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

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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

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

Results in 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

Results in less AAT than M, but significantly more than Z
Polymerizes slowly, so liver involvement is low
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 or 100-220 mg/dL	15-42 µM³ or 66-120 mg/dL	10-23 µM³ or 45-80 mg/dL	3.4-7 µM³ or 10-40 mg/dL
Mechanism	Balanced AAT and neutrophil elastase activity⁴	Variable AAT levels and partial or relative imbalance between AAT and neutrophil elastase^1,5 MZ individuals who smoke have a significantly increased risk for impaired lung function vs MZ nonsmokers⁷	Greater degree of imbalance between AAT and neutrophil elastase^1,3,5	Severe imbalance between AAT and neutrophil elastase^1,5
Implication	No AATD lung/liver disease⁵	Uncontrolled protease activity could lead to increase in destruction of elastin^1,5 Potentially faster lung function/density decline vs MM¹ Increased vasculitis and other inflammatory activity^1,8	Increased risk of emphysema³ Increased vasculitis and other inflammatory activity^1,8 Uncontrolled protease activity could lead to increase in destruction of elastin^1,5	High risk of emphysema^1,3 Neutrophilic airway inflammation⁹ Hepatic involvement⁹ Uncontrolled protease activity could lead to increase in destruction of elastin^1,5 Increased vasculitis and other inflammatory activity^1,8
Key Takeaway	Normal, no AATD⁵	Some increased risk^1,5	Increased risk^3,10	Maximum risk^3,5

What are the risks of below-normal AAT levels?

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

Historically, protective AAT levels have been benchmarked at 11 µM. However, the normal range is 20-53 µM.^3,8

Range of plasma AAT levels based on allele combination³

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 as mg/dL. MM: 90-200 mg/dL; MZ 66-120 mg/dL; SZ: 45-80 mg/dL; ZZ: 10-40 mg/dL.
Risk is multifactorial and can be influenced by lifestyle and environmental factors.¹¹

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

Consequences of AATD

AATD may lead to a poor prognosis with increased exacerbations and shorter lifespan.^10,12-14

Explore the impact →

Testing & Management

Guidelines recommend testing all patients with COPD for AATD.^1,15,16

Review the guidance →

Frequently asked questions

How do SERPINA1 genotypes influence AATD risk?

What serum AAT levels are considered protective?

How does AAT level correlate with emphysema risk?

Do intermediate genotypes (eg, MZ, SZ) carry risk?

Definitions: 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. 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 8. Stoller JK, Aboussouan LS. A review of α₁-antitrypsin deficiency. Am J Respir Crit Care Med. 2012;185(3):246-259. 9. 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. 10. Vijayasaratha K, Stockley RA. Reported and unreported exacerbations of COPD: analysis by diary cards. Chest. 2008;133(1):34-41. 11. 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 12. 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 13. 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. 14. 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. 15. Global Initiative for Chronic Obstructive Lung Disease. GOLD Report. Accessed April 14, 2026. https://goldcopd.org 16. 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