Alpha-1 antitrypsin (AAT) is a 52-kDa serine protease inhibitor primarily synthesized by hepatocytes, encoded by the highly polymorphic SERPINA1 gene.
Its main physiological role is to inhibit neutrophil elastase, thereby protecting lung tissue from proteolytic damage and regulating immune processes.
Deficiency of AAT, most commonly due to the PI*Z (Glu342Lys) allele, leads to a dual pathophysiology: loss-of-function in the lung predisposing to early-onset panacinar emphysema and COPD, and gain-of-toxic-function in the liver resulting in protein polymerization, hepatocyte injury, and increased risk of cirrhosis and hepatocellular carcinoma.
AAT deficiency is inherited in an autosomal codominant manner, with over 100 allelic variants described.
The most clinically relevant genotypes are PIZZ (severe deficiency), PISZ (mild-moderate deficiency), and various null alleles.
Diagnosis is made by measuring serum AAT levels and genotyping, with a protective threshold of 11 μM for serum AAT.
Therapy with pooled human plasma-derived AAT is indicated for patients with confirmed deficiency and evidence of airflow obstruction, aiming to slow lung function decline.
There is currently no disease-modifying therapy for liver involvement.