Lipoprotein Syndromes, Primary/Non-Genetic

At a Glance

Chances are that roughly 50% of patients suffer from primary, nongenetic hyperlipoproteinemia. This is because unhealthy cholesterol levels (≥200 mg/dL) are common in the United States.

Unlike most lab values, the thresholds used for cholesterol are "decision limits," rather than typical reference intervals (normal ranges). Typical reference intervals encompass the central 95% of values in an apparently healthy population, so that only 2.5% of healthy people have values above the upper limit (another 2.5% have values below the lower limit). Many studies have shown that the risk of coronary heart disease (CHD) increases on a continuum as cholesterol (more specifically, Low Density Lipoprotein cholesterol (LDLc)) levels increase. At a level of 200 mg/dL (or an LDLc of roughly 130 mg/dL), the increased risk of death from CHD is roughly two-fold; at 240 mg/dL (an LDLc of 160 mg/dL), roughly three-fold. More than 50% of American adults have cholesterol values greater than 200 mg/dL, thus, putting them at significantly increased risk.

The most recent guidelines from the Adult Treatment Panel (ATP III) of the National Cholesterol Education Program (NCEP) recommend all adults be screened beginning at 20 years of age. The primary target of therapy is LDLc, and the specific goal varies based on other cardiac risk factors:

  1. For patients with known CHD or its equivalents (e.g., symptomatic carotid artery disease, peripheral arterial disease, abdominal aortic aneurysm, or Diabetes Mellitus), the LDLc goal is less than 100 mg/dL.

  2. For other patients with two or more cardiac risk factors (i.e., cigarette smoking, hypertension, High Density Lipoprotein cholesterol (HDLc) <40 mg/dL, family history of premature CHD, men 45 years of age or older or women 55 years of age or older), the LDLc goal is less than 130 mg/dL. Note that an HDLc greater than or equal to 60 mg/dL counts as a negative cardiac risk factor; that is, you subtract 1 from the sum of the other factors for such patients

  3. For everyone else, the LDLc goal is less than 160 mg/dL

What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?

If LDLc is measured directly, either a nonfasting or a fasting sample can be used. Measurement of LDLc once required the use of ultracentrifugation, a technique beyond the capability of most clinical laboratories. Over the past decade or so, reasonably simple methods for measurement of LDLc have been developed and are offered by many clinical laboratories.

However, the most common method for determining LDLc is a calculation that does require the use of a fasting sample with a triglyceride value less than 400 mg/dL. One should order total cholesterol, HDLc, and triglcyerides, and the LDLc is calculated according to the Friedewald equation as follows:

Calculated LDLc = Total Cholesterol – HDLc – (Triglycerides/5)

In other words, the calculated LDLc is not valid on a nonfasting sample (even with a triglyceride <400 mg/dL) or on a fasting sample with a triglyceride value greater than 400 mg/dL. A fasting sample requires that the patient not take in any calories for 8-12 hours preceding the blood sample collection; it is acceptable to drink water.(Table 1)(Table 2)(Table 3)

Table 1.

Assessment: LDL Cholesterol
LDLc (mg/dL) Interpretation
<100 Optimal
100-129 Near Optimal
130-159 Borderline High
160-189 High
>189 Very High

Table 2.

Assessment: Total Cholesterol
Total Cholesterol (mg/dL) Interpretation
<200 Desirable
200-239 Borderline High
>239 High

Table 3.

Assessment: HDL Cholesterol
HDLc (mg/dL) Interpretation
<40 Higher Risk
>60 Lower Risk

Are There Any Factors That Might Affect the Lab Results? In particular, does your patient take any medications - OTC drugs or Herbals - that might affect the lab results?

If, on a fasting sample, the patient exceeds his or her LDLc goal, the test should be repeated on a second sample drawn 1-8 weeks later to ensure the value is a genuine reflection of the patient's true value. One uses the mean of the values from the two samples, unless the differences are substantial (e.g., >30 mg/dL in total cholesterol), in which a case third sample should be obtained.

Laboratory measurements are quite precise, but measurements of cholesterol on the same specimen in the same laboratory may vary by as much as 6%. More important, even if the laboratory measurements were perfectly reproducible, intra-individual, day-to-day variability is typically 10% and can be as high as 30%. In other words, a patient whose LDLc is reported as 145 mg/dL could easily have a value as low as 125 mg/dL or as high as 165 mg/dL, which are values spanning three LDLc target concentrations.

Similar statements apply to screening with nonfasting samples. NCEP guidelines allow for using nonfasting samples in which case one relies only on the total cholesterol and HDLc values. The guidelines state that a patient whose total cholesterol is less than 200 mg/dL and whose HDLc is greater than 40 mg/dL need not be tested again for 5 years. Given the analytic and physiologic variability cited, it makes more sense medically to retest patients whose total cholesterol is 180 mg/dL or higher or whose HDLc is 45 mg/dL or lower.

On a fasting sample, one should order cholesterol, HDLc, and triglcyerides. If the triglycerides are less than 400 mg/dL, the calculated LDLc can be used to assess whether the patient is at his LDLc goal. A second measurement should be made 1-8 weeks later to verify the concentrations before initiating or changing therapies.

If the initial sample is nonfasting, one should order total cholesterol and HDLc. If these values are not acceptable, a second sample should be drawn 1-8 weeks later. This second sample should be a fasting sample for cholesterol, HDLc, and triglycerides to allow for calculation of LDLc.

What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?

Plasma versus Serum

Although it is rarely an issue, it is important to note that all of the concentrations cited assume the sample is serum (obtained from a sample drawn into a tube without anticoagulants, typically a red top tube with or without a gel separator). If, instead, a plasma sample is used (e.g., a tube containing heparin or EDTA (ethylenediaminetetraacetic acid), the values obtained will be roughly 3% lower than serum, so the decision limits should all be lowered by 3%. Thus, the desirable level for total cholesterol would be 194 mg/dL, rather than 200 mg/dL.

Friedewald Equation Caveats

Several simplifying assumptions are embedded in the Friedewald equation. In truth, the total cholesterol concentration is the sum of contributions from several particles that may be circulating in any given patient's blood:

Total Cholesterol = HDLc + LDLc + VLDLc + IDLc + Lp(a)c,

where HDLc is the cholesterol contained in High Density Lipoprotein (HDL) particles; LDLc is the cholesterol contained in Low Density Lipoprotein (LDL) particles; VLDLc is the cholesterol contained in Very Low Density Lipoprotein (VLDL) particles; IDLc is the cholesterol contained in Intermediate Density Lipoprotein (IDL) particles (present in Type III Hyperlipidemia); and Lp(a)c is the cholesterol contained in Lipoprotein(a) (Lp(a)) particles. It is rare that samples contain either IDL or Lp(a) particles, so, as a reasonable assumption, the Friedewald equation assumes that neither is present and, thus, can be ignored.

The second, and more important assumption, is that no chylomicrons are present. Except for patients with hereditary conditions in which chylomicrons circulate in fasting samples (e.g., Type I and V Hyperlipidemias), a fasting sample should suffice to ensure the absence of chylomicrons. If this is the case, then assume that all the triglycerides come from VLDL particles, because there is very little triglyceride present in HDL and LDL particles. Given this assumption, one can divide the triglyceride concentration by 5 to estimate the cholesterol concentration in the VLDL particles. (If concentrations are reported in SI units (mmol/L), the underlying concepts are the same but a factor different from 5 is used.)

The final caveat in the Friedewald equation is that it works reasonably well so long as the triglyceride concentration in the fasting sample is no higher than 400 mg/dL. At higher concentrations, dividing the triglyceride concentration by 5 no longer provides a good estimate of the VLDLc concentration.


Because of some of the limitations in using calculated LDLc, some authorities advocate using, instead, "non-HDLc":

Non-HDLc = Total Cholesterol – HDLc

This parameter has several advantages over calculated LDLc. First, a fasting sample is not required. Second, VLDLc is included in this value, which makes sense, since VLDL particles are most likely somewhat atherogenic. Third, when the Friedewald equation is used on nonfasting samples (an all too common occurrence), the LDLc is underestimated, because the triglycerides in chylomicrons are ascribed to VLDL particles and the resulting cholesterol is subtracted from the total cholesterol. Finally, no assumptions are made about the absence of IDL particles or Lp(a) particles, both of which, if present, are probably atherogenic.

If one chooses to use non-HDLc, the decision limits are 30 mg/dL higher than the LDLc limits. That is, for a patient with no cardiac risk factors, the target non-HDLc is less than 190 mg/dL (rather than LDLc <160 mg/dL).


Variability in laboratory measurements is usually described in terms of the coefficient of variation (CV), which represents the standard deviation divided by the mean value of a series of measurements of the same specimen. A different way of thinking about this is to say that the mean value, plus or minus two times the CV, represents the range of values in which a measurement would fall 95% of the time. For most modern cholesterol methods, the CV is roughly 3%. Thus, a sample whose true value is 200 mg/dL would have measured values from as low as 188 (–2×3%) to as high as 212 (+2×3%). If trying to find patients whose true cholesterol is 200 or higher, it makes little sense not to repeat the measurement on a patient whose initial measurement is 199.

Similarly, it has been shown that any given individual's cholesterol concentration exhibits substantial variability from day to day. If you calculate the mean and standard deviation of a series of such values from any given individual, you can determine that individual's CV. In general, this physiologic CV is about 5%, but it can be much higher. Thus, even in the best case scenario with a CV of 5%, the cholesterol value from any one sample could be as much as 10% lower or higher than the true value for that individual.

Other Lab Tests for Cardiac Risk

This entire discussion has focused on the traditional lipid markers used in the assessment of cardiac risk: total cholesterol, HDLc, triglyceride, and LDLc. This is because there is little evidence to support the routine use of other markers, even though they are widely promoted in the lay press, by commercial laboratories, and online. Included among these tests are apo A-1, apo B-100, Lp(a), homocysteine, and C-Reactive Protein (CRP).

Apo A-1 and apo B-100 are the apolipoproteins uniquely associated with the HDL and LDL particles, respectively. Apo A-1 and apo B-100 levels are, thus, very highly correlated with HDLc and LDLc levels, respectively. Not surprisingly, low apo A-1 levels and high apo B-100 levels are associated with increased cardiac risk. However, neither parameter adds incremental information to that available from HDLc and LDLc. As a result, it is difficult to recommend their routine use. Conversely, these parameters can be helpful in confirming extremely high or low HDLc or LDLc results.

Lp(a) may be an atherogenic particle, but it is present in very few people. Modifying levels of Lp(a) is exceptionally difficult, so it is not clear that knowing its level is clinically useful. There are two ways to report Lp(a): one can measure the Lp(a) cholesterol (analogous to LDLc) or the apo (a) levels (analogous to Apo B-100). Standardization of both types of assay is poor. For these reasons, few people recommend measuring Lp(a).

More recently, homocysteine was touted as a new cardiac risk marker. In contrast to Lp(a), relatively well-standardized assays are widely available, but this marker has never been endorsed as useful by NCEP. Of note, with the routine supplementation of the foods in the United States with increased folate several years ago, population levels of homocysteine decreased, probably blunting the marginal utility of the parameter. Again, few people recommend measuring homocysteine as a cardiac risk marker.

Finally, the marker that received the most publicity is CRP. There are many studies showing that higher levels of CRP, within the normal range, are associated with higher levels of cardiac risk, and the notion that CHD is related as much to inflammation as to atherogenesis is widely accepted. However, the American Heart Association, the Centers for Disease Control, and the NCEP all agree that CRP levels should be measured and used only after the traditional lipid parameters have been assessed completely and, even then, only to classify patients whose categorization is otherwise borderline. According to these authorities, CRP levels should be interpreted as follows: less than 1.0 mg/L is low risk; 1.0-3.0 mg/L is intermediate risk; greater than 3.0 mg/L is high risk. Once again, this marker should not be used in place of the traditional cardiac risk markers; it is, at best, a secondary marker.

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