How Can AATD Cause Lung Damage?
On this page you'll learn:
- Alpha-1 antitrypsin deficiency (AATD) is a genetic condition caused by pathogenic variants in the SERPINA1 gene that may lead to low or undetectable levels of the alpha-1 antitrypsin protein (AAT)1,2
- Insufficient levels of AAT protein potentially increase risk of accelerated lung deterioration and liver injury3
- AAT protein levels are largely determined by genotype and correlate with risk of emphysema4,5
- Severe AAT deficiency is associated with an increased risk of more frequent and severe exacerbations, as well as early mortality6-8
- Risk of accelerated lung decline is exacerbated by factors such as a patient's environment (eg, pollutants, respiratory infections) and lifestyle (eg, smoking)9-11
AATD: A genetic condition where below-normal AAT levels may lead to irreversible lung damage5,12
What causes AATD?
Pathogenic variants in the SERPINA1 gene may lead to low or undetectable levels of serum AAT protein.1,2 Loss-of-function mutations in AAT protein result in less protein circulating to the lungs, leaving them exposed to potential tissue damage.13
How does lung damage occur in AATD?
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AAT protein levels are largely determined by genotype4,5
Genotype and AAT levels primarily contribute to risk and disease progression4
Risk is multifactorial and can be influenced by lifestyle and environmental factors (eg, smoking, air pollution, occupational inhalants, and pulmonary infection).9,11 Even heterozygous genotypes (eg, MZ, SZ) may carry increased risk for lung disease, especially in smokers or those with environmental exposure.15
Range of plasma AAT levels based on allele combination5
aAAT levels may also be measured as mg/dL. MM: 90-200 mg/dL; MZ: 66-120 mg/dL; SZ: 45-80 mg/dL; ZZ: 10-40 mg/dL.5,17
bThis is not a comprehensive list of genotypes. Patients may also be affected by additional genotypes, including F, I, and Q0/null.5
Severe AAT deficiency is associated with poor prognosis9
Exacerbations in patients with AATD-related COPD have been shown to be more frequent and severe than in those with COPD without AATD6,7
Median annualized exacerbation rates in AATD-related COPD are double that observed in COPD without AATD.18,19,a
14 days was the median duration of exacerbations (interquartile range 7-21).20,b
aComparison of 2 different studies. Study 1: 19 patients with AATD-related COPD. Average age was 52 years. Median total exacerbation rate of 5.0 per patient per year. Study 2: 132 patients with moderate-to-severe COPD without AATD. The study found an overall median exacerbation rate of 2.52 exacerbations per year.
bAs assessed in a review of 2 studies examining exacerbation duration: one study of patients with AATD-related COPD and severe AAT deficiency (N=265) with an average age of ~50
years. This study consisted of ex-smokers (n=187), never-smokers (n=61), and current smokers (n=17). Results were compared with another study of patients with moderate-to-severe
COPD without AATD with an average age of ~67 years (N=101).
Patients with severe deficiency of AAT face an increased risk of early mortality, most often due to emphysema8
Emphysema is the most common underlying cause of mortality in patients with severe deficiency of AAT.8
Of the 1129 registry enrollees, 204 subjects (18.1%) died over the course of follow-up. Of the 204 deaths, records were available for 120 subjects. Underlying cause of death was ascertained in 118 of the 120 subjects with records. In the overall cohort of 204 decedents, 13.7% were never-smokers, and 86.3% were ever-smokers.
AATD cannot be deduced based on age, smoking history, or severity of FEV1 decline.21
Frequently asked questions
Alpha-1 antitrypsin deficiency (AATD) is caused by pathogenic variants in the SERPINA1 gene, and an individual's alpha-1 antitrypsin (AAT) genotype is a primary determinant of circulating alpha-1 antitrypsin levels.1,2,4 Certain genotypes are associated with markedly reduced serum AAT concentrations, which may increase the risk of emphysema and progressive lung disease. In general, lower serum AAT levels are associated with greater disease risk.5,11
Behavioral, environmental, and pathophysiological factors may accelerate lung decline.9-11
Patients with severe AAT deficiency typically have markedly reduced circulating alpha-1 antitrypsin levels and may face a higher burden of disease than patients with normal AAT levels. Severe deficiency has been associated with increased risk of emphysema, more frequent pulmonary exacerbations, and poorer long-term prognosis.5-7,9
Without sufficient alpha-1 antitrypsin levels, neutrophil elastase activity goes unchecked. This protease-antiprotease imbalance may cause damage to lung tissue and restrict airflow.14
In addition to genetic determinants and circulating AAT levels, behavioral, environmental, and physiological factors contribute to disease risk by exacerbating protease-antiprotease imbalance and promoting ongoing alveolar injury. These include smoking, air pollution, occupational exposures, and respiratory infection.9-11
Definitions: AAT=alpha-1 antitrypsin; AATD=alpha-1 antitrypsin deficiency; COPD=chronic obstructive pulmonary disease; FEV1=forced expiratory volume in 1 second.
References: 1. Cazzola M, Stolz D, Rogliani P, Matera MG. α1-Antitrypsin deficiency and chronic respiratory disorders. Eur Respir Rev. 2020;29(155):190073. doi:10.1183/16000617.0073-2019 2. Karatas E, Bouchecareilh M. Alpha 1-antitrypsin deficiency: a disorder of proteostasis-mediated protein folding and trafficking pathways. Int J Mol Sci. 2020;21(4):1493. doi:10.3390/ijms21041493 3. Mazzuca C, Vitiello L, Travaglini S, et al. Immunological and homeostatic pathways of alpha-1 antitrypsin: a new therapeutic potential. Front Immunol. 2024;15:1443297. doi:10.3389/fimmu.2024.1443297 4. American Thoracic Society; European Respiratory Society. American Thoracic Society/European Respiratory Society statement: standards for the diagnosis and management of individuals with alpha-1 antitrypsin deficiency. Am J Respir Crit Care Med. 2003;168(7):818-900. 5. Mulkareddy V, Roman J. Pulmonary manifestations of alpha 1 antitrypsin deficiency. Am J Med Sci. 2024;368(1):1-8. 6. Hiller AM, Piitulainen E, Tanash H. The clinical course of severe alpha-1-antitrypsin deficiency in patients identified by screening. Int J Chron Obstruct Pulmon Dis. 2022;17:43-52. 7. Smith DJ, Ellis PR, Turner AM. Exacerbations of lung disease in alpha-1 antitrypsin deficiency. Chronic Obstr Pulm Dis. 2021;8(1):162-176. 8. Stoller JK, Tomashefski J Jr, Crystal RG, et al. Mortality in individuals with severe deficiency of α1-antitrypsin: findings from the National Heart, Lung, and Blood Institute Registry. Chest. 2005;127(4):1196-1204. 9. Torres-Durán M, Lopez-Campos JL, Barrecheguren M, et al. Alpha-1 antitrypsin deficiency: outstanding questions and future directions. Orphanet J Rare Dis. 2018;13(1):114. doi:10.1186/s13023-018-0856-9 10. Wang T, Shuai P, Wang Q, et al. α‑1 Antitrypsin is a potential target of inflammation and immunomodulation (Review). Mol Med Rep. 2025;31(4):107. doi:10.3892/mmr.2025.13472 11. Kokturk N, Khodayari N, Lascano J, Riley EL, Brantly ML. Lung inflammation in alpha-1-antitrypsin deficient individuals with normal lung function. Respir Res. 2023;24(1):40. doi:10.1186/s12931-023-02343-3 12. Teckman JH, Blomenkamp KS. Pathophysiology of alpha-1 antitrypsin deficiency liver disease. In: Borel F, Mueller C, eds. Alpha-1 Antitrypsin Deficiency: Methods in Molecular Biology. Humana Press; 2017:1-8. 13. Brantly M, Campos M, Davis AM, et al. Detection of alpha-1 antitrypsin deficiency: the past, present and future. Orphanet J Rare Dis. 2020;15(1):96. doi:10.1186/s13023-020-01352-5 14. University of Utah Health. Alpha-1 antitrypsin deficiency. Accessed August 19, 2026. https://learn.genetics.utah.edu/content/genetics/alpha1/ 15. de Serres F, Blanco I. Role of alpha-1 antitrypsin in human health and disease. J Intern Med. 2014:276(4):311-335. 16. Strnad P, McElvaney NG, Lomas DA. Alpha1-antitrypsin deficiency. N Engl J Med. 2020;382(15):1443-1455. 17. Barjaktarevic I, Campos M. Management of lung disease in alpha-1 antitrypsin deficiency: what we do and what we do not know. Ther Adv Chronic Dis. 2021;12:49-63. 18. Vijayasaratha K, Stockley RA. Reported and unreported exacerbations of COPD: analysis by diary cards. Chest. 2008;133(1):34-41. 19. Donaldson GC, Seemungal TA, Patel IS, Lloyd-Owen SJ, Wilkinson TM, Wedzicha JA. Longitudinal changes in the nature, severity and frequency of COPD exacerbations. Eur Respir J. 2003;22(6):931-936. 20. Needham M, Stockley RA. Exacerbations in α1-antitrypsin deficiency. Eur Respir J. 2005;25(6):992-1000. 21. Demeo DL, Sandhaus RA, Barker AF, et al. Determinants of airflow obstruction in severe alpha-1-antitrypsin deficiency. Thorax. 2007;62(9):806-813.
