Hepatic decompensation is accelerated in patients with cirrhosis and alpha-1 antitrypsin Pi*MZ genotype

Background & Aims: Alpha-1 antitrypsin deficiency is caused by mutations in SERPINA1, most commonly homozygosity for the Pi*Z variant, and can present as liver disease. While heterozygosity for Pi*Z (Pi*MZ) is linked to increased risk of cirrhosis, whether the Pi*MZ genotype is associated with an increased rate of decompensation among patients who already have compensated cirrhosis is not known. Methods: This was a retrospective study of Michigan Genomics Initiative participants with baseline compensated cirrhosis. The primary predictors were Pi*MZ or Pi*MS genotype (vs. Pi*MM). The primary outcomes were hepatic decompensation with ascites, hepatic encephalopathy, or variceal bleeding, or the combined endpoint of liver-related death or liver transplant, both modeled with Fine-Gray competing risk models. Results: We included 576 patients with baseline compensated cirrhosis who had undergone genotyping, of whom 474 had Pi*MM, 49 had Pi*MZ, and 52 had Pi*MS genotypes. Compared to Pi*MM genotype, Pi*MZ was associated with increased rates of hepatic decompensation (hazard ratio 1.81; 95% CI 1.22-2.69; p = 0.003) and liver transplant or liver-related death (hazard ratio 2.07; 95% CI 1.21-3.52; p = 0.078). These associations remained significant after adjustment for severity of underlying liver disease, and were robust across subgroup analyses based on etiology, sex, obesity, and diabetes status. Pi*MS was not associated with decompensation or death/transplantation. Conclusions: The SERPINA1 Pi*MZ genotype is associated with an increased rate of hepatic decompensation and decreased transplant-free survival among patients with baseline compensated cirrhosis. Lay summary: There is a mutation in the gene SERPINA1 called Pi*MZ which increases risk of liver scarring (cirrhosis); however, it is not known what effect Pi*MZ has if someone already has cirrhosis. In this study, we found that people who had cirrhosis and Pi*MZ developed complications from cirrhosis faster than those who did not have the mutation. (c) 2022 The Author(s). Published by Elsevier B.V. on behalf of European Association for the Study of the Liver (EASL). This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).