Longitudinal evaluation of individuals with severe alpha-1 antitrypsin deficiency (Pi*ZZ genotype).

Fibroscan SERPINA1 lung emphysema

Journal

Gastroenterology
ISSN: 1528-0012
Titre abrégé: Gastroenterology
Pays: United States
ID NLM: 0374630

Informations de publication

Date de publication:
14 Oct 2024
Historique:
received: 17 06 2024
revised: 23 09 2024
accepted: 04 10 2024
medline: 17 10 2024
pubmed: 17 10 2024
entrez: 16 10 2024
Statut: aheadofprint

Résumé

Homozygous Pi*Z mutation in alpha-1 antitrypsin (Pi*ZZ genotype) predisposes to pulmonary loss-of-function and hepatic gain-of-function injury. To facilitate selection into clinical trials typically targeting only one organ, we systematically evaluated an international, multicenter, longitudinal, Pi*ZZ cohort to uncover natural disease course and surrogates for future liver- and lung-related endpoints. Cohort 1 recruited 737 Pi*ZZ individuals from 25 different centers without known liver comorbidities that received a baseline clinical and laboratory assessment as well as liver stiffness measurement (LSM). A follow-up interview was performed after at least six months. Cohort 2 consisted of 135 Pi*ZZ subjects without significant liver fibrosis, who received a standardized baseline and follow-up examination at least two years later, both including LSM. During 2634 patient-years of follow-up, 39 individuals died, with liver and lung being responsible for 46% and 36% of deaths, respectively. 41 Pi*ZZ subjects who developed a hepatic endpoint presented with significantly higher baseline liver fibrosis surrogates, i.e., LSM (24 vs. 5 kPa, p<.001) and AST-to-platelet ratio index (APRI, 1.1 vs. 0.3 units, p<.001). Liver-related endpoints within five years were most accurately predicted by LSM (area under the curve [AUC] 0.95) followed by APRI (0.92). Baseline lung parameters displayed only a moderate predictive utility for lung-related endpoints within five years (FEV1 AUC 0.76). Fibrosis progression in those with no/mild fibrosis at baseline was rare and primarily seen in those with preexisting risk factors. Non-invasive liver fibrosis surrogates accurately stratify liver-related risks in Pi*ZZ individuals. Our findings have direct implications for routine care and future clinical trials of Pi*ZZ patients.

Sections du résumé

BACKGROUND AND AIMS OBJECTIVE
Homozygous Pi*Z mutation in alpha-1 antitrypsin (Pi*ZZ genotype) predisposes to pulmonary loss-of-function and hepatic gain-of-function injury. To facilitate selection into clinical trials typically targeting only one organ, we systematically evaluated an international, multicenter, longitudinal, Pi*ZZ cohort to uncover natural disease course and surrogates for future liver- and lung-related endpoints.
METHODS METHODS
Cohort 1 recruited 737 Pi*ZZ individuals from 25 different centers without known liver comorbidities that received a baseline clinical and laboratory assessment as well as liver stiffness measurement (LSM). A follow-up interview was performed after at least six months. Cohort 2 consisted of 135 Pi*ZZ subjects without significant liver fibrosis, who received a standardized baseline and follow-up examination at least two years later, both including LSM.
RESULTS RESULTS
During 2634 patient-years of follow-up, 39 individuals died, with liver and lung being responsible for 46% and 36% of deaths, respectively. 41 Pi*ZZ subjects who developed a hepatic endpoint presented with significantly higher baseline liver fibrosis surrogates, i.e., LSM (24 vs. 5 kPa, p<.001) and AST-to-platelet ratio index (APRI, 1.1 vs. 0.3 units, p<.001). Liver-related endpoints within five years were most accurately predicted by LSM (area under the curve [AUC] 0.95) followed by APRI (0.92). Baseline lung parameters displayed only a moderate predictive utility for lung-related endpoints within five years (FEV1 AUC 0.76). Fibrosis progression in those with no/mild fibrosis at baseline was rare and primarily seen in those with preexisting risk factors.
CONCLUSIONS CONCLUSIONS
Non-invasive liver fibrosis surrogates accurately stratify liver-related risks in Pi*ZZ individuals. Our findings have direct implications for routine care and future clinical trials of Pi*ZZ patients.

Identifiants

DOI: 10.1053/j.gastro.2024.10.010 PMID: 39414159
pubmed: 39414159
pii: S0016-5085(24)05572-0
doi: 10.1053/j.gastro.2024.10.010
pii:
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Informations de copyright

Copyright © 2024 AGA Institute. Published by Elsevier Inc. All rights reserved.

Auteurs

Malin Fromme (M)

Medical Clinic III, Gastroenterology, Metabolic Diseases and Intensive Care, University Hospital RWTH Aachen, Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN RARE LIVER), Aachen, Germany.

Audrey Payancé (A)

AP-HP, service d'hépatologie, Hôpital Beaujon, AP-HP, Clichy, France, DMU Digest, Centre de référence des Maladies Vasculaires du foie, FILFOIE, Clichy, France, Université Paris Cité, Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN RARE LIVER), Paris, France.

Mattias Mandorfer (M)

Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN RARE LIVER), Vienna, Austria.

Katrine H Thorhauge (KH)

Department of Gastroenterology and Hepatology, Odense University Hospital, Odense C, Denmark; Department of Clinical Research, Faculty of Health Sciences, University of Southern Denmark, Odense C, Denmark.

Monica Pons (M)

Liver Unit, Hospital Universitari Vall d'Hebron, Vall d'Hebron Institute of Research (VHIR), Vall d'Hebron Barcelona Hospital Campus, Universitat Autonoma de Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain.

Marc Miravitlles (M)

Pneumology Department, Hospital Universitari Vall d'Hebron, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Barcelona Hospital Campus, CIBER de Enfermedades Respiratorias (CIBERES), Health Care Provider of the European Reference Network on Rare Respiratory Diseases (ERN LUNG), Barcelona, Spain.

Jan Stolk (J)

Department of Pulmonology, Leiden University Medical Center, Leiden, The Netherlands.

Bart van Hoek (B)

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

Guido Stirnimann (G)

University Clinic for Visceral Surgery and Medicine, University Hospital Inselspital and University of Bern, Bern, Switzerland.

Sona Frankova (S)

Department of Hepatogastroenterology, Institute for Clinical and Experimental Medicine, Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN RARE LIVER), Prague, Czech Republic.

Jan Sperl (J)

Department of Hepatogastroenterology, Institute for Clinical and Experimental Medicine, Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN RARE LIVER), Prague, Czech Republic.

Andreas E Kremer (AE)

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

Barbara Burbaum (B)

Medical Clinic III, Gastroenterology, Metabolic Diseases and Intensive Care, University Hospital RWTH Aachen, Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN RARE LIVER), Aachen, Germany.

Christina Schrader (C)

Medical Clinic III, Gastroenterology, Metabolic Diseases and Intensive Care, University Hospital RWTH Aachen, Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN RARE LIVER), Aachen, Germany.

Amine Kadioglu (A)

Medical Clinic III, Gastroenterology, Metabolic Diseases and Intensive Care, University Hospital RWTH Aachen, Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN RARE LIVER), Aachen, Germany.

Michelle Walkenhaus (M)

Medical Clinic III, Gastroenterology, Metabolic Diseases and Intensive Care, University Hospital RWTH Aachen, Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN RARE LIVER), Aachen, Germany.

Carolin V Schneider (CV)

Medical Clinic III, Gastroenterology, Metabolic Diseases and Intensive Care, University Hospital RWTH Aachen, Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN RARE LIVER), Aachen, Germany.

Fabienne Klebingat (F)

Medical Clinic III, Gastroenterology, Metabolic Diseases and Intensive Care, University Hospital RWTH Aachen, Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN RARE LIVER), Aachen, Germany.

Lorenz Balcar (L)

Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN RARE LIVER), Vienna, Austria.

Naomi N Kappe (NN)

Department of Pulmonology, Leiden University Medical Center, Leiden, The Netherlands; Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands.

Benedikt Schaefer (B)

Department of Internal Medicine I, Medical University Innsbruck, Innsbruck, Austria.

Joanna Chorostowska-Wynimko (J)

Department of Genetics and Clinical Immunology, National Institute of Tuberculosis and Lung Diseases, Warsaw, Poland.

Elmar Aigner (E)

First Department of Medicine, Paracelsus Medical University Salzburg, Salzburg, Austria.

Sophie Gensluckner (S)

First Department of Medicine, Paracelsus Medical University Salzburg, Salzburg, Austria.

Philipp Striedl (P)

First Department of Medicine, Paracelsus Medical University Salzburg, Salzburg, Austria.

Pauline Roger (P)

AP-HP, service d'hépatologie, Hôpital Beaujon, AP-HP, Clichy, France, DMU Digest, Clichy, France.

John Ryan (J)

Irish Centre for Genetic Lung Disease, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin, Ireland.

Suzanne Roche (S)

Irish Centre for Genetic Lung Disease, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin, Ireland.

Marius Vögelin (M)

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

Aftab Ala (A)

Institute of Liver Studies, King's College Hospital NHS Foundation Trust, London, UK.

Heike Bantel (H)

Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany.

Jef Verbeek (J)

Department of Gastroenterology & Hepatology, KU Leuven University Hospitals, Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN RARE LIVER), Leuven, Belgium.

Zoe Mariño (Z)

Liver Unit, Hospital Clínic Barcelona, Instituto de Investigaciones Biomédicas August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN RARE LIVER), University of Barcelona, Barcelona, Spain.

Michael Praktiknjo (M)

Department of Medicine B, Gastroenterology, Hepatology, Endocrinology, Infectious Diseases, Universitätsklinikum Muenster, Muenster, Germany.

Tom J G Gevers (TJG)

Department of Gastroenterology and Hepatology, Maastricht University Medical Centre, Maastricht, The Netherlands.

Philipp A Reuken (PA)

Department of Internal Medicine IV, Jena University Hospital, Friedrich Schiller University, Jena, Germany.

Thomas Berg (T)

Division of Hepatology, Department of Medicine, Leipzig University Medical Center, Leipzig, Germany.

Jacob George (J)

Storr Liver Centre, The Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, Sydney, NSW, Australia.

Münevver Demir (M)

Department of Hepatology and Gastroenterology, Campus Virchow-Klinikum and Campus Charité Mitte, Charité Universitätsmedizin Berlin, Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN RARE LIVER), Berlin, Germany.

Tony Bruns (T)

Medical Clinic III, Gastroenterology, Metabolic Diseases and Intensive Care, University Hospital RWTH Aachen, Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN RARE LIVER), Aachen, Germany.

Christian Trautwein (C)

Medical Clinic III, Gastroenterology, Metabolic Diseases and Intensive Care, University Hospital RWTH Aachen, Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN RARE LIVER), Aachen, Germany; Department of Toxicology, Leibniz Research Centre for Working Environment and Human Factors (IfADo), Dortmund, Germany.

Heinz Zoller (H)

Department of Internal Medicine I, Medical University Innsbruck, Innsbruck, Austria.

Michael Trauner (M)

Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN RARE LIVER), Vienna, Austria.

Joan Genesca (J)

Liver Unit, Hospital Universitari Vall d'Hebron, Vall d'Hebron Institute of Research (VHIR), Vall d'Hebron Barcelona Hospital Campus, Universitat Autonoma de Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain.

William J Griffiths (WJ)

Department of Hepatology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.

Virginia Clark (V)

Division of Gastroenterology, Hepatology, and Nutrition, University of Florida, Gainesville, Florida, United States.

Aleksander Krag (A)

Department of Gastroenterology and Hepatology, Odense University Hospital, Odense C, Denmark; Department of Clinical Research, Faculty of Health Sciences, University of Southern Denmark, Odense C, Denmark.

Alice M Turner (AM)

Institute of Applied Health Research, University of Birmingham, Birmingham, UK.

Noel G McElvaney (NG)

Irish Centre for Genetic Lung Disease, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin, Ireland.

Pavel Strnad (P)

Medical Clinic III, Gastroenterology, Metabolic Diseases and Intensive Care, University Hospital RWTH Aachen, Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN RARE LIVER), Aachen, Germany. Electronic address: pstrnad@ukaachen.de.

Classifications MeSH