Why is Disease Penetration so Variable in Alpha-1 Antitrypsin Deficiency? The Contribution of Environmental Factors

Environmental influences on clinical phenotype in alpha-1 antitrypsin deficiency (AATD) include cigarette smoke, occupational exposures, airway/sputum bacteria and outdoor air pollution. This narrative review describes the impact of the major environmental exposures and summarizes their effect on clinical phenotype and outcomes. In general, patients with AATD are more susceptible to pulmonary damage as a result of the relatively unopposed action of neutrophil elastase, in the context of neutrophilic inflammation stimulated by environmental factors. However, the amount of phenotypic variability explicable by environmental factors is insufficient to account for the wide range of clinical presentations observed, suggesting that a combination of genetic and environmental factors is likely to be responsible.