With the inherited alpha-1 antitrypsin deficiency (AATD) variant Pi*Z having emerged as a genetic modifier of chronic hepatic disease, the relevance of heterozygous Pi*Z carriage as an additional risk factor for the development of progressive liver fibrosis in individuals with hepatitis C virus (HCV) remains debatable. A prospective cohort study on the topic was conducted in Germany, with the results published in the Journal of Clinical Medicine.

The researchers recruited 572 patients with chronic HCV infection from 2 tertiary centers—337 from the University of Frankfurt and 235 from the University of Leipzig. All individuals were recruited prior to the initiation of HCV therapy—between 2006 and 2008—at which time the participants consented to genetic testing and analyses.

Liver biopsy, aspartate aminotransferase (AST)-to-platelet ratio index score, and Fibrosis-4 score were used to assess the extent of liver fibrosis or cirrhosis in both cohorts, as well as liver stiffness measurement (LSM) via transient elastography in the Leipzig cohort only. Genomic DNA from all participants was genotyped for the presence of the Pi*Z variant of the SERPINA1 gene.

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The total study population comprised 281 men and 291 women. Among all of the participants, 26 individuals were identified as being heterozygous Pi*Z carriers. In the Frankfurt cohort of 337 HCV-positive patients, 16 individuals were heterozygous for the Pi*Z variant. In the Leipzig cohort of 235 HCV-positive patients, 10 individuals were heterozygous for the Pi*Z variant.

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Results showed that HCV-positive patients who were also heterozygous Pi*Z carriers exhibited slightly higher serum gamma-glutamyl transferase (GGT) levels than their HCV-positive counterparts who did not carry the Pi*Z variant (P =.046).

In both of the cohorts, the proportion of Pi*Z heterozygosity observed in patients with cirrhosis was no higher than that in those without cirrhosis or liver fibrosis. Thus, Pi*Z frequency did not differ in histologic or serologic stages of liver fibrosis (F0 to F4) and demonstrated no clear association with LSM.

The authors concluded, “Data from larger HCV cohorts with longitudinal follow-up evaluating the impact of the Pi*Z variant on the natural history of HCV infection and regression after [direct-acting antiviral] therapy are desirable.”


Mücke VT, Fischer J, Mücke MM, et al. Association of alpha-1 antitrypsin Pi*Z allele frequency and progressive liver fibrosis in two chronic hepatitis C cohorts. J Clin Med. 2022;12(1):253. doi:10.3390/jcm12010253