Page 257 - Concise Pathology for Exam Preparation ( PDFDrive )

242 SECTION II Diseases of Organ Systems

(g) Lifestyle: Type A behaviour characterized by the aggressiveness, competitiveness
and drive have increased risk.
(h) Hyperhomocystinaemia and homocystinuria: High levels of circulating homo-
cysteine may lead to endothelial injury and vascular disease.

Q. Write in brief on the pathogenesis of atherosclerosis.
Ans. The exact pathogenesis of atherosclerosis is not known; it is thought to be a multi-
factorial disease. Many theories have been put forward:
• Encrustation hypothesis proposed by Rokitansky in year 1852: Atheroma represents
lipid encrustation on the arterial wall and formation of thrombus by components of
blood (platelets, fibrin and leukocytes).
• Insudation hypothesis proposed by Virchow in year 1856: There is cellular prolif-
eration of intimal cells due to increased imbibing of lipids from blood (‘lipid theory’).
• Currently, the most accepted theory in circulation is reaction/response-to-injury
hypothesis (Flowchart 10.4). This theory identifies atherosclerosis as a chronic inflam-
matory and healing response to endothelial injury.

Endothelial cell injury
(endothelial dysfunction or denudation due to hyperlipidaemia, hypertension, toxins in cigarette smoke, viruses
and other infective agents, haemodynamic disturbances, immune complex
deposition, irradiation, homocysteine, etc.)

Platelet aggregation and platelet release reaction
↑ VCAM -1, IL-1 and TNF
Circulating monocytes and lymphocytes (both CD4+ and CD8+ T cells) adhere to the area of injury and
emigrate into the vessel wall (monocytes become macrophages)

The above cells release various cytokines (growth factors) some of which induce smooth muscle proliferation
and direct chemotaxis of the smooth muscle cells
to the intimal area of the vessel

Macrophages, lymphocytes and smooth muscle cells imbibe
LDL-containing cholesterol and become foam cells with subsequent
development of fatty streaks (reversible lesions)

Injured endothelial cells and macrophages also produce free radicals, which induce
formation of oxidized LDL, a potent enhancer of the atherosclerotic process
(oxidized LDL acts to attract, proliferate, immobilize and activate monocytes
and is cytotoxic for endothelium and smooth muscle cells; it is ingested
by macrophages through scavenger receptors different from LDL receptors)

Fatty streaks continue to enlarge and eventually disrupt the endothelial surface

Platelets adhere to the damaged endothelium overlying the fatty streaks and
increase PDGF, which further contributes to smooth muscle proliferation

Over time, the proliferating smooth muscle cells located at the base of the
fatty streak begin to synthesize collagen, elastin and proteoglycans,
which subsequently produce fibrous plaques

Fibrous plaques undergo dystrophic calcification, haemorrhage, thrombosis,
fissuring and ulceration to form a complicated atheromatous plaque
FLOWCHART 10.4. Reaction/response-to-injury hypothesis.

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