Low density lipoprotein laboratory findings

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [3]

Overview

Chemical measures of lipid concentration have long been the most-used clinical measurement, not because they have the best correlation with individual outcome, but because these lab methods are less expensive and more widely available. However, there is increasing evidence and recognition of the value of more sophisticated measurements. Specifically, LDL particle number (concentration), and to a lesser extent size, have shown much tighter correlation with atherosclerotic progression and cardiovascular events than is obtained using chemical measures of total LDL concentration contained within the particles. LDL cholesterol concentration can be low, yet LDL particle number high and cardiovascular events rates are high. Alternatively, LDL cholesterol concentration can be relatively high, yet LDL particle number low and cardiovascular events are also low. If LDL particle concentration is tracked against event rates, many other statistical correlates of cardiovascular events, such as diabetes mellitus, obesity and smoking, lose much of their additive predictive power.

Laboratory Tests

Measurement of LDL Cholesterol Concentration

Friedewald Equation: Estimation of LDL Particles via Cholesterol Content

Chemical measures of lipid concentration have long been the most-used clinical measurement, not because they have the best correlation with individual outcome, but because these lab methods are less expensive and more widely available. The lipid profile does not measure LDL particles directly but instead estimates them using the Friedewald equation[1][2] by subtracting the amount of cholesterol associated with other particles, such as HDL and VLDL, assuming a prolonged fasting state, etc.:

LDL Cholesterol = Total Cholesterol – HDL Cholesterol – (0.2 × Triglycerides) (mg/dl)

OR

LDL Cholesterol = Total Cholesterol – HDL Cholesterol – (0.45 × Triglycerides) (mmol/l)


There are limitations to this method, most notably that samples must be obtained following a 12 to 14 hour fasting period and that LDL-c cannot be calculated if plasma triglyceride is >4.52 mmol/L (400 mg/dL). Even at triglyceride levels 2.5 to 4.5 mmol/L, this formula is considered inaccurate.[3] If both total cholesterol and triglyceride levels are elevated then a modified formula may be used:

LDL Cholesterol = Total Cholesterol – HDL Cholesterol – (0.16 × Triglycerides) (mg/dl)


Friedewald equation provides an approximation with fair accuracy for most people, assuming the blood was drawn after fasting for about 14 hours or longer. However, the concentration of LDL particles, and to a lesser extent their size, has a slightly stronger correlation with individual clinical outcome than the amount of cholesterol within LDL particles, even if the LDL-C estimation is approximately correct. There is increasing evidence and recognition of the value of more targeted and accurate measurements of LDL particles. Specifically, LDL particle number (concentration), and to a lesser extent size, have shown slightly stronger correlations with atherosclerotic progression and cardiovascular events than LDL cholesterol concentration [4]. It is possible that the LDL cholesterol concentration is low, yet the LDL particle number and cardiovascular events rates are high. Correspondingly, it is possible that LDL cholesterol concentration is relatively high, yet the LDL particle number and cardiovascular events are low. If LDL particle concentration is used to estimate cardiovascular events, many other correlates of these clinical outcomes, such as diabetes mellitus, obesity and smoking, might decrease the accuracy of LDL particle concentration.

LDL Cholesterol Concentration Ranges

The American Heart Association, NIH, and NCEP provide a set of guidelines for fasting LDL-c concentrations, estimated or measured, and risk for heart disease. While prior approaches to the management of LDL plasma concentration aimed towards treating the subjects with dyslipidemia to a target LDL concentration,[4] the latest 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults no longer takes into consideration LDL cut-off concentration but rather identifies groups of patients among whom the benefit of statin outweighs the risk of adverse events.[5]

Shown below is a table summarizing the interpretation of the LDL cholesterol ranges according to the third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III):[6][7][8]

Level mg/dL Level mmol/L Interpretation
25 to <50 <1.3 Optimal LDL cholesterol, levels in healthy young children before onset of atherosclerotic plaque in heart artery walls
<70 <1.8 Optimal LDL cholesterol, corresponding to lower rates of progression of cardiovascular disease, promoted as a target option for those known to clearly have advanced symptomatic cardiovascular disease
<100 <2.6 Optimal LDL cholesterol, corresponding to lower rates for symptomatic cardiovascular disease events
100 to 129 2.6 to 3.3 Near optimal LDL level, corresponding to higher rates for developing symptomatic cardiovascular disease events
130 to 159 3.3 to 4.1 Borderline high LDL level, corresponding to even higher rates for developing symptomatic cardiovascular disease events
160 to 199 4.1 to 4.9 High LDL level, corresponding to much higher rates for developing symptomatic cardiovascular disease events
>200 >4.9 Very high LDL level, corresponding to highest increased rates of symptomatic cardiovascular disease events

Measurement of LDL Particle Concentration

There are several competing methods for measurement of lipoprotein particle size although the evidence in favor of their superiority to existing methods is weak, even by the statements of proponents.[9] Direct LDL particle measurement by NMR was mentioned by the ADA and ACC, in a 28 March 2008 joint consensus statement,[10] as having advantages for predicting individual risk of atherosclerosis disease events, but the statement noted that the test is not widely available and is more expensive (about $98.00 US without insurance coverage) than existing tests. Furthermore the authors also said it is "...unclear whether LDL particle size measurements add value to measurement of LDL particle concentration." Since the later 1990s, because of the development of NMR measurements, it has been possible to clinically measure lipoprotein particles at lower cost [under $100 US (including shipping) versus the previous costs of >$400 to >$5,000] and high accuracy. There are also other (less expensive) homogeneous assays for LDL, however most only estimate LDL.

Using NMR, the total LDL particle concentrations, in nmol/L plasma, are typically subdivided by percentiles referenced to the 5,382 men and women, not on any lipid medications, who participated in the MESA trial.[11]

LDL Particle Concentration Ranges

The LDL particle concentrations are typically categorized by percentiles, <20%, 20–50%, 50th–80th%, 80th–95% and >95% groups of the people participating and being tracked in the MESA trial, a medical research study sponsored by the United States National Heart, Lung, and Blood Institute.

MESA Percentile LDL particles nmol/L Interpretation
0–20% <1,000 Low rate of cardiovascular disease events
20–50% 1,000–1,299 Moderate rate of cardiovascular disease events
50–80% 1,300–1,599 Borderline-High rate of cardiovascular disease events
89–95% 1,600–2,000 High rate of cardiovascular disease events
>95% >2,000 Very high rate of cardiovascular disease events

The lowest incidence of atherosclerotic events over time occurs within the <20% group, with increased rates for the higher groups. Multiple other measures, including particle sizes, small LDL particle concentrations, total and large HDL particle concentrations, along with estimations of insulin resistance pattern and standard cholesterol lipid measurements (for comparison of the plasma data with the estimation methods discussed above) are also routinely provided.

References

  1. Warnick GR, Knopp RH, Fitzpatrick V, Branson L (1990). "Estimating low-density lipoprotein cholesterol by the Friedewald equation is adequate for classifying patients on the basis of nationally recommended cutpoints". Clinical Chemistry. 36 (1): 15–9. PMID 2297909. 
  2. Friedewald WT, Levy RI, Fredrickson DS (1972). "Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge". Clinical Chemistry. 18 (6): 499–502. PMID 4337382. 
  3. Sniderman AD, Blank D, Zakarian R, Bergeron J, Frohlich J (2003). "Triglycerides and small dense LDL: the twin Achilles heels of the Friedewald formula". Clinical Biochemistry. 36 (7): 499–504. PMID 14563441. doi:10.1016/S0009-9120(03)00117-6. 
  4. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (2001). "Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III).". JAMA. 285 (19): 2486–97. PMID 11368702. 
  5. Stone NJ, Robinson JG, Lichtenstein AH, Bairey Merz CN, Blum CB, Eckel RH; et al. (2014). "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.". J Am Coll Cardiol. 63 (25 Pt B): 2889–934. PMID 24239923. doi:10.1016/j.jacc.2013.11.002. 
  6. "Cholesterol Levels". American Heart Association. Retrieved 2009-11-14. 
  7. "What Do My Cholesterol Levels Mean?" (PDF). American Heart Association. September 2007. Retrieved 2009-11-14. 
  8. "Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) Executive Summary" (PDF). National Heart, Lung, and Blood Institute (NHLBI). National Institutes of Health. May 2001. 
  9. Krauss RM (2010). "Lipoprotein subfractions and cardiovascular disease risk". Curr. Opin. Lipidol. 21 (4): 305–11. PMID 20531184. doi:10.1097/MOL.0b013e32833b7756. 
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