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Blood Cholesterol Testing - don't let the routine standard lipid panel fool you!

 

The mere word “blood cholesterol” strikes horror in many people. We have been indoctrinated since the well-known Framingham Study in the 1980s that the higher the blood cholesterol level, the higher the risk of heart disease.[1-3] However, much has been discovered in medical research since then. 
 
Today there is compelling evidence showing that strict reliance on the traditional cholesterol test – aka the standard lipid panel - that is routinely run in primary care, can falsely indicate that you're fine, even when you aren't. 
 
Here you will find out what to look for when interpreting your cholesterol levels...
 

 

The traditional cholesterol test - standard lipid panel

 

When you do your annual health check-up and blood work (which you should do regularly as a preventive measure), the standard lipid panel that checks your cholesterol will only give you the following information:
 
- Total cholesterol level
 
- LDL-C (or just LDL, low-density lipoprotein cholesterol, the “bad" cholesterol) level
 
- HDL-C (or just HDL, high-density lipoprotein cholesterol, the “good" cholesterol) level
 
- VLDL-C (or just VLDL, very-low-density lipoprotein cholesterol) 
 
- Triglyceride level (a.k.a. blood fats)
 

 
Note: Lipid is a catch-all term for fats and cholesterol, which are characterized by being water insoluble. Hence the need for lipoproteins, which are protein molecules that transport cholesterol and fats in the blood, which is water based. For a handy glossary, see my other article “Why you need to look beyond your LDL - “bad cholesterol” – level”
 

 
Blood cholesterol gets its name based on the transport vehicle that carries it in the blood stream. Even though you often hear discussions about “bad” and “good” cholesterol, the cholesterol that is supposedly “bad” or “good” – is the same. The difference lies in their respective transport molecules, i.e. LDL and HDL.
 
What you need to know about the standard lipid panel is that it only directly measures total cholesterol, triglycerides (TG), and HDL cholesterol (HDL-C). The LDL cholesterol (LDL-C) is then calculated using the Friedewald formula (LDL-C = total cholesterol – HDL-C – TG/5). Thus, in the standard lipid panel, LDL-C is not directly measured, it is calculated from the other measurements. In people with normal triglyceride levels, calculated LDL-C and directly measured LDL-C (which is a more expensive test and only available upon request) are very strongly correlated and the difference between them is small.[4, 5] However, if the triglyceride levels are greater than 200mg/dL (which is common among people with large bellies) calculated LDL-C will be lower than the directly measured LDL-C level and in those cases the standard lipid panel will underestimate LDL-C levels.[4]
 
Doctors have historically blindly relied on this standard lipid panel (which is part of routine lab work) to assess their patients’ risk of cardiovascular disease and prescribe cholesterol lowering drugs based on people's LDL-C levels. However, there are serious limitations to relying solely on the standard cholesterol panel. Most importantly, it identifies only about 40% of people at risk for cardiovascular disease [6], and the extent of cardiovascular disease varies greatly among individuals with the same cholesterol levels, derived by the standard lipid test.[7, 8] 
 
Over the past decade, an immense amount of scientific research has shown that within each cholesterol class (LDL, HDL, VLDL and IDL) distinct subclasses exist, which confer different degrees of cardiovascular disease risk.[9] For example, many studies show that the small LDL particles are more dangerous than the larger LDL particles (more on that below).[10-13] 
 
This discovery has given rise to the "pattern A" and "pattern B" notation (see below) and explains why a simple total LDL-C level number won’t tell you the full story and thus can be dangerously misleading. For more info on the drawbacks of the standard lipid panel, see “Why you need to look beyond your LDL - “bad cholesterol” – level”
 

The Advanced Lipid Panel - next generation cholesterol testing

 
In contrast to the standard lipid panel, the advanced lipid panel provides this valuable information on lipoprotein subclasses. Specifically, advanced lipoprotein testing measures subclasses of lipoproteins, and gives information on your lipoprotein particle composition (i.e. the relative distribution of large and small lipoproteins).[14] 
 
LDL size
 
LDL particles vary greatly in size, and studies show that small dense LDL particles are more atherogenic than large LDL particles.[10-13] Small dense LDL are thought to be more atherogenic because they more easily penetrate the inner lining of blood vessels and bind to the arterial wall, are more susceptible to oxidation, and have a longer half time in the circulation than large LDL particles.[15]
 
Small LDL particles are typically seen in people with elevated triglyceride levels and decreased HDL-C levels (which is common among those with the metabolic syndrome, obesity, or type 2 diabetes).[16] Numerous studies have documented a link between small dense LDL particles and an increased risk of cardiovascular disease, even though this association is reduced when the analyses are adjusted for other factors.[17, 18]
 
LDL particle number
 
The cholesterol content of LDL particles is not constant and can vary greatly between individuals and can change over time in a particular individual.[19] LDL-C and LDL particle number are typically correlated in healthy people; those with low LDL-C tend to also have low LDL particle numbers, i.e. their LDL-C and LDL particle numbers are concordant. 
 
However, people with the metabolic syndrome (commonly manifested as large bellies) and diabetes, who often have elevated triglycerides and/or low HDL levels, have much higher LDL particle numbers than LDL-C levels.[20, 21] In these people, LDL-C and LDL particle numbers are discordant. Studies show that LDL particle number is more strongly associated with cardiovascular disease than LDL-C, particularly when the levels of LDL-C and LDL particle number are discordant (ie one is high while the other is low).[10, 22-26] 
 
HDL size and particle number
 
Like LDL, HDL comes in different sizes and particle numbers. While the research on HDL size and HDL particle levels is not as advanced as that for LDL size/particle levels, emerging studies show that a higher a HDL particle count (or level) protects against cardiovascular disease.[27, 28]
 
In the European Prospective Investigation into Cancer and Nutrition (EPIC)-Norfolk study of apparently healthy men and women, those who developed heart disease had significant lower total HDL particle concentration (level) at baseline.[29] Those with the highest HDL particle levels at baseline had half the risk for heart disease compared to those with the lowest HDL particle levels.[29] Notably, in contrast to LDL, it was found that HDL size and HDL particle concentration were only weakly correlated. HDL size was strongly associated with risk factors characteristic of the metabolic syndrome, including waist circumference, triglyceride level, and apolipoprotein B level, whereas HDL particle concentration was not.[29] Thus, the predictive power of HDL particle concentration remained even after accounting for risk factors related to the metabolic syndrome.
 
In the Multi-Ethnic Study of Atherosclerosis (MESA), which evaluated men and women without baseline CHD or lipid altering therapy, those with a high number of HDL particles had reduced risk of atherosclerosis and cardiac events.[30] HDL-C levels (which are measured in the standard lipid panel) had similar associations with atherosclerosis and cardiac events, however, after adjustment for LDL particle number, HDL-C lost its predictive power. This indicates that HDL particle number may be a more relevant therapeutic target than HDL-C.[28]
 
Other parameters – apoB, apoA and Lp(a)
 
Some advanced lipoprotein test also analyze apolipoproteins and lipoprotein (a) [Lp(a)]. Apolipoproteins are proteins that bind to lipoproteins and play a crucial role in lipoprotein metabolism.[31]The most studied are apolipoprotein B (apoB) and apolipoprotein A (apoA).
 
All potentially atherogenic lipoproteins carry one apolipoprotein B on their surface; thus, apolipoprotein B levels reflect the total number of atherogenic particles, especially LDL particles.[31] In contrast, apoA-I is only present in HDL particles, and reflects the HDL mass.[31] Although apoA-I measurement reflects the number of HDL particles, unlike the close relationship between apoB and LDL particle numbers, elevated apoA-I values does not as accurately reflect HDL number, because there can be several apoA per HDL particle.[32]
 
Lp(a) is a modified version of LDL. Lp(a) is a strong independent cardiovascular risk factor, that is more  genetically determined than the other lipoproteins.[33-35] 
 

What to look for in your Advanced Lipid Test results?

 
When you get your advanced lipid test results, all the numbers can make you dizzy (see sample test results below). No worry, one of the main things to find out is your LDL pattern. The size of LDL particles can be individually measured, or can be expressed as LDL particle patterns based on the size of the predominant subfraction: 
 
Pattern A = predominance of large LDL particles 
 
Pattern B = predominance of small LDL particles 
 
You want to know whether you are a pattern A or B because the risk attributable to “bad cholesterol” (commonly measured as LDL in the standard lipid panel) correlates more strongly with the number (and size) of circulating atherogenic particles (as measured by an advance lipid panel) than with the quantity of cholesterol carried by those particles (as measured by the standard lipid panel).[19] 
 
A limitation of the pattern A/B notation is that is only tells the predominant distribution of LDL size (ie, mostly large versus small LDL particles) but does not quantify the number of large and small LDL particles. This distinction may be important because a decrease in average LDL size does not necessarily translate into a greater number of small LDL particles because it could also result from having fewer large LDL particles.
 
Nevertheless, because the measurement of the number of large and small LDL particles is not currently standardized and different lab techniques will provide different readings, finding out whether you are a pattern A or B gives a good overall snapshot.
 
Figure 1 illustrates the pattern A vs pattern B in 2 people with the same LDL-C level (ie with the same level of “bad” cholesterol). Individual B has smaller average LDL particle size and concomitantly more LDL particles (= a higher concentration or level of LDL particles) than individual A, who has larger average LDL size and less LDL particles.
 
Figure 1: Two individuals may have an identical LDL “bad” cholesterol level but differ with respect to other measures of LDL, such as size and particle concentration.[36]
 
 
 
Some early studies which showed that smaller LDL particles are more “atherogenic” have been criticized because they did not adequately control for the inverse correlation between small and large LDL particle levels, and their possible differing associations with other lipoproteins, lipids, and cardiovascular risk factors.[25, 37] However, a more recent analysis confirmed that the association between small LDL particles and atherosclerosis is independent of standard lipid measurements.[13]
 
Aside finding out your LDL pattern, you want to make sure to check your Lp(a) level. Many doctors will tell you that there is no treatment for high Lp(a) levels... this is wrong! HIgh dose niacin - aka vitamin B3 - is the most effective Lp(a) lowering treatment available. For more info on that, see my previous article "Niacin – a.k.a vitamin B3 – the neglected broad spectrum cholesterol drug!".
 

Advanced Lipid Panel Labs

 
There are several different types of advanced lipid panels, based on different analysis techniques.[38] While they all provide information on some aspect of LDL size and particle number, the nomenclature of lipoprotein subfractions are not uniform across the different techniques and have not been standardized.[36] Therefore one cannot make straight comparisons of results from different advanced lipid panel assays. Thus, in order to compare changes over time, pick one lab and stick to it. What follows is a brief introduction to the main advanced lipid panel providers, along with sample reports.
 

LabCorp – NMR
 
The most frequently used and guideline recommended test that can count the number of particles is the NMR LipoProfile. In addition to counting the number of particles – one of the most important predictor of risk – NMR can also measure the size of each lipoprotein particle, which is valuable for predicting insulin resistance in drug naïve patients, before changes are noted in glucose or insulin levels. 
 
LipoProfile also provides an insulin resistance score. This insulin resistance score is strongly associated with more advanced techniques of measuring insulin resistance (such as the homeostasis model assessment of insulin resistance (HOMA-IR) and glucose disposal rates), and thus can tell you whether you are insulin resistant.[39]
 
To learn more about insulin resistacne and why you should care about it, see my previous article "Muscles – not just for bodybuilders!"
 
Link to lab page

Sample report LipoProfile

 
 
Boston Heart Lab - gel electrophoresis
 
Boston Heart Lab offers the advanced lipid parameters separately. It also offers interesting genotyping tests that can help you find tailor medication dosages, if indicated. 
 
Link to lab page

Sample report Boston Heart Lab

 
 
Quest Lab - ion mobility
 
 
Link to lab page
 

Sample report CardioIQ

 

 
Because these advance lipid panel labs use different techniques to measure LDL size, a study specifically compared them for their ability to relate lipoprotein subfractions to atherosclerotic progression.[13] It was found that the measures of small LDL by all methods were consistently associated with atherosclerosis progression.[13] This supports their use for assessing cardiovascular disease risk, and for monitoring progress with interventions aimed to convert people from pattern B to pattern A (such as carb restriction and exercise).
 

Who should get the advanced lipid panel test?

 
If your standard lipid panel shows that you have a high triglyceride level, and/or a low HDL level, you should definitely get an advanced lipid panel test, since a high ratio of triglyceride/HDL is often accompanied by small LDL particle sizes.[40, 41] Another simple way to tell if you could be at risk is if you have a tendency to store fat around your waist. Having a belly is not just an esthetic issue, it is also a great health risk that should be taken much more seriously than it is.
 
Another important reason to get an advanced lipid panel test is if you are on statins. I am not going to get into the evils of statins here. For the purpose of this article, I just want to inform you that they are the most lucrative drug ever developed by the pharma industry, and unfortunately the first-line drug prescribed by cardiologist to treat high LDL-C levels. The reason you should do an advanced lipid panel test if you are on statins is that statins lower your overall LDL level more than they lower your LDL particle number, and thus cause a dangerous discordance between your LDL-C and LDL particle number.[42, 43] Thus, statins can lower your LDL level to the normal range, but still leave you with lots of deleterious LDL particles (and other risk factors as well!), and thereby falsely give an impression of a successful treatment. Therefore, if your doctor is only monitoring your overall LDL level while prescribing you statins, get another doctor.
 
Also, if you are eating a lot of carbs, an advanced lipid panel test is recommended, because it is well-documented that a high-carb diet has detrimental effects on cardiovascular risk factors. Among other things, carbs increases both your blood fats (triglycerides) and your number of small deleterious LDL particles.[44-48]
 
In addition, certain health promoting supplements can actually elevate your total and LDL cholesterol levels, while beneficially affecting your LDL particle distribution. Notable examples are fish oil and algae oil supplements.[49, 50] With the advanced lipid panel you have your back covered if you start taking an effective dose of fish oil and your doctor frets and tells you to stop it because your LDL level has increased (trust me, there are doctors like that!).
 

References:

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3.            Castelli, W.P. and K. Anderson, A population at risk. Prevalence of high cholesterol levels in hypertensive patients in the Framingham Study. Am J Med, 1986. 80(2A): p. 23-32.

4.            Martin, S.S., et al., Friedewald-estimated versus directly measured low-density lipoprotein cholesterol and treatment implications. J Am Coll Cardiol, 2013. 62(8): p. 732-9.

5.            Mora, S., et al., Comparison of LDL cholesterol concentrations by Friedewald calculation and direct measurement in relation to cardiovascular events in 27,331 women. Clin Chem, 2009. 55(5): p. 888-94.

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13.          Williams, P.T., et al., Comparison of four methods of analysis of lipoprotein particle subfractions for their association with angiographic progression of coronary artery disease. Atherosclerosis, 2014. 233(2): p. 713-20.

14.          Chandra, A. and A. Rohatgi, The role of advanced lipid testing in the prediction of cardiovascular disease. Curr Atheroscler Rep, 2014. 16(3): p. 394.

15.          Berneis, K.K. and R.M. Krauss, Metabolic origins and clinical significance of LDL heterogeneity. J Lipid Res, 2002. 43(9): p. 1363-79.

16.          Krauss, R.M. and P.W. Siri, Metabolic abnormalities: triglyceride and low-density lipoprotein. Endocrinol Metab Clin North Am, 2004. 33(2): p. 405-15.

17.          Ip, S., et al., Systematic review: association of low-density lipoprotein subfractions with cardiovascular outcomes. Ann Intern Med, 2009. 150(7): p. 474-84.

18.          Krauss, R.M., Lipoprotein subfractions and cardiovascular disease risk. Curr Opin Lipidol, 2010. 21(4): p. 305-11.

19.          Davidson, M.H., et al., Clinical utility of inflammatory markers and advanced lipoprotein testing: advice from an expert panel of lipid specialists. J Clin Lipidol, 2011. 5(5): p. 338-67.

20.          Cromwell, W.C. and J.D. Otvos, Heterogeneity of low-density lipoprotein particle number in patients with type 2 diabetes mellitus and low-density lipoprotein cholesterol <100 mg/dl. Am J Cardiol, 2006. 98(12): p. 1599-602.

21.          Otvos, J.D., E.J. Jeyarajah, and W.C. Cromwell, Measurement issues related to lipoprotein heterogeneity. Am J Cardiol, 2002. 90(8A): p. 22i-29i.

22.          Mora, S., J.E. Buring, and P.M. Ridker, Discordance of low-density lipoprotein (LDL) cholesterol with alternative LDL-related measures and future coronary events. Circulation, 2014. 129(5): p. 553-61.

23.          Mora, S., et al., Lipoprotein particle profiles by nuclear magnetic resonance compared with standard lipids and apolipoproteins in predicting incident cardiovascular disease in women. Circulation, 2009. 119(7): p. 931-9.

24.          Otvos, J.D., et al., Clinical implications of discordance between low-density lipoprotein cholesterol and particle number. J Clin Lipidol, 2011. 5(2): p. 105-13.

25.          Blake, G.J., et al., Low-density lipoprotein particle concentration and size as determined by nuclear magnetic resonance spectroscopy as predictors of cardiovascular disease in women. Circulation, 2002. 106(15): p. 1930-7.

26.          El Harchaoui, K., 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(5): p. 547-53.

27.          Connelly, M.A., I. Shalaurova, and J.D. Otvos, High-density lipoprotein and inflammation in cardiovascular disease. Transl Res, 2016.

28.          Kontush, A., HDL particle number and size as predictors of cardiovascular disease. Front Pharmacol, 2015. 6: p. 218.

29.          El Harchaoui, K., et al., High-density lipoprotein particle size and concentration and coronary risk. Ann Intern Med, 2009. 150(2): p. 84-93.

30.          Mackey, R.H., et al., High-density lipoprotein cholesterol and particle concentrations, carotid atherosclerosis, and coronary events: MESA (multi-ethnic study of atherosclerosis). J Am Coll Cardiol, 2012. 60(6): p. 508-16.

31.          Feingold, K.R. and C. Grunfeld, Introduction to Lipids and Lipoproteins, in Endotext, L.J. De Groot, et al., Editors. 2000: South Dartmouth (MA).

32.          Superko, H.R., Advanced lipoprotein testing and subfractionation are clinically useful. Circulation, 2009. 119(17): p. 2383-95.

33.          Nordestgaard, B.G., et al., Lipoprotein(a) as a cardiovascular risk factor: current status. Eur Heart J, 2010. 31(23): p. 2844-53.

34.          Jacobson, T.A., Lipoprotein(a), cardiovascular disease, and contemporary management. Mayo Clin Proc, 2013. 88(11): p. 1294-311.

35.          Kassner, U., et al., Lipoprotein(a)--An independent causal risk factor for cardiovascular disease and current therapeutic options. Atheroscler Suppl, 2015. 18: p. 263-7.

36.          Mora, S., Advanced lipoprotein testing and subfractionation are not (yet) ready for routine clinical use. Circulation, 2009. 119(17): p. 2396-404.

37.          Kuller, L., et al., Nuclear magnetic resonance spectroscopy of lipoproteins and risk of coronary heart disease in the cardiovascular health study. Arterioscler Thromb Vasc Biol, 2002. 22(7): p. 1175-80.

38.          Schaefer, E.J., et al., The Measurement of Lipids, Lipoproteins, Apolipoproteins, Fatty Acids, and Sterols, and Next Generation Sequencing for the Diagnosis and Treatment of Lipid Disorders, in Endotext, L.J. De Groot, et al., Editors. 2000: South Dartmouth (MA).

39.          Shalaurova, I., et al., Lipoprotein insulin resistance index: a lipoprotein particle-derived measure of insulin resistance. Metab Syndr Relat Disord, 2014. 12(8): p. 422-9.

40.          Grundy, S.M., et al., Comparisons of apolipoprotein B levels estimated by immunoassay, nuclear magnetic resonance, vertical auto profile, and non-high-density lipoprotein cholesterol in subjects with hypertriglyceridemia (SAFARI Trial). Am J Cardiol, 2011. 108(1): p. 40-6.

41.          McLaughlin, T., et al., Is there a simple way to identify insulin-resistant individuals at increased risk of cardiovascular disease? Am J Cardiol, 2005. 96(3): p. 399-404.

42.          Sniderman, A.D., Differential response of cholesterol and particle measures of atherogenic lipoproteins to LDL-lowering therapy: implications for clinical practice. J Clin Lipidol, 2008. 2(1): p. 36-42.

43.          Rosenson, R.S. and J.A. Underberg, Systematic review: Evaluating the effect of lipid-lowering therapy on lipoprotein and lipid values. Cardiovasc Drugs Ther, 2013. 27(5): p. 465-79.

44.          Faghihnia, N., et al., Changes in lipoprotein(a), oxidized phospholipids, and LDL subclasses with a low-fat high-carbohydrate diet. J Lipid Res, 2010. 51(11): p. 3324-30.

45.          Krauss, R.M., Dietary and genetic probes of atherogenic dyslipidemia. Arterioscler Thromb Vasc Biol, 2005. 25(11): p. 2265-72.

46.          Dreon, D.M., et al., Low-density lipoprotein subclass patterns and lipoprotein response to a reduced-fat diet in men. FASEB J, 1994. 8(1): p. 121-6.

47.          Parks, E.J. and M.K. Hellerstein, Carbohydrate-induced hypertriacylglycerolemia: historical perspective and review of biological mechanisms. Am J Clin Nutr, 2000. 71(2): p. 412-33.

48.          Kasim-Karakas, S.E., et al., Effects of dietary fat restriction on particle size of plasma lipoproteins in postmenopausal women. Metabolism, 1997. 46(4): p. 431-6.

49.          Maki, K.C., et al., Lipid responses to a dietary docosahexaenoic acid supplement in men and women with below average levels of high density lipoprotein cholesterol. J Am Coll Nutr, 2005. 24(3): p. 189-99.

50.          Neff, L.M., et al., Algal docosahexaenoic acid affects plasma lipoprotein particle size distribution in overweight and obese adults. J Nutr, 2011. 141(2): p. 207-13.

Last modified on Tuesday, 27 March 2018 06:30
Monica

Medical Writer & Nutritionist

MSc Nutrition

University of Stockholm & Karolinska Institute, Sweden 

   Baylor University, TX, USA

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