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Alpha-1-antitrypsin (A1A) is the most abundant serum protease inhibitor and inhibits trypsin and elastin, as well as several other proteases. The release of proteolytic enzymes from plasma onto organ surfaces and into tissue spaces results in tissue damage unless inhibitors are present. Congenital deficiency of A1A is associated with the development of emphysema at an unusually early age and with an increased incidence of neonatal hepatitis, usually progressing to cirrhosis.
Most normal individuals have the M phenotype (M, M1, or M2). Over 99% of M phenotypes are genetically MM. In the absence of family studies, the phenotype (M) and quantitative level can be used to infer the genotype (MM). The most common alleles associated with a quantitative deficiency are Z and S.
See Alpha-1-Antitrypsin-A Comprehensive Testing Algorithm in Special Instructions.
Identification of homozygous and heterozygous phenotypes of the alpha-1-antitrypsin deficiency
There are >40 alpha-1-antitrypsin (A1A) phenotypes (most of these are associated with normal quantitative levels of protein). The most common normal phenotype is M (M, M1, or M2), and >90% of Caucasians are genetically homozygous M (MM).
A1A deficiency is usually associated with the Z phenotype (homozygous ZZ), but SS and SZ are also associated with decreased A1A levels.
This assay identifies the phenotype of the circulating alpha-1-antitrypsin (A1A) protein. If the patient is already on replacement therapy, the phenotype will detect patient and replacement protein.
If 2 bands are seen, such as an M band and a Z bands, it is reported as MZ (eg, heterozygous)
If 1 band is seen, such as the Z band and the quantitative level is consistent with a homozygote, the phenotype is assumed to be homozygous and is reported as ZZ.
The interpretive report will identify the alleles present. For rare alleles, the report will indicate whether or not they have been associated with reduced quantitative levels of alpha-1-antitrypsin.
1. Morse JO: Alpha-1-antitrypsin deficiency. N Engl J Med 1978;299:1045-1048;1099-1105
2. Donato LJ, Jenkins SM, Smith C, et al: Reference and interpretive ranges for alpha(1)-antitrypsin quantitation by phenotype in adult and pediatric populations. Am J Clin Pathol 2012 Sep;138(3):398-405