Alpha-1 Antitrypsin Augmentation and the Liver Phenotype of Adults With Alpha-1 Antitrypsin Deficiency (Genotype Pi∗ZZ).

Augmentation Therapy Fibroscan Liver Fibrosis Pi∗Z SERPINA1 α(1)-Antitrypsin Deficiency

Journal

Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association
ISSN: 1542-7714
Titre abrégé: Clin Gastroenterol Hepatol
Pays: United States
ID NLM: 101160775

Informations de publication

Date de publication:
15 Sep 2023
Historique:
received: 28 04 2023
revised: 24 07 2023
accepted: 23 08 2023
pubmed: 17 9 2023
medline: 17 9 2023
entrez: 16 9 2023
Statut: aheadofprint

Résumé

α1-Antitrypsin (AAT) is a major protease inhibitor produced by hepatocytes. The most relevant AAT mutation giving rise to AAT deficiency (AATD), the 'Pi∗Z' variant, causes harmful AAT protein accumulation in the liver, shortage of AAT in the systemic circulation, and thereby predisposes to liver and lung injury. Although intravenous AAT augmentation constitutes an established treatment of AATD-associated lung disease, its impact on the liver is unknown. Liver-related parameters were assessed in a multinational cohort of 760 adults with severe AATD (Pi∗ZZ genotype) and available liver phenotyping, of whom 344 received augmentation therapy and 416 did not. Liver fibrosis was evaluated noninvasively via the serum test AST-to-platelet ratio index and via transient elastography-based liver stiffness measurement. Histologic parameters were compared in 15 Pi∗ZZ adults with and 35 without augmentation. Compared with nonaugmented subjects, augmented Pi∗ZZ individuals displayed lower serum liver enzyme levels (AST 71% vs 75% upper limit of normal, P < .001; bilirubin 49% vs 58% upper limit of normal, P = .019) and lower surrogate markers of fibrosis (AST-to-platelet ratio index 0.34 vs 0.38, P < .001; liver stiffness measurement 6.5 vs 7.2 kPa, P = .005). Among biopsied participants, augmented individuals had less pronounced liver fibrosis and less inflammatory foci but no differences in AAT accumulation were noted. The first evaluation of AAT augmentation on the Pi∗ZZ-related liver disease indicates liver safety of a widely used treatment for AATD-associated lung disease. Prospective studies are needed to confirm the beneficial effects and to demonstrate the potential efficacy of exogenous AAT in patients with Pi∗ZZ-associated liver disease.

Sections du résumé

BACKGROUND & AIMS OBJECTIVE
α1-Antitrypsin (AAT) is a major protease inhibitor produced by hepatocytes. The most relevant AAT mutation giving rise to AAT deficiency (AATD), the 'Pi∗Z' variant, causes harmful AAT protein accumulation in the liver, shortage of AAT in the systemic circulation, and thereby predisposes to liver and lung injury. Although intravenous AAT augmentation constitutes an established treatment of AATD-associated lung disease, its impact on the liver is unknown.
METHODS METHODS
Liver-related parameters were assessed in a multinational cohort of 760 adults with severe AATD (Pi∗ZZ genotype) and available liver phenotyping, of whom 344 received augmentation therapy and 416 did not. Liver fibrosis was evaluated noninvasively via the serum test AST-to-platelet ratio index and via transient elastography-based liver stiffness measurement. Histologic parameters were compared in 15 Pi∗ZZ adults with and 35 without augmentation.
RESULTS RESULTS
Compared with nonaugmented subjects, augmented Pi∗ZZ individuals displayed lower serum liver enzyme levels (AST 71% vs 75% upper limit of normal, P < .001; bilirubin 49% vs 58% upper limit of normal, P = .019) and lower surrogate markers of fibrosis (AST-to-platelet ratio index 0.34 vs 0.38, P < .001; liver stiffness measurement 6.5 vs 7.2 kPa, P = .005). Among biopsied participants, augmented individuals had less pronounced liver fibrosis and less inflammatory foci but no differences in AAT accumulation were noted.
CONCLUSIONS CONCLUSIONS
The first evaluation of AAT augmentation on the Pi∗ZZ-related liver disease indicates liver safety of a widely used treatment for AATD-associated lung disease. Prospective studies are needed to confirm the beneficial effects and to demonstrate the potential efficacy of exogenous AAT in patients with Pi∗ZZ-associated liver disease.

Identifiants

DOI: 10.1016/j.cgh.2023.08.038 PMID: 37716616
pubmed: 37716616
pii: S1542-3565(23)00708-5
doi: 10.1016/j.cgh.2023.08.038
pii:
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Informations de copyright

Copyright © 2023 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.

Karim Hamesch (K)

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.

Mattias Mandorfer (M)

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

Monica Pons (M)

Liver Unit, Hospital Universitari Vall d'Hebron, Vall d'Hebron Institute of Research, Vall d'Hebron Barcelona Hospital Campus, Universitat Autonoma de Barcelona, Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN RARE LIVER), Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain.

Katrine H Thorhauge (KH)

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

Vitor Pereira (V)

Department of Gastroenterology, Centro Hospitalar do Funchal, Madeira, Portugal.

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.

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.

Matthias C Reichert (MC)

Department of Medicine II, Saarland University Medical Center, Saarland University, Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN RARE LIVER), Homburg, Germany.

Federica Benini (F)

Gastroenterology Unit, Department of Medicine, Spedali Civili and University, Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN RARE LIVER), Brescia, Italy.

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.

Moritz Kleinjans (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.

Samira Amzou (S)

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.

Laura Rademacher (L)

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.

Lisa Bewersdorf (L)

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.

Jef Verbeek (J)

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

Frederik Nevens (F)

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

Joan Genesca (J)

Liver Unit, Hospital Universitari Vall d'Hebron, Vall d'Hebron Institute of Research, Vall d'Hebron Barcelona Hospital Campus, Universitat Autonoma de Barcelona, Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN RARE LIVER), 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, Vall d'Hebron Barcelona Hospital Campus, CIBER de Enfermedades Respiratorias, Barcelona, Spain.

Alexa Nuñez (A)

Pneumology Department, Hospital Universitari Vall d'Hebron, Vall d'Hebron Institut de Recerca, Vall d'Hebron Barcelona Hospital Campus, CIBER de Enfermedades Respiratorias, Barcelona, Spain.

Benedikt Schaefer (B)

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

Heinz Zoller (H)

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

Sabina Janciauskiene (S)

Clinic for Pneumology, Medical University Hannover, Hannover, Germany.

Johan Waern (J)

Gastroenterology and Hepatology Unit, Department of Medicine, Sahlgrenska University Hospital, Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN RARE LIVER), Gothenburg, Sweden.

António Oliveira (A)

Department of Gastroenterology, Centro Hospitalar do Funchal, Madeira, Portugal.

Luís Maia (L)

Centro Hospitalar Universitário do Porto, Porto, Portugal.

Carolina Simões (C)

Hospital Santa Maria, Lisboa, Portugal.

Ravi Mahadeva (R)

Department of Respiratory Medicine, Cambridge University Hospitals, Cambridge, United Kingdom.

Daniel D Fraughen (DD)

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

Michael Trauner (M)

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

Aleksander Krag (A)

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

Frank Lammert (F)

Department of Medicine II, Saarland University Medical Center, Saarland University, Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN RARE LIVER), Homburg, Germany; Hannover Medical School, Hannover, Germany.

Robert Bals (R)

Department of Medicine V, Saarland University Medical Center, Saarland University, Homburg, Germany.

Nadine T Gaisa (NT)

Institute of Pathology, University Hospital RWTH Aachen, Aachen, Germany.

Elmar Aigner (E)

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

William J Griffiths (WJ)

Department of Hepatology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom.

Helmut Denk (H)

Institute of Pathology, Medical University of Graz, Graz, Austria.

Alexander Teumer (A)

Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany; DZHK (German Center for Cardiovascular Research), partner site Greifswald, Greifswald, Germany.

Noel G McElvaney (NG)

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

Alice M Turner (AM)

Institute of Applied Health Research, University of Birmingham, Birmingham, United Kingdom.

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.

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