Association between alpha1 antitrypsin (AAT) circulating polymers (CP) and lung and liver disease in patients with AAT deficiency (AATD)

Abstract

AATD is characterised by the misfolding and intracellular polymerization of mutant AAT protein within hepatocytes. Polymers can also be found in peripheral blood after secretion into circulation.

This was a cross-sectional study to analyse the relationship between CP and lung and liver disease in patients with AATD. Patients with mixed phenotypes of AATD, COPD without AATD and healthy controls were included. To quantify CP, a sandwich ELISA was performed using the 2C1 monoclonal antibody against AAT polymers. Sociodemographic data, clinical characteristics, and liver and lung parameters were collected.

A cohort of 117 individuals was recruited: 32(27%) ZZ(11 on augmentation therapy);29(25%) Z-heterozygous;16(14%) with at least one S allele;5(4%) rare variants; and 35(30%) MM. ZZ patients had higher CP(p<0.001) than other phenotypes. ZZ also had higher levels of liver stiffness measurements (LSM) than the remaining AATD patients (p<0.05). ZZ and Z-heterozygous non-augmented patients were classified into 4 groups according to lung(FEV1/FVC<and>=0.7); and liver impairment(LSM < and > =6kPa). Two patients with lung and liver impairment had the highest concentrations of CP(47.5 µg/ml), followed by liver abnormality only (n=6, CP=34µg/ml), lung only (n=18, CP=26.5µg/ml) and no abnormalities(n=23, CP=14.3µg/ml). Differences were highly significant (p=0.004).

Non-augmented ZZ and Z-patients with impaired lung function and increased liver stiffness presented higher levels of CP than other clinical phenotypes. Therefore, CP may help to identify patients at higher risk of developing lung and liver disease and may provide some insight into the mechanisms of disease.