α1-Antitrypsin Deficiency and Emphysema

Published on 22/03/2015 by admin

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Chapter 385 α1-Antitrypsin Deficiency and Emphysema

Although it rarely causes lung disease in children, homozygous deficiency of α1-antitrypsin (α-AT) is an important cause of early-onset severe panacinar pulmonary emphysema in adults in the 3rd and 4th decades of life and an important cause of liver disease in children (Chapter 349.5). It has been associated with panniculitis and vasculitis in adults.

Pathogenesis

The type and concentration of α1-AT are inherited as a series of codominant alleles on chromosomal segment 14q31-32.3. See Chapter 349.5 for discussion of genotypes and liver disease. The autosomal recessive deficiency affects 1/1,600-2,500 people, or ∼100,000 people in the USA but is underdiagnosed. It occurs most commonly in whites of Northern European ancestry, but recent surveys reveal significant prevalence in populations from the Middle East and North Africa, Central and Southern Africa, and Central and Southeast Asia. Worldwide there are an estimated 116,000,000 carriers and 1,100,000 subjects with severe α1-AT deficiency. The normal α1-AT PiM protein is secreted by the liver into the circulation at a rate of ∼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 α1-AT deficiency occurs most commonly with PiZZ (mutation in SERPINA1 gene), although Pi (null) (null) and, to a lesser extent, other mutant Pi types such as SZ have been associated with emphysema.

α1-AT and other serum antiproteases help 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. Furthermore, polymerized mutant protein in the lungs may be proinflammatory. The concentration of proteases (elastase) in the patients’ leukocytes may also be an important factor in determining the severity of clinical pulmonary disease with a given level of α1-AT.

Clinical Manifestations

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