Hepatobiliary phenotypes of adults with alpha-1 antitrypsin deficiency. Issue 2 (25th February 2021)

• Record Type: Journal Article
• Authors: Fromme, Malin; Schneider, Carolin V; Pereira, Vitor; Hamesch, Karim; Pons, Monica; Reichert, Matthias C; Benini, Federica; Ellis, Paul; H Thorhauge, Katrine; Mandorfer, Mattias; Burbaum, Barbara; Woditsch, Vivien; Chorostowska-Wynimko, Joanna; Verbeek, Jef; Nevens, Frederik; Genesca, Joan; Miravitlles, Marc; Nuñez, Alexa; Schaefer, Benedikt; Zoller, Heinz; Janciauskiene, Sabina; Abreu, Nélia; Jasmins, Luís; Gaspar, Rui; Liberal, Rodrigo; Macedo, Guilherme; Mahadeva, Ravi; Gomes, Catarina; Schneider, Kai Markus; Trauner, Michael; Krag, Aleksander; Gooptu, Bibek; Thorburn, Douglas; Marshall, Aileen; Hurst, John R; Lomas, David A; Lammert, Frank; Gaisa, Nadine T; Clark, Virginia; Griffiths, William; Trautwein, Christian; Turner, Alice M; McElvaney, Noel G; Strnad, Pavel;
• Is Part Of: Gut. Volume 71:Issue 2(2022)
• Page Start: 415
• Page End: 423
• Publication Date: 2021-02-25
• Subjects: fibrosis -- liver -- liver cirrhosis -- cancer; Gastroenterology -- Periodicals; 616.33
• DOI: 10.1136/gutjnl-2020-323729
• Languages: English
• ISSNs: 0017-5749

Abstract

Abstract : Objective: Alpha-1 antitrypsin deficiency (AATD) is a common, potentially lethal inborn disorder caused by mutations in alpha-1 antitrypsin (AAT). Homozygosity for the 'Pi*Z' variant of AAT (Pi*ZZ genotype) causes lung and liver disease, whereas heterozygous 'Pi*Z' carriage (Pi*MZ genotype) predisposes to gallstones and liver fibrosis. The clinical significance of the more common 'Pi*S' variant remains largely undefined and no robust data exist on the prevalence of liver tumours in AATD. Design: Baseline phenotypes of AATD individuals and non-carriers were analysed in 482 380 participants in the UK Biobank. 1104 participants of a multinational cohort (586 Pi*ZZ, 239 Pi*SZ, 279 non-carriers) underwent a comprehensive clinical assessment. Associations were adjusted for age, sex, body mass index, diabetes and alcohol consumption. Results: Among UK Biobank participants, Pi*ZZ individuals displayed the highest liver enzyme values, the highest occurrence of liver fibrosis/cirrhosis (adjusted OR (aOR)=21.7 (8.8–53.7)) and primary liver cancer (aOR=44.5 (10.8–183.6)). Subjects with Pi*MZ genotype had slightly elevated liver enzymes and moderately increased odds for liver fibrosis/cirrhosis (aOR=1.7 (1.2–2.2)) and cholelithiasis (aOR=1.3 (1.2–1.4)). Individuals with homozygous Pi*S mutation (Pi*SS genotype) harboured minimally elevated alanine aminotransferase values, but no other hepatobiliary abnormalities. Pi*SZ participants displayed higher liver enzymes, more frequent liver fibrosis/cirrhosis (aOR=3.1 (1.1–8.2)) and primary liver cancer (aOR=6.6 (1.6–26.9)). The higher fibrosis burden was confirmed in a multinational cohort. Male sex, age ≥50 years, obesity and the presence of diabetes were associated with significant liver fibrosis. Conclusion: Our study defines the hepatobiliary phenotype of individuals with the most relevant AATD genotypes including their predisposition to liver tumours, thereby allowing evidence-based advice and individualised hepatological surveillance.