Hepatology (Baltimore, Md.) · 2026
Beyond cirrhosis: Major adverse liver outcomes across homozygous and heterozygous alpha-1 antitrypsin deficiency-associated liver disease.
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Bastaich Dustin, Dahman Bassam, Hentschel Austen, Karki Chitra, Nussbaum Tami, Park Suna, Hagiwara May, Spector Seth A, Bigford Gregory E, Garnet Brian, Campos Michael, John Binu V, Veterans Analysis of Liver Diseases (VALID) group of investigators
Аннотация
BACKGROUND AND AIMS: 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 remain limited. We assessed the risk of MALO across AATD Pi*MZ, Pi*SZ, and Pi*ZZ genotypes compared with the wildtype Pi*MM.
APPROACH AND RESULTS: 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. Among 22,537 participants with genotype testing (19,665 Pi*MM, 1656 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 per 1000 person-years, respectively, while 5-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 a 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 a 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.
APPROACH AND RESULTS: 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. Among 22,537 participants with genotype testing (19,665 Pi*MM, 1656 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 per 1000 person-years, respectively, while 5-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 a 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 a 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.