The association of alpha-1 antitrypsin deficiency and arterial aneurysms

Alpha-1 antitrypsin deficiency (AATD) is an autosomal co-dominant disorder caused by SERPINA1 mutations, leading to reduced circulating AAT levels. The PIZZ genotype confers the most severe deficiency and highest risk for lung and liver disease. Emerging evidence suggests a potential association with arterial aneurysms, based on a protease-antiprotease imbalance and extracellular matrix degradation of elastin in vessel walls. Several studies have reported increased frequencies of AATD alleles in patients with abdominal aortic aneurysms and intracranial aneurysms, with some showing statistically significant associations. PIZZ patients also have larger aortic diameters and greater aortic stiffness. However, evidence is inconsistent, as large studies have failed to demonstrate significant associations. Overall, current evidence suggests an association, but AATD alone is not sufficient to increase the risk of new-onset arterial aneurysms.

Introduction

AAT is a serine proteinase inhibitor primarily produced by hepatocytes, encoded by the SERPINA1 gene on chromosome 14. Over 150 alleles exist; the normal genotype is PIMM. Deficient alleles include PIS and PIZ. PIZZ homozygotes have very low AAT and high risk of lung disease; PISZ carriers have intermediate risk; PIMZ carriers have slightly increased risk. Phenotypes are identified by measuring AAT variants: normal MM (20–53 µmol/L), SZ (<23 µmol/L), ZZ (<7 µmol/L). Null and dysfunctional phenotypes cause severe lung disease without liver involvement. Misfolded AAT polymers accumulate in hepatocytes, causing ER stress and cirrhosis. Because elastin is a key arterial component, deficient AAT may also affect vessel walls.

Epidemiology of AATD

AATD occurs worldwide but is more prevalent in European ancestry populations. Mean PIS/PIZ gene frequencies are ~3% in Central Europe versus ~1% in East Asia. Approximately 557,475 individuals in the US and over 3.3 million worldwide have AATD-associated genotypes. COPD prevalence in PI*ZZ is up to 57%; clinically significant liver fibrosis occurs in up to 35%.

Proposed Pathogenesis of Aneurysms in AATD

Aneurysms result from vascular smooth muscle cell death, ECM degradation (mainly elastin), oxidative stress, and immune infiltration. Serine proteinases degrade elastin directly and induce smooth muscle cell apoptosis. AAT normally inhibits neutrophil elastase. In AATD, uninhibited elastase leads to excessive elastin degradation and increased susceptibility to aneurysm formation.

Clinical Evidence Linking AATD and Aneurysms

Several studies have explored this association:

• Cohen et al. (1990) found PI*MZ significantly more frequent in 47 AAA patients compared to the general population.

• Schievink et al. (1996) reported significantly higher PIMS and PIMZ rates in 100 intracranial aneurysm patients (OR 2.56, P=0.005); 1% had PI*ZZ versus expected 0.015% (OR 67.0, P=0.015).

• Pini et al. (2021) showed a higher PI*S allele frequency (6.5% vs. 2.5%) in 138 AAA patients using PCR.

However, contradictory findings exist:

• St Jean et al. (1996) found no increased PIZ or PIS frequencies in 173 AAA or 72 intracranial aneurysm patients compared to controls.

• The American Thoracic Society considers the evidence weak and does not recommend routine AATD screening in aneurysm patients.

Additional evidence includes:

• Gaglio et al. (2000) reported a relative risk of 277 for splenic artery aneurysm rupture in AATD patients (P<0.01).

• PI*ZZ patients have significantly larger aortic diameters, greater stiffness, and less distensibility compared to controls.

• A study of atrial septal aneurysm found PI*M3M3 significantly more frequent (OR 6.68, P=0.001).

Conclusions

A protease-antiprotease imbalance and ECM degradation provide a plausible pathophysiological rationale for an association between AATD and arterial aneurysms. Some studies have reported highly significant associations, particularly for PIZ with intracranial aneurysms and PIS with AAA. However, other large studies have found no significant association. Expert opinion favours an association, but AATD alone is not sufficient for aneurysm development—it is likely one of several cofactors. Current data are insufficient to recommend routine screening for AATD in aneurysm patients or vice versa. No studies have evaluated whether augmentation therapy affects aneurysm formation. Future well-designed, adequately powered studies with comprehensive genotyping and standardised phenotyping are needed.

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https://www.xiahepublishing.com/2310-8819/JCTH-2026-00043

The study was recently published in the Journal of Clinical and Translational Hepatology.

The Journal of Clinical and Translational Hepatology (JCTH) is owned by the Second Affiliated Hospital of Chongqing Medical University and published by XIA & HE Publishing Inc. JCTH publishes high quality, peer reviewed studies in the translational and clinical human health sciences of liver diseases. JCTH has established high standards for publication of original research, which are characterized by a study’s novelty, quality, and ethical conduct in the scientific process as well as in the communication of the research findings. Each issue includes articles by leading authorities on topics in hepatology that are germane to the most current challenges in the field. Special features include reports on the latest advances in drug development and technology that are relevant to liver diseases. Regular features of JCTH also include editorials, correspondences and invited commentaries on rapidly progressing areas in hepatology. All articles published by JCTH, both solicited and unsolicited, must pass our rigorous peer review process.

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