α 1 -Antitrypsin Deficiency and Emphysema

Pathogenesis

The type and concentration of α ₁ -AT are inherited as a series of codominant alleles on chromosomal segment 14q31-32.3. (See Chapter 384.5 for a discussion of genotypes and liver disease.) The autosomal recessive deficiency affects 1 in 1,600-2,500 people, but it remains underdiagnosed. The highest risk for α ₁ -AT deficiency is found in whites, followed by Hispanics and blacks, with the lowest prevalence among Mexican Americans and little to no risk for Asians. Worldwide there are an estimated 116,000,000 carriers and 1,100,000 subjects with severe α ₁ -AT deficiency. The normal α ₁ -AT PiM protein is secreted by the liver into the circulation at a rate of approximately 34 mg/kg/day; it is also produced by lung epithelial cells and monocytes. Mutant protein is not produced (null) or is misfolded (PiZ and others); it can polymerize in the endoplasmic reticulum or be degraded, with subsequent low serum levels. Early adult-onset emphysema associated with α ₁ -AT deficiency occurs most commonly with PiZZ (mutation in SERPINA1 gene), although Pi (null) (null) and, to less extent, other mutant Pi types such as SZ have been associated with emphysema.

α ₁ -AT and other serum antiproteases help to inactivate proteolytic enzymes released from dead bacteria or leukocytes in the lung. Deficiency of these antiproteases leads to an accumulation of proteolytic enzymes in the lung, resulting in destruction of pulmonary tissue with subsequent development of emphysema. Polymerized mutant protein in the lungs may also be proinflammatory, and there is evidence of increased oxidative stress. The concentration of proteases (elastase) in an individual's leukocytes may also be an important factor in determining the severity of clinical pulmonary disease with a given level of α ₁ -AT.