Adequate versus deep response to ursodeoxycholic acid in primary biliary cholangitis: To what extent and under what conditions is normal alkaline phosphatase level associated with complication-free survival gain?

Hepatology, vol. 79, pp. 39–48

Abstract

BACKGROUND AND AIMS: Normal alkaline phosphatase (ALP) levels in ursodeoxycholic acid (UDCA)-treated patients with primary biliary cholangitis (PBC) are associated with better long-term outcome. However, second-line therapies are currently recommended only when ALP levels remain above 1.5 times the upper limit of normal (×ULN) after 12-month UDCA. We assessed whether, in patients considered good responders to UDCA, normal ALP levels were associated with significant survival gains. APPROACH AND RESULTS: We performed a retrospective cohort study of 1047 patients with PBC who attained an adequate response to UDCA according to Paris-2 criteria. Time to liver-related complications, liver transplantation, or death was assessed using adjusted restricted mean survival time (RMST) analysis. The overall incidence rate of events was 17.0 (95% CI: 13.7-21.1) per 1000 out of 4763.2 patient-years. On the whole population, normal serum ALP values (but not normal gamma-glutamyl transpeptidase (GGT), alanine aminotransferase (ALT), or aspartate aminotransferase (AST); or total bilirubin < 0.6 ×ULN) were associated with a significant absolute complication-free survival gain at 10 years (mean 7.6 months, 95% CI: 2.7 - 12.6 mo.; p = 0.003). In subgroup analysis, this association was significant in patients with a liver stiffness measurement ≥ 10 kPa and/or age ≤ 62 years, with a 10-year absolute complication-free survival gain of 52.8 months (95% CI: 45.7-59.9, p < 0.001) when these 2 conditions were met. CONCLUSIONS: PBC patients with an adequate response to UDCA and persistent ALP elevation between 1.1 and 1.5 ×ULN, particularly those with advanced fibrosis and/or who are sufficiently young, remain at risk of poor outcome. Further therapeutic efforts should be considered for these patients.

Authors 55

1. Christophe Corpechot corresponding

   Inserm · Sorbonne Université · Assistance Publique – Hôpitaux de Paris · Hôpital Saint-Antoine · Centre de Recherche Saint-Antoine

   Affiliation as printed

   Reference Center for Inflammatory Biliary Diseases and Autoimmune Hepatitis, European Reference Network on Hepatological Diseases (ERN Rare-Liver), Saint-Antoine Hospital, Assistance Publique—Hôpitaux de Paris; Inserm UMR_S938, Saint-Antoine Research Center, Sorbonne University, Paris, France

2. Sara Lemoinne

   Inserm · Sorbonne Université · Assistance Publique – Hôpitaux de Paris · Hôpital Saint-Antoine · Centre de Recherche Saint-Antoine

   Affiliation as printed

   Reference Center for Inflammatory Biliary Diseases and Autoimmune Hepatitis, European Reference Network on Hepatological Diseases (ERN Rare-Liver), Saint-Antoine Hospital, Assistance Publique—Hôpitaux de Paris; Inserm UMR_S938, Saint-Antoine Research Center, Sorbonne University, Paris, France

3. Pierre‐Antoine Soret

   Inserm · Sorbonne Université · Assistance Publique – Hôpitaux de Paris · Hôpital Saint-Antoine · Centre de Recherche Saint-Antoine

   Affiliation as printed

   Reference Center for Inflammatory Biliary Diseases and Autoimmune Hepatitis, European Reference Network on Hepatological Diseases (ERN Rare-Liver), Saint-Antoine Hospital, Assistance Publique—Hôpitaux de Paris; Inserm UMR_S938, Saint-Antoine Research Center, Sorbonne University, Paris, France

4. Bettina E. Hansen

   University Health Network · University of Toronto · Erasmus MC

   Affiliation as printed

   Department of Epidemiology & Biostatistics, Erasmus MC, Rotterdam, The Netherlands

   Toronto Centre for Liver Disease, University Health Network, University of Toronto, Toronto, Ontario, Canada

5. Gideon Morris Hirschfield

   University Health Network · University of Toronto

   Affiliation as printed

   Toronto Centre for Liver Disease, University Health Network, University of Toronto, Toronto, Ontario, Canada

6. Aliya F. Gulamhusein

   University Health Network · University of Toronto

   Affiliation as printed

   Toronto Centre for Liver Disease, University Health Network, University of Toronto, Toronto, Ontario, Canada

7. Aldo J. Montaño‐Loza

   University of Alberta

   Affiliation as printed

   Division of Gastroenterology and Liver Unit, University of Alberta, Edmonton, Alberta, Canada

8. Ellina Lytvyak

   University of Alberta

   Affiliation as printed

   Division of Preventive Medicine, University of Alberta, Edmonton, Alberta, Canada

9. Albert Rodrigo Parés

   Universitat de Barcelona

   Affiliation as printed

   Liver Unit, Hospital Clínic, University of Barcelona, The August Pi i Sunyer Biomedical Research Institute, Biomedical Research Networking Center in Hepatic and Digestive Diseases, European Reference Network on Hepatological Diseases (ERN Rare-Liver), Barcelona, Spain

10. Ignasi Olivas

    Universitat de Barcelona

    Affiliation as printed

    Liver Unit, Hospital Clínic, University of Barcelona, The August Pi i Sunyer Biomedical Research Institute, Biomedical Research Networking Center in Hepatic and Digestive Diseases, European Reference Network on Hepatological Diseases (ERN Rare-Liver), Barcelona, Spain

11. John E. Eaton

    Mayo Clinic

    Affiliation as printed

    Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota

12. Karim T. Osman

    Mayo Clinic

    Affiliation as printed

    Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota

13. Christoph Schramm

    University Medical Center Hamburg-Eppendorf · ERN RARE-LIVER

    Affiliation as printed

    Department of Medicine I and Martin Zeitz Center for Rare Diseases, European Reference Network on Hepatological Diseases (ERN Rare-Liver), University Medical Center Hamburg–Eppendorf, Hamburg, Germany

14. Marcial Sebode

    University Medical Center Hamburg-Eppendorf · ERN RARE-LIVER

    Affiliation as printed

    Department of Medicine I and Martin Zeitz Center for Rare Diseases, European Reference Network on Hepatological Diseases (ERN Rare-Liver), University Medical Center Hamburg–Eppendorf, Hamburg, Germany

15. Ansgar Wilhelm Lohse

    University Medical Center Hamburg-Eppendorf · ERN RARE-LIVER

    Affiliation as printed

    Department of Medicine I and Martin Zeitz Center for Rare Diseases, European Reference Network on Hepatological Diseases (ERN Rare-Liver), University Medical Center Hamburg–Eppendorf, Hamburg, Germany

16. George Ν. Dalekos

    University Hospital of Larissa

    Affiliation as printed

    Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, European Reference Network on Hepatological Diseases (ERN Rare-Liver), General University Hospital, Larissa, Greece

17. Nikolaos Gatselis

    University Hospital of Larissa

    Affiliation as printed

    Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, European Reference Network on Hepatological Diseases (ERN Rare-Liver), General University Hospital, Larissa, Greece

18. Frederik Nevens

    KU Leuven

    Affiliation as printed

    Division of Hepatology and Liver Transplantation, European Reference Network on Hepatological Diseases (ERN Rare-Liver), University Hospitals KU, Leuven, Belgium

19. Nora Cazzagon

    University of Padua

    Affiliation as printed

    Department of Surgery, Oncology and Gastroenterology, European Reference Network on Hepatological Diseases (ERN Rare-Liver), University of Padova, Padova, Italy

20. Alessandra Zago

    University of Padua

    Affiliation as printed

    Department of Surgery, Oncology and Gastroenterology, European Reference Network on Hepatological Diseases (ERN Rare-Liver), University of Padova, Padova, Italy

21. Francesco Paolo Russo

    University of Padua

    Affiliation as printed

    Department of Surgery, Oncology and Gastroenterology, European Reference Network on Hepatological Diseases (ERN Rare-Liver), University of Padova, Padova, Italy

22. Annarosa Floreani

    University of Padua

    Affiliation as printed

    Department of Surgery, Oncology and Gastroenterology, European Reference Network on Hepatological Diseases (ERN Rare-Liver), University of Padova, Padova, Italy

23. Nadir Abbas

    National Health Service · University Hospitals Birmingham NHS Foundation Trust · Queen Elizabeth Hospital Birmingham

    Affiliation as printed

    Liver Unit, University Hospitals Birmingham National Health Service Foundation Trust Queen Elizabeth, Birmingham, UK

24. Palak Jitendrakumar Trivedi

    National Institute for Health and Care Research · NIHR Birmingham Biomedical Research Centre · University of Birmingham

    Affiliation as printed

    National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre (BRC), Institute of Immunology and Immunotherapy, Centre for Liver and Gastrointestinal Research, University of Birmingham, Birmingham, UK

25. Douglas Thorburn

    The Royal Free Hospital · University College London

    Affiliation as printed

    University College London Institute for Liver and Digestive Health, Royal Free Hospital, London, UK

26. Francesca Saffioti

    The Royal Free Hospital · University College London

    Affiliation as printed

    University College London Institute for Liver and Digestive Health, Royal Free Hospital, London, UK

27. László Barkai

    The Royal Free Hospital · University College London

    Affiliation as printed

    University College London Institute for Liver and Digestive Health, Royal Free Hospital, London, UK

28. Davide Roccarina

    The Royal Free Hospital · University College London

    Affiliation as printed

    University College London Institute for Liver and Digestive Health, Royal Free Hospital, London, UK

29. Vincenza Calvaruso

    University of Palermo

    Affiliation as printed

    Section of Gastroenterology and Hepatology, PROMISE, University of Palermo, Palermo, Italy

30. Adèle Delamarre

    Centre Hospitalier Universitaire de Bordeaux

    Affiliation as printed

    Department of Hepatology, University Hospitals of Bordeaux, Pessac, France

31. Natalia Sobenko

    Hospital Italiano de Buenos Aires

    Affiliation as printed

    Department of Hepatology & Liver Transplantation, Italian Hospital of Buenos Aires, Buenos Aires, Argentina

32. Alejandra Villamil

    Hospital Italiano de Buenos Aires

    Affiliation as printed

    Department of Hepatology & Liver Transplantation, Italian Hospital of Buenos Aires, Buenos Aires, Argentina

33. Esli Medina‐Morales

    Beth Israel Deaconess Medical Center

    Affiliation as printed

    Department of Medicine, Division of Gastroenterology, Beth Israel Deaconess Medical Center, Boston, Massachusetts

34. Alan Bonder

    Beth Israel Deaconess Medical Center

    Affiliation as printed

    Department of Medicine, Division of Gastroenterology, Beth Israel Deaconess Medical Center, Boston, Massachusetts

35. Vilas R. Patwardhan

    Beth Israel Deaconess Medical Center

    Affiliation as printed

    Department of Medicine, Division of Gastroenterology, Beth Israel Deaconess Medical Center, Boston, Massachusetts

36. Cristina Rigamonti

    Università degli Studi del Piemonte Orientale “Amedeo Avogadro”

    Affiliation as printed

    9Department of Internal Medicine, Università del Piemonte Orientale, Novara, Italy

37. Marco Carbone

    University of Milano-Bicocca

    Affiliation as printed

    Division of Gastroenterology, Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, European Reference Network on Hepatological Diseases (ERN Rare-Liver), University of Milano-Bicocca, Monza, Italy

38. Pietro Invernizzi

    University of Milano-Bicocca

    Affiliation as printed

    Division of Gastroenterology, Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, European Reference Network on Hepatological Diseases (ERN Rare-Liver), University of Milano-Bicocca, Monza, Italy

39. Laura Cristoferi

    University of Milano-Bicocca

    Affiliation as printed

    Division of Gastroenterology, Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, European Reference Network on Hepatological Diseases (ERN Rare-Liver), University of Milano-Bicocca, Monza, Italy

40. Adriaan J. van der Meer

    Erasmus MC

    Affiliation as printed

    Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, The Netherlands

41. Rozanne de Veer

    Erasmus MC

    Affiliation as printed

    Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, The Netherlands

42. Ehud Zigmond

    Tel Aviv Sourasky Medical Center

    Affiliation as printed

    The Research Center for Digestive Tract and Liver Diseases, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel

43. Eyal Yehezkel

    Tel Aviv Sourasky Medical Center

    Affiliation as printed

    The Research Center for Digestive Tract and Liver Diseases, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel

44. Andreas Emanuel Kremer

    University Hospital Zurich

    Affiliation as printed

    Department of Gastroenterology and Hepatology, University Hospital Zürich, Zürich, Switzerland

45. Ansgar Deibel

    University Hospital Zurich

    Affiliation as printed

    Department of Gastroenterology and Hepatology, University Hospital Zürich, Zürich, Switzerland

46. Tony Bruns Aachen Department of Medicine III

    Universitätsklinikum Aachen · RWTH Aachen University

    Affiliation as printed

    Department of Medicine III, University Hospital RWTH Aachen, European Reference Network on Hepatological Diseases (ERN Rare-Liver), Aachen, Germany

47. Karsten Große Aachen Department of Medicine III

    Universitätsklinikum Aachen · RWTH Aachen University

    Affiliation as printed

    Department of Medicine III, University Hospital RWTH Aachen, European Reference Network on Hepatological Diseases (ERN Rare-Liver), Aachen, Germany

48. Aaron Wetten

    Newcastle upon Tyne Hospitals NHS Foundation Trust · Newcastle upon Tyne Hospital · Newcastle University

    Affiliation as printed

    Department of Hepatology and Liver Transplantation, Newcastle Upon Tyne Hospitals NHS Foundation Trust and Newcastle University, Newcastle Upon Tyne, UK

49. Jessica Katharine Dyson

    Newcastle upon Tyne Hospitals NHS Foundation Trust · Newcastle upon Tyne Hospital · Newcastle University

    Affiliation as printed

    Department of Hepatology and Liver Transplantation, Newcastle Upon Tyne Hospitals NHS Foundation Trust and Newcastle University, Newcastle Upon Tyne, UK

50. David E. Jones

    Newcastle upon Tyne Hospitals NHS Foundation Trust · Newcastle upon Tyne Hospital · Newcastle University

    Affiliation as printed

    Department of Hepatology and Liver Transplantation, Newcastle Upon Tyne Hospitals NHS Foundation Trust and Newcastle University, Newcastle Upon Tyne, UK

51. Jérôme Dumortier

    Hospices Civils de Lyon · Hôpital Edouard Herriot

    Affiliation as printed

    Department of Gastroenterology and Hepatology, Edouard Herriot Hospital, Hospices Civils de Lyon, Claude Bernard University, Lyon, France

52. Georges‐Philippe Pageaux

    Centre Hospitalier Universitaire de Montpellier

    Affiliation as printed

    Department of Hepatology and Liver Transplantation, University Hospital, Montpellier, France

53. Victor de Lédinghen

    Centre Hospitalier Universitaire de Bordeaux

    Affiliation as printed

    Department of Hepatology, University Hospitals of Bordeaux, Pessac, France

54. Olivier Chazouillères

    Inserm · Sorbonne Université · Assistance Publique – Hôpitaux de Paris · Hôpital Saint-Antoine · Centre de Recherche Saint-Antoine

    Affiliation as printed

    Reference Center for Inflammatory Biliary Diseases and Autoimmune Hepatitis, European Reference Network on Hepatological Diseases (ERN Rare-Liver), Saint-Antoine Hospital, Assistance Publique—Hôpitaux de Paris; Inserm UMR_S938, Saint-Antoine Research Center, Sorbonne University, Paris, France

55. Fabrice Carrat

    Inserm · Sorbonne Université · Assistance Publique – Hôpitaux de Paris · Hôpital Saint-Antoine · Institut Pierre Louis d‘Épidémiologie et de Santé Publique

    Affiliation as printed

    Pierre Louis Institute of Epidemiology and Public Health, Sorbonne University, Inserm, Paris, France

    Public Health Unit, Saint-Antoine Hospital, Assistance Publique—Hôpitaux de Paris