Characterization of alpha-1 antitrypsin in a Pi∗ZZ patient with emphysema: a case report

Lung disease severity and progression vary widely among individuals with severe alpha-1 antitrypsin deficiency (AATD; Pi∗ZZ, Glu342Lys). In addition to low levels of polymerized Z mutant AAT (Z-AAT), this variability may result from other genetic and environmental factors and individual differences in Z-AAT's biochemical properties.

We examined a 55-year-old female with Pi∗ZZ genotype, a history of smoking (8 pack-years), and exertional dyspnea, who is not receiving augmentation therapy. She was diagnosed with COPD at the age of 40, and also has asthma, psoriasis, and a history of non-ST-elevation myocardial infarction. Plasma Z-AAT was isolated twice (6 months apart) and analyzed via Western blotting, anti-elastase activity, and N-glycan profiling, alongside comparisons to Z-AAT from other non-augmented donors.

The patient had an FEV1 of 1.96 L (56 % of predicted) and a DLCO of 4.56 mmol/(min∗kPa) (50 % of predicted). HRCT revealed basal panlobular emphysema with a global emphysema index of 23 % and early-stage bronchiectasis. Compared to other Pi∗ZZ cases, she exhibited lower plasma levels of Z-AAT polymers and HA but higher levels of PAI-1, MPO, and NGAL. Her isolated Z-AAT protein demonstrated significantly reduced anti-elastase activity and lower levels of complex-type bi-antennary N-glycans compared to Z-AAT from non-augmented Pi∗ZZ donors.

The severe dysfunction of Z-AAT in this Pi∗ZZ case most likely contributed to early-onset psoriasis and the progression of pulmonary disease, highlighting its systemic impact. Our findings emphasize the importance of studying individual Z-AAT properties to improve diagnosis and personalized treatment for AATD patients.