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?

Journal

Hepatology (Baltimore, Md.)
ISSN: 1527-3350
Titre abrégé: Hepatology
Pays: United States
ID NLM: 8302946

Informations de publication

Date de publication:
03 Jul 2023
Historique:
received: 18 03 2023
accepted: 09 06 2023
pubmed: 3 7 2023
medline: 3 7 2023
entrez: 3 7 2023
Statut: aheadofprint

Résumé

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. 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. 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.

Sections du résumé

BACKGROUND AND AIMS OBJECTIVE
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 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 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.

Identifiants

DOI: 10.1097/HEP.0000000000000529 PMID: 37399238
pubmed: 37399238
doi: 10.1097/HEP.0000000000000529
pii: 01515467-990000000-00497
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Informations de copyright

Copyright © 2023 American Association for the Study of Liver Diseases.

Références

Lleo A, Wang GQ, Gershwin ME, Hirschfield GM. Primary biliary cholangitis. Lancet. 2020;396:1915–1926.
Poupon RE, Balkau B, Eschwege E, Poupon R. A multicenter, controlled trial of ursodiol for the treatment of primary biliary cirrhosis. N Engl J Med. 1991;324:1548–1554.
Poupon RE, Lindor KD, Cauch-Dudek K, Dickson ER, Poupon R, Heathcote EJ. Combined analysis of randomized controlled trials of ursodeoxycholic acid in primary biliary cirrhosis. Gastroenterology. 1997;113:884–890.
Harms MH, van Buuren HR, Corpechot C, Thorburn D, Janssen HLA, Lindor KD, et al. Ursodeoxycholic acid therapy and liver transplant-free survival in patients with primary biliary cholangitis. J Hepatol. 2019;71:357–365.
Pares A, Caballeria L, Rodes J. Excellent long-term survival in patients with primary biliary cirrhosis and biochemical response to ursodeoxycholic acid. Gastroenterology. 2006;130:715–720.
Corpechot C, Abenavoli L, Rabahi N, Chretien Y, Andreani T, Johanet C, et al. Biochemical response to ursodeoxycholic acid and long-term prognosis in primary biliary cirrhosis. Hepatology. 2008;48:871–877.
Lammers WJ, van Buuren HR, Hirschfield GM, Janssen HL, Invernizzi P, Mason AL, et al. Levels of alkaline phosphatase and bilirubin are surrogate end points of outcomes of patients with primary biliary cirrhosis: an international follow-up study. Gastroenterology. 2014;147:1338–1349.
Nevens F, Andreone P, Mazzella G, Strasser SI, Bowlus C, Invernizzi P, et al. A placebo-controlled trial of obeticholic acid in primary biliary cholangitis. N Engl J Med. 2016;375:631–643.
Corpechot C, Chazouilleres O, Rousseau A, Le Gruyer A, Habersetzer F, Mathurin P, et al. A placebo-controlled trial of bezafibrate in primary biliary cholangitis. N Engl J Med. 2018;378:2171–2181.
Tanaka A, Hirohara J, Nakano T, Matsumoto K, Chazouilleres O, Takikawa H, et al. Association of bezafibrate with transplant-free survival in patients with primary biliary cholangitis. J Hepatol. 2021;75:565–571.
Murillo Perez CF, Fisher H, Hiu S, Kareithi D, Adekunle F, Mayne T, et al. Greater transplant-free survival in patients receiving obeticholic acid for primary biliary cholangitis in a clinical trial setting compared to real-world external controls. Gastroenterology. 2022;163:1630–1642 e1633.
Hirschfield G, Beuers U, Corpechot C, Invernizzi P, Jones D, Marzioni M, et al. EASL Clinical Practice Guidelines: The diagnosis and management of patients with primary biliary cholangitis. J Hepatol. 2017;67:145–172.
Lindor KD, Bowlus CL, Boyer J, Levy C, Mayo M. Primary Biliary Cholangitis: 2018 Practice Guidance from the American Association for the Study of Liver Diseases. Hepatology. 2019;69:394–419.
Hirschfield GM, Dyson JK, Alexander GJM, Chapman MH, Collier J, Hubscher S, et al. The British Society of Gastroenterology/UK-PBC primary biliary cholangitis treatment and management guidelines. Gut. 2018;67:1568–1594.
Murillo Perez CF, Harms MH, Lindor KD, van Buuren HR, Hirschfield GM, Corpechot C, et al. Goals of treatment for improved survival in primary biliary cholangitis: treatment target should be bilirubin within the normal range and normalization of alkaline phosphatase. Am J Gastroenterol. 2020;115:1066–1074.
de Veer RC, Harms MH, Corpechot C, Thorburn D, Invernizzi P, Janssen HLA, et al. Liver transplant-free survival according to alkaline phosphatase and GLOBE score in patients with primary biliary cholangitis treated with ursodeoxycholic acid. Aliment Pharmacol Ther. 2022;56:1408–1418.
Corpechot C, Carrat F, Gaouar F, Chau F, Hirschfield G, Gulamhusein A, et al. Liver stiffness measurement by vibration-controlled transient elastography improves outcome prediction in primary biliary cholangitis. J Hepatol. 2022;77:1545–1553.
Corpechot C, Carrat F, Poujol-Robert A, Gaouar F, Wendum D, Chazouilleres O, et al. Noninvasive elastography-based assessment of liver fibrosis progression and prognosis in primary biliary cirrhosis. Hepatology. 2012;56:198–208.
Kloecker DE, Davies MJ, Khunti K, Zaccardi F. Uses and limitations of the restricted mean survival time: illustrative examples from cardiovascular outcomes and mortality trials in type 2 diabetes. Ann Intern Med. 2020;172:541–552.
Jansen PL, Peters WH, Janssens AR. Clinical value of serum bilirubin subfractionation by high-performance liquid chromatography and conventional methods in patients with primary biliary cirrhosis. J Hepatol. 1986;2:485–494.
Gerussi A, Bernasconi DP, O’Donnell SE, Lammers WJ, Van Buuren H, Hirschfield G, et al. Measurement of gamma glutamyl transferase to determine risk of liver transplantation or death in patients with primary biliary cholangitis. Clin Gastroenterol Hepatol. 2021;19:1688–1697 e1614.
Harms MH, de Veer RC, Lammers WJ, Corpechot C, Thorburn D, Janssen HLA, et al. Number needed to treat with ursodeoxycholic acid therapy to prevent liver transplantation or death in primary biliary cholangitis. Gut. 2020;69:1502–1509.

Auteurs

Christophe Corpechot (C)

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.

Sara Lemoinne (S)

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.

Pierre-Antoine Soret (PA)

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.

Bettina Hansen (B)

Department of Epidemiology & Biostatistics, Erasmus MC, Rotterdam, The Netherlands.
Toronto Centre for Liver Disease, University Health Network, University of Toronto, Toronto, Ontario, Canada.

Gideon Hirschfield (G)

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

Aliya Gulamhusein (A)

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

Aldo J Montano-Loza (AJ)

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

Ellina Lytvyak (E)

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

Albert Pares (A)

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.

Ignasi Olivas (I)

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.

John E Eaton (JE)

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

Karim T Osman (KT)

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

Christoph Schramm (C)

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.

Marcial Sebode (M)

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.

Ansgar W Lohse (AW)

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.

George Dalekos (G)

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.

Nikolaos Gatselis (N)

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.

Frederik Nevens (F)

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

Nora Cazzagon (N)

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

Alessandra Zago (A)

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

Francesco Paolo Russo (FP)

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

Annarosa Floreani (A)

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

Nadir Abbas (N)

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

Palak Trivedi (P)

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.

Douglas Thorburn (D)

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

Francesca Saffioti (F)

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

Laszlo Barkai (L)

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

Davide Roccarina (D)

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

Vicenza Calvaruso (V)

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

Anna Fichera (A)

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

Adèle Delamarre (A)

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

Natalia Sobenko (N)

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

Alejandra Maria Villamil (AM)

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

Esli Medina-Morales (E)

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

Alan Bonder (A)

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

Vilas Patwardhan (V)

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

Cristina Rigamonti (C)

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

Marco Carbone (M)

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.

Pietro Invernizzi (P)

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.

Laura Cristoferi (L)

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.

Adriaan van der Meer (A)

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

Rozanne de Veer (R)

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

Ehud Zigmond (E)

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

Eyal Yehezkel (E)

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

Andreas E Kremer (AE)

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

Ansgar Deibel (A)

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

Tony Bruns (T)

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

Karsten Große (K)

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

Aaron Wetten (A)

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

Jessica Katharine Dyson (JK)

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

David Jones (D)

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

Jérôme Dumortier (J)

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

Georges-Philippe Pageaux (GP)

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

Victor de Lédinghen (V)

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

Olivier Chazouillères (O)

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.

Fabrice Carrat (F)

Public Health Unit, Saint-Antoine Hospital, Assistance Publique-Hôpitaux de Paris.
Pierre Louis Institute of Epidemiology and Public Health, Sorbonne University, Inserm, Paris, France.

Classifications MeSH