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Stratification of hepatocellular carcinoma risk in primary biliary cirrhosis: a multicentre international study
  1. Palak J Trivedi1,2,
  2. Willem J Lammers3,
  3. Henk R van Buuren3,
  4. Albert Parés4,
  5. Annarosa Floreani5,
  6. Harry L A Janssen3,6,
  7. Pietro Invernizzi7,
  8. Pier Maria Battezzati8,
  9. Cyriel Y Ponsioen9,
  10. Christophe Corpechot10,
  11. Raoul Poupon10,
  12. Marlyn J Mayo11,
  13. Andrew K Burroughs12,,
  14. Frederik Nevens13,
  15. Andrew L Mason14,
  16. Kris V Kowdley15,16,
  17. Ana Lleo7,
  18. Llorenç Caballeria4,
  19. Keith D Lindor17,18,
  20. Bettina E Hansen3,
  21. Gideon M Hirschfield1,2
  22. On behalf of the Global PBC Study Group
    1. 1National Institute for Health Research (NIHR) Birmingham Liver Biomedical Research Unit (BRU) and Centre for Liver Research, University of Birmingham, Birmingham, UK
    2. 2Liver Unit, Queen Elizabeth Hospital, Birmingham, UK
    3. 3Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, The Netherlands
    4. 4Liver Unit, Hospital Clínic, CIBERehd, IDIBAPS, University of Barcelona, Barcelona, Spain
    5. 5Department of Surgical, Oncological and Gastroenterological, University of Padua, Padua, Italy
    6. 6Toronto Center for Liver Diseases, Toronto Western & General Hospital, University Health Network, Toronto, Ontario, Canada
    7. 7Liver Unit and Center for Autoimmune Liver Diseases, Humanitas Clinical and Research Center, Rozzano (MI), Italy
    8. 8Department of Health Sciences, Università degli Studi di Milano, Milan, Italy
    9. 9Department of Gastroenterology and Hepatology, Academic Medical Center Amsterdam, The Netherlands
    10. 10Center de Référence des Maladies Inflammatoires des Voies Biliaires, Hôpital Saint-Antoine, APHP, Paris, France
    11. 11Department of Digestive and Liver diseases, UT Southwestern Medical Center, Dallas, Texas, USA
    12. 12The Sheila Sherlock Liver Center, The Royal Free Hospital, London, UK
    13. 13Department of Hepatology, University Hospitals Leuven, KU Leuven, Leuven, Belgium
    14. 14Division of Gastroenterology and Hepatology, University of Alberta, Edmonton, Alberta, Canada
    15. 15Liver Center of Excellence, Digestive Disease Institute, Virginia Mason Medical Center, Seattle, Washington, USA
    16. 16Liver Care Network, Swedish Medical Center, Seattle, Washington, USA
    17. 17Department of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
    18. 18Arizona State University, Phoenix, Arizona, USA
    1. Correspondence to Dr Gideon M Hirschfield, National Institute for Health Research Biomedical Research Unit, University of Birmingham, Birmingham B15 2TT, UK; g.hirschfield{at}


    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.

    Design 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.


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