Liver Phenotypes of European Adults Heterozygous or Homozygous for Pi∗Z Variant of AAT (Pi∗MZ vs Pi∗ZZ genotype) and Noncarriers.

Adult Aged Counseling Cross-Sectional Studies Elasticity Imaging Techniques Female Heterozygote Homozygote Humans Liver / diagnostic imaging Liver Cirrhosis / blood Liver Function Tests Longitudinal Studies Male Middle Aged Phenotype Prospective Studies United Kingdom alpha 1-Antitrypsin / genetics alpha 1-Antitrypsin Deficiency / blood
ALT FibroScan GGT SERPINA1

Journal

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

Informations de publication

Date de publication:
08 2020
Historique:
received: 07 08 2019
revised: 26 03 2020
accepted: 20 04 2020
pubmed: 8 5 2020
medline: 7 4 2021
entrez: 8 5 2020
Statut: ppublish

Résumé

Homozygosity for the Pi∗Z variant of the gene that encodes the alpha-1 antitrypsin peptide (AAT), called the Pi∗ZZ genotype, causes a liver and lung disease called alpha-1 antitrypsin deficiency. Heterozygosity (the Pi∗MZ genotype) is a risk factor for cirrhosis in individuals with liver disease. Up to 4% of Europeans have the Pi∗MZ genotype; we compared features of adults with and without Pi∗MZ genotype among persons without preexisting liver disease. We analyzed data from the European Alpha-1 Liver Cohort, from 419 adults with the Pi∗MZ genotype, 309 adults with the Pi∗ZZ genotype, and 284 individuals without the variant (noncarriers). All underwent a comprehensive evaluation; liver stiffness measurements (LSMs) were made by transient elastography. Liver biopsies were analyzed to define histologic and biochemical features associated with the Pi∗Z variant. Levels of serum transaminases were retrieved from 444,642 participants, available in the United Kingdom biobank. In the UK biobank database, levels of serum transaminases were increased in subjects with the Pi∗MZ genotype compared with noncarriers. In the Alpha-1 Liver Cohort, adults with Pi∗MZ had lower levels of gamma-glutamyl transferase in serum and lower LSMs than adults with the Pi∗ZZ variant, but these were higher than in noncarriers. Ten percent of subjects with the Pi∗MZ genotype vs 4% of noncarriers had LSMs of 7.1 kPa or more (adjusted odds ratio, 4.8; 95% confidence interval, 2.0-11.8). Obesity and diabetes were the most important factors associated with LSMs ≥7.1 kPa in subjects with the Pi∗MZ genotype. AAT inclusions were detected in liver biopsies of 63% of subjects with the Pi∗MZ genotype, vs 97% of subjects with the Pi∗ZZ genotype, and increased with liver fibrosis stages. Subjects with the Pi∗MZ genotype did not have increased hepatic levels of AAT, whereas levels of insoluble AAT varied among individuals. Adults with the Pi∗MZ genotype have lower levels of serum transaminases, fewer AAT inclusions in liver, and lower liver stiffness than adults with the Pi∗ZZ genotype, but higher than adults without the Pi∗Z variant. These findings should help determine risk of subjects with the Pi∗MZ genotype and aid in counseling.

Sections du résumé

BACKGROUND & AIMS
Homozygosity for the Pi∗Z variant of the gene that encodes the alpha-1 antitrypsin peptide (AAT), called the Pi∗ZZ genotype, causes a liver and lung disease called alpha-1 antitrypsin deficiency. Heterozygosity (the Pi∗MZ genotype) is a risk factor for cirrhosis in individuals with liver disease. Up to 4% of Europeans have the Pi∗MZ genotype; we compared features of adults with and without Pi∗MZ genotype among persons without preexisting liver disease.
METHODS
We analyzed data from the European Alpha-1 Liver Cohort, from 419 adults with the Pi∗MZ genotype, 309 adults with the Pi∗ZZ genotype, and 284 individuals without the variant (noncarriers). All underwent a comprehensive evaluation; liver stiffness measurements (LSMs) were made by transient elastography. Liver biopsies were analyzed to define histologic and biochemical features associated with the Pi∗Z variant. Levels of serum transaminases were retrieved from 444,642 participants, available in the United Kingdom biobank.
RESULTS
In the UK biobank database, levels of serum transaminases were increased in subjects with the Pi∗MZ genotype compared with noncarriers. In the Alpha-1 Liver Cohort, adults with Pi∗MZ had lower levels of gamma-glutamyl transferase in serum and lower LSMs than adults with the Pi∗ZZ variant, but these were higher than in noncarriers. Ten percent of subjects with the Pi∗MZ genotype vs 4% of noncarriers had LSMs of 7.1 kPa or more (adjusted odds ratio, 4.8; 95% confidence interval, 2.0-11.8). Obesity and diabetes were the most important factors associated with LSMs ≥7.1 kPa in subjects with the Pi∗MZ genotype. AAT inclusions were detected in liver biopsies of 63% of subjects with the Pi∗MZ genotype, vs 97% of subjects with the Pi∗ZZ genotype, and increased with liver fibrosis stages. Subjects with the Pi∗MZ genotype did not have increased hepatic levels of AAT, whereas levels of insoluble AAT varied among individuals.
CONCLUSIONS
Adults with the Pi∗MZ genotype have lower levels of serum transaminases, fewer AAT inclusions in liver, and lower liver stiffness than adults with the Pi∗ZZ genotype, but higher than adults without the Pi∗Z variant. These findings should help determine risk of subjects with the Pi∗MZ genotype and aid in counseling.

Identifiants

DOI: 10.1053/j.gastro.2020.04.058 PMID: 32376409
pubmed: 32376409
pii: S0016-5085(20)30577-1
doi: 10.1053/j.gastro.2020.04.058
pii:
doi:

Substances chimiques

SERPINA1 protein, human 0
alpha 1-Antitrypsin 0

Types de publication

Journal Article Multicenter Study Observational Study Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

534-548.e11

Subventions

Organisme : Medical Research Council
ID : MC_PC_17228
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_QA137853
Pays : United Kingdom
Organisme : Department of Health
Pays : United Kingdom

Commentaires et corrections

Type : CommentIn
Type : CommentIn
Type : CommentIn

Informations de copyright

Copyright © 2020 AGA Institute. Published by Elsevier Inc. All rights reserved.

Auteurs

Carolin V Schneider (CV)

Medical Clinic III, Gastroenterology, Metabolic diseases and Intensive Care, University Hospital RWTH Aachen, Aachen, Germany.

Karim Hamesch (K)

Medical Clinic III, Gastroenterology, Metabolic diseases and Intensive Care, University Hospital RWTH Aachen, Aachen, Germany; Coordinating Center for alpha-1 antitrypsin deficiency-related liver disease of the European Reference Network (ERN) "Rare Liver" and the European Association for the Study of the Liver (EASL) registry group "Alpha-1 Liver," University Hospital Aachen, Aachen, Germany.

Annika Gross (A)

Medical Clinic III, Gastroenterology, Metabolic diseases and Intensive Care, University Hospital RWTH Aachen, Aachen, Germany.

Mattias Mandorfer (M)

Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University Vienna, Vienna, Austria; Rare Liver Disease (RALID) Center of the European Reference Network (ERN) RARE-LIVER, Medical University Vienna, Vienna, Austria.

Linda S Moeller (LS)

Department of Gastroenterology and Hepatology, Odense University Hospital, Odense, Denmark.

Vitor Pereira (V)

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

Monica Pons (M)

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

Pawel Kuca (P)

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

Matthias C Reichert (MC)

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

Federica Benini (F)

Gastroenterology Unit, Department of Medicine, Spedali Civili and University, Brescia, Italy.

Barbara Burbaum (B)

Medical Clinic III, Gastroenterology, Metabolic diseases and Intensive Care, University Hospital RWTH Aachen, Aachen, Germany.

Jessica Voss (J)

Medical Clinic III, Gastroenterology, Metabolic diseases and Intensive Care, University Hospital RWTH Aachen, Aachen, Germany.

Marla Gutberlet (M)

Medical Clinic III, Gastroenterology, Metabolic diseases and Intensive Care, University Hospital RWTH Aachen, Aachen, Germany.

Vivien Woditsch (V)

Medical Clinic III, Gastroenterology, Metabolic diseases and Intensive Care, University Hospital RWTH Aachen, Aachen, Germany.

Cecilia Lindhauer (C)

Medical Clinic III, Gastroenterology, Metabolic diseases and Intensive Care, University Hospital RWTH Aachen, Aachen, Germany.

Malin Fromme (M)

Medical Clinic III, Gastroenterology, Metabolic diseases and Intensive Care, University Hospital RWTH Aachen, Aachen, Germany.

Julia Kümpers (J)

Medical Clinic III, Gastroenterology, Metabolic diseases and Intensive Care, University Hospital RWTH Aachen, Aachen, Germany.

Lisa Bewersdorf (L)

Medical Clinic III, Gastroenterology, Metabolic diseases and Intensive Care, University Hospital RWTH Aachen, Aachen, Germany.

Benedikt Schaefer (B)

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

Mohammed Eslam (M)

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

Robert Bals (R)

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

Sabina Janciauskiene (S)

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

Joana Carvão (J)

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

Daniel Neureiter (D)

Institute of Pathology, Paracelsus Medical University/Salzburger Landeskliniken (SALK), Salzburg, Austria.

Biaohuan Zhou (B)

Medical Clinic III, Gastroenterology, Metabolic diseases and Intensive Care, University Hospital RWTH Aachen, Aachen, Germany.

Katharina Wöran (K)

Department of Pathology, Medical University Vienna, Vienna, Austria.

Heike Bantel (H)

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

Andreas Geier (A)

Department of Hepatology, University of Wuerzburg, Wuerzburg, Germany.

Timm Dirrichs (T)

Department of Diagnostic and Interventional Radiology, RWTH Aachen University Hospital, Aachen, Germany.

Felix Stickel (F)

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

Alexander Teumer (A)

Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany; DZHK (German Center for Cardiovascular Research), partner site Greifswald, Greifswald, Germany.

Jef Verbeek (J)

Department of Gastroenterology & Hepatology, University Hospitals KU Leuven, Leuven, Belgium.

Frederik Nevens (F)

Department of Gastroenterology & Hepatology, University Hospitals KU Leuven, Leuven, Belgium.

Olivier Govaere (O)

Translational & Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK; Newcastle NIHR Biomedical Research Centre, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.

Marcin Krawczyk (M)

Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany; Department of Medicine II Saarland University Medical Center Saarland University Homburg Germany Laboratory of Metabolic Liver Diseases, Centre for Preclinical Research, Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland.

Tania Roskams (T)

Department of Pathology, University Hospitals KU Leuven, Leuven, Belgium.

Johannes Haybaeck (J)

Department of Pathology, Neuropathology, and Molecular Pathology, Medical University of Innsbruck, Innsbruck, Austria; Diagnostic & Research Center for Molecular Biomedicine, Institute of Pathology, Medical University of Graz, Austria.

Georg Lurje (G)

Department of Surgery and Transplantation, University Hospital RWTH Aachen, Aachen, Germany; Department of Surgery, Campus Charité Mitte I Campus Virchow Klinikum Charité - Universitätsmedizin Berlin, Berlin, Germany.

Joanna Chorostowska-Wynimko (J)

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

Joan Genesca (J)

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

Thomas Reiberger (T)

Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University Vienna, Vienna, Austria; Rare Liver Disease (RALID) Center of the European Reference Network (ERN) RARE-LIVER, Medical University Vienna, Vienna, Austria.

Frank Lammert (F)

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

Aleksander Krag (A)

Department of Gastroenterology and Hepatology, Odense University Hospital, Odense, Denmark.

Jacob George (J)

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

Quentin M Anstee (QM)

Translational & Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK; Newcastle NIHR Biomedical Research Centre, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.

Michael Trauner (M)

Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University Vienna, Vienna, Austria; Rare Liver Disease (RALID) Center of the European Reference Network (ERN) RARE-LIVER, Medical University Vienna, Vienna, Austria.

Christian Datz (C)

Department of Internal Medicine, Hospital Oberndorf, Teaching Hospital of the Paracelsus Private University of Salzburg, Oberndorf, Austria.

Nadine T Gaisa (NT)

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

Helmut Denk (H)

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

Christian Trautwein (C)

Medical Clinic III, Gastroenterology, Metabolic diseases and Intensive Care, University Hospital RWTH Aachen, Aachen, Germany; Coordinating Center for alpha-1 antitrypsin deficiency-related liver disease of the European Reference Network (ERN) "Rare Liver" and the European Association for the Study of the Liver (EASL) registry group "Alpha-1 Liver," University Hospital Aachen, Aachen, Germany.

Elmar Aigner (E)

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

Pavel Strnad (P)

Medical Clinic III, Gastroenterology, Metabolic diseases and Intensive Care, University Hospital RWTH Aachen, Aachen, Germany; Coordinating Center for alpha-1 antitrypsin deficiency-related liver disease of the European Reference Network (ERN) "Rare Liver" and the European Association for the Study of the Liver (EASL) registry group "Alpha-1 Liver," University Hospital Aachen, Aachen, Germany. Electronic address: pstrnad@ukaachen.de.

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Classifications MeSH

questionsmedicales.fr › Personnes › Tranches d'âge › Adulte › Liver Phenotypes of European Adults...
questionsmedicales.fr › Personnes › Tranches d'âge › Adulte › Sujet âgé › Liver Phenotypes of European Adults...
questionsmedicales.fr › Établissements, main d'oeuvre et services de soins de santé › Services de santé › Services de santé mentale › Assistance › Liver Phenotypes of European Adults...
questionsmedicales.fr › Environnement et santé publique › Santé publique › Méthodes épidémiologiques › Caractéristiques des études épidémiologiques › Études épidémiologiques › Études transversales › Liver Phenotypes of European Adults...
questionsmedicales.fr › Diagnostic › Techniques et procédures diagnostiques › Imagerie diagnostique › Échographie › Imagerie d'élasticité tissulaire › Liver Phenotypes of European Adults...
questionsmedicales.fr › Phénomènes génétiques › Génotype › Hétérozygote › Liver Phenotypes of European Adults...
questionsmedicales.fr › Phénomènes génétiques › Génotype › Homozygote › Liver Phenotypes of European Adults...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Liver Phenotypes of European Adults...
questionsmedicales.fr › Système digestif › Foie › Liver Phenotypes of European Adults...
questionsmedicales.fr › États, signes et symptômes pathologiques › Processus pathologiques › Fibrose › Cirrhose du foie › Liver Phenotypes of European Adults...
questionsmedicales.fr › Diagnostic › Techniques et procédures diagnostiques › Techniques de diagnostic digestif › Tests de la fonction hépatique › Liver Phenotypes of European Adults...
questionsmedicales.fr › Environnement et santé publique › Santé publique › Méthodes épidémiologiques › Caractéristiques des études épidémiologiques › Études épidémiologiques › Études de cohortes › Études longitudinales › Liver Phenotypes of European Adults...
questionsmedicales.fr › Personnes › Tranches d'âge › Adulte › Adulte d'âge moyen › Liver Phenotypes of European Adults...
questionsmedicales.fr › Phénomènes génétiques › Phénotype › Liver Phenotypes of European Adults...
questionsmedicales.fr › Environnement et santé publique › Santé publique › Méthodes épidémiologiques › Caractéristiques des études épidémiologiques › Études épidémiologiques › Études de cohortes › Études prospectives › Liver Phenotypes of European Adults...
questionsmedicales.fr › Régions géographiques › Europe › Royaume-Uni › Liver Phenotypes of European Adults...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › alpha-1-Antitrypsine › Liver Phenotypes of European Adults...
questionsmedicales.fr › États, signes et symptômes pathologiques › Processus pathologiques › Emphysème › Emphysème sous-cutané › Déficit en alpha-1-antitrypsine › Liver Phenotypes of European Adults...