Sven Graham, aged 28 years, presents for a check up. His brother recently died from an acute myocardial infarction aged 30 years. He advises that his father also died at 32 from a heart attack. On examination Sven has normal blood pressure. You order some investigations and these confirm a diagnosis of severe hypercholesterolaemia and hypertriglyceridaemia.
Cholesterol is exported to the peripheral tissues in LDL and VLDL. About 70% of the cholesterol molecules in LDL are esterified with a fatty acid (for example, palmitate) on the OH group. Cells take up cholesterol from the LDL by means of LDL receptors in the outer cell membrane.
The pathway for uptake involves several steps:
Regulation:
A close connection exists between the regulation of cholesterol biosynthesis and uptake. When HMG-CoA reductase is inhibited, the cell responds by synthesising more LDL receptors to ensure the uptake of cholesterol from the serum. When cholesterol is present in a high enough concentration in the cell, LDL receptors are not exported to the cell surface (down-regulation).
Clinical relevance:
If little cholesterol is available in the diet, cells of peripheral tissues respond by up-regulating the number of LDL receptors on the cell surface. The higher concentration of receptors means that more cholesterol will be removed from the circulatory system, reducing the risk of artery disease. Conversely, if large amounts of cholesterol exist in the diet, cells will synthesise fewer LDL receptors, less cholesterol will be removed from circulation, and risk of artery disease increases.
Common causes for high cholesterol:
Secondary hypercholesterolaemia:
Congenital causes to consider in Sven:
The association of elevated lipids and cholesterol with strong family history of premature cardiac death suggests:
LDL and HDL are plasma lipoproteins which are complexes of lipid and proteins. Lipoproteins carry the hydrophobic lipids. They possess surface proteins (apoproteins) that are cofactors and ligands for lipid-processing enzymes. They are important because high levels of low-density lipoproteins (LDLs) and low levels of high-density lipoproteins (HDLs) are major risk factors for atherosclerotic heart disease.
LDL (Low-Density Lipoprotein):
HDL (High-Density Lipoprotein):
| Medication | Action |
|---|---|
| Bile acid sequestrants (Cholestyramine, Colestipol) |
These prevent reabsorption of bile acids, therefore increasing de novo bile acid synthesis from hepatic cholesterol. The resultant depletion of hepatic cholesterol up-regulates LDL-receptor activity and reduces LDL cholesterol. |
| Nicotinic acid derivatives | This reduces peripheral fatty acid release with the result that cholesterol and triglycerides decline whilst HDL cholesterol increases. |
| HMGCoA reductase inhibitors (statins) | Statins inhibit cholesterol synthesis thereby upregulating the activity of the LDL receptor. This increases clearance of LDL and its precursor, IDL, thereby leading to a second mechanism by which LDL is reduced. |
| Fibrates | These medications stimulate peroxisome proliferators activator receptor (PPAR)-alpha which controls the expression of the gene products that mediate the metabolism of triglycerides and HDL. As a result the synthesis of fatty acids, triglycerides and VLDL is reduced whilst that of lipoprotein lipase that catabolises TG is increased. In addition, the promoter regions of genes such as apolipoprotein A1 and the ATP binding cassette A1 are up-regulated, leading to increased cholesterol reverse transport via HDL. |
Given Sven's severe hypercholesterolaemia and hypertriglyceridaemia, combination therapy is required:
Options include either:
Treatment algorithm:
Principles of dietary management:
Foods low in cholesterol include: