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Alpha1-antitrypsin (AAT) circulates in the plasma as a 52-kD glycoprotein. It is synthesized primarily in hepatocytes and to a lesser extent in macrophages and monocytes. AAT is produced at a basal level, which results in plasma concentrations of 11 micromole or greater. AAT is also an acute phase reactant, with levels increasing dramatically during periods of stress, fever, or infection.1-6 Some individuals with AAT deficiency manifest with neonatal liver disease, as discussed in Chapter 421. This chapter discusses the pulmonary manifestations of AAT deficiency.

Epidemiology and Genetics

Approximately 4% of northern Europeans and North Americans of European descent possess at least one mutant AAT allele. This predicts that 1 in 2500 live births in this population will possess two mutant alleles, either being homozygous mutant alleles or compound heterozygous mutant alleles. Up to 100,000 Americans could be AAT deficient, but only approximately 6000 Americans have been diagnosed as such. This discrepancy may represent the incomplete penetrance of the disorder or a failure to diagnose affected individuals. There is evidence that a combination of both of these explanations may be true.

Several studies have tested the utility of targeted detection of AAT deficiency within populations of adult chronic lung disease patients. These studies have consistently shown that 3% to 4% of such populations are AAT deficient. Given that approximately 11 million adults are symptomatic with chronic obstructive pulmonary disease, this targeted detection could yield a total of 30,000 to 40,000 American AAT-deficient patients. Thus, the best estimate is that there is an as-yet-undiagnosed population of 25,000 to 35,000 symptomatic AAT-deficient individuals. There may then be another 60,000 or more asymptomatic “healthy” AAT-deficient individuals.7,8

As mentioned above, mutations of the AAT gene are quite common in individuals of northern European ancestry. In particular, the one missense mutant genotype (Glu 342→Lys) that results in the PiZ phenotype on isoelectric focusing (IEF) gel electrophoresis accounts for 95% of AAT mutants in this population. Several other AAT alleles have been associated with deficiency states (eTable 516.1). These include numerous missense and null alleles. Environmental factors may play a role in determining which AAT-deficient individuals develop clinically evident deficiency disease. Tobacco smoke exposure (either directly from smoking or from environmental exposure) is a key risk factor for the development and severity of lung disease in AAT-deficient individuals.9 Infections have also been implicated, including both viral and bacterial infections. A number of studies have attempted to identify gene modifiers, which might significantly affect the disease phenotype in AAT-deficient individuals. Only recently has a study identified IL-10 as a potential modifier gene for the development of chronic obstructive pulmonary disease (COPD) in individuals who are PiZ homozygotes. The study suggests an association with patients carrying the high IL-10-producing allele having higher lung function; conversely, the lower IL-10-producing allele is strongly associated with lower lung function.10,11 To date, no other modifiers ...

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