Liver and Bile

Gut. 2022;71(2):415–23

Fromme M, Schneider CV, Pereira V, Hamesch K, Pons M, Reichert MC, Benini F, Ellis P, Thorhauge KH, Mandorfer M, Burbaum B, Woditsch V, Chorostowska-Wynimko J, Verbeek J, Nevens F, Genesca J, Miravitlles M, Nuñez A, Schaefer B, Zoller H, Janciauskiene S, Abreu N, Jasmins L, Gaspar R, Liberal R, Macedo G, Mahadeva R, Gomes C, Schneider KM, Trauner M, Krag A, Gooptu B, Thorburn D, Marshall A, Hurst JR, Lomas DA, Lammert F, Gaisa NT, Clark V, Griffiths W, Trautwein C, Turner AM, McElvaney NG, Strnad P

Hepatobiliary phenotypes of adults with alpha-1 antitrypsin deficiency

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 tumors in AATD.
Design: Baseline phenotypes of AATD individuals and non-carriers were analyzed 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 odds ratio [aOR] = 21.7, 95% confidence interval [CI]: 8.8–53.7) and primary liver cancer (aOR = 44.5, 95% CI: 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, 95% CI: 1.2–2.2) and cholelithiasis (aOR = 1.3, 95% CI: 1.2–1.4). Individuals with homozygous Pi*S mutation (Pi*SS genotype) harbored 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, 95% CI: 1.1–8.2) and primary liver cancer (aOR = 6.6, 95% CI: 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: This study defines the hepatobiliary phenotype of individuals with the most relevant alpha-1 antitrypsin deficiency genotypes including their predisposition to liver tumors, thereby allowing evidence-based advice and individualized hepatological surveillance.

DOI: DOI: 10.1136/gutjnl-2020-323729