
authors.lastname: Trivedi
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Willem J
authors.initials: WJ
authors.lastname: Lammers
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Henk R
authors.initials: HR
authors.lastname: van Buuren
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 Surgical, Oncological and Gastroenterological, University of Padua, Padua, Italy.
authors.forename: Annarosa
authors.initials: A
authors.lastname: Floreani
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, The Netherlands Toronto Center for Liver Diseases, 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 (MI), Italy.
authors.forename: Pietro
authors.initials: P
authors.lastname: Invernizzi
authors.affiliation: Department of Health Sciences, Università degli Studi di Milano, Milan, Italy.
authors.forename: Pier Maria
authors.initials: PM
authors.lastname: Battezzati
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: Center de Référence des Maladies Inflammatoires des Voies Biliaires, Hôpital Saint-Antoine, APHP, Paris, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Corpechot
authors.affiliation: Center de Référence des Maladies Inflammatoires des Voies Biliaires, Hôpital Saint-Antoine, APHP, Paris, France.
authors.forename: Raoul
authors.initials: R
authors.lastname: Poupon
authors.affiliation: Department of Digestive and Liver diseases, UT Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Marlyn J
authors.initials: MJ
authors.lastname: Mayo
authors.affiliation: The Sheila Sherlock Liver Center, The Royal Free Hospital, London, UK.
authors.forename: Andrew K
authors.initials: AK
authors.lastname: Burroughs
authors.affiliation: Department of Hepatology, University Hospitals Leuven, KU Leuven, Leuven, Belgium.
authors.forename: Frederik
authors.initials: F
authors.lastname: Nevens
authors.affiliation: Division of Gastroenterology and Hepatology, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Mason
authors.affiliation: Liver Center of Excellence, Digestive Disease Institute, Virginia Mason Medical Center, Seattle, Washington, USA Liver Care Network, Swedish Medical Center, Seattle, Washington, USA.
authors.forename: Kris V
authors.initials: KV
authors.lastname: Kowdley
authors.affiliation: Liver Unit and Center for Autoimmune Liver Diseases, Humanitas Clinical and Research Center, Rozzano (MI), Italy.
authors.forename: Ana
authors.initials: A
authors.lastname: Lleo
authors.affiliation: Liver Unit, Hospital Clínic, CIBERehd, IDIBAPS, University of Barcelona, Barcelona, Spain.
authors.forename: Llorenç
authors.initials: L
authors.lastname: Caballeria
authors.affiliation: Department of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA Arizona State University, Phoenix, Arizona, USA.
authors.forename: Keith D
authors.initials: KD
authors.lastname: Lindor
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Bettina E
authors.initials: BE
authors.lastname: Hansen
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, Birmingham, UK.
authors.forename: Gideon M
authors.initials: GM
authors.lastname: Hirschfield
mesh_terms: D001219:Aspartate Aminotransferases / Q000097:blood; D006528:Carcinoma, Hepatocellular / Q000453:epidemiology / Q000209:etiology*; D005060:Europe / Q000453:epidemiology; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008105:Liver Cirrhosis, Biliary / Q000150:complications* / Q000453:epidemiology / Q000378:metabolism; D008113:Liver Neoplasms / Q000453:epidemiology / Q000209:etiology*; D016015:Logistic Models; D008297:Male; D009656:North America / Q000453:epidemiology; D016016:Proportional Hazards Models; D012306:Risk; D012307:Risk Factors; D012737:Sex Factors; D013921:Thrombocytopenia / Q000150:complications; D014580:Ursodeoxycholic Acid / Q000627:therapeutic use
chemical_list: D014580:Ursodeoxycholic Acid; D001219:Aspartate Aminotransferases
keywords: AUTOIMMUNE LIVER DISEASE; CHOLESTATIC LIVER DISEASES; PRIMARY BILIARY CIRRHOSIS