PA2.{3,6-7} | Cellular Adaptations, Accumulations & Aging — Summary & Reflection

REFLECT

Consider a 52-year-old chronic smoker with a recent diagnosis of Barrett's oesophagus (columnar metaplasia without dysplasia) and an incidental finding of early CIN 1 on cervical screening.

1. Both lesions involve a change in epithelial cell type — yet one is more clinically urgent than the other. Why? What determines the urgency of surveillance?
2. Both 'metaplasia' and 'dysplasia' represent departures from normal. If you were explaining these diagnoses to the patient in plain language, how would you distinguish them?
3. The smoker's bronchial biopsy also shows squamous metaplasia. If she stops smoking today, what changes in the adaptation spectrum are reversible, and at what stage does reversibility become unlikely?

KEY TAKEAWAYS

Key take-home points from this module:

• Five cellular adaptations respond to sublethal stress:
• Atrophy — ↓ cell size; driven by autophagy + ubiquitin–proteasome
• Hypertrophy — ↑ cell size (non-dividing cells); physiologic (exercise, pregnancy) or pathologic (cardiac, hypertension)
• Hyperplasia — ↑ cell number (dividing cells); controlled, stimulus-dependent; platform for neoplasia if mutated
• Metaplasia — cell-type switch; reversible; driven by stem cell reprogramming; risk of malignant transformation
• Dysplasia — disordered growth; cytological atypia; pre-neoplastic; graded (CIN 1→3); high-grade treated

• Intracellular accumulations:
• Lipids: macrovesicular steatosis (alcoholic/NAFLD liver), cholesterol in atheroma/xanthomas
• Proteins: Mallory bodies (alcoholic hepatitis), Russell bodies (plasma cells)
• Glycogen: PAS+/diastase-digestible; glycogen storage diseases
• Pigments: lipofuscin (ageing/autophagy), melanin (melanocytes), haemosiderin (Perl's +ve, iron overload/haemolysis), bilirubin (cholestasis), anthracosis (carbon, exogenous)

• Cellular ageing is driven by:
1. Telomere shortening → replicative senescence (p53 pathway)
2. DNA damage accumulation + defective repair → SASP
3. Impaired proteostasis (↓ chaperones, ↓ autophagy) → protein aggregates
4. ↓ Replicative capacity of stem cells

• Apoptosis = programmed, ATP-dependent, no inflammation; necrosis = accidental, inflammatory
• BCL-2 family balance (anti- vs pro-apoptotic) governs the apoptotic threshold
• Telomerase overexpression is a hallmark of cancer; SASP links cellular senescence to tissue ageing