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. 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.
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.
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 antitrypsindeficiency. 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.
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