In alpha-1 antitrypsin (A1AT) deficiency-related emphysema, the panacinar emphysema (involving entire acinus including respiratory bronchioles) is predominantly lower-lobe in distribution. Why does the PiZZ genotype cause both liver disease and lung disease?
- A Misfolded Z-A1AT protein polymerizes and is retained in hepatocyte ER causing hepatocellular injury, while serum deficiency impairs neutrophil elastase inhibition in lung ✓
- B Z-A1AT is secreted normally but has reduced binding affinity for neutrophil elastase
- C Z-A1AT activates the unfolded protein response exclusively in alveolar epithelial cells
- D PiZZ homozygotes have absent A1AT secretion due to a stop-codon mutation causing NMD
Correct answer: A. Misfolded Z-A1AT protein polymerizes and is retained in hepatocyte ER causing hepatocellular injury, while serum deficiency impairs neutrophil elastase inhibition in lung
Explanation
The Z allele encodes a Glu342Lys substitution causing A1AT misfolding; the misfolded protein polymerizes and is retained in hepatocyte endoplasmic reticulum, causing ER stress-mediated hepatocellular injury (cirrhosis, HCC). Simultaneously, markedly reduced serum A1AT levels fail to neutralize neutrophil elastase in lung alveoli, leading to elastin degradation and panacinar emphysema. This dual mechanism — gain of toxic function in liver (protein accumulation) and loss of protective function in lung (elastase inhibition) — is unique to A1AT deficiency.
Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.
High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP
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