Keto and ME/CFS (part IV): Beyond basic cholesterol testing

Many people are shocked to see their LDL cholesterol (LDL-C) shoot up after starting a low-carb/high-fat (LCHF) diet. If you are in this boat some additional testing may be needed to understand why this is happening and what to do about it. Most people will be given a statin and not think about it any further. For many, however, there may be reasons for pursuing alternatives.

While there are many benefits of going low carb, are the health gains enough to offset the risks of having higher LDL-C? There is a tremendous amount of uncertainty around this question currently. Accordingly, people who are concerned about high LDL-C may need to dig a little deeper to understand their risk.

This piece explores four advanced cholesterol tests that refine cardiovascular risk beyond the information found on the standard cholesterol panel: 1) LDL particle count and distribution; 2) apoB; 3) lp(a); and 4) sterols. Combined with markers of inflammation and metabolic health these tests help weigh the benefits of LCHF against its possible risks.

Before diving into more advanced testing, some might find it helpful to brush up first here on basic cholesterol testing.

Beyond cholesterol

Views on the role of cholesterol in atherogenesis have evolved over the past few decades. At first, total cholesterol was the relevant number until researchers discovered the beneficial role of HDL cholesterol (HDL-C) and LDL-C became the new target. Many doctors now prefer non-HDL-C because it captures all lipoproteins involved with atherosclerosis (e.g., VLDL, IDL, LDL).

It is not necessarily the cholesterol contained within the various types of lipoproteins, as measured on a standard lipid panel, but rather the lipoprotein particles themselves that start the trouble.

The chances that an LDL particle will get through the endothelium depends on LDL particle concentration, endothelial health, blood pressure, and whether lipoproteins are bound to proteoglycans, a type of glycated protein that makes LDL particles “sticky” and unable to leave the artery wall once they get in. When LDL particles are retained in this way it triggers an inflammatory cascade leading to atherogenesis.

Response-to-retention model. When particles get retained inside of the artery wall a complex immune response triggers atherogenesis. Image credit: https://www.ahajournals.org/doi/10.1161/JAHA.118.009778.

1 | LDL particle count and size distribution

In 1982, Krauss and Burke outlined a method for classifying LDL particles based on size using nuclear magnetic resonance (NMR), called the lipid fractionation test. Since then, NMR has become a standard tool for assessing cardiovascular risk.

LDL particle number

Several studies have shown that LDL particle number (LDL-P) is a far better predictor of atherogenic risk than LDL-C. In general, the two markers are well correlated as long as there are no metabolic impairments. People with diabetes and metabolic syndrome often show discordant particle counts, values that are higher than would be expected based on LDL-C. This means that people can have normal LDL-C but still be at risk of atherogenesis due to a high particle count. The only way to know is with an NMR panel. Thus, two people could have the same LDL-C, a measure of the cholesterol found in LDL, but differ in particle count and therefore their risk of atherogenesis.

In general, LDL-P tracks with LDL-C by a factor of 10, more or less. For example, on one of my NMR panels, my LDL-P was 2407 nmol/L and LDL-C was 238 mg/dL, showing nearly perfect concordance (Table 1).

Table 1. NMR panel and additional markers. Apart from LDL-P and apoB, which put me in a high-risk category, my other markers are good. This is a typical profile for someone on an LCHF diet.

Marker Reference range 5/8/19 5/10/19
LDL-C < 99 mg/dL 238 219
LDL-P < 935 nmol/L 2407 1845
Small LDL-P < 467 nmol/L 154 111
LDL size > 20.5 nm 23.1 22.2
HDL-P > 30.5 umol/L 33.7 31
Large HDL-P > 7.2 umol/L 16.8
HDL size > 9 nm 10.3
Large VLDL-P < 3.7 nmol/L <1.5
VLDL size < 47.1 nm 40.2
ApoB < 90 mg/dL 158
hbA1C < 5.7 % 4.6
hsCRP <1 mg/L 0.2 0.2
IR <=45 percentile   <25

Particle size: Pattern A vs. pattern B

Krauss noticed that when people switch to a high carb/low fat (HCLF) diet an interesting thing can happen: the size of LDL particles shifts from the healthier large particles to the more atherogenic small particles. This is referred to as pattern B and is riskier to have relative to pattern A, which is characterized by large LDL particles. The standard lipid panel does not indicate pattern type; only NMR provides this information.

The smaller particles are more likely to be atherogenic than the larger ones because they stick around in the bloodstream longer, increasing the chances they will make it into the artery. They are also more likely to adhere to the artery wall and trigger an inflammation cascade. Smaller particles are more prone to oxidation and glycation – a glucose-triggered modification – which also increases the chances that arterial plaques will form. In short, these are some shady actors to have around and should be addressed through lifestyle changes or other interventions (see Table 2 below).

Pattern A vs. pattern B. It is possible for two people to have the same LDL-cholesterol level but have a very different risk profile if their LDL particle pattern differs. People with pattern B are at a higher risk of atherogenesis. Most cardiologists view a high particle count, regardless of pattern type, to be risky. Image is based on one by Peter Attia.
Ratio
Trig: HDL
Risk Level
1:1 Optimum
2:1 Low
3:1 Medium
4:1 High

Pattern B is associated with metabolic abnormalities, such as insulin resistance, which is an additional risk factor for heart disease. The triglyceride: HDL ratio provides an indirect proxy for metabolic health (high triglycerides and low HDL). Those with a high trig: HDL ratio tend to have smaller LDL particles (pattern B). If you have a high ratio an NMR panel may be helpful in determining if pattern B is also present.

2 | ApoB

Apolipoprotein B (apoB) is a protein that plays an important role in lipoprotein formation and transport. ApoB allows for clearance in the liver by activating LDL receptors. ApoB also plays pathologic roles in atherosclerosis – once inside of the artery wall, ApoB proteins can undergo further modifications that accelerate and promote particle aggregation and atherosclerosis.

The apoB test measures the number of apoB-containing particles circulating in the blood and is a better indicator of cardiovascular risk than LDL cholesterol levels. ApoB is found in chylomicrons, VLDLs, IDLs, and LDLs. As such, an apoB test measures all types of atherogenic particles. However, the vast majority of apoB-containing lipoproteins are LDLs.

Many cardiologists have been advocating to include apoB as part of the standard lipid work up for well over a decade. It is a cheap blood test (as little as $20) and is more informative than a standard LDL-C test because it gets at the number of particles vs. the amount of cholesterol within lipoproteins. Despite this, the 2019 guidelines from the American Heart Association (AHA) and the American Association for Cardiology (ACC) have rejected adding apoB, citing it would be too confusing for doctors to implement.

ApoB and the NMR tests provide similar information, yet also have some differences. ApoB and NMR provide a measure of the number (apoB test) or concentration (NMR rest) of potentially atherogenic particles, but NRM is the only test that looks at particle size. NMR provides information on different lipoproteins and is the only test that gives a breakdown of VLDL and LDL particles (as well as HDL). Both tests can reveal discordance between LDL-C and the number of LDL particles, as is often the case with insulin resistance. Both capture the highly-atherogenic lipoprotein remnants, but neither provides a breakdown of remnant vs. non-remnant lipoproteins. Both NMR and apoB are similar at predicting risk and are better than non-HDL-C and LDL-C.

ApoB appears to be the preferable biomarker for guideline adoption (over NMR) because of its availability, scalability, standardization, and relatively low cost. Hopefully, with time, it will become standard practice to screen people for apoB as well.

Finally, apoB and LDL-P offer different therapeutic targets (Table 2) and having information on each could be helpful in identifying the best course of treatment as well as providing markers for monitoring treatment response.

3 | Lp(a)

There are millions of people who are walking around with a silent killer in their bloodstream called lp(a). Most physicians are unaware of it and therefore do not screen for it. Many with elevated lp(a) are lean, eat a healthy diet, and exercise. When you hear of athletic people dying in their 50s from a heart attack and who otherwise have no known risk factors, suspect lp(a).

Lp(a) (pronounced l-p-little-a) is an LDL particle with apolipoprotein(a) bound to the apoB protein. The terminology is confusing, especially since there is another apolipoprotein called ApoA1, which is associated with HDL. Just as with LDL particles, lp(a) can vary in mass. More accurate tests are aimed at measuring lp(a) particle counts.

Lp(a) particle is an LDL particle with an apo(a) protein covalently bonded to the apoB protein on the LDL particle. Apo(a) can have varying molecular weights due to variation in the kringle domains. LDL particles can also vary in mass due to varying amounts of cargo. Due to this variation, lp(a) particle count is better for determining risk than an estimate of lp(a) mass. Image credit: peterattia.com/lpa.

You can have normal lipid numbers but have high cardiovascular risk due to lp(a). It is a genetic trait and families with this condition often experience pre-mature heart disease (before age 60). An lp(a) test should be part of a thorough work-up for anyone who is trying to determine their cardiovascular risk. Recent European clinical practice guidelines suggest that everyone should be screened at least once for lp(a).

There is still much that is unknown about lp(a). It is believed to increase the risk of heart attack and stroke because these particles are more likely to be retained in the artery wall and are more prone to oxidation. Oxidized particles that get stuck in the artery wall can trigger the inflammatory cascade that causes atherogenesis. However, there is no definitive proof that it is more atherosclerotic than an LDL particle.

The other reason lp(a) is in a class of its own is that there are currently no simple ways to lower it. Statins, which are highly effective at reducing LDL-C and LDL-P, do not lower lp(a). Likewise, lifestyle interventions, such as heart-healthy diet and exercise, may not be sufficient.

Cardiac MRI image. Photo credit.

People with high lp(a) are at increased risk of hypercoagulation, which may have been a benefit before the days of modern medicine but detrimental for cardiovascular health when placed within the context of poor eating and stress. Some cardiologists use aspirin as prophylaxis for clotting events, niacin, and/or a PCSK9 inhibitor [an expensive drug not approved for lp(a)]. In extreme cases, aphaeresis – a type of blood filtering – may be warranted. Because lp(a) is associated with aortic stenosis, regular echocardiograms could play a role in prevention. Similarly, a cardiac MRI can give vital information on morphology and pressure gradients in the heart, two factors that can increase the risk of lp(a).

4 | Sterols

Sterols are a class of organic compounds that share a similar chemical structure. Cholesterol is the best-known sterol but there are many others found in both animals and plants.

Measuring non-cholesterol sterols can help pinpoint whether high LDL-C is a result of increased cholesterol synthesis vs. absorption from the diet. This distinction can help with targeting personalized lipid-lowering strategies.

Cholesterol synthesis: Lathosterol and desmosterol are markers of cholesterol production and elevation of these sterols indicates increased cholesterol synthesis in the Kandutsch-Russell (K-R) pathway (lathosterol) or the Bloch pathway (desmosterol). Reducing saturated fat can help lower LDL-C/LDL-P when these sterols are elevated.

The two pathways of cholesterol synthesis – the Bloch and Kandutsch-Russell pathways. Lathosterol is the penultimate sterol precursor in the K-R pathway and desmosterol is the final precursor in the Bloch pathway. Elevations in either may indicate increased cholesterol synthesis in response to increased saturated fat intake.

Cholesterol absorption. Most of our cholesterol is endogenous, meaning we make it. Only about 15% comes from dietary sources. Typically, the gut absorbs cholesterol only if more is needed.

Phytosterols – sterols made by plants – include sitosterol and campesterol. Normally, the human gut does not absorb plant sterols but rare mutations in the ABCG5 or ABCG8 gene allow phytosterols to be absorbed, a condition called phytosterolemia. People who absorb phytosterols also absorb more dietary cholesterol. In this case, reducing cholesterol-rich foods may help to bring down LDL-C.

Phytosterols are highly atherogenic and increase susceptibility to early heart disease. Despite this, some doctors suggest that patients take phytosterols to reduce LDL-cholesterol. Many prominent lipidologists and cardiologists caution against taking phytosterol supplements, especially in patients who are hyper-absorbers.

People who are high cholesterol synthesizers tend to compensate by being low absorbers, and vice versa. A sterol panel is the only way to determine if elevated LDL-C may be due to increased cholesterol synthesis or absorption from the diet. Each condition offers different treatment targets.

Translating test results into treatment

Results from advanced cholesterol testing can help determine the best treatment approaches. Statins are widely-studied and highly effective at reducing LDL-C. While statins work great for many people, others are unable to tolerate them due to their many side effects. While statins lower LDL-C and LDL-P, they are not effective in treating certain conditions, such as elevated lp(a). Similarly, other classes of drugs may be more effective than statins at treating certain aspects of dyslipidemia. An excellent and more in-depth discussion of statins and other pharmaceutical approaches – and the evidence supporting each – can be found here.

Table 2. Non-statin treatment options for treating different aspects of dyslipidemia as indicated by NMR, apoB, lp(a), and sterol testing. This is not meant to be an exhaustive list, but it does touch on the main approaches involving pharmaceuticals, supplements, and diet.

TestResultApproachesComment
NMRIf high large particle countReduce saturated fats ~20% experience hyper-response to keto; reducing sat fats can lower LDL-C
Ezetimibe (Zetia)Upregulates LDL receptors which help with clearance 
PCSK9 inhibitorLowers small and large particle concentration (though all trial data are with statins)
Bile acid sequestrants (cholestyramine)Upregulates LDL receptors to bring more cholesterol to the liver so it can make more bile salts
If high small particle countRestrict carbohydratesHelps with insulin resistance, but increased dietary fat could contribute to LDL-C problem
Intermittent fastingHelps insulin resistance 
FibratesSmall particles can indicate metabolic syndrome. Fibrates inhibit synthesis of trigs; reduces trig pool in liver, raises HDL, reduces particle count (but only 10-15% reduction)
Omega 3 fatty acids (DHA)Decreases rate of triglyceride production
ApoBNiacin Accelerates degradation of apoB protein, but can have serious side effects
Ezetimibe (Zetia)Targets apoB production
EPA (fish oil)Inhibits oxidation of apoB
PCSK9 inhibitorReduces production of apoB and increase rate of clearance
Lp(a)Aspirin Prophylaxis for prothrombotic events
Niacin~20% reduction
PCSK9 inhibitorReduce lp(a) concentration by 25-30% but drug not approved for this purpose
Anti-sense nucleotidesThis is a class of drugs that is currently in clinical trials and is not yet FDA-approved
SterolsIf high desmosterol, lathosterolReduce saturated fats Reduces LDL-C (and LDL-P) in hyper-responders
If high campesterol, sitosterolReduce dietary cholesterolMight help with reducing LDL-C (and LDL-P)
Ezetimibe (Zetia)Blocks the intestine from internalizing cholesterol, but prevents the liver from internalizing cholesterol from a biliary source 
Bile acid sequestrants (cholestyramine)See above
Berberine Reduces cholesterol with high fat, high cholesterol diets

Putting dyslipidemia into context

Many cardiology researchers concede that high cholesterol is necessary but not sufficient for atherogenesis. In addition to the four tests discussed here, it is vitally important to look at markers of inflammation and metabolic health as they are also linked to an increased risk of cardiovascular disease. I briefly mention some tests here and encourage readers to explore them further.

The most commonly-measured marker of inflammation is high sensitivity CRP (hsCRP). Other markers of inflammation include Lp-PLA2 activity, myeloperoxidase, asymmetrical dimethylarginine (ADMA), and symmetrical dimethylarginine (SDMA). F2-isoprostanes, fibrinogen, and homocysteine also get at different aspects of vascular health and/or inflammation. Markers of oxidation, include oxLDL, and oxPL, can also provide information on inflammation.

Markers of metabolic health include fasting glucose, hbA1C, oral glucose tolerance test (measuring both glucose and insulin), insulin resistance marker (IR), insulin and an experimental test called TMAO. Similarly, a high triglyceride: HDL ratio could be indicative of metabolic syndrome.

Finally, imaging also can be helpful for ruling out existing cardiovascular disease. The coronary artery calcium (CAC) scan looks at calcifying arteries, the carotid intima-media thickness (CIMT) looks at artery thickening, and a CT angiogram helps to visualize soft plaques.

Advanced cholesterol testing, combined with inflammatory and metabolic markers and imaging, is the best way to understand the overall risk of cardiovascular disease. In the end, even if metabolic and inflammatory markers are excellent, the fact remains that elevated apoB and LDL-P are independent risk factors for heart disease.

Understanding why LDL-C has gone up and the context in which it occurs is essential for finding the best treatment options if elevated LDL cholesterol is a concern.

Up next: Keto and ME/CFS (part V): linking ME/CFS to high cholesterol.

For an in-depth discussion of lipid-lowering drugs listen to Peter Attia’s interview with Tom Dayspring Part IV.

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