A 45-year-old woman develops hepatocellular injury after acetaminophen overdose. Liver biopsy shows centrilobular necrosis with loss of nuclear detail and cytoplasmic swelling. The predominant cell death mechanism here is:

• A Apoptosis via death receptor (extrinsic) pathway
• B Necrosis from toxic CYP2E1-generated NAPQI binding cellular proteins and depleting glutathione ✓
• C Pyroptosis via NLRP3 inflammasome activation
• D Autophagic cell death via mTOR inhibition

Explanation

Acetaminophen (APAP) is metabolized predominantly by CYP2E1 (and CYP3A4) in centrilobular hepatocytes to the reactive metabolite NAPQI (N-acetyl-p-benzoquinone imine). When glutathione stores are depleted (as in overdose), NAPQI covalently binds mitochondrial and cellular proteins, causing oxidative stress, mitochondrial permeability transition, and ATP depletion, resulting in oncotic necrosis — specifically in zone 3 (centrilobular) where CYP2E1 is most abundant. This is predominantly necrosis, not apoptosis, explaining the inflammatory hepatitis pattern.

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

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.