Alpha-1 antitrypsin (A1AT) deficiency causes panacinar emphysema predominating in the lung bases and liver disease. The liver disease results from a specific protein quality control failure. What is the mechanism of hepatocyte injury in A1AT deficiency (PiZZ genotype)?

• A Retained misfolded Z-A1AT polymer aggregates within hepatocyte endoplasmic reticulum trigger ER stress and hepatocyte apoptosis ✓
• B Absence of A1AT causes uninhibited neutrophil elastase destruction of hepatic sinusoidal cells
• C Z-A1AT secreted into blood deposits in hepatic Disse space causing inflammatory injury
• D Lysosomal dysfunction due to A1AT deficiency impairs autophagy causing lipid accumulation

Explanation

The Z-allele encodes a single amino acid change (Glu342Lys) causing Z-A1AT to spontaneously misfold and form polymer aggregates that are retained in the endoplasmic reticulum of hepatocytes rather than being secreted. This ER accumulation (visible as PAS-positive, diastase-resistant globules) triggers ER stress responses, unfolded protein response (UPR) activation, and hepatocyte apoptosis — causing chronic liver disease independent of the protease inhibitor function. The lung disease results from insufficient circulating A1AT and consequent uninhibited neutrophil elastase causing alveolar destruction.

Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

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