Panacinar emphysema is highly associated with alpha-1 antitrypsin (AAT) deficiency. AAT, synthesized in the liver, is an acute phase reactant of the serpin family of protease inhibitors. Although its bestknown function is the inhibition of neutrophil elastase, AAT inhibits a wide range of proteases, leading to its alternate designation “alpha1-protease.” The disease is inherited in an autosomal recessive fashion and depends on the inheritance of specific allelic variants.

The gene SERPINA1 has two codominant alleles, with 75 variations designated by letters reflected by electrophoretic mobility. The most prevalent genotype is PiMM (PI, protease inhibitor; M, allele type). The Pi*Z allele is the most important and strongest genetic variant responsible for decreased plasma AAT levels. The frequency of PiZZ homozygotes, which represent a large proportion of symptomatic patients, is approximately 1 in 2,000 to 1 in 5,000 persons.^2,3 The other genotype responsible for the majority of remaining emphysematous patients is PiSZ, occurring at about half the rate of PiZZ. In directed studies of patients with obstructive lung disease, the proportion of PiSZ or ZZ patients varies widely, from 1% to 3% in patients with some degree of airway obstruction or COPD^4,5,6 to up to 12% with severe emphysema.⁷

Approximately 3% of North Americans are PI*MZ heterozygotes. PI*MZ heterozygotes are not considered to be at increased risk for emphysema; however, meta-analyses have suggested the possibility of an increased risk in some patients.^8,9

Because of the lack of cost-effectiveness of population-based screening, and frequent presence of other risk factors, there are little data regarding the actual relative risk of a patient with PiZZ of PiSZ developing emphysema.

The mechanism of AAT deficiency and emphysema lies in its inhibitory effect on serine proteases, such as elastase and proteinase 3 (PR3), and other anti-inflammatory and tissue-protective effects that are independent of protease inhibition. These include interactions with dendritic cells, T-cell regulation, and inhibition of interleukin-1 receptor and IL-10, among others.

The risk for developing emphysema with the genetic background of AAT deficiency is enhanced by risk factors, primarily cigarette smoking.¹⁰