Alpha-1 antitrypsin (AAT) deficiency is a genetic disorder with an autosomal inheritance pattern and codominant expression of alleles.
Allele mutations cause ineffective activity of alpha-1 antitrypsin, the enzyme responsible for neutralizing neutrophil elastase.
Pulmonary and hepatic manifestations include emphysema, COPD, bronchiectasis, and cirrhosis.
Granulomatosis with polyangiitis (formerly known as Wegener granulomatosis) and necrotizing panniculitis are infrequent complications but can prompt diagnosis.
Plasma AAT levels, protein phenotyping (called PI-typing), and genotyping may be necessary for diagnosis. Rare alleles may require gene sequencing.
Intravenous AAT augmentation therapy benefits some patients.
Alpha-1 antitrypsin (AAT) deficiency is an autosomal codominant genetic disorder (i.e., 1 allele is inherited from each parent and each allele is expressed equally). It results from allele mutations in the SERPINA1 gene at the protease inhibitor (PI) locus.
The PI locus is highly polymorphic. Different protein variants have different charges because of amino acid alterations. The charge affects the speed of protein migration on serum electrophoresis. Alleles are assigned a letter from A to Z depending on their relative speed of migration, with A being the fastest and Z the slowest. The allele most widely associated with clinical AAT deficiency is allele Z. The pattern of protein migration observed on serum electrophoresis is called the PI phenotype, which is written in form PI*[allele A][allele B].
PI* allele mutations cause ineffective activity of the specific protease inhibitor AAT, the enzyme responsible for neutralizing neutrophil elastase and preventing inflammatory tissue damage in the lungs. Variants of the enzyme may also polymerize and accumulate in the liver, resulting in hepatic failure in some patients.
AAT is also known as alpha-1 proteinase inhibitor.
History and exam
Key diagnostic factors
- productive cough
- shortness of breath on exertion
- current cigarette smoker
- exposure to gas, fumes, and/or dust
Other diagnostic factors
- age 32-41
- male sex
- chest hyperinflation
- scleral icterus/jaundice
- family history of AAT deficiency
1st investigations to order
- plasma AAT level
- pulmonary function testing
- chest x-ray
- chest CT
Investigations to consider
- gene sequencing
- exercise testing with ABG analysis
- liver ultrasound
- abdominal CT
low plasma AAT
- Global strategy for diagnosis, management, and prevention of COPD 2022
- British Thoracic Society guideline for bronchiectasis in adults
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