eMedicine Specialties > Endocrinology > Metabolic Disorders
Hypercholesterolemia, Polygenic
Updated: May 15, 2006
Introduction
Background
Polygenic hypercholesterolemia (nonfamilial hypercholesterolemia is the preferred term) is the most common form of elevated serum cholesterol concentrations. Generally, nonfamilial hypercholesterolemia manifests as moderate hypercholesterolemia (240-350 mg/dL) with serum triglyceride concentrations within the reference range. However, practically speaking, the material in this article is also relevant to patients with mixed dyslipidemias with triglyceride levels of less than 350 mg/dL.
This condition is caused by a susceptible genotype aggravated by excessive saturated fat, trans fatty acid, and cholesterol intake (although the actual effect of cholesterol intake is small). The involved genes have yet to be discovered. Nonfamilial hypercholesterolemia is associated with an increased risk for coronary heart disease (CHD), as displayed in Image 1. Recent studies that show the efficacy of cholesterol-reduction strategies in the reduction of CHD events, even in patients with serum cholesterol concentrations of less than 240 mg/dL, suggest that lower cholesterol concentrations should be viewed as desirable.
The first guidelines of the US National Cholesterol Education Program (NCEP) were published in 1988 and revised in 1993 and 2001.
Pathophysiology
Low-density lipoprotein (LDL) particles are the major plasma carriers of cholesterol. Therefore, the serum cholesterol measurement is usually a surrogate for the low-density lipoprotein cholesterol (LDL-C) concentration, except in patients with excessive very low-density lipoprotein (VLDL) levels and chylomicron particles that manifest as high serum triglyceride levels. For a simplified diagram of cholesterol metabolism, see Image 2. Elevated LDL-C concentrations may be the consequence of elevated LDL production or decreased LDL cellular uptake. Diets high in saturated fat, trans fat, and cholesterol appear to cause a reduction in LDL receptors in the liver, thus retarding LDL catabolism.
Although the liver may directly secrete some LDL, whether increased direct hepatic LDL output is a factor in elevated LDL states is unknown. Overproduction of VLDL can obviously lead to increased LDL levels because VLDL is converted to LDL; however, many patients with elevated VLDL (triglyceride) levels have reduced LDL concentrations due to accelerated VLDL metabolism. Some patients with mixed dyslipidemias probably have nonfamilial hypercholesterolemia that manifests as elevated LDL-C concentrations and insulin resistance that manifests as low high-density lipoprotein cholesterol (HDL-C) levels, high triglyceride values, or both.
Frequency
United States
The guidelines of the American Heart Association and the NCEP Adult Treatment Panel III (ATP III) define hypercholesterolemia as a blood cholesterol concentration of greater than or equal to 240 mg/dL. Desirable cholesterol concentrations are less than 200 mg/dL. The National Health and Nutrition Examination Survey III, performed from 1988-1991, discovered that 26% of American adults had high blood cholesterol concentrations and 49% had desirable values. According to the NCEP ATP III guidelines, all adults aged 20 years or older should have a fasting lipid profile determined at least every 5 years to assess CHD risk. Sixty-five million American adults qualify for therapeutic lifestyle changes, while 36 million US adults need pharmacologic therapy to reach NCEP ATP III goals.
International
Serum cholesterol concentrations vary widely throughout the world. Generally, countries associated with low serum cholesterol concentrations (eg, Japan) have lower CHD event rates, while countries associated with very high serum cholesterol concentrations (eg, Finland) have very high CHD event rates. However, some populations with similar total cholesterol levels have very different CHD event rates, suggesting that other factors also influence CHD risk.
Mortality/Morbidity
The primary manifestation of hypercholesterolemia is increased CHD risk. Data from epidemiological studies (eg, the Multiple Risk Factor Intervention Trial and the Framingham Heart Study) show a relationship between an increase in serum cholesterol concentrations and CHD events and CHD mortality rates. Recent studies have shown that CHD morbidity and mortality can be reduced with therapies that lower serum LDL-C levels. More recent data also suggest a relationship between thrombotic, but not hemorrhagic, stroke rates and serum cholesterol concentrations; furthermore, recent data indicate that therapy with statins reduces atherothrombotic stroke risk in patients with CHD.
Race
Among adults, National Health and Nutrition Examination Survey III data (1988-1992) show more frank hypercholesterolemia among non-Hispanic white persons (19%) than Mexican Americans (15%) or non-Hispanic black persons (16%).
Sex
Hypercholesterolemia is more common in men younger than 55 years and in women older than 55 years.
Age
Hypercholesterolemia increases with advancing age in adults (see Image 3).
Clinical
History
Hypercholesterolemia is usually discovered during routine screening and does not produce symptoms. Hypercholesterolemia is more common in individuals with a family history of the condition, but lifestyle factors (eg, a diet high in saturated fat) clearly play a major role.
Physical
Tendon xanthomas are not present in persons with nonfamilial hypercholesterolemia. If tendon xanthomas are present, familial hypercholesterolemia or familial defective apoprotein B-100 is the correct diagnosis. Eruptive xanthomas signify extreme hypertriglyceridemia. Xanthelasma may be present but does not necessarily indicate hypercholesterolemia. Secondary hypercholesterolemia is suggested by stigmata of liver disease, hypothyroidism, hypopituitarism, nephrotic syndrome, and chronic renal disease.
Causes
Several drugs and disease states are associated with hypercholesterolemia; however, for the overwhelming majority of patients, the Western lifestyle of a high-fat diet superimposed on a susceptible genotype appears to cause hypercholesterolemia. Nonetheless, ensuring that the patient does not have untreated hypothyroidism, renal disease, or liver disease is important. Furthermore, progestins, anabolic steroids, and glucocorticoids may adversely affect low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) values.The risk factors for coronary heart disease (CHD), other than LDL-C, in the US National Cholesterol Education Program (NCEP) screening and treatment algorithm are as follows:
- Age and sex
- Men aged 45 years or older
- Women aged 55 years or older
- Family history of premature CHD (male first-degree relative <55 y, female first-degree relative <65 y)
- Current cigarette smoking
- Hypertension - Blood pressure greater than or equal to 140/90 mm Hg or current antihypertensive drug therapy
- Low HDL-C concentration - Less than 40 mg/dL, but 1 risk factor subtracted if HDL-C concentration is more than 60 mg/dL (This level has been increased from <35 mg/dL compared with the value from the NCEP Adult Treatment Panel II [NCEP ATP II].)
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Further Reading
Keywords
polygenic hypercholesterolemia, nonfamilial hypercholesterolemia, non-familial hypercholesterolemia cholesterol, coronary heart disease, CHD, atherothrombotic stroke, statin therapy, atherosclerosis, heart disease, high cholesterol
