Alpha-1 antitrypsin deficiency and primary liver cancers

Primary liver cancers (PLCs) remain a major challenge to global health and an escalating threat to human life, with a growing incidence worldwide. PLCs are composed of hepatocellular carcinoma (HCC), cholangiocarcinoma (CCA), and mixed HCC-CCA, accounting for 85 %, 10 %, and 5 % of cases, respectively. Among the numerous identified risk factors associated with liver cancers, Alpha 1-AntiTrypsin Deficiency (AATD) genetic disease emerges as an intriguing one. AATD-related liver disease may lead to chronic hepatitis, cirrhosis, and PLCs in adulthood. Although our knowledge about the natural history of AATD-liver disease has improved recently, liver cancers associated with AATD remain poorly understood and explored, while this specific population is at a 20 to 50 times higher risk of developing PLC. Thus, we review here current knowledge about AATD-associated PLCs, describing the impact of AATD genotypes on their occurrence. We also discuss emerging hypotheses regarding the AATD PiZZ genotype-related hepatic carcinogenesis process. Finally, we perform an updated analysis of the United Kingdom Biobank database that highlights and confirms AATD PiZZ genotype as an important HCC risk factor.