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LDL Cholesterol CalculationsTest code(s) 7600, 19543, 14852, 92061, 92145
Question 1. Why is LDL cholesterol important?
Low-density lipoprotein cholesterol (LDL-C) is an important contributor to atherosclerotic cardiovascular disease (ASCVD) risk. As cholesterol carried by LDL (ie, LDL-C) is deposited in the arterial wall, plaque builds up. Occlusion of the artery, and/or plaque rupture resulting in clots, impedes the flow of blood to the heart muscle or the brain, causing a heart attack or stroke, respectively.
Quantitation of LDL-C is useful for assessing ASCVD risk, stratifying individuals into statin benefit groups, and monitoring risk reduction therapy.1
Question 2. Why is the LDL cholesterol concentration usually calculated, not measured directly?
LDL-C can be quantitated directly or indirectly. Indirect quantitation (ie, Friedewald calculation2) was developed in the 1970s and is based on a calculation from total cholesterol, HDL-cholesterol, and triglyceride concentrations. Calculated LDL-C is still considered an excellent initial test and is considered adequate for use in patient classification.3 However, if the triglycerides are abnormally high (>400 mg/dL) or the patient has not appropriately fasted (recommended fast is 12 hours), the calculated LDL-C will be artificially low or non-reportable.
Direct measurement of LDL-C, developed in the 1990s, provides accurate and precise measurement and is not affected by elevated triglyceride concentrations. However, since direct LDL-C measurement has not been used in the bulk of clinical studies, there is less clinical correlation information available relative to that for calculated LDL-C. The direct LDL-C test is limited in that it only provides LDL-C concentration and not total cholesterol, HDL-cholesterol, or triglyceride concentrations, which are also useful for assessing ASCVD risk. It is also more expensive than calculated LDL-C quantitation.
Question 3. What is the Friedewald equation?
The Friedewald equation is the equation typically used to calculate LDL-C concentration when a lipid panel is performed. The equation is:
LDL cholesterol (mg/dL) = total cholesterol – HDL cholesterol – (triglycerides/5),
where “triglycerides/5” is used to represent very low density lipoprotein-C (VLDL-C). This equation provides a reliable estimate of LDL-C in most cases when the triglycerides concentration is between 1.13 and 4.35 mmol/L (100 to 400 mg/dL). It assumes the patient has fasted for ≥12 hours prior to specimen collection so triglycerides levels are stable and unaffected by a recent meal.
Question 4. Are there more accurate alternatives to the Friedewald equation?
Yes, although the Friedewald equation remains the commonly used equation. The shortcomings of the Friedewald equation have been extensively studied, and successor equations continue to be proposed.4-7
A key component of the Friedewald equation is the representation of VLDL as triglycerides (TG) divided by 5.0. However, applying a factor of 5 to every individual patient is problematic given variance in the TG:VLDL-C ratio across the range of triglyceride and non–HDL-C levels. Indeed, Friedewald and colleagues noted that simply dividing triglyceride values by 5 does not give an accurate estimate of VLDL-C.2 DeLong and colleagues proposed a fixed factor of 6, effectively resetting the population mean, although not addressing inter-individual variance in the TG:VLDL-C ratio.8
The Friedewald and DeLong equations were proposed many years before the common use of statins and LDL-C targets of <100 mg/dL or <70 mg/dL. Some of the new PCSK-9 inhibitors will drive LDL-C levels even lower, to <40 mg/dL. Such low LDL-C concentrations are below the concentrations considered when the Friedewald equation was developed.2 Thus, the Friedewald equation may not accurately calculate these low LDL-C concentrations. The Friedewald equation also has reduced reliability when the triglycerides concentration is very low.10
Experts recognized that the factor used to divide triglycerides depends upon both the triglycerides and non-HDL cholesterol (total cholesterol minus HDL cholesterol) concentrations. In an attempt to address this issue, researchers from Johns Hopkins developed a novel LDL-C calculation (LDL-CN) that accurately estimates LDL-C in the face of variable triglyceride levels.11 A validation study using clinical lipid profiles from 1.35 million individuals across age groups in the United States revealed promising results.11 Overall, for people with TG levels below 400 mg/dL, the LDL-CN calculation had better concordance with risk classification based on directly measured LDL-C than did the Friedewald calculation. The improvement was greatest for people with estimated LDL-C levels below 70 mg/dL, especially those with higher TG levels (Table). Thus, the primary advantage of the LDL-CN equation is that it is applicable to low LDL-C levels even in the presence of elevated triglycerides concentrations.11
Question 5. Does Quest Diagnostics offer a test code that provides an LDL-C value that is more accurate than that provided by the Friedewald equation?
Yes, test code 8293 (Direct LDL) and test code 91723 (Cardio IQ® Direct LDL) are available. When triglycerides might be >400 mg/dL, test code 14852 (Lipid Panel with Reflex to Direct LDL) can be ordered. Direct LDL measurement provides a reliable result even when triglyceride levels are up to 1,000 mg/dL.
Another alternative is measurement of LDL particle number and size, which is available using test code 91604 (Cardio IQ® Lipoprotein Fractionation, Ion Mobility). A number of prospective studies have found that lipoprotein subfractions are associated with CVD events.12 13 Some studies even suggest that lipoprotein subfraction measurements add value to standard lipid measurements, though others do not (see review by Krauss14). This apparent discrepancy could be due to different methods of measurement, which include vertical ultracentrifugation, nuclear magnetic resonance, gradient gel electrophoresis, and ion mobility. All but ion mobility use algorithms to indirectly calculate concentrations. In contrast, the ion mobility method, also known as gas-phase electrophoretic mobility, is the only one that directly measures particle size and concentration.15 And unlike some methods, ion mobility separation of subfractions does not cause lipoprotein modification that could potentially affect the accuracy of the assay.14,16 Ion mobility has been used in multiple lipoprotein studies11,12,16 and is the method used in the Cardio IQ Lipoprotein Fractionation, Ion Mobility test.
Question 6. My patient’s LDL cholesterol concentration could not be calculated because the triglycerides were too high (>4.35 mmol/L; >400 mg/dL). What options do I have for getting an LDL cholesterol concentration?
If the LDL concentration could not be calculated because the triglyceride level was too high, test code 91723 (Cardio IQ® Direct LDL) may be ordered. The table below lists panels that reflex to Cardio IQ Direct LDL testing when the triglyceride level is too high:
- Stone NJ, Robinson J, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014;129 (suppl 2):S1-S45.
- Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem. 1972;18:499–502.
- Warnick GR, Knopp RH, Fitzpatrick V, et al. Estimating low-density lipoprotein cholesterol by the Friedewald equation is adequate for classifying patients on the basis of nationally recommended cutpoints. Clin Chem. 1990;36:15-19.
- Rao A, Parker AH, El-Sheroni NA, et al. Calculation of low-density lipoprotein cholesterol with use of triglyceride/cholesterol ratios in lipoproteins compared with other calculation methods. Clin Chem. 1988;34:2532-2534.
- Hata Y, Nakajima K. Application of Friedewald’s LDL-cholesterol estimation formula to serum in the Japanese population. Jpn Circ J. 1986;50:1191-2000.
- Wilson PW, Abbott RD, Garrison RJ, et al. Estimation of very-low-density lipoprotein cholesterol from data on triglyceride concentration in plasma. Clin Chem. 1981;27:2008-2010.
- Friedlander Y, Kark JD, Eisenberg S, et al. Calculation of LDL-cholesterol from total cholesterol, triglyceride and HDL-cholesterol: a comparison of methods in the Jerusalem Lipid Research Clinic Prevalence Study. Isr J Med Sci. 1982;18:1242-1252.
- DeLong DM, DeLong ER, Wood PD, et al. A comparison of methods for the estimation of plasma low- and very low-density lipoprotein cholesterol: the Lipid Research Clinics Prevalence Study. JAMA. 1986;256:2372-2377.
- Ahmadi SA, Boroumand MA, Gohari-Moghaddam K, et al. The impact of low serum triglyceride on LDL-cholesterol estimation. Arch Iran Med. 2008;11:318-321.
- Wang TY, Haddad M, Wang TS. Low triglyceride levels affect calculation of low-density lipoprotein cholesterol values.Arch Pathol Lab Med. 2001;125:404-405.
- Martin SS, Blaha MJ, Elshazly MB, et al. Comparison of a novel method vs the Freidewald equation for estimating low-density lipoprotein cholesterol levels from the standard lipid panel. JAMA. 2013;310:2061-2068.
- Melander O, Shiffman D, Caulfield MP, et al. LDL particle number is associated with incident atherosclerotic cardiovascular disease among persons with a 10-year risk of <7.5% [ATVB abstract A590]. Arterioscler Thromb Vasc Biol. 2014;34:A590.
- Musunuru K, Orho-Melander M, Caulfield MP, et al. Ion mobility analysis of lipoprotein subfractions identifies three independent axes of cardiovascular risk. Arterioscler Thromb Vasc Biol. 2009;29:1975-1980.
- Krauss RM. Lipoprotein subfractions and cardiovascular disease risk. Curr Opin Lipidol. 2010;21:305-311.
- Caulfield MP, Li S, Lee G, et al. Direct determination of lipoprotein particle sizes and concentrations by ion mobility analysis. Clin Chem. 2008;54:1307-1316.
- Mora S, Caulfield MP, Wohlgemuth J,et al. Lipoprotein subclasses by ion mobility and first cardiovascular events: an analysis of 11,227 participants from the JUPITER trial [ATVB abstract A630]. Arterioscler Thromb Vasc Biol. 2014;34:A630.