DESCRIPTION
Numerous lipid and non-lipid biomarkers have been proposed as potential risk markers for cardiovascular disease.
This policy addresses apolipoprotein A-1, apolipoprotein B, apolipoprotein E, HDL subclass, LDL subclass, and lipoprotein(a) only.
Apolipoprotein A-I: HDL contains two associated apolipoproteins, A-I and A-II. HDL particles can also be classified by whether they contain apolipoprotein A-I (apo A-I) only or whether they contain both apo A-I and A-II. All lipoproteins contain apo A-I and some also contain apo A-II. Since all HDL particles contain apo A-I, this lipid marker can be used as an approximation for HDL number, similar to the way apo B has been proposed as an approximation of the LDL number. Direct measurement of apolipoprotein A-I has been proposed as more accurate than the traditional use of HDL level in evaluation of the cardio-protective, or “good,” cholesterol.
Apolipoprotein B: Apolipoprotein B (apo B) is the major protein moiety of all lipoproteins except for high-density lipoprotein (HDL). The most abundant form of apo B, large B or B-100, constitutes the apo B found in low-density lipoproteins (LDL) and very-low-density lipoproteins (VLDL). Since both LDL and VLDL each contain 1 molecule of apolipoprotein B, measurement of apo B reflects the total number of these atherogenic particles, 90% of which are LDL. Since LDL particles can vary both in size and in cholesterol content, for a given concentration of LDL-C, there can be a wide variety of both size and numbers of LDL particles. Thus, it has been proposed that apo B is a better measure of the atherogenic potential of serum LDL than is LDL concentration.
Apolipoprotein E: Apolipoprotein E (apo E) is the primary binding protein for LDL receptors in the liver and is it is proposed that it plays an important role in lipid metabolism. The apo E gene is polymorphic, consisting of 3 alleles (e2, e3, and e4) that code for 3 protein isoforms, known as E2, E3, and E4, which differ from one another by one amino acid. These molecules mediate lipid metabolism through their different interactions with the LDL receptors. The genotype of apo E alleles can be assessed by gene amplification techniques, or the apo E phenotype can be assessed by measuring plasma levels of apolipoprotein E. It has been proposed that various apo E genotypes are more atherogenic than others, that apo E measurement may provide information on risk of coronary artery disease above traditional risk factor measurements, and that the apo E genotype may be useful in the selection of specific components of lipid-lowering therapy, such as drug selection.
HDL subclass: It has been proposed that various subclasses of HDL may have a greater role in protection from atherosclerosis. Particles of HDL can be characterized based on size/density and/or on the apolipoprotein composition. Using size/density, HDL can be classified into HDL2 which is a larger, less dense particle that may have the greatest degree of cardioprotection and the HDL3 is a smaller denser particle. HDL particles can also be classified by whether they contain apolipoprotein A-I (apo A-I) only or whether they contain both apo A-I and A-II. Particle size can be measured by nuclear magnetic resonance (NMR) spectroscopy or by gradient-gel electrophoresis. Several commercial labs offer these measurements of HDL particle size and number. Measurement of apo A-I has used measurement of HDL particle number as a surrogate, based on the premise that each HDL particle contains one apo A-I molecule.
LDL subclass: Low-density lipoprotein (LDL) subclass testing has been proposed as a source of quantitative and qualitative LDL information. The test provides the number of LDL particles, particle size, and concentrations of subclasses including intermediate density lipoprotein (IDL), subclasses of high-density lipoprotein (HDL), and subclasses of very low-density lipoprotein (VLDL). Much of serum cholesterol is transported in LDL particles. Approximately three fourths of the total cholesterol in normal human plasma is contained within LDL particles. Each major class of plasma lipoprotein (VLDL, LDL, and HDL) comprises subclass particles of varying sizes. Subclass pattern B is a commonly inherited disorder associated with a more atherogenic lipoprofile. It consists of higher levels of triglyceride, apoprotein B, IDL, VLDL and lower levels of HDL.
Lipoprotein(a): Lipoprotein(a) (lp[a]) is a lipid-rich particle similar to low density lipoprotein (LDL). The apolipoprotein (a) molecule is structurally similar to plasminogen, suggesting that Lp(a) may contribute to the thrombotic and atherogenic basis of cardiovascular disease. Levels of Lp(a) are relatively stable in individuals over time, but vary up to 1000-fold between individuals, presumably on a genetic basis. In addition, the distribution of Lp(a) varies among racial and ethnic groups. The similarity between apolipoprotein (a) and fibrinogen has stimulated intense interest in Lp(a) as a link between atherosclerosis and thrombosis. Blood levels of Lp(a) have been extensively studied as a cardiovascular risk factor in a variety of settings using a variety of study methodologies.
POLICY
Measurement of lipid risk factors (i.e., apolipoprotein A-I, apolipoprotein B, apolipoprotein E, LDL subclass, HDL subclass, lipoprotein(a) as an adjunct to LDL cholesterol in the risk assessment and management of cardiovascular disease is considered investigational.
See also:
IMPORTANT REMINDER
We develop Medical Policies to provide guidance to Members and Providers. This Medical Policy relates only to the services or supplies described in it. The existence of a Medical Policy is not an authorization, certification, explanation of benefits or a contract for the service (or supply) that is referenced in the Medical Policy. For a determination of the benefits that a Member is entitled to receive under his or her health plan, the Member's health plan must be reviewed. If there is a conflict between the Medical Policy and a health plan, the express terms of the health plan will govern.
ADDITIONAL INFORMATION
In the absence of well-designed randomized controlled trials, no conclusions can be drawn about whether lipoprotein(a) enzyme immunoassay in the management of cardiovascular disease has an effect on health outcomes.
While studies show that the application of apolipoprotein B testing does predict the risk of cardiovascular disease, there are no studies to demonstrate that knowledge of apo B test results would change the treatment regiment or improve outcome. The National Heart, Lung, and Blood Institute, the American College of Cardiology Foundation, and the American Heart Association endorsed a recommendation to lower the LDL-C target levels by 30 mg/dL. With these more aggressive targets of therapy the necessity of measuring apo B comes into question. None of the major guidelines, such as NCEP ATP III, have formally incorporated the measurement of apo B into their recommendations.
Some evidence suggests that apolipoprotein E (apo E) isoforms have different effects on serum cholesterol and triglyceride levels and may influence the risk of developing cardiovascular disease. However, the effect of the apo E isoform types on lipid metabolism and development of atherosclerosis is complex and incompletely understood and, to date, no health benefit has been associated with apo E testing. The current literature is limited and does not provide evidence that apo E testing will change treatment choices or health outcomes.
Small LDL size is one component of an atherogenic lipid profile that also includes increased triglycerides, increased apolipoprotein B, and decreased HDL. Some studies have reported that LDL size is an independent risk factor for coronary artery disease, and others have reported that a shift in LDL size may be a useful marker of treatment response. However, the direct clinical application of measuring small, dense lipoprotein particles is still unclear. Moreover, improved ability to predict risk and/or treatment response does not by itself result in better health outcomes.
The published data is yet inadequate to determine how such measurements should guide treatment decisions and whether these treatment decisions result in beneficial outcomes. Other associated lipid parameters, such as triglycerides and HDL levels may be more useful than LDL size in assessing risk and treatment response. The Adult Treatment Panel (ATP) III practice guidelines continue to tie clinical decision making to conventional lipid measures, such as total cholesterol, LDL-C, and HDL-C.
SOURCES
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ORIGINAL EFFECTIVE DATE: 12/12/2011
MOST RECENT REVIEW DATE: 12/12/2011
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