Cholesterol

Cholesterol, cholesterol esters, and triglycerides are fats, or lipids. On their own these would not be soluble enough to circulate, so to circulate in blood, these lipids are combined with phospholipids and protein in particles called lipoproteins. Generally, only three lipoproteins—very low density lipoproteins (VLDL), low density lipoproteins (LDL), and high density lipoproteins (HDL)—are found in the serum of fasting persons.

Cholesterol is absorbed from the intestine and transported to the liver where it is taken up by the LDL receptors. Cholesterol from the liver enters the circulation as VLDL and is metabolized to remnant lipoproteins after an enzyme (lipoprotein lipase) removes triglycerides. The remnant lipoproteins are removed by LDL receptors or further metabolized to LDL and then removed by LDL receptors. Cholesterol also is transported from peripheral cells to the liver by HDL. Cholesterol is recycled to LDL and VLDL or is taken up in the liver by an enzyme known as hepatic lipase. Cholesterol is excreted in bile.

LDL is the major cholesterol-containing lipoprotein, the major lipoprotein implicated in the development of atherosclerosis, and the primary target of therapeutic interventions. LDL cholesterol may be increased because of increased dietary saturated fat and cholesterol, obesity, or genetic disorders, or because of other secondary causes such as hypothyroidism, a kidney disorder known as nephrotic syndrome, biliary cirrhosis, and renal failure.

HDL is synthesized in both the liver and intestine and exerts a protective effect on the development of atherosclerotic vascular disease, a condition also sometimes referred to as "hardening of the arteries." HDL reverses cholesterol transport and removes cholesterol from cells to be delivered directly to the liver or indirectly via transfer of other lipoproteins for catabolism (breakdown into simpler substances with the release of energy). HDL also prevents oxidation and aggregation of LDL in the arterial wall. Low HDL cholesterol may be genetically determined or associated with nutritional habits, cigarette smoking, and lack of exercise.

VLDL is a triglyceride-rich lipoprotein synthesized and secreted by the liver. Hypertriglyceridemia is associated with genetic disorders, obesity, heavy alcohol intake, diabetes mellitus, renal failure, and drugs such as estrogens.

The measurement of levels of LDL cholesterol, HDL cholesterol, and triglycerides in the serum is used to assess risk for atherosclerotic vascular disease. Serum total cholesterol = LDL cholesterol + HDL cholesterol + 1/5 triglycerides. Hypercholesterolemia is a serum total cholesterol of 200 mg/dL or higher. An elevated serum LDL cholesterol is 130 mg/dL or higher. An abnormally low serum HDL cholesterol is 35 mg/dL or lower. Hypertriglyceridemia is serum triglycerides of 190 mg/dL or higher.

An elevated serum total cholesterol, an elevated serum LDL cholesterol, and a low serum HDL cholesterol are risk factors for coronary artery disease, stroke, and peripheral arterial disease in older and younger men and women. The higher the serum total cholesterol, the higher the serum LDL cholesterol, and the lower the serum HDL cholesterol, the greater the incidence of atherosclerotic vascular disease in older and younger men and women.

Elevated serum triglycerides is associated with an increased risk of atherosclerotic vascular disease. However, except for being a weak independent risk factor for new coronary events in elderly women, hypertriglyceridemia is not an independent risk factor for atherosclerotic vascular disease in older or younger men and women.

Because the incidence of atherosclerotic vascular disease is much higher in older men and women than in younger men and women, hypercholesterolemia, an elevated serum LDL cholesterol, and a low serum HDL cholesterol contribute more to the absolute incidence of atherosclerotic vascular disease in older than in younger men and women.

In addition to dyslipidemia, cigarette smoking, hypertension, and diabetes mellitus are major risk factors for atherosclerotic vascular disease. The greater the number and severity of major risk factors, the higher the incidence of atherosclerotic vascular disease.

Persons with dyslipidemia should have secondary causes of dyslipidemia treated, lose weight if obese, and begin dietary treatment. A Step II American Heart Association diet should be used if drug therapy is being considered. The Step II diet contains no more than 30 percent of calories from fat, less than 7 percent of calories from saturated fatty acids, and less than 200 mg of cholesterol daily. Other major risk factors for atherosclerotic vascular disease must be treated.

Increased plasma homocysteine is also an independent risk factor for atherosclerotic vascular Figure 1 The effects of high cholesterol on the human body. SOURCE: Drawing by Hans and Cassidy for the Gale Group. disease in older and younger men and women. The presence of both increased plasma homocysteine and dyslipidemia increases independently the incidence of atherosclerotic vascular disease.

Statins are drugs that reduce the synthesis of cholesterol and the secretion of VLDL and increase the activity of LDL receptors. Bile acid– binding resins increase the secretion of bile acids. Nicotinic acid reduces the secretion of VLDL and the formation of LDL and increases the formation of HDL. Fibrates reduce the secretion of VLDL and increase the activity of lipoprotein lipase, thereby increasing the removal of triglycerides.

Older and younger men and women with atherosclerotic vascular disease and a serum LDL cholesterol greater than 125 mg/dL despite dietary treatment should be treated with statin drugs to lower the serum LDL cholesterol to below 100 mg/dL. Statins will decrease serum total and LDL cholesterol and triglycerides, increase serum HDL cholesterol, and reduce in these patients all-cause mortality, cardiovascular mortality, major coronary events, stroke, heart failure, angina pectoris, and peripheral arterial disease. Because mortality rates and cardiovascular events increase with age, statins will reduce all-cause mortality, cardiovascular mortality, and cardiovascular events approximately twice as much in men and women sixty-five years of age and older than in men and women younger than sixty-five years.

Older and younger men and women with atherosclerotic vascular disease and a normal serum LDL cholesterol but a low serum HDL cholesterol should be treated with nicotinic acid or gemfibrozil to reduce cardiovascular events.

Older and younger persons without atherosclerotic vascular disease with a serum LDL cholesterol of 160 mg/dL or higher and two other coronary risk factors (including older age, male gender, smoking, hypertension, diabetes mellitus, low serum HDL cholesterol, and family history), or with a serum LDL cholesterol of 130 mg/dL or higher and a low serum HDL cholesterol, or with a serum LDL cholesterol of 190 mg/dL or higher and no other coronary risk factors should be treated with statins to reduce cardiovascular events.