YOU HAVE A NEW JOB: Monitor the lipid profile
The standard panel provides more details than you might imagine about your patient’s risk of cardiovascular disease
IN THIS ARTICLE
Dr. Dayspring serves on the advisory board for LipoScience. Dr. Helmbold reports no financial relationships relevant to this article.
Add another item to your ever-growing list of responsibilities: monitoring your patients’ risk of atherosclerosis.
This task used to be the purview of internists and cardiologists but, because gynecologists are increasingly serving as a primary care provider, you need to learn to recognize and diagnose the many clinical expressions of atherosclerosis in your aging patients.
A crucial part of that knowledge is a thorough understanding of each and every lipid concentration parameter reported within the standard lipid profile. This article reviews those parameters, explains how to interpret them individually and in combination, and introduces a new paradigm: the analysis of lipoprotein particle concentrations as a more precise way to determine risk.
If used in its entirety, the lipid profile provides a significant amount of information about the presence or absence of pathologic lipoprotein concentrations. Far too many clinicians focus solely on low-density lipoprotein cholesterol (LDL-C) and ignore the rest of the profile. Failure to consider the other variables is one reason why atherosclerotic disease is underdiagnosed and undertreated in the United States in many patients—especially women. 1
How to read a lipid panel in 6 quick steps
1. Look at the triglyceride (TG) level. If it is >500 mg/dL, treatment is indicated, and TG reduction takes precedence over all other lipid concentrations. If TG is <500 mg/dL, go to Step 2.
2. Look at the low-density lipoprotein cholesterol (LDL-C) level. If it is >190 mg/dL, drug therapy is indicated regardless of other findings. At lower levels, the need for therapy is based on the patient’s overall risk of cardiovascular disease (CVD). Therapeutic lifestyle recommendations are always indicated.
3. Look at high-density lipoprotein cholesterol (HDL-C). Increased risk is present if it is <50 mg/dL, the threshold for women. Do not assume that high HDL-C always means low CVD risk.
4. Calculate the total cholesterol (TC)/HDL-C ratio (a surrogate of apoB/apoA-I ratio). Increased risk is present if it is >4.0.
5. Calculate the non-HDL-C level (TC minus HDL-C). If it is >130 mg/dL (or >100 mg/dL in very-high-risk women), therapy is warranted. Newer data reveal that this calculation is always equal to, or better than, LDL-C at predicting CVD risk. Non-HDL-C is less valuable if TG is >500 mg/dL.
6. Calculate the TG/HDL-C ratio to estimate the size of LDL. If the ratio is >3.8, the likelihood of small LDL is 80%. (Small LDL usually has very high LDL-P.)
Why lipoproteins are important
There is only one absolute in atherosclerosis: Sterols—predominantly cholesterol—enter the artery wall, where they are oxidized, internalized by macrophages, and transformed into foam cells, the histologic hallmark of atherosclerosis. With the accumulation of foam cells, fatty streaks develop and, ultimately, so does complex plaque.
- noncholesterol sterols such as sitosterol, campesterol, and others of mostly plant or shellfish origin
- triacylglycerol, or triglycerides (TG)
Because lipids are insoluble in aqueous solutions such as plasma, they must be “trafficked” within protein-enwrapped particles called lipoproteins. The surface proteins that provide structure and solubility to lipoproteins are called apolipoproteins. A key concept is that, with their surface apolipoproteins and cholesterol core, certain lipoproteins are potential agents of atherogenesis in that they transport sterols into the artery wall. 2
Estimation of the risk of CVD involves careful analysis of all standard lipid concentrations and their various ratios, and prediction of the potential presence of atherogenic lipoproteins. Successful prevention or treatment of atherosclerosis entails limiting the presence of atherogenic lipoproteins.
A new paradigm is on its way
The atherogenicity of lipoprotein particles is determined by particle concentration as well as other variables, including particle size, lipid composition, and distinct surface apolipoproteins.
Lipoproteins smaller than 70 nm in diameter are driven into the arterial intima primarily by concentration gradients, regardless of lipid composition or particle size. 3 A recent Consensus Statement from the American Diabetes Association and the American College of Cardiology observed that quantitative analysis of these potentially atherogenic lipoproteins is one of the best lipid/lipoprotein-related determinants of CVD risk. 4 Lipoprotein particle concentrations have emerged not only as superb predictors of risk, but also as goals of therapy. 5-7
Because of cost, third-party reimbursement, varying test availability, and lack of interpretive knowledge, few clinicians routinely order lipoprotein quantification. Historically, CVD risk and goals of therapy have been based on lipid concentrations (the amount of lipids trafficked within lipoprotein cores) reported in the lipid profile. Guidelines from the National Cholesterol Education Program, Adult Treatment Panel III (NCEP ATP-III) 8,9 and the American Heart Association (AHA) CVD Prevention in Women 10,11 use lipid concentrations such as total cholesterol (TC), LDL-C, high-density lipoprotein cholesterol (HDL-C), and TG as estimates or surrogates of lipoprotein concentrations ( TABLE 1 ).
The day is rapidly approaching, however, when lipoprotein concentrations may replace the lipid profile in clinical practice. It is critical that clinicians develop a solid understanding of lipoprotein physiology and pathology. 7,12 It also is crucial that we be as skilled as possible in accurately predicting lipoprotein pathology using all of the lipid concentration parameters present in the lipid panel.
Desirable lipid values for women
Low-density lipoprotein (LDL) cholesterol
High-density lipoprotein (HDL) cholesterol
FOR VERY HIGH-RISK PATIENTS
Source: American Heart Association
How lipoproteins are analyzed
Lipoproteins can be separated into their components using any of several methodologies, including ultracentrifugation, electrophoresis, apolipoprotein content analysis, and nuclear magnetic resonance (NMR) spectroscopy. Of these, only the last two provide information on particle concentrations. 13,14
Apolipoprotein content analysis reveals two major categories of particles:
- alpha-lipoproteins, or HDL, which contain two to four molecules of apolipoprotein A-I (apoA-I)
- beta-lipoproteins, a collective group of chylomicrons, very-low-density lipoproteins (VLDL), intermediate-density lipoproteins (IDL), and LDL, each containing a single molecule of apolipoprotein B (apoB). Because of very different half-lives (chylomicrons, 1 hour; VLDL, 2–6 hours; IDL, 1–2 hours; LDL, 2–3 days), the great majority (90% to 95%) of apoB-containing particles are LDL. Although apoB measurement yields quantification of all beta-lipoproteins, it is primarily a surrogate of LDL particle (LDL-P) concentration. 15
Several epidemiologic studies that enrolled both genders found the best predictors of risk to be:
- elevated levels of apoB or LDL-P and reduced levels of apoA-I or HDL-P
- a high apoB/apoA-I ratio or LDL-P/HDL-P ratio. 6,13,14
After adjustment for lipoprotein concentration data (apoB or LDL-P), other lipoprotein characteristics such as particle lipid content, size, or composition, for the most part, had no statistically significant relationship with the risk of cardiovascular disease. 16,17
Lipids and lipoproteins: A glossary
What is it?
The triacylglycerol concentration within all of the TG-trafficking lipoproteins in 100 mL or 1 dL of plasma
Total cholesterol (TC)
Cholesterol content of all lipoproteins in 1 dL of plasma
Low-density lipoprotein (LDL) cholesterol
Cholesterol content of all intermediate-density lipoprotein (IDL) and LDL particles in 1 dL of plasma
High-density lipoprotein (HDL) cholesterol
Cholesterol content of all HDL particles in 1 dL of plasma
Very-low-density lipoprotein (VLDL) cholesterol
Cholesterol content of all VLDL particles in 1 dL of plasma
Cholesterol content of all remnants in 1 dL of plasma
Lipoprotein (a) [Lp(a)] cholesterol
Cholesterol content of LDL particles that have apo(a) attached
Concentration of apo(a) in 1 dL of plasma
Cholesterol within all apoB particles in 1 dL of plasma
Number of LDL particles in 1 L of plasma (expressed in nmol/L).
Number of small and intermediate LDL particles in 1 L of plasma (nmol/L)
Number of HDL particles in 1 L of plasma (μmol/L). HDL-P is also reported as large, intermediate, and small HDL-P (μmol/L)
Number of VLDL particles in 1 L of plasma (nmol/L)
Number of IDL particles in 1 L of plasma (nmol/L)
Diameter of the predominant LDL species:
Using lipid measurements to estimate lipoproteins
Total cholesterol represents the cholesterol content within all lipoproteins in 1 dL of plasma. Because beta-lipoproteins are considerably larger than alpha-lipoproteins, approximately 75% of total cholesterol is carried in the apoB-containing particles, making TC an apoB surrogate.
VLDL-C, an often ignored variable, is not measured but calculated using the Friedewald formula, dividing TG by five. This calculation assumes—often erroneously as TG levels rise—that TG consists only of VLDL particles and that VLDL composition contains five times more TG than cholesterol molecules.
A desirable TG level is <150 mg/dL, so normal VLDL-C is 150/5 or <30 mg/dL.
LDL-C is also an apoB surrogate
Although VLDL-C is a weak apoB surrogate, 15 data from the Framingham Heart Study showed it to be a good predictor of VLDL remnant particles. 18 However, because the vast majority of beta-lipoproteins are LDL, LDL-C (especially if elevated) is a better apoB surrogate than VLDL-C and is the primary CVD risk factor and goal of therapy in every current guideline.
LDL-C is usually a calculated value using the formula:
LDL-C = TC – (HDL-C + VLDL-C)
Upon special order, laboratories can directly measure LDL-C. This option is most useful when TG levels are high, rendering the Friedewald formula less accurate ( TABLE 2 ). 19 For population cut points and desirable goals of therapy for lipid and lipoprotein concentrations, see the FIGURE .
How lipid concentrations are determined
TC = apoA-I-C + apoB-C
TC = HDL-C + LDL-C + VLDL-C + IDL-C + Chylomicron-C + Lp(a)-C + Remnant-C
In a fasting patient under normal circumstances, there are no chylomicrons and remnants (smaller chylomicrons or VLDL particles) and very few, if any, IDL particles. These are postprandial lipoproteins. Most patients do not have Lp(a) pathology. Therefore, the lipid concentration formula simplifies:
TC = HDL-C + LDL-C + VLDL-C
VLDL-C is estimated by TG/5 (assumes that all TG is in VLDL and that VLDL TG:cholesterol composition is 5:1). Therefore:
TC = HDL-C + LDL-C + TG/5
LDL-C = TC – (HDL-C + TG/5)
Non-HDL-C = TC – HDL-C
In actuality, the calculated or directly measured LDL-C values in the standard lipid panel represent LDL-C + IDL-C + Lp(a)-C. However, because labs do not usually separate IDL and Lp(a) particles from LDL (without significant added expense), only total LDL-C is reported.
FIGURE Population percentile cut points and goals for LDL-C, LDL-P, ApoB, and non-HDL-C
HDL-C, apoA-I are inversely related to cardiovascular risk
The epidemiologic data strongly indicate that both HDL-C and apoA-I are strongly and inversely related to CVD risk. 6 HDL particles are a heterogenous collection of:
- unlipidated apoA-I
- very small pre-beta HDL
- more mature, lipidated HDL3 and HDL2 species (HDL3 smaller than HDL2).
NMR nomenclature identifies the smaller HDL species as H1 and H2 and the larger HDL species as H4 and H5. 14 The smaller HDL species also contain apoA-II.
Although HDL can acquire cholesterol from any cell, including arterial-wall foam cells, the majority of HDL lipidation occurs in the liver or proximal small intestine, after which it is trafficked to steroidogenic tissue, adipocytes, or back to the liver. Normally, HDL carries little TG. 20 The only lipid concentration that can serve as a surrogate of apoA-I or HDL-P is HDL-C, where the assumption is that higher HDL-C indicates higher apoA-I, and vice versa.