A 30-year-old non-smoker develops panacinar emphysema predominantly in the lower lobes. Serum shows markedly reduced alpha-1 antitrypsin levels. What is the mechanism of emphysema in alpha-1 antitrypsin deficiency?
- A Misfolded alpha-1 antitrypsin accumulates in lung macrophages, triggering emphysematous inflammation
- B Reduced alpha-1 antitrypsin allows MMP-9 overactivity to destroy bronchial cartilage
- C Unopposed neutrophil elastase activity destroys alveolar walls in the absence of alpha-1 antitrypsin inhibitor ✓
- D Absent alpha-1 antitrypsin activates the complement cascade, causing alveolar basement membrane destruction
Correct answer: C. Unopposed neutrophil elastase activity destroys alveolar walls in the absence of alpha-1 antitrypsin inhibitor
Explanation
Alpha-1 antitrypsin is the principal inhibitor of neutrophil elastase. In its absence (usually PiZZ genotype), elastase from neutrophils and macrophages acts unopposed, proteolytically destroying alveolar walls and leading to panacinar emphysema. The lower-lobe predominance contrasts with smoking-related centrilobular emphysema (upper-lobe dominant). The misfolded Z-variant protein also accumulates in hepatocytes (not macrophages), causing hepatic cirrhosis via a distinct gain-of-toxic-function mechanism.
Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.
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