SERPINA1 genotype determines the severity of alpha-1 antitrypsin deficiency (AATD) and the serum levels of alpha-1 antitrypsin (AAT), concluded a new study published in the International Journal of Molecular Sciences. It also influences the risk of hepatocellular carcinoma (HCC) in patients with liver cirrhosis.

SERPINA1 provides instructions for the production of AAT, a protein mainly produced by the liver that exerts protective activity in the lungs.

The M allele is known as the wild-type allele and most (88%) people have the MM genotype. Alleles Z and S are 2 pathogenic alleles that lead to the production of deficient AAT protein, both quantitatively and functionally.

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In this study, the authors observed lower serum AAT levels in MZ and MS heterozygotes than in MM homozygotes (medians, 0.90 g/L, 1.40 g/L, and 1.67 g/L, respectively).

The number of cirrhotic patients with HCC was significantly different when compared MZ (5/55) and MS (1/32) heterozygotes with MM homozygotes (243/1022). The authors concluded that the risk of HCC was lower in MZ and MS heterozygotes than in MM homozygotes (odds ratio [OR], 0.3202, 95% CI, 0.1361-0.7719 and OR, 0.1522, 95% CI, 0.02941-0.7882, respectively).

Hence, MZ and MS genotypes might confer some kind of protection against HCC in individuals with advanced liver cirrhosis.

In their cohort, Rabekova et al found a higher frequency of the MZ genotype in patients with alcoholic liver
disease (ALD) and nonalcoholic steatohepatitis (NASH). However, this genotype was not associated with an increased risk of liver cirrhosis in chronic liver diseases of autoimmune, cholestatic, viral, and metabolic etiologies.

Circulating AAT Polymers in AATD Possibly Associated With Lung and Liver Disease

“The pro-cirrhotic effect of the MZ genotype was associated with the presence of intrahepatic AAT aggregates, which were of greater extent and density in liver explants in patients with ALD and NASH than in cirrhotic patients with other chronic liver diseases,” they explained.

Thus, this pro-cirrhotic effect seems to be specifically associated with precipitating properties of this AAT variant as they found that the S allele, which encodes a nonpolymerizing AAT variant, was not associated with this effect.


Rabekova Z, Frankova S, Jirsa M, et al. Alpha-1 antitrypsin and hepatocellular carcinoma in liver cirrhosis: SERPINA1 MZ or MS genotype carriage decreases the risk. Int J Mol Sci. 2021;22(19). doi:10.3390/ijms221910560