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

Carolin V Schneider¹, Karim Hamesch², Annika Gross¹, Mattias Mandorfer³, Linda S Moeller⁴, Vitor Pereira⁵, Monica Pons⁶, Pawel Kuca⁷, Matthias C Reichert⁸, Federica Benini⁹, Barbara Burbaum¹, Jessica Voss¹, Marla Gutberlet¹, Vivien Woditsch¹, Cecilia Lindhauer¹, Malin Fromme¹, Julia Kümpers¹, Lisa Bewersdorf¹, Benedikt Schaefer¹⁰, Mohammed Eslam¹¹, Robert Bals¹², Sabina Janciauskiene¹³, Joana Carvão⁵, Daniel Neureiter¹⁴, Biaohuan Zhou¹, Katharina Wöran¹⁵, Heike Bantel¹⁶, Andreas Geier¹⁷, Timm Dirrichs¹⁸, Felix Stickel¹⁹, Alexander Teumer²⁰, Jef Verbeek²¹, Frederik Nevens²¹, Olivier Govaere²², Marcin Krawczyk²³, Tania Roskams²⁴, Johannes Haybaeck²⁵, Georg Lurje²⁶, Joanna Chorostowska-Wynimko⁷, Joan Genesca⁶, Thomas Reiberger³, Frank Lammert⁸, Aleksander Krag⁴, Jacob George¹¹, Quentin M Anstee²², Michael Trauner³, Christian Datz²⁷, Nadine T Gaisa²⁸, Helmut Denk²⁹, Christian Trautwein², Elmar Aigner³⁰, Pavel Strnad³¹; European Alpha-1 Liver Study Group

Affiliations

¹ Medical Clinic III, Gastroenterology, Metabolic diseases and Intensive Care, University Hospital RWTH Aachen, Aachen, Germany.
² 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.
³ 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.
⁴ Department of Gastroenterology and Hepatology, Odense University Hospital, Odense, Denmark.
⁵ Department of Gastroenterology, Centro Hospitalar do Funchal, Madeira, Portugal.
⁶ 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.
⁷ Department of Genetics and Clinical Immunology, National Institute of Tuberculosis and Lung Diseases, Warsaw, Poland.
⁸ Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany.
⁹ Gastroenterology Unit, Department of Medicine, Spedali Civili and University, Brescia, Italy.
¹⁰ Department of Internal Medicine, Medical University of Innsbruck, Innsbruck, Austria.
¹¹ Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, NSW, Australia.
¹² Department of Internal Medicine V, Saarland University Medical Center, Homburg, Germany.
¹³ Clinic for Pneumology, Medical University Hannover, Hannover, Germany.
¹⁴ Institute of Pathology, Paracelsus Medical University/Salzburger Landeskliniken (SALK), Salzburg, Austria.
¹⁵ Department of Pathology, Medical University Vienna, Vienna, Austria.
¹⁶ Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
¹⁷ Department of Hepatology, University of Wuerzburg, Wuerzburg, Germany.
¹⁸ Department of Diagnostic and Interventional Radiology, RWTH Aachen University Hospital, Aachen, Germany.
¹⁹ Department of Gastroenterology and Hepatology, University Hospital of Zurich, Zürich, Switzerland.
²⁰ Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany; DZHK (German Center for Cardiovascular Research), partner site Greifswald, Greifswald, Germany.
²¹ Department of Gastroenterology & Hepatology, University Hospitals KU Leuven, Leuven, Belgium.
²² 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.
²³ 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.
²⁴ Department of Pathology, University Hospitals KU Leuven, Leuven, Belgium.
²⁵ 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.
²⁶ 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.
²⁷ Department of Internal Medicine, Hospital Oberndorf, Teaching Hospital of the Paracelsus Private University of Salzburg, Oberndorf, Austria.
²⁸ Institute of Pathology, University Hospital RWTH Aachen, Aachen, Germany.
²⁹ Institute of Pathology, Medical University of Graz, Graz, Austria.
³⁰ First Department of Medicine, Paracelsus Medical University, Salzburg, Austria.
³¹ 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.

PMID: 32376409
DOI: 10.1053/j.gastro.2020.04.058

Observational Study

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

Carolin V Schneider et al. Gastroenterology. 2020 Aug.

. 2020 Aug;159(2):534-548.e11.

doi: 10.1053/j.gastro.2020.04.058. Epub 2020 May 4.

Authors

Affiliations

¹ Medical Clinic III, Gastroenterology, Metabolic diseases and Intensive Care, University Hospital RWTH Aachen, Aachen, Germany.
² 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.
³ 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.
⁴ Department of Gastroenterology and Hepatology, Odense University Hospital, Odense, Denmark.
⁵ Department of Gastroenterology, Centro Hospitalar do Funchal, Madeira, Portugal.
⁶ 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.
⁷ Department of Genetics and Clinical Immunology, National Institute of Tuberculosis and Lung Diseases, Warsaw, Poland.
⁸ Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany.
⁹ Gastroenterology Unit, Department of Medicine, Spedali Civili and University, Brescia, Italy.
¹⁰ Department of Internal Medicine, Medical University of Innsbruck, Innsbruck, Austria.
¹¹ Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, NSW, Australia.
¹² Department of Internal Medicine V, Saarland University Medical Center, Homburg, Germany.
¹³ Clinic for Pneumology, Medical University Hannover, Hannover, Germany.
¹⁴ Institute of Pathology, Paracelsus Medical University/Salzburger Landeskliniken (SALK), Salzburg, Austria.
¹⁵ Department of Pathology, Medical University Vienna, Vienna, Austria.
¹⁶ Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
¹⁷ Department of Hepatology, University of Wuerzburg, Wuerzburg, Germany.
¹⁸ Department of Diagnostic and Interventional Radiology, RWTH Aachen University Hospital, Aachen, Germany.
¹⁹ Department of Gastroenterology and Hepatology, University Hospital of Zurich, Zürich, Switzerland.
²⁰ Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany; DZHK (German Center for Cardiovascular Research), partner site Greifswald, Greifswald, Germany.
²¹ Department of Gastroenterology & Hepatology, University Hospitals KU Leuven, Leuven, Belgium.
²² 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.
²³ 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.
²⁴ Department of Pathology, University Hospitals KU Leuven, Leuven, Belgium.
²⁵ 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.
²⁶ 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.
²⁷ Department of Internal Medicine, Hospital Oberndorf, Teaching Hospital of the Paracelsus Private University of Salzburg, Oberndorf, Austria.
²⁸ Institute of Pathology, University Hospital RWTH Aachen, Aachen, Germany.
²⁹ Institute of Pathology, Medical University of Graz, Graz, Austria.
³⁰ First Department of Medicine, Paracelsus Medical University, Salzburg, Austria.
³¹ 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.

PMID: 32376409
DOI: 10.1053/j.gastro.2020.04.058

Abstract

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.

Keywords: ALT; FibroScan; GGT; SERPINA1.

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Comment in

Is Heterozygosity for the Alpha-1 Antitrypsin Risk Allele Pi∗MZ a Disease Modifier or Genetic Risk Factor?
Zoller H, Wagner S, Tilg H. Zoller H, et al. Gastroenterology. 2020 Aug;159(2):433-434. doi: 10.1053/j.gastro.2020.06.035. Epub 2020 Jun 20. Gastroenterology. 2020. PMID: 32569768 No abstract available.
The Pi∗MZ Allele in Alpha-1 Antitrypsin Increases Liver-Related Outcomes in a Population-Based Study.
Luukkonen PK, Salomaa V, Åberg F. Luukkonen PK, et al. Gastroenterology. 2021 Apr;160(5):1874-1875. doi: 10.1053/j.gastro.2020.10.061. Epub 2020 Dec 29. Gastroenterology. 2021. PMID: 33385428 No abstract available.
Reply.
Schneider CV, Hamesch K, Strnad P. Schneider CV, et al. Gastroenterology. 2021 Apr;160(5):1875-1877. doi: 10.1053/j.gastro.2021.01.002. Epub 2021 Jan 5. Gastroenterology. 2021. PMID: 33417942 No abstract available.

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

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

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