An adult with emphysema and cryptogenic cirrhosis undergoes liver biopsy. Periodic acid-Schiff stain after diastase digestion shows numerous round eosinophilic globules within periportal hepatocytes. Immunostaining confirms accumulation of a misfolded glycoprotein retained in the endoplasmic reticulum. What is the underlying defect?

• A Autosomal recessive CFTR mutation causing thick secretions and duct obstruction
• B Autosomal dominant ATP7B mutation impairing copper excretion into bile
• C Autosomal recessive SERPINA1 mutation impairing secretion of alpha-1 antitrypsin ✓
• D Autosomal recessive UGT1A1 deficiency causing unconjugated hyperbilirubinemia

Explanation

PAS-positive, diastase-resistant globules in periportal hepatocytes represent polymerized misfolded alpha-1 antitrypsin retained within hepatocyte ER, classically in homozygous PiZZ disease. The lung disease results from unopposed neutrophil elastase because circulating antitrypsin levels are low, while the liver injury is a toxic gain of function from retained mutant protein. ATP7B causes copper accumulation without such globules, and CFTR disease produces fatty change and focal biliary cirrhosis instead.

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.