The Alpha‐1 Pi * MZ Genotype Is an Independent Risk Factor for Hepatocellular Carcinoma Development in Patients With ACLD

BACKGROUND AND AIMS: Homozygosity for the SERPINA1 Pi*Z deficiency allele is the culprit of alpha-1 antitrypsin deficiency-related liver disease, while harbouring a single Z-allele (e.g., the common Pi*MZ genotype) is the strongest genetic risk factor for advanced chronic liver disease (ACLD) and its progression. However, the impact of the Pi*MZ genotype on hepatocellular carcinoma (HCC) development in patients who have already progressed to ACLD has yet to be established. Thus, we investigated the impact of the Pi*MZ genotype on the development of HCC among longitudinally followed ACLD patients. METHODS: Patients undergoing hepatic venous pressure gradient (HVPG) measurement and genotyping at the Vienna Hepatic Haemodynamic Lab were included, excluding those with HCC. Competing risk analyses with HCC as the outcome of interest and death/liver transplantation as competing events were performed. RESULTS: We included 815 patients (mean age: 54 ± 11 years; viral hepatitis: 53%, alcohol-related liver disease: 37% and metabolic dysfunction-associated steatotic liver disease: 10%). Overall, 30 patients (4%) harboured the Pi*MZ genotype. During a median follow-up of 47.3 months, 68 patients developed an HCC (8/30 with Pi*MZ). The Pi*MZ genotype was associated with increased risks of HCC development in univariable as well as in multivariable analyses, accounting for other important factors (i.e., age, sex, removal of the primary aetiological factor, aspartate-aminotransferase, albumin and HVPG) identified in our study (adjusted subdistribution hazard ratio [aSHR]: 3.31 [95% confidence interval (CI): 1.26-8.65]; p = 0.015). The impact of the Pi*MZ genotype was confirmed adjusting for the aMAP score (aSHR: 2.94 [95% CI: 1.45-5.97]; p = 0.003). CONCLUSION: The SERPINA1 Pi*MZ genotype is associated with an increased risk of HCC development in patients with ACLD, independently of other HCC risk factors.