From the Guidelines
Alpha-1 antitrypsin (A1A) deficiency is primarily classified into several types, including PiMM, PiMS, PiSS, PiMZ, PiSZ, and PiZZ, with PiZZ being the most severe form, causing significantly reduced A1A levels and the highest risk for developing emphysema and liver disease. The types of A1A deficiency are determined by the specific genetic mutations in the SERPINA1 gene, which codes for the A1A protein. According to the American Thoracic Society/European Respiratory Society statement 1, the AAT protein is an extremely polymorphic molecule, with approximately 100 alleles of the AAT gene identified, and more than 30 genetic variants leading to deficient levels of AAT.
The main types of A1A deficiency include:
- PiMM: normal genotype
- PiMS and PiMZ: carrier states with mildly reduced protein levels, generally posing minimal health risks
- PiSS: associated with plasma levels about 60% of normal
- PiSZ: causes moderately reduced levels, with intermediate disease risk
- PiZZ: the most severe form, causing significantly reduced A1A levels (typically below 15% of normal) and the highest risk for developing emphysema and liver disease
The severity of A1A deficiency correlates with the amount of functional protein produced, with the Z mutation causing the protein to misfold and accumulate in the liver, leading to both lung damage (due to insufficient protection against elastase) and potential liver damage (from protein buildup) 1. Early diagnosis is crucial, as treatment options include augmentation therapy with purified A1A protein for those with severe deficiency, along with lifestyle modifications like smoking cessation to prevent accelerated lung damage.
The diagnosis of A1A deficiency can be confirmed quantitatively and qualitatively, with quantitative plasma AAT levels determined by methods such as rocket immunoelectrophoresis, radial immunodiffusion, or nephelometry 1. Qualitative evaluation of the AAT disorder is also necessary, especially for subjects with abnormal blood levels or borderline normal AAT plasma levels.
From the FDA Drug Label
Alpha1-PI deficiency is a chronic, autosomal, co-dominant hereditary disorder characterized by reduced levels of Alpha1-PI in the blood and lungs A large number of phenotypic variants of Alpha1-PI deficiency exist, not all of which are associated with the clinical disease. Approximately 95% of identified Alpha1-PI deficient individuals have the PiZZ variant, typically characterized by Alpha1-PI serum levels < 35% of normal. Individuals with the Pi(null)(null) variant have no Alpha1-PI protein in their serum PiSZ individuals, whose serum Alpha1-PI levels range from approximately 9 to 23 μM are considered to have moderately increased risk for developing emphysema
The types of A1A deficiency are:
- PiZZ variant: characterized by Alpha1-PI serum levels < 35% of normal
- Pi(null)(null) variant: individuals have no Alpha1-PI protein in their serum
- PiSZ variant: serum Alpha1-PI levels range from approximately 9 to 23 μM, with moderately increased risk for developing emphysema 2
From the Research
Types of A1A Deficiency
- The most common deficiency is in the Z variant, with more than 3 million people worldwide having combinations of alleles associated with severe AATD 3.
- Other types of A1A deficiency include:
- MZ: associated with reduced pulmonary function in individuals with clinically established COPD, and may produce marked aggravation of airway obstruction in individuals prone to develop COPD 4.
- SZ: associated with reduced pulmonary function in smokers, and has a risk of lung disease comparable to MZ, not ZZ-AATD 5.
- ZZ: associated with lower FEV1pp than SZ, and an increased risk of lung disease, regardless of smoking status 4, 5.
- At least 100 allelic variants of the polymorphic PI locus have been described, with different associations with A1AT plasma levels and functions 6.
Genetic Basis
- A1AT deficiency is a genetic autosomal recessive disease, characterized by low serum levels of A1AT 6.
- The condition is caused by mutations in the SERPINA1 gene, leading to changes in the AAT glycoprotein, which can alter its concentration, conformation, and function 3.