Clinical Review

YOU HAVE A NEW JOB: Monitor the lipid profile

OBG Manag. 2008 December;20(12):45-53

References

1. Lloyd-Jones DM, O’Donnell CJ, D’Agostino RB, et al. Applicability of cholesterol-lowering primary prevention trials to a general population. The Framingham Heart Study. Arch Intern Med. 2001;161:949-954.

2. Biggerstaff KD, Wooten JS. Understanding lipoproteins as transporters of cholesterol and other lipids. Adv Physiol Educ. 2004;28:105-106.

3. Nordestgaard BG, Wooten R, Lewis B. Selective retention of VLDL, IDL and LDL in the arterial intima of genetically hyperlipidemic rabbits in vivo. Molecular size as a determinant of fractional loss from the intima-inner media. Arterioscler Thromb Vasc Biol. 1995;15:534-542.

4. Brunzell JD, Davidson M, Furberg CD, et al. Lipoprotein management in patients with cardiometabolic risk. Consensus statement from the American Diabetes Association and the American College of Cardiology Foundation. Diabetes Care. 2008;31:811-822.

5. Barter PJ, Ballantyne CM, Carmena R, et al. ApoB versus cholesterol in estimating cardiovascular risk and in guiding therapy: report of the thirty-person/ten-country panel. J Intern Med. 2006;259:247-258.

6. Walldius G, Jungner I, Holme I, Aastveit AH, Kolar W, Steiner E. High apolipoprotein B, low apolipoprotein A-I, and improvement in the prediction of fatal myocardial infarction (AMORIS study): a prospective study. Lancet. 2001;358:2026-2033.

7. Mudd JO, Borlaug BA, Johnson PV, et al. Beyond low-density lipoprotein cholesterol: defining the role of low-density lipoprotein heterogeneity in coronary artery disease. J Am Coll Cardiol. 2007;50:1735-1741.

8. 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. 2001;285:2486-2497.

9. Grundy SM, Cleeman JI, Merz CN, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines. Circulation. 2004;110:227-239.

10. Mosca L, Appel LJ, Benjamin EJ, et al. Evidence-based guidelines for cardiovascular disease prevention in women. Circulation. 2004;109:672-693.

11. Mosca L, Banka CL, Benjamin EJ, et al. Evidence-based guidelines for cardiovascular disease prevention in women: 2007 update. Circulation. 2007;115:1481.-

12. Sniderman AD. Apolipoprotein B versus non-high-density lipoprotein cholesterol. And the winner is… Circulation. 2005;112:3366-3367.

13. Sniderman AD, Marcovina SM. Apolipoprotein A-I and B. Clin Lab Med. 2006;26:733-750.

14. Jeyarajah EJ, Cromwell WC, Otvos JD. Lipoprotein particle analysis by nuclear magnetic resonance spectroscopy. Clin Lab Med. 2006;26:847-870.

15. Cromwell WC, Otvos JD, Keyes MJ, et al. LDL particle number and risk of future cardiovascular disease in the Framingham Off spring Study—implications for LDL management. J Clin Lipidol. 2007;1:583-592.

16. El Harchaoui K, van der Steeg WA, Stroes ES, et al. Value of low-density lipoprotein particle number and size as predictors of coronary artery disease in apparently healthy men and women: the EPIC-Norfolk Prospective Population Study. J Am Coll Cardiol. 2007;49:547-553.

17. Mora S, Szklo M, Otvos JD, et al. LDL particle subclasses, LDL particle size, and carotid atherosclerosis in the Multi-Ethnic Study of Atherosclerosis (MESA). Atherosclerosis. 2007;192:211-217.

18. Liu J, Sempos CT, Donahue RP, et al. Non-high-density lipoprotein and very-low-density lipoprotein cholesterol and their predictive risk values in coronary heart disease. Am J Cardiol. 2006;98:1363-1368.

19. National Cholesterol Education Program. Recommendations on lipoprotein measurement from the Working Group on Lipoprotein Measurement. National Institutes of Health. National Heart, Lung, and Blood Institute. NIH Publication No. 95-3044. Bethesda, Md: September 1995.

20. Dayspring T. High density lipoproteins: emerging knowledge. J Cardiometabol Syndr. 2007;2:59-62.

21. Cromwell WC. High-density lipoprotein associations with coronary heart disease: does measurement of cholesterol content give the best result? J Clin Lipidol. 2007;1:57-64.

22. Ridker PM, Rifai N, Cook NR, et al. Non-HDL cholesterol, apolipoproteins A-I and B100, standard lipid measures, lipid ratios, and CRP as risk factors for cardiovascular disease in women. JAMA. 2005;294:326.-

23. Blake GJ, Otvos JD, Rifai N, Ridker PM. Low-density lipoprotein particle concentration and size as determined by nuclear magnetic resonance spectroscopy as predictors of cardiovascular disease in women. Circulation. 2002;106:1930-1937.

24. Ingelsson E, Schaefer EJ, Contois JH, et al. Clinical utility of different lipid measures for prediction of coronary heart disease in men and women. JAMA. 2007;298:776-785.

25. Szapary PO, Rader DJ. The triglyceride-high-density lipoprotein axis: an important target of therapy. Am Heart J. 2004;148:211-221.

26. Davidson MH, Yannicelli D. New concepts in dyslipidemia in the metabolic syndrome and diabetes. Metab Syndr Relat Disord. 2006;4:299-314.

27. Hanak V, Munoz J, Teague J, Stanley A, Jr, Bittner V. Accuracy of the triglyceride to high-density lipoprotein cholesterol ratio for prediction of the low-density lipoprotein phenotype B. Am J Cardiol. 2004;94:219-222.

28. Kathiresan S, Otvos JD, Sullivan LM, et al. Increased small low-density lipoprotein particle number: a prominent feature of the metabolic syndrome in the Framingham Heart Study. Circulation. 2006;113:20-29.

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.

TABLE 1

Desirable lipid values for women

Lipid	Level (mg/dL)
Total cholesterol	<200
Low-density lipoprotein (LDL) cholesterol	<100
High-density lipoprotein (HDL) cholesterol	≥50
Triglycerides	<150
Non-HDL-cholesterol	<130
FOR VERY HIGH-RISK PATIENTS
LDL-C	<70
Non-HDL-C	<100
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

Individual particle concentrations, determined by NMR spectroscopy, are reported as VLDL-P, IDL-P, LDL-P, and HDL-P (see the “Glossary”).¹⁴

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

Variable	What is it?
Triglycerides (TG)	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
Remnant-C	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
Lp(a) concentration	Concentration of apo(a) in 1 dL of plasma
Non-HDL cholesterol	Cholesterol within all apoB particles in 1 dL of plasma
LDL-P	Number of LDL particles in 1 L of plasma (expressed in nmol/L). This represents LDL particles of all sizes
Small LDL-P	Number of small and intermediate LDL particles in 1 L of plasma (nmol/L)
HDL-P	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)
VLDL-P	Number of VLDL particles in 1 L of plasma (nmol/L)
IDL-P	Number of IDL particles in 1 L of plasma (nmol/L)
LDL size	Diameter of the predominant LDL species: Pattern or phenotype A refers to predominantly large, buoyant LDL particles Pattern or phenotype B refers to predominantly small, dense LDL particles

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 .