Association of circulating Z‐polymer with adverse clinical outcomes and liver fibrosis in adults with alpha‐1 antitrypsin deficiency

Abstract

Background

Circulating polymerized mutant Z‐alpha‐1 antitrypsin (Z‐polymer) constitutes a characteristic feature in alpha‐1 antitrypsin deficiency (AATD), but there is limited knowledge about its association with adverse clinical outcomes and liver fibrosis. We explored this association using data from a large cohort of adults with AATD.

Methods

A total of 836 (431 PiZZ, 405 PiMZ) adults with AATD and 312 controls (PiMM) from the European Alpha‐1 Liver Cohort (2015–2020) were included. Time‐to‐event analyses were conducted for adults with the PiZZ genotype followed for adverse clinical outcomes (earliest occurrence of liver‐related hospitalization, liver transplant or all‐cause mortality). Cox proportional hazard models were used to describe the association between binary circulating Z‐polymer levels and adverse clinical outcomes. Correlations between baseline circulating Z‐polymer levels and baseline liver fibrosis (liver stiffness measurement [LSM] determined by transient elastography [FibroScan®]) were evaluated. The analyses were stratified by augmentation therapy status.

Results

Of 324 adults with the PiZZ genotype and longitudinal follow‐up data, 28 reported adverse clinical outcomes. Higher baseline circulating Z‐polymer levels were associated with an increased risk of adverse clinical outcomes in both crude (hazard ratio [95% confidence interval, CI], 2.88 [1.21, 6.87]) and age‐adjusted (1.96 [0.78, 4.94]) analyses. In adults with the PiZZ genotype, circulating Z‐polymer levels were weakly positively correlated with baseline LSM (Spearman's rho [95% CI]: 0.21 [0.11, 0.31]). Similar results were observed after stratification by augmentation therapy status.

Conclusions

In adults with the PiZZ genotype, higher circulating Z‐polymer levels were associated with a shorter time to adverse clinical outcome, and positively correlated with baseline LSM. Circulating Z‐polymer levels may be a prognostic biomarker of clinically relevant disease in AATD.

Abstract