Genotypes and resultant AAT levels drive increased risk of irreversible lung damage^1,2

In individuals without alpha-1 antitrypsin deficiency (AATD) (MM genotype), normal alpha-1 antitrypsin (AAT) levels are between 20 to 53 µM³
Pathogenic variants of the SERPINA1 gene reduce circulating AAT protein⁴
AAT levels vary across genotypes and span a spectrum of severity^3,5
Reduced AAT levels increase vulnerability to faster progression such as loss of lung function over time^1,6
Behavioral, environmental, and physiologic factors can further influence this risk^6-9

AATD risk assessment begins with defining the underlying genetics^1,5

AATD is caused by pathogenic variants of SERPINA1, the gene that encodes the AAT protein. Key alleles include^1,4:

M allele
(Baseline, normal function)^1,5

Produces normal, functional AAT
Not associated with increased lung or liver risk
Most common allele in the general population

S allele
(Mild to moderate deficiency)^1,5

Produces less AAT than M, but significantly more than Z
Polymerizes slowly, so liver involvement is uncommon
Lung risk increases when paired with Z (eg, SZ genotype)

Z allele
(Highest clinical impact)^1,5

Severely reduced circulating AAT levels
Misfolded AAT accumulates in hepatocytes, contributing to liver injury
ZZ individuals have the highest risk for both lung disease and liver complications
Most common disease-causing variant

Q0/Null allele
(No AAT production)^1,5

No detectable AAT in circulation
High lung risk due to complete absence of AAT
Not associated with liver disease because no misfolded protein accumulates

The risks of AATD fall on a spectrum of severity^3,5

^{Risk Spectrum}

	MM	MZ	SZ	ZZ
	Normal⁵	Mild to moderate AAT deficiency⁵	Moderate AAT deficiency^3,5	Severe AAT deficiency⁵
Plasma AAT Levels	20-53 µM³	15-42 µM³	10-23 µM³	3.4-7 µM³
Mechanism	Balanced AAT and neutrophil elastase activity⁴	Variable AAT protection and intermittent unopposed neutrophil elastase^1,5 MZ individuals who smoke have a significantly increased risk for impaired lung function vs MZ nonsmokers¹⁰	More frequent imbalance between AAT and neutrophil elastase^1,3,5	Persistent imbalance between AAT and neutrophil elastase^1,5
Implication	No AATD lung/liver disease⁵	Increased elastin degradation markers^1,5 Faster lung function/density decline vs MM¹	Increased risk of emphysema³ Increased vasculitis and other inflammatory activity^1,11 Increased protease activity—could lead to destruction of elastin^1,5	High risk of emphysema^1,3 Neutrophilic airway inflammation¹² Hepatic involvement¹²
Key Takeaway	Normal, no AATD⁵	Variable protection, some increased risk^1,5	Intermediate protection, increased risk^3,13	Minimal protection, maximum risk^3,5

The lower AAT levels are, the higher the risk of AATD-associated emphysema³

Historically, protective AAT levels have been benchmarked at 11 µM. However, the normal range is 20-53 µM.^3,11

Bar chart showing typical range of AAT levels and associated relative emphysema risk by genotype, with a callout defining normal AAT levels in the MM genotype as 20 to 53 µM

Data from Mulkareddy V et al. Am J Med Sci. 2024;368(1):1-8.
^aAAT levels may also be measured in mg/dL.
Risk is multifactorial and can be influenced by lifestyle and environmental factors.⁷

Genotype is a determinant of risk, and all intermediate and severe genotypes carry potential risk.³

Besides genotype, other factors can contribute to risk in AATD^1,6-8

Additional risk factors include^6-8:

Behavioral

Smoking

Environmental

Air pollution, occupational inhalants

Pathophysiologic

Respiratory infections

Smoking can significantly accelerate the rate of lung decline in patients with AATD⁹

Bar chart with whiskers showing lung function range in MM and MZ patients by smoking status

Figure adapted from Molloy K et al. Am J Respir Crit Care Med. 2014;189(4):419-427.
^bIncluded 99 individuals with MM genotype and 89 individuals with MZ genotype.

In MZ individuals, FEV₁ was significantly lower in ever-smokers compared with never-smokers⁹

Never-smoker was defined as less than 20 packs of cigarettes, with 12 oz of tobacco in a lifetime, or less than 1 cigarette a day for 1 year⁹
Approximately 2% to 3% of the Caucasian population is born with the MZ genotype¹

Consequences of AATD

AATD may lead to a poor prognosis with increased exacerbations and shorter lifespan.^13-16

Explore the impact →

Testing & Management

Guidelines recommend testing all patients with COPD for AATD.^1,17,18

Review the guidance →

AAT=alpha-1 antitrypsin; AATD=alpha-1 antitrypsin deficiency; COPD=chronic obstructive pulmonary disease; FEV₁=forced expiratory volume in 1 second.

References: 1. 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. 2. Meseeha M, Sankari A, Attia M. Alpha-1 antitrypsin deficiency. In: StatPearls [Internet]. StatPearls Publishing; August 17, 2024. Accessed April 14, 2026. https://www.ncbi.nlm.nih.gov/books/NBK442030/ 3. Mulkareddy V, Roman J. Pulmonary manifestations of alpha 1 antitrypsin deficiency. Am J Med Sci. 2024;368(1):1-8. 4. 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 5. Feitosa PHR, de Oliveira Castellano MVC, da Costa CH, et al. Recommendations for the diagnosis and treatment of alpha-1 antitrypsin deficiency. J Bras Pneumol. 2024;50(5):e20240235. doi:10.36416/1806-3756/e20240235 6. 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 7. 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 8. Kokturk N et al. Lung inflammation in alpha‑1‑antitrypsin deficient individuals with normal lung function. Respir Res. 2023;24(1):40. 9. Molloy K, Hersh CP, Morris VB, et al. Clarification of the risk of chronic obstructive pulmonary disease in α1-antitrypsin deficiency PiMZ heterozygotes. Am J Respir Crit Care Med. 2014;189(4):419-427. 10. McElvaney GN, Sandhaus RA, Miravitlles M, et al. Clinical considerations in individuals with α1-antitrypsin PI*SZ genotype. Eur Respir J. 2020;55(6):1902410. doi: 10.1183/13993003.02410-2019 11. Stoller JK, Aboussouan LS. A review of α₁-antitrypsin deficiency. Am J Respir Crit Care Med. 2012;185(3):246-259. 12. Turino GM, Barker AF, Brantly ML, et al. Clinical features of individuals with PI*SZ phenotype of alpha 1-antitrypsin deficiency. Alpha 1-Antitrypsin Deficiency Registry Study Group. Am J Respir Crit Care Med. 1996;154(6)(pt 1):1718-1725. 13. Vijayasaratha K, Stockley RA. Reported and unreported exacerbations of COPD: analysis by diary cards. Chest. 2008;133(1):34-41. 14. 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. doi:10.1183/09031936.03.00038303 15. Wahlin S, Widman L, Hagström H. Epidemiology and outcomes of alpha-1 antitrypsin deficiency in Sweden 2002-2020: a population-based cohort study of 2286 individuals. J Intern Med. 2025;297(3):300-311. 16. Stoller JK, Tomashefski J Jr, Crystal RG, et al. Mortality in individuals with severe deficiency of alpha1-antitrypsin: findings from the National Heart, Lung, and Blood Institute Registry. Chest. 2005;127(4):1196-1204. 17. Global Initiative for Chronic Obstructive Lung Disease. GOLD Report. Accessed April 14, 2026. https://goldcopd.org 18. Sandhaus RA, Turino G, Brantly ML, et al. The diagnosis and management of alpha-1 antitrypsin deficiency in the adult. Chron Obstr Pulm Dis. 2016;3(3):668-682.

Genotypes and resultant AAT levels drive increased risk of irreversible lung damage1,2

AATD risk assessment begins with defining the underlying genetics1,5

M allele (Baseline, normal function)1,5

S allele (Mild to moderate deficiency)1,5

Z allele (Highest clinical impact)1,5

Q0/Null allele (No AAT production)1,5

The risks of AATD fall on a spectrum of severity3,5

Risk Spectrum

The lower AAT levels are, the higher the risk of AATD-associated emphysema3

Genotype is a determinant of risk, and all intermediate and severe genotypes carry potential risk.3

Besides genotype, other factors can contribute to risk in AATD1,6-8