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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.
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Epidemiology
and Genetics
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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.
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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
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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 have ...