Alpha-1-Antitrypsin Pi*MZ variant increases risk of developing hepatic events in nonalcoholic fatty liver disease patients.

Aims: Heterozygous alpha-1-antitrypsin (A1AT) Pi*MZ variant has been shown to increase the risk of developing liver cirrhosis in patients with non-alcoholic fatty liver disease (NAFLD). We aimed to determine the association between heterozygous Pi*MZ and Pi*MS variants and development of hepatic decompensation events in NAFLD patients.

Methods: We included patients with NAFLD who also had A1AT genotyping performed from 2005 to 2020. We recorded demographic and clinical variables, and data on hepatic events (ascites, hepatic encephalopathy, esophageal variceal bleed, or hepatocellular carcinoma), if any. We performed binary logistic regression analysis to assess the association between A1AT variants and hepatic events, and calculated Odds ratio (OR) with their 95% confidence intervals (Cl).

Results: We included 1532 patients with NAFLD, of which 1249 patients had Pi*MM, 121 had Pi*MS, and 162 had Pi*MZ. Of the 1532 patients, hepatic events developed in 521 (34%) patients. The percentage of patients with Pi*MZ variant was significantly higher in patients with hepatic events as compared to patients without hepatic events (18.7 % vs 8.1%, p<0.0001). Pi*MZ variant was noted to significantly increase the odds of developing hepatic events in NAFLD patients, unadjusted OR: 1.82 (1.3-2.5, p<0.001), adjusted OR (for age, sex, body mass index, and diabetes mellitus) 1.76 (1.2-2.5, p = 0.002). Pi*MS variant did not increase the odds of hepatic events in NAFLD patients, OR: 0.92 (0.6-1.4, p = 0.70).

Conclusion: Patients with NAFLD and A1AT Pi*MZ variant are at increased risk for developing hepatic decompensation. NAFLD patients should be offered A1AT genotyping for risk stratification, counseling, and multidisciplinary intervention for NAFLD.