AATD is caused by pathogenic variants in the SERPINA1 gene, inherited in an autosomal recessive pattern. SERPINA1 encodes the alpha-1-antitrypsin protein, which functions as a protease inhibitor primarily protecting lung tissue from neutrophil elastase-mediated damage and influencing hepatic protein processing. GeneReviews describes well-characterized genotype-phenotype correlations: individuals with the PI*ZZ genotype (homozygous for severe deficiency alleles) have markedly reduced serum AAT concentrations and face the highest risk for chronic obstructive pulmonary disease and liver disease. Individuals with the PI*MZ genotype generally have a lower risk profile, particularly if they are non-smokers. The Z allele and certain other alleles (Mmalton, Siiyama) are associated with intrahepatic protein accumulation, explaining the hepatic disease component of AATD through a distinct mechanism of protein misfolding and intracellular retention.

GeneReviews describes AATD as a diagnostic consideration in individuals presenting with evidence of chronic obstructive pulmonary disease — including emphysema, persistent airflow obstruction, chronic bronchitis, or bronchiectasis — as well as in individuals with liver disease at any age, including obstructive jaundice in infancy. C-ANCA positive vasculitis is also noted as a suggestive finding. A biochemically documented phenotype — reduced circulating alpha-1-antitrypsin concentration — appears in the structured phenotype data at very high frequency (80–99%). GeneReviews highlights that under-recognition of AATD frequently causes a prolonged delay before the correct diagnosis is established. Detailed diagnostic testing protocols and confirmatory criteria are described in the GeneReviews chapter but extend beyond the scope of this summary.

No FDA-approved treatments are recorded in the approved treatments dataset for this packet. GeneReviews describes management of AATD manifestations across organ systems: lung disease is managed with approaches tailored to the specific type of obstruction present. For individuals with liver involvement, management is directed toward hepatic manifestations as they develop. GeneReviews identifies active investigation of multiple novel therapeutic strategies, including intravenous augmentation therapy with alpha-1-antitrypsin protein (including alternate dosing regimens), inhaled and liquid AAT preparations, recombinant AAT formulations, oral neutrophil elastase inhibitors, orally available corrector molecules designed to restore protein secretion, molecules targeting polymer formation, and gene therapy approaches using various viral vectors and delivery routes. Exposure to tobacco smoke — both active and passive — and certain occupational and environmental pollutants has been associated in GeneReviews with accelerated progression of lung disease. Excessive alcohol use is similarly noted as an associated risk factor for disease progression in the GeneReviews source.

The natural course of AATD is closely tied to SERPINA1 genotype, serum AAT concentration, and environmental exposures. GeneReviews describes that individuals homozygous for severe deficiency alleles face an increased risk for progressive obstructive lung disease and hepatic complications, including cirrhosis. The degree of clinical progression varies substantially among individuals with the same genotype, reflecting environmental and modifier influences. No specific survival statistics or life expectancy figures are available in the current knowledge packet. The chronic and progressive nature of both hepatic and pulmonary manifestations characterizes the long-term disease course for individuals with severe SERPINA1 deficiency.

Numerous active clinical trial records are documented for alpha-1-antitrypsin deficiency, including Phase 1, Phase 3, and Phase 4 investigations. Active studies include trials of novel targeted therapies such as TSRA-196 (a gene editing approach) and BMN 349 in individuals with the PiZZ genotype, Phase 3 pharmacokinetic studies comparing subcutaneous and intravenous augmentation therapy administration, and a Phase 4 study evaluating the effect of weekly augmentation therapy on CT-measured lung density decline over three years. GeneReviews also catalogues a broad pipeline of investigational approaches including gene therapy using viral vectors, molecules to block polymer formation, oral correctors, and alternative delivery formulations. The active research landscape across multiple trial phases and therapeutic modalities reflects ongoing investigational momentum in AATD.