1 Antitrypsin Deficiency

Many variants of the protease inhibitor (PI or SERPINA1) locus that encodes 1AT have been described. The common M allele is associated with normal 1AT levels. The S allele, associated with slightly reduced 1AT levels, and the Z allele, associated with markedly reduced 1AT levels, also occur with frequencies >1% in most Caucasian populations. Rare individuals inherit null alleles, which lead to the absence of any 1AT production through a heterogeneous collection of mutations. Individuals with two Z alleles or one Z and one null allele are referred to as PiZ, which is the most common form of severe 1AT deficiency.

Although only 1–2% of COPD patients are found to have severe 1AT deficiency as a contributing cause of COPD, these patients demonstrate that genetic factors can have a profound influence on the susceptibility for developing COPD. PiZ individuals often develop early-onset COPD, but the ascertainment bias in the published series of PiZ individuals—which have usually included many PiZ subjects who were tested for 1AT deficiency because they had COPD—means that the fraction of PiZ individuals who will develop COPD and the age-of-onset distribution for the development of COPD in PiZ subjects remain unknown. Approximately 1 in 3000 individuals in the United States inherits severe 1AT deficiency, but only a small minority of these individuals has been recognized. The clinical laboratory test used most frequently to screen for 1AT deficiency is measurement of the immunologic level of 1AT in serum (see "Laboratory Findings," below).

A significant percentage of the variability in pulmonary function among PiZ individuals is explained by cigarette smoking; cigarette smokers with severe 1AT deficiency are more likely to develop COPD at early ages. However, the development of COPD in PiZ subjects, even among current or ex-smokers, is not absolute. Among PiZ nonsmokers, impressive variability has been noted in the development of airflow obstruction. Other genetic and/or environmental factors likely contribute to this variability.

Specific treatment in the form of 1AT augmentation therapy is available for severe 1AT deficiency as a weekly intravenous infusion (see "Treatment," below).

The risk of lung disease in heterozygous PiMZ individuals, who have intermediate serum levels of 1AT (~60% of PiMM levels), is controversial. Although previous general population surveys have not typically shown increased rates of airflow obstruction in PiMZ compared to PiMM individuals, case-control studies that compared COPD patients to control subjects have usually found an excess of PiMZ genotypes in the COPD patient group. Several recent large population studies have suggested that PiMZ subjects are at slightly increased risk for the development of airflow obstruction, but it remains unclear if all PiMZ subjects are at slightly increased risk for COPD or if a subset of PiMZ subjects are at substantially increased risk for COPD due to other genetic or environmental factors.