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

Malin Fromme; Laura Rademacher; Samira Amzou; Christi D Cook; Isabel Zacharias; Lanju Zhang; John E Ripollone; Pavel Strnad

doi:10.1002/ueg2.12629

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

United European Gastroenterol J. 2024 Oct;12(8):1091-1101. doi: 10.1002/ueg2.12629. Epub 2024 Jul 18.

Authors

Malin Fromme¹, Laura Rademacher¹, Samira Amzou¹, Christi D Cook², Isabel Zacharias², Lanju Zhang², John E Ripollone², Pavel Strnad¹

Affiliations

¹ Medical Clinic III, Gastroenterology, Metabolic Diseases and Intensive Care, University Hospital RWTH Aachen, Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN RARE LIVER), Aachen, Germany.
² Vertex Pharmaceuticals, Boston, Massachusetts, USA.

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.

Keywords: FibroScan®; SERPINA1; alpha‐1 antitrypsin deficiency; augmentation therapy; liver fibrosis; transient elastography.

MeSH terms

Adult
Aged
Biomarkers / blood
Case-Control Studies
Elasticity Imaging Techniques
Female
Genotype*
Humans
Liver / diagnostic imaging
Liver / pathology
Liver Cirrhosis* / blood
Liver Cirrhosis* / diagnosis
Liver Cirrhosis* / etiology
Liver Cirrhosis* / pathology
Liver Transplantation
Male
Middle Aged
Mutation
Proportional Hazards Models
alpha 1-Antitrypsin Deficiency* / blood
alpha 1-Antitrypsin Deficiency* / complications
alpha 1-Antitrypsin Deficiency* / diagnosis
alpha 1-Antitrypsin Deficiency* / genetics
alpha 1-Antitrypsin* / blood
alpha 1-Antitrypsin* / genetics

Substances

alpha 1-Antitrypsin
Biomarkers
SERPINA1 protein, human

Grants and funding

Vertex Pharmaceuticals