Palak J Trivedi1, Tony Bruns2, Angela Cheung3, Ka-Kit Li1, Clemens Kittler4, Teru Kumagi5, Husnain Shah1, Christopher Corbett1, Nadya Al-Harthy6, Unsal Acarsu3, Catalina Coltescu3, Dhiraj Tripathi7, Andreas Stallmach4, James Neuberger8, Harry L A Janssen9, Gideon M Hirschfield10. 1. 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. 2. 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. 3. Toronto Center for Liver Diseases, Toronto Western Hospital, University Health Network, Toronto, Ontario, Canada. 4. Department of Internal Medicine IV, Jena University Hospital, Friedrich Schiller University Jena, Jena, Germany. 5. 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. 6. Toronto Center for Liver Diseases, Toronto Western Hospital, University Health Network, Toronto, Ontario, Canada; Royal Hospital, Sultanate of Oman, Oman. 7. Liver Unit, Queen Elizabeth Hospital, Edgbaston, Birmingham, UK. 8. Liver Unit, Queen Elizabeth Hospital, Edgbaston, Birmingham, UK; Organ Donation and Transplant, NHS Blood and Transplant, Bristol, UK. 9. 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. 10. 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.
Abstract
BACKGROUND & AIMS: 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). CONCLUSION: 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.
BACKGROUND & AIMS: 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). CONCLUSION: 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: Gideon M Hirschfield; Jessica K Dyson; Graeme J M Alexander; Michael H Chapman; Jane Collier; Stefan Hübscher; Imran Patanwala; Stephen P Pereira; Collette Thain; Douglas Thorburn; Dina Tiniakos; Martine Walmsley; George Webster; David E J Jones Journal: Gut Date: 2018-03-28 Impact factor: 23.059
Authors: Alena Laschtowitz; Rozanne C de Veer; Adriaan J Van der Meer; Christoph Schramm Journal: United European Gastroenterol J Date: 2020-04-16 Impact factor: 4.623
Authors: Maren H Harms; Willem J Lammers; Douglas Thorburn; Christophe Corpechot; Pietro Invernizzi; Harry L A Janssen; Pier M Battezzati; Frederik Nevens; Keith D Lindor; Annarosa Floreani; Cyriel Y Ponsioen; Marlyn J Mayo; George N Dalekos; Tony Bruns; Albert Parés; Andrew L Mason; Xavier Verhelst; Kris V Kowdley; Jorn C Goet; Gideon M Hirschfield; Bettina E Hansen; Henk R van Buuren Journal: Am J Gastroenterol Date: 2017-12-12 Impact factor: 10.864