BlueCross and BlueShield of Montana Medical Policy/Codes
High Density Lipoprotein Subclass Testing in the Diagnosis and Management of Cardiovascular Disease
Chapter: Medicine: Tests
Current Effective Date: August 27, 2013
Original Effective Date: September 18, 2003
Publish Date: August 27, 2013
Revised Dates: August 20, 2012; July 26, 2013

High density lipoprotein (HDL) particles exhibit considerable heterogeneity, and 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, the larger, less dense particles that may have the greatest degree of cardioprotection, and HDL3, which are smaller, denser particles. HDL contains 2 associated apolipoproteins, i.e., 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 apolipoprotein A-II (apo A-II). There has been substantial interest in determining whether subclasses of HDL can be used to provide additional information on cardiovascular risk compared to HDL alone.

An alternative to measuring the concentration of subclasses of HDL, such as HDL2 and HDL3, is direct measurement of HDL particle size and/or number. Particle size can be measured by nuclear magnetic resonance (NMR) spectroscopy or by gradient-gel electrophoresis. HDL particle numbers can be measured by NMR spectroscopy. 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.


Each benefit plan, summary plan description or contract defines which services are covered, which services are excluded, and which services are subject to dollar caps or other limitations, conditions or exclusions. Members and their providers have the responsibility for consulting the member's benefit plan, summary plan description or contract to determine if there are any exclusions or other benefit limitations applicable to this service or supply. If there is a discrepancy between a Medical Policy and a member's benefit plan, summary plan description or contract, the benefit plan, summary plan description or contract will govern.


Blue Cross and Blue Shield of Montan (BCBSMT) considers high density lipoprotein (HDL) subclass testing experimental, investigational and unproven for the diagnosis and management of cardiovascular disease.


This policy was originally developed in 2003 and has been updated with searches of scientific literature through April 2013. This section of the current policy has been substantially revised. The following is a summary of the key literature to date.

High density lipoprotein (HDL) subclass as a predictor of cardiovascular risk

A large number of prospective observational studies have examined the relationship between HDL subclass and cardiovascular risk. A representative sample of some of the most salient studies is discussed below.

In the Kuopio Ischemic Heart Disease Risk Factor Study, both total HDL-C and levels of HDL-2 had significant independent associations with risk of acute myocardial infarction (MI). (3) The Quebec Cardiovascular Study investigated the association of HDL-2 and HDL-3 subclasses with ischemic heart disease in a subsample of 944 French-Canadian men participating in the larger trial. (1) During the 10-year follow-up, levels of HDL-2 were statistically significant as independent predictors of CAD events, but the difference in predictive value with and without HDL subclasses was not considered clinically significant.

In contrast, some studies have not reported HDL subclassification to be an independent predictor of coronary artery disease (CAD). The Atherosclerosis Risk in Communities (ARIC) study, a large prospective cohort study, followed 12,000 middle-aged individuals free of CAD at baseline for 10 years. (2) In this study, prediction of CAD was not improved by the addition of either apo A-I levels or HDL density. Similarly, in the Physicians’ Health Study (4) and the Caerphilly and Speedwell Collaborative Heart Disease Studies, (5) both of which were studies of middle-aged men, risk prediction based on HDL-C was also not improved by HDL subclassification.

Measurement of HDL Particle Size and Concentration by NMR

The relationship between HDL particle size and the risk of coronary heart disease was examined in the European Prospective Investigation of Cancer (EPIC)- -Norfolk cohort study using a nested case-control design. (6) In the EPIC-Norfolk study, healthy individuals between the ages of 45-79 years were enrolled and followed for the development of coronary disease. The nested case control study matched 1,035 individuals who developed coronary disease with 1,920 controls who did not develop coronary disease. Small particle size was associated with an adverse cardiometabolic risk profile, and an increased risk of coronary disease in men (odds ratio [OR]: 1.43; 95% confidence interval (CI): 1.01-2.03) but not in women (OR: 0.84; 95% CI: 0.52-1.35).

In a post-hoc analysis from the EPIC-Norfolk study, El Harchaoui et al. (7) measured HDL particle size and number using NMR spectroscopy and gradient gel electrophoresis. The authors reported numerous multivariate regression models, controlling for various combinations of other lipid measures. HDL particle number was an independent predictor of CAD risk in all of the models reported. HDL particle size was an independent predictor in some models, but significance was lost when apo B was included as a covariate.


Numerous measures have been used in HDL subclass testing. The current evidence generally supports the contention that HDL subclass testing may add independent predictive information to standard lipid measurements. To improve outcomes, clinicians must have the tools to translate this information into clinical practice. The tools for linking HDL subclasses to clinical decision making (both in risk assessment and treatment response) are currently not available. HDL subclassification has not been incorporated into quantitative risk assessment models or treatment guidelines that can be used in clinical practice, such as the Adult Treatment Panel (ATP) III. The ATP III practice guidelines continue to tie clinical decision making to conventional lipid measures, such as total cholesterol, Low density lipoprotein cholesterol (LDL-C), and high density lipoprotein cholesterol (HDL-C). Therefore, it is not yet possible to conclude that these measures improve outcomes or that they should be adopted in routine clinical care.

None of the available evidence is sufficient to demonstrate impact on clinical outcomes or to prompt reconsideration of the current policy statement, which remains unchanged.


Disclaimer for coding information on Medical Policies

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.

The presence or absence of procedure, service, supply, device or diagnosis codes in a Medical Policy document has no relevance for determination of benefit coverage for members or reimbursement for providers. Only the written coverage position in a medical policy should be used for such determinations.

Benefit coverage determinations based on written Medical Policy coverage positions must include review of the member’s benefit contract or Summary Plan Description (SPD) for defined coverage vs. non-coverage, benefit exclusions, and benefit limitations such as dollar or duration caps. 

ICD-9 Codes
Investigational for all diagnoses.
ICD-10 Codes
Investigational for all diagnoses.
Procedural Codes: 83701, 83704
  1. Lamarche B, Moorjani S, Lupien PJ et al. Apolipoprotein A-I and B levels and the risk of ischemic heart disease during a five-year follow-up of men in the Quebec cardiovascular study. Circulation 1996; 94(3):273-8.
  2. Sharrett AR, Ballantyne CM, Coady SA et al. Coronary heart disease prediction from lipoprotein cholesterol levels, triglycerides, lipoprotein (a), apolipoproteins A-I and B, and HDL density subfractions: The Atherosclerosis Risk in Communities (ARIC) Study. Circulation 2001; 104(10):1108-13.
  3. Salonen JT, Salonen R, Seppanen K et al. HDL, HDL2, and HDL3 subfractions, and the risk of acute myocardial infarction. A prospective population study in eastern Finnish men. Circulation 1991; 84(1):129-39. 71. Stampfer MJ, Sacks FM, Salvini S et al. A prospective study of cholesterol, apolipoproteins, and the risk of myocardial infarction. N Engl J Med 1991; 325(6):373-81.
  4. Stampfer MJ, Sacks FM, Salvini S et al. A prospective study of cholesterol, apolipoproteins, and the risk of myocardial infarction. N Engl J Med 1991; 325(6):373-81.
  5. Sweetnam PM, Bolton CH, Yarnell JW et al. Associations of the HDL2 and HDL3 cholesterol subfractions with the development of ischemic heart disease in British men. The Caerphilly and Speedwell Collaborative Heart Disease Studies. Circulation 1994; 90(2):769-774.
  6. Arsenault BJ, Lemieux I, Despres JP et al. HDL particle size and the risk of coronary heart disease in apparently healthy men and women: the EPIC-Norfolk prospective population study. Atherosclerosis 2009; 206(1):276-81.
  7. El Harchaoui K, Arsenault BJ, Franssen R et al. High-density lipoprotein particle size and concentration and coronary risk. Ann Intern Med 2009; 150(2):84-93.
  8. Novel Lipid Risk Factors in Risk Assessment and Management of Cardiovascular Disease Chicago, Illinois: Blue Cross Blue Shield Association Medical Policy Reference Manual (2012 July) Pathology/Laboratory 2.04.65.
August 2012  Policy re-created from Cardiac Risk Factors Policy with literature search through May 2012. Measurement of novel lipid risk factors (i.e., apolipoprotein B, apolipoprotein A-I, apolipoprotein E, LDL subclass, HDL subclass, lipoprotein[a]) is considered investigational as an adjunct to LDL cholesterol in the risk assessment and management of cardiovascular disease.
August 2013 Policy formatting and language revised.  Title changed from "Novel Lipid Risk Factors in Risk Assessment and Management of Cardiovascular Disease" to "High Density Lipoprotein Subclass Testing in the Diagnosis and Management of Cardiovascular Disease".  Removed CPT codes 82172, 82664, 83695, 83700, and 84181.
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High Density Lipoprotein Subclass Testing in the Diagnosis and Management of Cardiovascular Disease