Quick Take: Liver Fibrosis and Metabolic Alterations in Adults with Alpha1 Antitrypsin Deficiency Caused by the Pi*ZZ Mutation

Alpha-1 antitrypsin (AAT) is a major protease inhibitor responsible for the inhibition of neutrophil elastase and proteinase 3. Alpha-1 antitrypsin deficiency (AATD) is a genetic disease that can lead to accelerated destruction of lung parenchyma and accumulation of AAT in hepatocytes. Severe AATD is caused mainly by the homozygous Pi*Z (Glu342Lys) mutation. While lung disease has been well-described in Pi*Z homozygotes (Pi*ZZ carriers), liver disease remains poorly characterized in these patients. In this cohort study, 554 Pi*ZZ carriers (403 in an exploratory cohort, and 151 in a confirmatory cohort) and 234 adults without the Pi*Z mutation (non-carriers), all without previously known liver disease, were studied to assess liver disease burden. Researchers found that the mean alanine aminotransferase (ALT), aspartate aminotransferase (AST) and gamma-glutamyl transferase (GGT) activities were higher in Pi*ZZ carriers than non-carriers (80% vs. 66% of the upper limit of normal (ULN), 74% vs. 62% of ULN, and 100% vs. 58% of ULN, respectively, p<0.001 for all). Furthermore, transient elastography revealed that the average liver stiffness measurements were higher in Pi*ZZ carriers than in non-carriers (6.7±5.8 versus 4.6±1.7 kPa respectively, p<0.001). Additional tests for liver fibrosis corroborated this result, overall suggesting that 20 to 36% of Pi*ZZ carriers had significant liver fibrosis, and that advanced liver fibrosis was 9 to 20 times more likely in Pi*ZZ carriers as compared to non-carriers. Male sex, age over 50 years, increased levels of ALT, AST, or GGT, and low numbers of platelets were associated with higher liver fibrosis burden, but there was no correlation between the severity of lung and liver involvement. Pi*ZZ carriers had a higher burden of liver steatosis than non-carriers as revealed by controlled attenuation parameter measurements (267±57 versus 246±56 dB/m respectively, p<0.001). Carriers of Pi*ZZ also had lower serum concentrations of triglyceride, low, and very low-density lipoprotein cholesterol than non-carriers. Similarly, Pi*Z-overexpressing mice showed more liver steatosis and less expression of apolipoproteins A4 and C2 than their non-transgenic littermates, consistent with impaired hepatic secretion of lipid. A limitation of this study was the lack of invasive methods to measure liver fibrosis. Overall, this study represents the largest systematic phenotypic evaluation of liver disease in Pi*ZZ carriers to date, and underlines the importance of regular assessment of liver enzymes and liver fibrosis in Pi*ZZ carriers.

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