Familial Hypercholesterolemia (FH)

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Familial hypercholesterolaemia is a condition defined as a level of LDL‑C exceeding a cut-off point determined by national guidelines as conferring increased risk of cardiovascular disease (CVD). FH is a hereditary disease meaning that individuals with FH typically have mutations affecting their LDL receptor which can be inherited by their offspring. The result of these mutations is a higher than normal level of serum cholesterol. Individuals with the rare homozygous form (1 in a million) have grossly elevated levels of serum cholesterol (16-25mmol/l) and usually die of heart disease before the age of 20. People heterozygous to the disease (1 in 500) have relatively high levels of serum cholesterol (6.5-13mmol/l) and are at high risk for heart attacks. In Westernized countries it is by far the most prevalent form of elevated LDL‑C. It reflects diet (intake of saturated and trans-unsaturated fats, and obesity) and multiple genetic determinants including the Apo E4 gene. It is a clinically important subset of the primary causes of this lipoprotein pattern (elevated LDL‑C) and is itself composed of several subsets. In FH, there is also an autosomal recessive form (ARH) attributable to defects in the function of a chaperone protein. Mutations affecting the receptor binding region of the apo-B100 receptor ligand cause a less severe dominantly inherited clinical syndrome known as familial defective Apo B (FDB).

 

Another subgroup is due to a gain-of-function mutation of the PCSK9 gene, which tends to cause a relatively severe clinical picture. The risk of cardiovascular disease is related to plasma levels of total cholesterol and LDL-cholesterol. The desirable level of LDL appears to be below 305 mmol/L. The risk of cardiovascular disease increases when the total cholesterol level is above 6 mmol/l.

 

Treatment options:

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• Dietary restriction of cholesterol to less than 300 mg/day, restriction of total fat intake to less than 30% of total calories.

• The administration of bile salt-binding drugs such as cholestyramine and colestipol. These drugs promote excretion of bile salts in the stool. This in turn increases the synthesis of hepatic bile salt synthesis and of LDL uptake by the liver. 

• Drugs called statins are used as treatment which work by inhibiting cholesterol synthesis. An example of a statin is Lovastatin. Lovastatin is an inhibitor of HMG-CoA reductase, therefore decreases endogenous synthesis of cholesterol and stimulates uptake of LDL via the LDL receptor.

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Diabetes & Coronary Heart Disease

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According to Athyros et al. (2018), insulin resistance is prevalent in obese individuals, partly due to the elevated amount of free fatty acids in the blood. Elevated free fatty acids contribute to several effects: they inhibit glucose degradation in tissues such as muscle, they interfere with the insulin-stimulated transport of glucose into muscle by blocking GLUT4 glucose transporter, they stimulate gluconeogenesis in the liver, may inhibit transcription of insulin, and may bind to and inhibit the insulin receptor. 

 

According to Freeman (2006) atherosclerosis is the process by which atherosclerotic plaques form. The key event in early atherosclerosis is damage to the endothelium which may be caused by oxidised LDLs, hypertension and cigarette smoking. Then, LDL penetrates the vascular wall and deposit in the intima where they undergo oxidation. The presence of oxidized LDL attracts monocytes to the arterial wall. Monocytes enter the arterial wall and transform into macrophages. These macrophages are immobilised in the subendothelial space. The oxidized Apo B100 can no longer bind to the LDL receptor. 

 

The oxidized LDL is engulfed by the macrophage via the scavenger receptor. Since the scavenger receptor is not regulated, the cells become overloaded with lipid and become foam cells. Conglomerates of foam cells form streaky yellow patches visible in the arterial wall. Dying foam cells release lipids that form pools within the arterial wall.  

 

The surrounding smooth muscle cells and endothelial cells secrete cell growth regulators such as cytokines, growth factor, interleukin-1 and tumour necrosis factor. These peptides stimulate smooth muscle cells to proliferate and to migrate towards the lumen side of the arterial wall. At this time the smooth muscle cells start secreting collagen. This results in the formation of a cap that covers the lipid pool which forms the mature atherosclerotic plaque. 

 

Hypertriglyceridemia

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Hypertriglyceridemia is a condition which is caused by very high levels of chylomicrons and VLDLs which then leads to high levels of triglycerides in the blood. This condition is mostly caused by excess intake of fat or alcohol, obesity and also Type 2 diabetes.

 

Stroke

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Lipoproteins play a role in predicting strokes and also coronary heart disease. There is a link between levels of lipoprotein (a) and plasma fibrinogen, with an increase in the level of fibrinogen in the blood being an indicator of vascular events such as strokes. Lipoproteins also demonstrate protective properties against acute stroke by helping reverse the effects caused when there is a lack of oxygen being supplied to the brain (Meilhac, 2015).

 

Sources:

• Meilhac O. (2015) High-Density Lipoproteins in Stroke. In: von Eckardstein A., Kardassis D. (eds) High Density Lipoproteins. Handbook of Experimental Pharmacology, vol 224. Springer, Cham. Obtained from: https://doi.org/10.1007/978-3-319-09665-0_16

• Athyros, V. G., Doumas, M., Imprialos, K. P., Stavropoulos, K., Georgianou, E., Katsimardou, A., & Karagiannis, A. (2018). Diabetes and lipid metabolism. Hormones (Athens, Greece), 17(1), 61-67. doi:10.1007/s42000-018-0014-8

• Freeman, M. W. (2006). Lipid metabolism and coronary artery disease. In M. S. Runge, & C. Patterson (Eds.), Principles of molecular medicine (pp. 130-137). Totowa, NJ: Humana Press. doi:10.1007/978-1-59259-963-9_15 Retrieved from https://doi.org/10.1007/978-1-59259-963-9_15