Author information
1Reference 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.
2Department of Epidemiology & Biostatistics, Erasmus MC, Rotterdam, The Netherlands.
3Toronto Centre for Liver Disease, University Health Network, University of Toronto, Toronto, Ontario, Canada.
4Division of Gastroenterology and Liver Unit, University of Alberta, Edmonton, Alberta, Canada.
5Division of Preventive Medicine, University of Alberta, Edmonton, Alberta, Canada.
6Liver 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.
7Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota.
8Department 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.
9Department 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.
10Division of Hepatology and Liver Transplantation, European Reference Network on Hepatological Diseases (ERN Rare-Liver), University Hospitals KU, Leuven, Belgium.
11Department of Surgery, Oncology and Gastroenterology, European Reference Network on Hepatological Diseases (ERN Rare-Liver), University of Padova, Padova, Italy.
12Liver Unit, University Hospitals Birmingham National Health Service Foundation Trust Queen Elizabeth, Birmingham, UK.
13National 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.
14University College London Institute for Liver and Digestive Health, Royal Free Hospital, London, UK.
15Section of Gastroenterology and Hepatology, PROMISE, University of Palermo, Palermo, Italy.
16Department of Hepatology, University Hospitals of Bordeaux, Pessac, France.
17Department of Hepatology & Liver Transplantation, Italian Hospital of Buenos Aires, Buenos Aires, Argentina.
18Department of Medicine, Division of Gastroenterology, Beth Israel Deaconess Medical Center, Boston, Massachusetts.
199Department of Internal Medicine, Università del Piemonte Orientale, Novara, Italy.
20Division 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.
21Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, The Netherlands.
22The Research Center for Digestive Tract and Liver Diseases, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.
23Department of Gastroenterology and Hepatology, University Hospital Zürich, Zürich, Switzerland.
24Department of Medicine III, University Hospital RWTH Aachen, European Reference Network on Hepatological Diseases (ERN Rare-Liver), Aachen, Germany.
25Department of Hepatology and Liver Transplantation, Newcastle Upon Tyne Hospitals NHS Foundation Trust and Newcastle University, Newcastle Upon Tyne, UK.
26Department of Gastroenterology and Hepatology, Edouard Herriot Hospital, Hospices Civils de Lyon, Claude Bernard University, Lyon, France.
27Department of Hepatology and Liver Transplantation, University Hospital, Montpellier, France.
28Public Health Unit, Saint-Antoine Hospital, Assistance Publique-Hôpitaux de Paris.
29Pierre Louis Institute of Epidemiology and Public Health, Sorbonne University, Inserm, Paris, France.
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.