Circulating Z-Polymer Levels Show Potential as Prognostic Biomarker in AATD

Pavel Strnad, MD

Credit: RWTH Aachen

Circulating polymerized mutant Z-alpha-1 antitrypsin (Z-polymer) levels may have prognostic value as a biomarker of clinically relevant disease in individuals with alpha-1 antitrypsin deficiency (AATD), according to findings from a recent study.¹

Results showed increased circulating Z-polymer levels were associated with a greater risk of having an adverse clinical outcome and positively correlated with baseline liver stiffness measurement in adults with the PiZZ genotype, suggesting their potential utility as a non-invasive indicator of risk of AATD-related liver disease.¹

“Higher circulating Z-polymer levels among adults with the PiZZ genotype have been associated with increased liver fibrosis on biopsy,” Pavel Strnad, MD, full professor and senior physician at University Hospital Rheinisch–Westfälisch Technische Hochschule Aachen in Germany, and colleagues wrote.¹ “However, there is a lack of data associated with circulating Z-polymer levels and long-term clinically relevant adverse outcomes.”

A hereditary disorder characterized by low levels of alpha-1 antitrypsin in the blood, AATD may predispose an individual to several illnesses and most commonly manifests as chronic obstructive pulmonary disease or liver disease. Mutations in the SERPINA1 gene are responsible for both deficiency and the presence of abnormal alpha-1 antitrypsin, and most patients with AATD-related liver disease are homozygous for the Z allele (PiZZ genotype).2 Underdiagnosis or misdiagnosis of adults with the PiZZ genotype is common and hinders care, highlighting the need for biomarkers specific to AATD-associated liver disease to help identify high-risk patients.¹

To assess the role of circulating Z-polymer in the progression of AATD-related liver disease and its potential utility as a prognostic biomarker of disease progression, investigators conducted a cross-sectional analysis of data collected from adults with genetically confirmed AATD with the PiZZ, PiMZ, and PiMM genotypes in the European Alpha-1 Liver Cohort. A total of 836 (PiZZ n = 431; PiMZ n = 405) adults with AATD and 312 controls (PiMM) were included in the present study.¹

Among the entire cohort, the majority of participants were female (53%) with a mean age of 50.5 years. By genotype, the mean ages of adults with the PiZZ, PiMZ, and PiMM genotypes were 55 (Standard deviation [SD], 12.5), 45 (SD, 15.5), and 51.4 (SD, 15.1) years of age, respectively. In the PiMZ and PiMM groups, the majority of participants were female (60% and 53%), whereas in the PiZZ group, the majority were male (54%). Approximately 59% of adults with the PiZZ genotype received augmentation therapy.¹

Average circulating Z-polymer levels were greater among adults with the PiZZ genotype (mean, 23.4 μg/mL; SD, 13.8 μg/mL) than among those with the PiMZ genotype (mean, 3.5 μg/mL; SD, 2.3 μg/mL). Additionally, investigators noted circulating Z-polymer levels were increased among adults with the PiZZ genotype who received augmentation therapy (mean, 26.0 μg/mL; SD, 13.5 μg/mL) compared with adults with the PiZZ genotype who did not receive augmentation therapy (mean, 19.3 μg/mL; SD, 13.1 μg/mL).¹

Of the 431 participants with the PiZZ genotype, 324 adults or their family members responded to an adverse clinical outcome assessment questionnaire for the earliest occurrence of liver-related hospitalization, liver transplant (received or listed), or all-cause mortality. During a median follow-up of 4 years, 28 adverse clinical outcomes were reported, including 20 all-cause mortality events, 4 liver-related hospitalization events, and 4 liver-transplant events. Of the 20 all-cause mortality outcomes, 6 had a liver-related cause of death, 4 had a lung-related cause of death, and 10 had another cause of death.¹

Investigators noted adults with the PiZZ genotype with greater baseline circulating Z-polymer levels (median >21.5 μg/mL) had an increased risk of adverse clinical outcome in both crude (Hazard ratio [HR], 2.88; 95% CI, 1.21 to 6.87) and age-adjusted (HR, 1.96; 95% CI, 0.78 to 4.94) models, compared with those with lower baseline circulating Z-polymer levels (median ≤21.5 μg/mL). Among adults with the PiZZ genotype receiving augmentation therapy, the corresponding crude and age-adjusted HRs were 3.62 (95% CI, 1.16 to 11.27) and 2.97 (95% CI, 0.95 to 9.33), respectively. Among those not receiving augmentation therapy, the corresponding crude and age-adjusted HRs were 4.53 (95% CI, 0.96 to 21.4) and 3.52 (95% CI, 0.73 to 17.1), respectively.¹

Investigators also observed a weak positive correlation between circulating Z-polymer levels and baseline FibroScan liver stiffness measurement in adults with the PiZZ genotype (Spearman's rho, 0.21; 95% CI, 0.11 to 0.31), while there appeared to be no notable correlation between circulating Z-polymer levels and baseline FibroScan liver stiffness measurement among adults with the PiMZ genotype (Spearman's rho, 0.05; 95% CI, −0.06 to 0.15). Of note, results were consistent among adults with the PiZZ genotype receiving augmentation therapy (Spearman's rho, 0.21; 95% CI, 0.07 to 0.35) and those not receiving augmentation therapy (Spearman's rho, 0.29; 95% CI, 0.13 to 0.44).¹

Investigators acknowledged multiple limitations to these findings, including the lack of certain information pertaining to augmentation therapy; the inability to assess changes in circulating Z-polymer levels over time; the reliance on self-reported questionnaire items to report adverse clinical outcomes; the small number of adverse clinical outcomes, especially pertaining to the liver; and the limited range of liver disease severity among patients with histological data in the cohort.¹

“To our knowledge, this is by far the largest study to demonstrate a possible link between circulating Z-polymer levels and adverse clinical outcomes in AATD,” investigators concluded.¹ “The results of this study indicate that circulating Z-polymer levels are a prognostic biomarker of clinically relevant disease in adults with the PiZZ and PiMZ genotypes. Further research is warranted to establish circulating Z-polymer as a critical indicator of increased risk of adverse clinical outcomes in AATD and to define its changes during disease progression.”

References

1. ^{Fromme M, Rademacher L, Amzou S, et al. Association of circulating Z-polymer with adverse clinical outcomes and liver fibrosis in adults with alpha-1 antitrypsin deficiency. United European Gastroenterol J. doi:10.1002/ueg2.12629}
2. ^{Meseeha M, Sankari A, Attia M. Alpha-1 Antitrypsin Deficiency. StatPearls. February 12, 2024. Accessed July 30, 2024. https://www.ncbi.nlm.nih.gov/books/NBK442030/}