From The Merck Manual of Diagnosis and Therapy, Seventeenth Edition, Merck Research Laboratories, Whitehouse Station N.J. pages 201-202, (1999)

Diagnosis

In diagnosing hyperlipoproteinemia, a normal plasma TC levels is difficult to define. Prospective studies have shown that the incidence of coronary artery disease (CAD) rises continuously with plasma TC and that values previously considered normal in, the USA are higher, than those found among populations, with a low incidence of atherosclerosis In addition. evidence (from well-designed prospective clinical trials) shows that lowering even average American levels of TC (and LDL) in patients with CAD slows or reverses the progression of CAD.

The optimal plasma TC for a middle-aged adult free of CAD is probably $\leq$ 200 mg/dL $\leq$ 5.18 mmol/dL). Hypereholosterolemia has usually been defined as a value above the 95th percentile for the population, which ranges from 210 mg/dL (5.44 mmol/dL) in Americans <20 yr. old to > 280 mg/dL (>7.25 mmol/dL) in those > 60 yr. old. However, these limits are clearly excessive because of the known high risk of cardiovascular disease at these levels. A consensus of the National Cholesterol Education Program (NCEP) defines TC levels <200 mg/dL (5.18 mmol/dL) as desirable, levels between 200 and 240 mg/dL (5.18 and 6.22 mmol/dL) as borderline high, and levels >240 mg/dL (> 6.22 rnmol/dL) as high.

For patients without clinical evidence of coronary or other atherosclerotic vascular disease, the NCEP recommends health screening, including measurement of TC and HDL cholesterol, at least once every 5 yr. Further evaluation is performed for those patients with a high TC, for those with low HDL cholesterol < 35 mg/dL (< 0.91 mmol/dL), or for those with borderline TC who have at least two CAD risk factors (age > 45 for men or > 55 for women [or postmenopausal state without estrogen replacement], high BP, smoking, diabetes, HDL < 35 mg/dL, or a family history of CAD before age 55 in a male first-degree relative or before age 65 in a female first-degree relative). This evaluation should include fasting levels of TC, triglyceride, and HDL. LDL is then calculated by applying the following formula: LDL cholesterol = TC - HDL cholesterol - triglyceride/5. (This formula is valid only when triglyceride is < 400 mg/dL (< 4.52 mmol/dL). A high HDL level (> 60 mg/dL (> 1.55 mmol/dL) is considered a negative risk factor and reduces the number of risk factors by one. The NCEP recommends that treatment decisions be based on the calculated level of LDL For patients with an elevated LDL ($\geq$ 160 mg/dL ($\geq$ 4.14 mmol/dL) who have fewer than two risk factors in addition to elevated LDL and who do not have clinical evidence of atherosclerotic disease, the goal of treatment is an LDL level < 160 mg/dL. For those who have at least two other risk factors, the goal of treatment is an LDL level < 130 mg/dL (< 3.37 mmol/dL). When LDL levels remain > 160 mg/dL despite dietary measures and the patient has two or more risk factors (in addition to high LDL), or when LDL levels remain > 190 mg/dL (> 4.92 mmol/dL) even without added risk factors, the addition of drug treatment should be considered. For those with CAD, peripheral vascular disease, or cerebrovascular disease, the goal of treatment is an LDL < 100 mg/dL (< 2.59 mmol/dL). All patients with clinical evidence of coronary or other atherosclerotic disease should be evaluated with a fasting blood sample for measurement of TC, triglyceride, and HDL. LDL is again calculated, as described above. In contrast to plasma TC, it is unclear whether plasma triglycerides are independent risk variables; like TC, they vary with age. A triglyceride level of < 200 mg/dL (< 2.26 mmol/dL) is considered normal, 200 to 400 mg/dL (2.26 to 4.52 mmol/dL) is borderline high, and > 400 mg/dL (> 4.52 mmol/dL) is high. Hypertriglyceridemia has been associated with diabetes, hyperuricemia, and pancreatitis (when levels are > 600 mg/dL).

As indicated below, even more information can be obtained about CAD risk by considering plasma TC as only one of several units of lipid transport-the lipoproteins. Sixty to 75 transported on LDL, the levels of which are directly related to cardiovascular risk. HDL, which normally accounts for 20 to 25 percent of the plasma TC, is inversely associated with cardiovascular risk. HDL levels are positively correlated with exercise, moderate alcohol intake, and estrogen replacement therapy and are inversely correlated with smoking, obesity, and the use of most progestin-containing contraceptives. Studies show that CAD prevalence at HDL levels of 30 mg/dL (0.78 mmol/dL) is more than double that at 60 mg/dL, and high levels of LDL or low levels of HDL are independently associated with increased CAD risk. One must determine, therefore, whether elevated TC levels are due to increased LDL or HDL. In countries or in groups (e.g., lactovegetarians, Seventh-Day Adventists) where TC and LDL cholesterol are low because of nutritional habits (marked reduction in ingestion of total saturated fats and cholesterol), HDL levels are often relatively low and the risk for CAD is low. In the U.S.- based Framingham Study, however, men and women (eating the typical high-fat American diet) with relatively normal LDL levels (120 to 160 mg/dL 4.14 mmol/dL) with HDL < 30 mg/dL were at increased risk for CAD.