Details

Autor(en) / Beteiligte

• Trautwein, Christian
• Eslam, Mohammed
• Bals, Robert
• George, Jacob
• Geier, Andreas
• Teumer, Alexander
• Lindhauer, Cecilia
• Denk, Helmut
• Strnad, Pavel
• Mandorfer, Mattias
• Reiberger, Thomas
• Janciauskiene, Sabina
• Nevens, Frederik
• Reichert, Matthias C
• Gutberlet, Marla
• Woditsch, Vivien
• Stickel, Felix
• Schneider, Carolin V
• Gross, Annika
• Fromme, Malin
• Roskams, Tania
• Bantel, Heike
• Genesca, Joan
• Trauner, Michael
• Bewersdorf, Lisa
• Kuca, Pawel
• Krawczyk, Marcin
• Gaisa, Nadine T
• Pereira, Vitor
• Krag, Aleksander
• Aigner, Elmar
• Neureiter, Daniel
• Haybaeck, Johannes
• Verbeek, Jef
• Govaere, Olivier
• Lammert, Frank
• Moeller, Linda S
• Burbaum, Barbara
• Kumpers, Julia
• Zhou, Biaohuan
• Schaefer, Benedikt
• Anstee, Quentin M
• Woran, Katharina
• Benini, Federica
• Pons, Monica
• Carvao, Joana
• Lurje, Georg
• Dirrichs, Timm
• Datz, Christian
• Chorostowska-Wynimko, Joanna
• Hamesch, Karim
• Voss, Jessica

Titel

Liver Phenotypes of European Adults Heterozygous or Homozygous for PiZ Variant of AAT (PiMZ vs PiZZ genotype) and Noncarriers

Ist Teil von

• Gastroenterology (New York, N.Y. 1943), 2020-08, Vol.159 (2), p.534

Ort / Verlag

Elsevier B.V

Erscheinungsjahr

2020

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• on behalf of the European Alpha-1 Liver Study Group Keywords FibroScan; SERPINA1; GGT; ALT 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 [greater than or equal to]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. Abbreviations used in this paper AAT, alpha-1 antitrypsin; AATD, alpha-1 antitrypsin deficiency; ALD/NAFLD, alcoholic/nonalcoholic fatty liver disease; ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BMI, body mass index; CAP, controlled attenuation parameter; GGT, gamma-glutamyl transferase; IHC, immunohistochemistry; LSM, liver stiffness measurements; OR, odds ratio; PAS-D, periodic acid--Schiff--diastase; Pi, Protease inhibitor; Pi*M, normal AAT allele; Pi*S, mutant SERPINA1 allele variant termed 'S'; Pi*Z, mutant SERPINA1 allele variant termed 'Z'; Pi*MZ, AAT genotype with heterozygosity for the Pi*Z variant; Pi*ZZ, AAT genotype with homozygosity for the Pi*Z variant; SERPINA1, AAT gene; TE, transient elastography (FibroScan); ULN, upper limit of normal Author Affiliation: (1) Medical Clinic III, Gastroenterology, Metabolic diseases and Intensive Care, University Hospital RWTH Aachen, Aachen, Germany (2) 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 (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 (7) Centro de Investigacion Biomedica en Red de Enfermedades Hepaticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid (8) Department of Genetics and Clinical Immunology, National Institute of Tuberculosis and Lung Diseases, Warsaw, Poland (9) Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany (10) Gastroenterology Unit, Department of Medicine, Spedali Civili and University, Brescia, Italy (11) Department of Internal Medicine, Medical University of Innsbruck, Innsbruck, Austria (12) Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, NSW, Australia (13) Department of Internal Medicine V, Saarland University Medical Center, Homburg, Germany (14) Clinic for Pneumology, Medical University Hannover, Hannover, Germany (15) Institute of Pathology, Paracelsus Medical University/Salzburger Landeskliniken (SALK), Salzburg, Austria (16) Department of Pathology, Medical University Vienna, Vienna, Austria (17) Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany (18) Department of Hepatology, University of Wuerzburg, Wuerzburg, Germany (19) Department of Diagnostic and Interventional Radiology, RWTH Aachen University Hospital, Aachen, Germany (20) Department of Gastroenterology and Hepatology, University Hospital of Zurich, Zurich, Switzerland (21) Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany (22) DZHK (German Center for Cardiovascular Research), partner site Greifswald, Greifswald, Germany (23) Department of Gastroenterology & Hepatology, University Hospitals KU Leuven, Leuven, Belgium (24) Translational & Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK (25) Newcastle NIHR Biomedical Research Centre, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK (26) 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 (27) Department of Pathology, University Hospitals KU Leuven, Leuven, Belgium (28) Department of Pathology, Neuropathology, and Molecular Pathology, Medical University of Innsbruck, Innsbruck, Austria (29) Department of Surgery and Transplantation, University Hospital RWTH Aachen, Aachen, Germany (30) Department of Surgery, Campus Charite Mitte I Campus Virchow Klinikum Charite -- Universitatsmedizin Berlin, Berlin, Germany (31) Department of Internal Medicine, Hospital Oberndorf, Teaching Hospital of the Paracelsus Private University of Salzburg, Oberndorf, Austria (32) Institute of Pathology, University Hospital RWTH Aachen, Aachen, Germany (33) Institute of Pathology, Medical University of Graz, Graz, Austria (34) First Department of Medicine, Paracelsus Medical University, Salzburg, Austria (35) Rare Liver Disease (RALID) Center of the European Reference Network (ERN) RARE-LIVER, Medical University Vienna, Vienna, Austria (36) Diagnostic & Research Center for Molecular Biomedicine, Institute of Pathology, Medical University of Graz, Austria * Correspondence Address correspondence to: Pavel Strnad, MD, 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, Pauwelsstr. 30, 52074 Aachen, Germany. Article History: Received 7 August 2019; Accepted 20 April 2020 (footnote) Conflict of interest The authors disclose no conflicts. (footnote) Funding This work was supported by the EASL registry grant on alpha-1 antitrypsin-related liver disease, the Deutsche Forschungsgemeinschaft (DFG) consortium SFB/TRR57 "Liver fibrosis" (both to PS and CT), the Interdisciplinary Center for Clinical Research (IZKF) within the medical faculty at RWTH Aachen University (to PS), the Else Kroener Excellence Fellowship (to PS), unrestricted research grants from Grifols and CSL Behring (to PS), the START program within the medical faculty at RWTH Aachen University (to KH), the German Liver Foundation (to KH), the German Gastroenterological Association (to KH), the Peter-Scriba-MD-Scholarship (to CVS), the Joseph-Skoda Award of the Austrian Society of Internal Medicine (to MM), the Swiss National Funds (SNF no. 310030_169196; to FS), the Swiss Foundation for Alcohol Research (SSA; to FS), the Newcastle NIHR Biomedical Research Centre (to QMA), and the EPoS (Elucidating Pathways of Steatohepatitis) consortium funded by the Horizon 2020 Framework Program of the European Union under Grant Agreement 634413 (to QMA). We attest that we did not use any copyright protected material in our manuscript. No writing assistance was provided. (footnote) Author names in bold designate shared co-first authorship. (footnote) Author names in bold designate shared co-first authorship. (footnote)* Authors share co-first authorship. Byline: Carolin V. Schneider (1,*), Karim Hamesch (1,2,*), Annika Gross (1), Mattias Mandorfer (3,35), Linda S. Moeller (4), Vitor Pereira (5), Monica Pons (6,7), Pawel Kuca (8), Matthias C. Reichert (9), Federica Benini (10), Barbara Burbaum (1), Jessica Voss (1), Marla Gutberlet (1), Vivien Woditsch (1), Cecilia Lindhauer (1), Malin Fromme (1), Julia Kumpers (1), Lisa Bewersdorf (1), Benedikt Schaefer (11), Mohammed Eslam (12), Robert Bals (13), Sabina Janciauskiene (14), Joana Carvao (5), Daniel Neureiter (15), Biaohuan Zhou (1), Katharina Woran (16), Heike Bantel (17), Andreas Geier (18), Timm Dirrichs (19), Felix Stickel (20), Alexander Teumer (21,22), Jef Verbeek (23), Frederik Nevens (23), Olivier Govaere (24,25), Marcin Krawczyk (9,26), Ta