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While predisposition to COPD is widely known to have a significant genetic basis,1 the only known monogenic cause is the genetic mutation that results in α-1 antitrypsin deficiency (AATD). AATD was first identified in 1963 by Laurell and Eriksson, who initially described a cohort of five individuals lacking the α1 globulin fraction, as revealed with serum protein electrophoresis. Three of the five suffered from significant pulmonary disease.2 Subsequently, AATD was shown to result from the homozygous inheritance of a single base-pair mutation in the SERPINA1 gene, which encodes α1-antitrypsin protein.

Misfolded AAT proteins are poorly secreted and functionally abnormal—features that collectively predispose affected individuals to developing panlobular emphysema and COPD. While the prevalence in the population is not precisely known, AATD is estimated to afflict approximately 100,000 individuals in the United States and to account for approximately 1% to 4.5% of cases of COPD.3–7 Coupled with the observation that the cysteine protease inhibitor papain induces emphysema in rats when instilled intratracheally,8 the discovery of AATD and its association with emphysema led to the formation of the protease/antiprotease hypothesis as a basis for the pathogenesis of COPD (emphysema).


The Z mutation is believed to have arisen from a single origin approximately 2000 years ago, potentially in the Viking population,9,10 who then disseminated it in southern Scandinavia. Studies of gene frequency have demonstrated significant variance among European nations, in which a gradient of gene frequency has been found, including high levels in the Northwest that decrease toward the Southeast.10 In Europe, the highest levels are found in regions of Estonia, Latvia, Sweden, France, Ireland, southern England, and northern Spain.10 Outside of Europe, the Z mutation is found at high levels in countries where it was introduced by European migration, including the United States, Australia, and New Zealand.9,11 Z gene frequency varies across African nations, but, on average, is approximately half of that seen in the United States; the frequency is significantly lower in other parts of the world, including China, South Korea, and Japan.11,12

The overall prevalence of the Pi*ZZ phenotype has been estimated from population-based studies. A screening study of 200,000 newborns in Sweden in 1972–1974 demonstrated a prevalence of 1 in 1600 newborns.13 Studies in U.S. populations have estimated a prevalence ranging from 1 in 2857 to 1 in 5097.14–16 Based on sampling of limited numbers of patients, the Pi*ZZ phenotype is estimated to account for 1% to 4.5% of cases of COPD in the United States.3,4,6,7


Mechanisms responsible for the development of lung or liver disease resulting from AATD have been extensively studied (Fig. 39-1), and an understanding of these mechanisms continues to evolve as modern molecular methods and animal ...

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