Validation of Biomarkers Z-AAT Polymers and Fibrinopeptide Aα-Val541 in Peripheral Blood of Patients With pi*ZZ Alpha-1 Antitrypsin Deficiency

Abstract

Alpha-1 antitrypsin (AAT) deficiency is a monogenetic condition caused by various single mutations in the SERPINA1 gene. Homozygous carriage of the Z allele (Pi*ZZ) increases the risk of pulmonary emphysema and liver cirrhosis. Z-AAT polymerises and accumulates in hepatocytes, causing liver damage. Secretion of Z-AAT polymers into the circulation is thought to contribute to lung inflammation. Fibrinopeptide Aα-Val⁵⁴¹ is a biomarker of neutrophil-derived proteinase 3 (PR3) enzyme activity, which is inhibited by AAT. We hypothesised that liver transplantation (LT), which results in normal levels of circulating wild-type AAT, reduces circulating polymers and Aα-Val⁵⁴¹ in Pi*ZZ individuals. Plasma was obtained from five Pi*ZZ individuals before and after LT. Z-AAT polymers were measured using a mouse monoclonal antibody (LG96), and fibrinopeptide Aα-Val⁵⁴¹ levels were assessed using a Europium-based immunoassay. After transplantation, polymers were absent or nearly absent, and Aα-Val⁵⁴¹ levels were substantially reduced. Circulating polymers and Aα-Val⁵⁴¹ levels were markedly reduced in Pi*ZZ individuals receiving a LT.