Background and Objectives: Alpha-1 antitrypsin deficiency (AATD) is a rare genetic condition associated with chronic respiratory diseases such as chronic obstructive pulmonary disease (COPD) and emphysema, and with liver involvement through a distinct toxic gain-of-function mechanism. Despite its clinical relevance, AATD remains underdiagnosed and exhibits marked phenotypic heterogeneity. Artificial intelligence (AI) has shown growing potential in respiratory medicine, yet its application to AATD is still limited. This systematic review synthesizes the clinical evidence on AI in AATD, primarily in the respiratory domain and, where available, in hepatic outcomes. Materials and Methods: We conducted a PRISMA-guided search (PubMed, Web of Science, IEEE Xplore) for original, peer-reviewed articles (January 2014–September 2025) applying AI to detection, classification, stratification, or prediction tasks in AATD. Results: Six studies met eligibility criteria. Supervised models (e.g., XGBoost, penalized regression, Transformer-based architectures) and one unsupervised approach were identified. Applications included screening in COPD populations, prediction of emphysema progression from CT, proteomic modeling of lung function, identification of clinical subgroups, and prediction of clinical outcomes in AATD-associated liver disease. External validation and genotype diversity remained limited across studies. Conclusions: Although AI shows promise in improving detection, prognosis, and patient stratification in AATD across both respiratory and hepatic manifestations, the current evidence remains limited. Broader, multicenter validation in genotype-diverse cohorts is required to confirm its clinical utility and support the implementation of precision medicine in AATD.

Alpha-1 antitrypsin deficiency (AATD) is a codominant genetic condition characterised by reduced serum alpha-1 antitrypsin (AAT) levels and an increased risk of lung and liver disease.1 AAT is a ne...

α₁-Antitrypsin deficiency (α₁-ATD) is a rare genetic condition caused by mutations in the SERPINA1 gene, whose predominant clinical manifestation in adults is the development of early-onset pulmonary emphysema in individuals with a history of tobacco smoke exposure [1]. It is also associated with various forms of liver disease, which may arise during childhood or adulthood. In adult patients with α₁-ATD, obesity and exposure to environmental factors, such as alcohol consumption or certain medications, may modulate the development of liver disease [2]. Although most research has focused on these clinical manifestations, other less frequent presentations – such as anti-nuclear cytoplasmic antibody-positive vasculitis or panniculitis – have also been described [3].

Background: Alpha-1 antitrypsin deficiency (AATD) has been linked to chronic inflammation and protease–antiprotease imbalance involved in lung carcinogenesis. Evidence regarding the relationship between the most common AAT-deficient genotypes and lung cancer (LC) is inconsistent. We aimed to evaluate the association between the most common AAT-deficient genotypes carrying S or Z alleles and LC, considering clinical, environmental and molecular factors. Methods: A hospital-based case-control study was conducted including 407 patients with a recent diagnosis of LC and 1201 controls. AAT genotypes were determined and clinical and environmental data were collected, including residential radon measurements. Multivariable logistic regression models adjusted for age, sex, smoking status and radon exposure were used. Analyses were further stratified by histological type, age at diagnosis and tumour molecular alterations. Results: Most participants carrying deficient SERPINA1 genotypes had common mild deficiency variants (predominantly Pi*MS), and no individuals with the Pi*ZZ genotype were identified. The prevalence of AAT-deficient alleles was 24.4% in cases and 32.4% in controls. Carriage of AAT-deficient alleles was inversely associated with LC compared with individuals with the Pi*MM genotype (adjusted OR = 0.71; 95% CI: 0.53–0.97). Active smoking, older age and radon > 300 Bq/m³ were significantly associated with LC. No associations were observed between AAT genotype and histological type, age at diagnosis or EGFR mutations. High PD-L1 expression (≥ 50%) was more frequent in tumours from carriers of AAT-deficient alleles (adjusted OR = 1.82; 95% CI: 1.00–3.33). Conclusions: In this study, carriage of common AAT-deficient alleles was inversely associated with LC after adjustment for major confounding factors. The association with higher PD-L1 expression suggests that these common AAT-deficient genotypes may be associated with differences in tumour phenotype rather than acting as a direct aetiological factor.