A 45-year-old lifelong smoker presents with progressive exertional dyspnoea and abnormal liver enzymes. Chest imaging shows bibasilar panacinar emphysema out of proportion to his smoking history. Liver biopsy reveals periodic acid-Schiff positive, diastase-resistant eosinophilic globules within hepatocytes. What is the underlying defect?

• A Keratin 8 and 18 mutation causing Mallory-Denk body formation
• B Defective ATP7B transporter causing copper accumulation
• C Hepcidin deficiency causing parenchymal iron overload
• D Mutated SERPINA1 gene causing misfolded protein retention in hepatocytes ✓

Explanation

Alpha-1 antitrypsin deficiency results from mutations in the SERPINA1 gene, classically the ZZ phenotype, where misfolded polymerised protein accumulates in hepatocyte endoplasmic reticulum as PAS positive, diastase resistant globules. Low circulating enzyme permits unopposed neutrophil elastase activity, producing basal panacinar emphysema. Copper accumulation defines Wilson disease and iron overload defines haemochromatosis, neither of which produces these characteristic globules.

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

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.