Validation of Biomarkers Z‐<scp>AAT</scp> Polymers and Fibrinopeptide Aα‐Val⁵⁴¹ in Peripheral Blood of Patients With pi*<scp>ZZ</scp> 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‐Val 541 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‐Val 541 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‐Val 541 levels were assessed using a Europium‐based immunoassay. After transplantation, polymers were absent or nearly absent, and Aα‐Val 541 levels were substantially reduced. Circulating polymers and Aα‐Val 541 levels were markedly reduced in Pi*ZZ individuals receiving a LT.