Sudden cholesterol increase? It may be psychological

There are many published studies with evidence that cholesterol levels are positively associated with heart disease. In multivariate analyses the effects are usually small, but they are still there. On the other hand, there is also plenty of evidence that cholesterol is beneficial in terms of health. Here of course I am referring to the health of humans, not of the many parasites that benefit from disease.

For example, there is evidence () that cholesterol levels are negatively associated with mortality (i.e., higher cholesterol leading to lower mortality), and are positively associated with vitamin D production from skin exposure to sunlight ().

Most of the debris accumulated in atheromas are made up of macrophages, which are specialized cells that “eat” cell debris (ironically) and some pathogens. The drug market is still hot for cholesterol-lowering drugs, often presented in TV and Internet ads as effective tools to prevent formation of atheromas.

But what about macrophages? What about calcium, another big component of atheromas? If drugs were to target macrophages for atheroma prevention, drug users may experience major muscle wasting and problems with adaptive immunity, as macrophages play a key role in muscle repair and antibody formation. If drugs were to target calcium, users may experience osteoporosis.

So cholesterol is the target, because there is a “link” between cholesterol and atheroma formation. There is also a link between the number of house fires in a city and the amount of firefighting activity in the city, but we don’t see mayors announcing initiatives to reduce the number of firefighters in their cities to prevent house fires.

When we talk about variations in cholesterol, we usually mean variations in cholesterol carried by LDL particles. That is because LDL cholesterol seems to be very “sensitive” to a number of factors, including diet and disease, presenting quite a lot of sudden variation in response to changes in those factors.

LDL particles seem to be intimately involved with disease, but do not be so quick to conclude that they cause disease. Something so widespread and with so many functions in the human body could not be primarily an agent of disease that needs to be countered with statins. That makes no sense.

Looking at the totally of evidence linking cholesterol with health, it seems that cholesterol is extremely important for the human body, particularly when it is under attack. So the increases in LDL cholesterol associated with various diseases, notably heart disease, may not be because cholesterol is causing disease, but rather because cholesterol is being used to cope with disease.

LDL particles, and their content (including cholesterol), may be used by the body to cope with conditions that themselves cause heart disease, and end up being blamed in the process. The lipid hypothesis may be a classic case of reverse causation. A case in point is that of cholesterol responses to stress, particularly mental stress.

Grundy and Griffin () studied the effects of academic final examinations on serum cholesterol levels in 2 groups of medical students in the winter and spring semesters (see table below). During control periods, average cholesterol levels in the two groups were approximately 213 and 216 mg/dl. During the final examination periods, average cholesterol levels were 248 and 240 mg/dl. These measures were for winter and spring, respectively.



One could say that even the bigger increase from 213 to 248 is not that impressive in percentage terms, approximately 16 percent. However, HDL cholesterol does not go up significantly response to sustained (e.g., multi-day) stress, it actually goes down, so the increases reported can be safely assumed to be chiefly due to LDL cholesterol. For most people, LDL particles are the main carriers of cholesterol in the human body. Thus, in percentage terms, the increases in LDL cholesterol are about twice those reported for total cholesterol.

A 32-percent increase (16 x 2) in LDL cholesterol would not go unnoticed today. If one’s LDL cholesterol were to be normally 140 mg/dl, it would jump to 185 mg/dl with a 32-percent increase. It looks like the standard deviations were more than 30 in the study. (This is based on the standard errors reported, and assuming that the standard deviation equals the standard error multiplied by the square root of the sample size.) So we can guess that several people might go from 140 to 215 or more (this is LDL cholesterol, in mg/dl) in response to the stress from exams.

And the effects above were observed with young medical students, in response to the stress from exams. What about a middle-aged man or woman trying to cope with chronic mental stress for months or years, due to losing his or her job, while still having to provide for a family? Or someone who has just been promoted, and finds himself or herself overwhelmed with the new responsibilities?

Keep in mind that sustained dieting can be a major stressor for some people, particular when one gets to that point in the dieting process where he or she gets regularly into negative nitrogen balance (muscle loss). So you may have heard from people saying that, after months or years of successful dieting, their cholesterol levels are inexplicably going up. Well, this post provides one of many possible explanations for that.

The finding that cholesterol goes up with stress has been replicated many times. It has been known for a long time, with studies dating back to the 1950s. Wertlake and colleagues () observed an increase in average cholesterol levels from 214 to 238 (in mg/dl); also among medical students, in response to the mental and emotional stress of an examination week. A similar study to the one above.

Those enamored with the idea of standing up the whole day, thinking that this will make them healthy, should know that performing cognitively demanding tasks while standing up is a known stressor. It is often used in research where stress must be induced to create an experimental condition. Muldoon and colleagues () found that people performing a mental task while standing experienced an increase in serum cholesterol of approximately 22 points (in mg/dl).

What we are not adapted for is sitting down for long hours in very comfortable furniture (, ). But our anatomy clearly suggests adaptations for sitting down, particularly when engaging in activities that resemble tool-making, a hallmark of the human species. Among modern hunter-gatherers, tool-making is part of daily life, and typically it is much easier to accomplish sitting down than standing up.

Modern urbanites could be seen as engaging in activities that resemble tool-making when they produce things at work for internal or external customers, whether those things are tangible or intangible.

So, stress is associated with cholesterol levels, and particularly with LDL cholesterol levels. Diehard lipid hypothesis proponents may argue that this is how stress is associated with heart disease: stress increases cholesterol which increases heart disease. Others may argue that one of the reasons why LDL cholesterol levels are sometimes found to be associated with heart disease-related conditions, such as chronic stress, and other health conditions is that the body is using LDL cholesterol to cope with those conditions.

Specifically regarding mental stress, a third argument has been put forth by Patterson and colleagues, who claimed that stress-mediated variations in blood lipid concentrations are a secondary result of decreased plasma volume. The cause, in their interpretation, was unspecified – “vascular fluid shifts”. However, when you look at the numbers reported in their study, you still see a marked increase in LDL cholesterol, even controlling for plasma volume. And this is all in response to “10 minutes of mental arithmetic with harassment” ().

I tend to think that the view that cholesterol increases with stress because cholesterol is used by the body to cope with stress is the closest to the truth. Among other things, stress increases the body’s overall protein demand, and cholesterol is used in the synthesis of many proteins. This includes proteins used for signaling, also known as hormones.

Cholesterol also seems to be a diet marker, tending to go up in high fat diets. This is easier to explain. High fat diets increase the demand for bile production, as bile is used in the digestion of fat. Most of the cholesterol produced by the human body is used to make bile.

The anatomy of a VAP test report

The vertical auto profile (VAP) test is an enhanced lipid profile test. It has been proposed, chiefly by the company Atherotech (), as a more complete test that relies on direct measurement of previously calculated lipid measures. The VAP test is particularly known for providing direct measurements of LDL cholesterol, instead of calculating them through equations ().

At the time of this writing, a typical VAP test report would provide direct measures of the cholesterol content of LDL, Lp(a), IDL, HDL, and VLDL particles. It would also provide additional measures referred to as secondary risk factors, notably particle density patterns and apolipoprotein concentrations. Finally, it would provide a customized risk summary and some basic recommendations for treatment. Below is the top part of a typical VAP test report (from Atherotech), showing measures of the cholesterol content of various particles. LDL cholesterol is combined for four particle subtypes, the small-dense subtypes 4 and 3, and the large-buoyant subtypes 2 and 1. A breakdown by LDL particle subtype is provided later in the VAP report.

In the table above, HDL cholesterol is categorized in two subtypes, the small-dense subtype 2, and the large-buoyant subtype 3. Interestingly, most of the HDL cholesterol in the table is supposedly of the least protective subtype, which seems to be a common finding in the general population. VLDL cholesterol is categorized in a similar way. IDL stands for intermediate-density lipoprotein; this is essentially a VLDL particle that has given off some of its content, particularly its triglyceride (or fat) cargo, but still remains in circulation.

Lp(a) is a special subtype of the LDL particle that is purported to be associated with markedly atherogenic factors. Mainstream medicine generally considers Lp(a) particles themselves to be atherogenic, which is highly debatable. Among other things, cardiovascular disease (CVD) risk and Lp(a) concentration follow a J-curve pattern, and Lp(a)’s range of variation in humans is very large. A blog post by Peter (Hyperlipid) has a figure right at the top that illustrates the former J-curve assertion (). The latter fact, related to range of variation, generally leads to a rather wide normal distribution of Lp(a) concentrations in most populations; meaning that a large number of individuals tend to fall outside Lp(a)’s optimal range and still have a low risk of developing CVD.

Below is the middle part of a typical VAP report, showing secondary risk factors, such as particle density patterns and apolipoprotein concentrations. LDL particle pattern A is considered to be the most protective, supposedly because large-buoyant LDL particles are less likely to penetrate the endothelial gaps, which are about 25 nm in diameter. Apolipoproteins are proteins that bind to fats for their transport in lipoproteins, to be used by various tissues for energy; free fatty acids also need to bind to proteins, notably albumin, to be transported to tissues for use as energy. Redundant particles and processes are everywhere in the human body!

Below is the bottom part of a typical VAP report, providing a risk summary and some basic recommendations. One of the recommendations is “to lower” the LDL target from 130mg/dL to 100mg/dL due to the presence of the checked emerging risk factors on the right, under “Considerations”. What that usually means in practice is a recommendation to take drugs, especially statins, to reduce LDL cholesterol levels. A recent post here and the discussion under it suggest that this would be a highly questionable recommendation in the vast majority of cases ().

What do I think about VAP tests? I think that they are useful in that they provide a lot more information about one’s lipids than standard lipid profiles, and more information is better than less. On the other hand, I think that people should be very careful about what they do with that information. There are even more direct tests that I would recommend before a decision to take drugs is made (, ), if that decision is ever made at all.

The 2012 Atherosclerosis egg study: Plaque decreased as LDL increased with consumption of 2.3 eggs per week or more

A new study by David Spence and colleagues, published online in July 2012 in the journal Atherosclerosis (), has been gaining increasing media attention (e.g., ). The article is titled: “Egg yolk consumption and carotid plaque”. As the title implies, the study focuses on egg yolk consumption and its association with carotid artery plaque buildup.

The study argues that “regular consumption of egg yolk should be avoided by persons at risk of cardiovascular disease”. It hints at egg yolks being unhealthy in general, possibly even more so than cigarettes. Solid critiques have already been posted on blogs by Mark Sisson, Chris Masterjohn, and Zoe Harcombe (, , ), among others.

These critiques present valid arguments for why the key findings of the study cannot be accepted, especially the finding that eggs are more dangerous to one’s health than cigarettes. This post is a bit different. It uses the data reported in the study to show that it (the data) suggests that egg consumption is actually health-promoting.

I used the numbers in Table 2 of the article to conduct a test that is rarely if ever conducted in health studies – a moderating effect test. I left out the “egg-yolk years” variable used by the authors, and focused on weekly egg consumption (see Chris’s critique). My analysis, using WarpPLS (), had to be done only visually, because using values from Table 2 meant that I had access only to data on a few variables organized in quintiles. That is, my analysis here using aggregate data is an N=5 analysis; a small sample indeed. The full-text article is not available publicly; Zoe was kind enough to include the data from Table 2 in her critique post.

Below is the model that I used for the moderating effect test. It allowed me to look into the effect that the variable EggsWk (number of eggs consumed per week) had on the association between LDL (LDL cholesterol) and Plaque (carotid plaque). This type of effect, namely a moderating effect, is confusing to many people, because it is essentially the effect that a variable has on the effect of another variable on a third. Still, being confusing does not mean being less important. I should note that this type of effect is similar to a type of conditional association tested via Bayesian statistics – if one eats more eggs, what is the association between having a high LDL cholesterol and plaque buildup?

You can see what is happening visually on the graph below. The plot on the left side is for low weekly egg consumption. In it, the association between LDL cholesterol and plaque is positive – eating fewer eggs, plaque and LDL increase together. The plot on the right side is for high weekly egg consumption. In this second plot, the association between LDL cholesterol and plaque is negative – eating more eggs, plaque decreases as LDL increases. And what is the turning point? It is about 2.3 eggs per week.

So the “evil” particle, the LDL, is playing tricks with us; but thankfully the wonderful eggs come to the rescue, right? Well, it looks a bit like it, but maybe other foods would have a similar effect. In part because of the moderating effect discussed above, the multivariate association between LDL cholesterol and plaque was overall negative. This multivariate association was estimated controlling for the moderating effect of weekly egg consumption. You can see this on the plot below.

The highest amount of plaque is at the far left of the plot. It is associated with the lowest LDL cholesterol quintile. (So much for eggs causing plaque via LDL cholesterol eh!?) What is happening here? Maybe egg consumption above a certain level shifts the size of the LDL particles from small to large, making the potentially atherogenic ones harmless. (Saturated fat consumption, in the context of a nutritious diet in lean individuals, seems to have a similar effect.) Maybe eggs contain nutrients that promote overall health, leading LDL particles to "behave" and do what they are supposed to do. Maybe it is a combination of these and other effects.