Editorial: Understanding the Role of the Alpha‐1 Pi* MZ Genotype in the Development of Hepatocellular Carcinoma for Patients With ACLD

Advanced chronic liver disease (ACLD) is the strongest risk factor for the development of HCC, the third leading cause of cancer-death worldwide [1]. Studies show that within the population of ACLD, there is wide heterogeneity in the individual risk for HCC development and more study into individual risk factors is needed [2]. Alpha-1-antitrypsin deficiency (AATD) is a genetic disorder caused by mutations in the SERPINA1 gene and is a rare cause of both advanced liver and lung disease. Patients with two copies of a diseased allele (Pi*ZZ) are likely to have clinically significant disease, while carriers with one diseased allele (Pi*MS or MZ) are at higher risk for ACLD but generally require another co-factor to progress to ACLD [3]. The role of the heterozygous diseased genotypes in the development of HCC is yet to be determined. In this study, Balcar et al. [4] examined the role of the heterozygous Pi*MZ genotype in the development of HCC in patients with ACLD. They retrospectively studied a cohort of 815 patients with ACLD caused by viral disease or steatotic liver diseases (alcohol, MASLD) from a single center; they included patients who had HVPG measurements and genetic data available. Patients were followed to time of death, liver transplant, HCC development or date of last follow-up; the median time of follow-up was 47.3 months. 68 (8%) patients developed HCC during the study period, including 8 (27%) with the Pi*MZ genotype. Using univariable and multivariable competing risk regression analysis, the authors showed that the Pi*MZ genotype was independently associated with increased risk for HCC including when adjusted for other variables including aMAP score and in a smaller cohort which included AFP data. Previous epidemiological data is limited but has not suggested a relationship between the heterozygous diseased genotypes and HCC development in the ACLD population [5, 6]. This work [4] marks the first epidemiologic study where the Pi*MZ allele has been implicated in the development of HCC, although limited autopsy and animal data have also supported this conclusion. In interpreting these findings, it is vital to consider the study cohort carefully. The group defined ACLD based on HVPG, a robust way to ensure that patients had ACLD. However, it only included patients with viral or steatotic etiologies of liver disease, leaving out at least one major group (autoimmune) as well as those with cryptogenic disease. This limits the generalizability of these findings largely to the steatotic and viral liver diseases. In comparison, other tests that evaluate risk for HCC in ACLD are validated across etiologies, including FIB-4 and liver stiffness [7, 8]. In addition, this was a single-center study in Europe and included patients who received HVPG measurements; the results may not be generalizable to other demographic groups. This study constitutes a step forward in understanding the role that the Pi*MZ genotype plays in the development of HCC in patients with ACLD; in the future it may be possible to target therapeutics using this information. More data, including validation studies, will be needed to understand the generalizability of these results across all demographics and etiologies of ACLD. Kaitlyn Carlson: writing – original draft, conceptualization, writing – review and editing. Abbey Barnard Giustini: conceptualization, writing – review and editing. The authors have nothing to report. This article is linked to Balcar et al. papers. To view this article, visit https://doi.org/10.1111/apt.70530. Data sharing not applicable to this article as no datasets were generated or analysed during the current study.