Hepatocytes show ballooning degeneration and Mallory-Denk bodies (MDB) in a patient with alcoholic hepatitis. Which cytoskeletal proteins are the major constituents of MDB and what is the mechanism of their abnormal aggregation?
- A Alpha-actinin and desmin aggregates due to mitochondrial oxidative damage
- B Vimentin and GFAP aggregates secondary to ER stress-induced misfolding
- C Ubiquitinated and p62/sequestosome-1-positive aggregates of CK8 and CK18 resulting from impaired proteasomal degradation ✓
- D Aggregated albumin and transferrin due to impaired secretion by ethanol-damaged Golgi
Explanation
Mallory-Denk bodies are intracytoplasmic aggregates predominantly composed of cytokeratins 8 and 18 (CK8/CK18), ubiquitin, and the autophagy receptor p62/sequestosome-1. Alcohol and its metabolites (acetaldehyde, reactive oxygen species) impair the ubiquitin-proteasome system and autophagy, preventing clearance of damaged, hyperphosphorylated CK8/CK18. The proteins aggregate, cross-linked by transglutaminase, forming the MDB. They are a hallmark of advanced alcoholic hepatitis, NASH, and certain drug reactions. Vimentin/GFAP aggregates characterise Rosenthal fibres in astrocytes; desmin aggregates occur in desminopathies.
Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.
High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP
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