This is possibly the most frequent mendelian disorder, caused by mutation of the gene for LDL (low density lipoprotein) receptor leading to decreased functional LDL receptor to cause increased plasma cholesterol leading to premature atherosclerosis to cause increased risk of myocardial infarction and other complications of atherosclerosis. The occurrence of xanthomas (which are raised yellow lesions filled with lipid-laden macrophages in the skin and tendons).
Familial hypercholesterolemia is caused by different types of mutations in the gene for LDL receptor → No functional LDL receptor → Leads to:
- Impaired plasma LDL clearance. This leads to the accumulation of LDL in plasma (i.e. hypercholesterolemia).
- Impaired IDL uptake by the liver (because IDL uses hepatic LDL receptors for this uptake).→ Diversion of a greater proportion of plasma IDL into the precursor pool for plasma LDL. → Hypercholesterolemia.
- Increased scavenger receptor – mediated clearance of LDL into the cells of the mononuclear phagocyte system and possibly the vascular walls. This leads to xanthomas and contributes to premature atherosclerosis.
This knowledge of the pathogenesis of familial hypercholesterolemia has led to a logical discovery of its treatment. The logical treatment is to increase the number of LDL receptors. (I.e. to remove the basic problem). This can be done by:-
These are drugs which inhibit hepatic HMG CoA reductase→ Inhibits intracellular cholesterol synthesis→ leads to greater synthesis of LDL receptors (See the normal cholesterol metabolism above)
2. Gene therapy (under investigation)
By giving normal LDL receptor genes via a viral vector.