Hepatobiliary phenotypes of adults with alpha-1 antitrypsin deficiency

• Published in: Gut Vol. 71; no. 2; pp. 415 - 423
• Main 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
• Format: Journal Article
• Language: English
• Published: England BMJ Publishing Group Ltd and British Society of Gastroenterology 01.02.2022; BMJ Publishing Group LTD
• Subjects: Adult; Aged; Alanine; Alanine transaminase; Alcohol; alpha 1-Antitrypsin Deficiency - complications; Biobanks; Body mass index; cancer; Case-Control Studies; Cholelithiasis - epidemiology; Chronic illnesses; Chronic obstructive pulmonary disease; Cirrhosis; Cohort Studies; Diabetes; Diabetes mellitus; Enzymes; Female; Fibrosis; Genotype & phenotype; Genotypes; Hepatology; Humans; Laboratories; liver; Liver cancer; Liver cirrhosis; Liver Cirrhosis - epidemiology; Liver diseases; Liver Neoplasms - epidemiology; Lung diseases; Male; Metabolism; Middle Aged; Mutation; Normal distribution; Phenotype; Phenotypes; Population; Prevalence; Tumors; United Kingdom; United Kingdom; Austria; United Kingdom > UK; United States > US; Germany; cancer; fibrosis; liver; liver cirrhosis
• ISSN: 0017-5749; 1468-3288; 1468-3288
• DOI: 10.1136/gutjnl-2020-323729

ObjectiveAlpha-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.DesignBaseline 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.ResultsAmong 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.ConclusionOur 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.