Abstract Rationale Alpha-1 antitrypsin (AAT) is an anti-protease and anti-inflammatory glycoprotein. AAT deficiency (AATD) is classically characterized by retention of polymerized Z AAT in the liver, leading to low plasma and lung AAT levels, and resulting in substantial liver and lung disease. The present consensus is that AATD liver disease results from retained polymers in the liver- a gain of function, while the lung disease results from lack of functional AAT in the lung- a loss of function. Another form of AAT protein, S, leads to low AAT levels but polymerizes much less readily than the Z form. Higher levels of circulating polymers have been shown to positively correlate with an increased degree of liver fibrosis, suggesting that circulating polymer levels may be used as a biomarker in the future. Aims: This project aims to measure polymers in plasma from patients with AATD from the Irish national clinic and correlate with clinical outcomes. Methods Total polymeric content was determined in the plasma of 102 AATD patients. A polymer specific ELISA was performed using anti-polymer mAb 2C1 (Hycult Bio) as the capture antibody and the non-conformation-specific mAb 3C11-HRP (Hycult Bio) as the detection antibody. Polymer standards were made by heating purified AAT protein (Merck) for 40 hours at 55 degrees C. Results Circulating polymers were quantified in 102 patients with AATD. The phenotypes were MZ (N = 38), ZZ (N = 34), SS (N = 15) and SZ (N = 15). ZZ samples had the highest levels of circulating polymers followed by SZ, MZ and finally SS had the lowest levels. There were statistically significant differences between the phenotypes, MZ vs ZZ (p 0.001), MZ vs SS (p 0.001), ZZ vs SS (p 0.001), ZZ vs SZ (p 0.001) and SS vs SZ (p = 0.01). The only phenotypes that were not statistically different from each other were MZ vs SZ. Conclusions There have been recent suggestions that polymers in AATD can contribute to disease burden. MZ patients had significantly more circulating polymers than SS patients despite, having similar expression of total AAT protein. Future work will be needed to fully understand the impact of a higher polymer burden in MZ compared to SS patients. Clinical markers including index status, smoking history, lung function tests and liver function tests will be examined to identify any associations between circulating polymers and patient outcomes. With the goal of identifying whether circulating polymers may be effective as a biomarker for liver or lung disease in AATD individuals. This abstract is funded by: Alpha-1 Foundation (US)
Fitzgerald et al. (Fri,) studied this question.