Alpha-1 is a genetic disease

Alpha-1-antitrypsin (A1AT) deficiency (also known as alpha-1) is a genetic disease defined by decreased plasma levels of A1AT. This decrease in A1AT levels is due to the inheritance of 2 abnormal alleles, which affects the production and release of A1AT from the liver.1

At least 120 variants of the A1AT gene exist, and these are associated with specific A1AT plasma levels.2

For clinical purposes, A1AT variants have been classified into 3 major categories:

  • Normal: characterized by normal plasma levels, common M types
  • Deficiency decreased, but still detectable, A1AT plasma levels
    • Z variant: the most common deficient variant. Produces conformational changes of the Z-AAT causing liver accumulation and low circulating levels associated with an increased risk of developing liver or lung disease
    • S variant: plasma levels approximately 60% of normal in homozygotes
    • Other deficient variants are grouped within the terms "M-like" or "S-like" Types
  • Null: rare variants associated with no detectable circulating A1AT in plasma

Family risk associated with the presence of A1AT-deficient alleles3

Examples of inheritance of A1AT-deficient alleles:

A. If 1 parent is homozygous normal (2 M alleles) and 1 parent is homozygous abnormal (2 Z alleles):

  • Children have a 100% chance of being MZ

B. If both parents are heterozygous carriers of abnormal alleles (1 normal M allele and 1 abnormal Z allele):

  • Children have a:
    • 25% chance of having alpha-1
    • 50% chance of being heterozygotes (MZ)
    • 25% chance of having 2 normal alleles

Relationship between serum AAT concentrations and proteinase inhibitor (Pi) genotype3,6,7,8


Although the maintenance of blood serum levels of alpha-1 proteinase inhibitor (PI) (antigenically measured) above 11 μM (or 80 mg/dL [RID]) has been historically postulated to provide therapeutically relevant antineutrophil elastase protection, this has not been proven.

Alpha-1 is the major known genetic risk factor for chronic obstructive pulmonary disease, COPD4

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Alpha-1 is a genetic disorder — any deficient allele should prompt a discussion of testing the whole family3,5

To learn more about alpha-1 testing, go to Test to rule out alpha-1

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  1. Alpha-1 Foundation. What is Alpha-1? Accessed July 14, 2016.
  2. Ferrarotti I, Scabini R, Campo I, et al. Laboratory diagnosis of alpha-1 antitrypsin deficiency. Translational Research. 2007;150:267-274.
  3. 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.
  4. World Health Organization. alpha-1 antitrypsin deficiency: memorandum from a WHO meeting. Bull World Health Organ. 1997;75(5):397-415.
  5. Campos MA, Wanner A, Zhang G, et al. Trends in the diagnosis of symptomatic patients with alpha-1 antitrypsin deficiency between 1968 and 2003. Chest. 2005;128(3):1179-1186.
  6. Brantly Ml, Willes JT, Vogelmeier CF, Hubbard RC, Fells GA, Crystal RG. Use of a highly purified alpha 1-antitrypsin standard to establish ranges for the common normal and deficient alpha-1 antitrypsin phenotypes. Chest. 1991;100:703-708.
  7. Gorrini M, Ferrarotti I, Lupi A, et al. Validation of rapid and simple method to measure α1-antitrypsin in human dried blood spots. Clin Chem. 2006;52:899-901.
  8. Ferrarotti I, Thun GA, Zorzetto M, et al. Serum levels and genotype distribution of α1-antitrypsin in the general population. Thorax. 2012;67:669-674.

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