Beyond cirrhosis: Major adverse liver outcomes across homozygous and heterozygous Alpha-1 antitrypsin deficiency associated liver disease

BACKGROUND: Alpha-1 antitrypsin deficiency (AATD) may cause chronic lung and liver disease, yet data on major adverse liver outcomes (MALO) across heterozygous and homozygous Z-allele genotypes remains limited. We assessed the risk of MALO across AATD Pi*MZ, Pi*SZ, and Pi*ZZ genotypes compared to the wildtype Pi*MM. METHODS: This retrospective cohort study utilized the Veterans Analysis of Liver Disease cohort (January 2000-April 2025). Genotypes were identified using validated natural language processing (κ=0.89). Multivariable Fine-Gray models estimated the hazard of MALO. RESULTS: Among 22,537 participants with genotype testing (19,665 Pi*MM, 1,656 Pi*MZ, 281 Pi*SZ, and 935 Pi*ZZ) and 352,612 person-years of follow up, MALO risk increased sequentially with allele burden: Pi*MZ (aHR 1.25, 1.11-1.40), Pi*SZ (aHR 1.51, 1.17-1.94), and Pi*ZZ (aHR 1.80, 1.57-2.07), versus Pi*MM. MALO incidence rates for Pi*MM, Pi*MZ, Pi*SZ, and Pi*ZZ, were 11.3, 13.0, 14.6, and 19.2 for 1,000 person-years respectively, while five-year MALO probability was 3.5%, 5.5%, 5.3%, and 8.1% respectively. Pi*ZZ was associated with significantly increased risk of all individual MALO components: decompensation, HCC, liver transplantation (LT), and liver-related death (LRD). Pi*SZ and Pi*MZ were associated with higher risk of decompensation, LT, and LRD, but not HCC. A sensitivity analysis restricted to participants with MASLD showed consistent findings. CONCLUSION: In this national longitudinal cohort of veterans with documented AATD genotype testing and median follow-up of 15.9 years, we observed an increased risk of MALO in both homozygous and heterozygous Z-allele carriers, underscoring the need for timely diagnosis and enhanced clinical surveillance among veterans with known AATD genotypes.