Familial hypercholesteromia: Why rely on cholesterol levels when more direct measures are available?

There are two forms of familial hypercholesteromia (FH), namely heterozygous and homozygous FH. In heterozygous FH only one copy of the gene that causes it is present, inherited either from the father or the mother. In homozygous FH, which is the most lethal form, two copies of the gene are present. FH is associated with early-onset cardiovascular disease (CVD).

Homozygous FH may happen if both the father and mother have heterozygous or homozygous FH. If both the father and mother have heterozygous FH, the likelihood that at least one in four children will have homozygous FH will be high. If both parents have homozygous FH the likelihood that all children will have homozygous FH will be high.

In fact, in the latter case, homozygous FH in the children is almost certain. One case in which it won’t occur is if the combining FH gene from the father or mother mutates into a non-FH gene before it is used in the assembly of the genome of the child. A gene mutation in a specific locus, only for the father or mother, is an unlikely event, and would lead to heterozygous FH. Two gene mutations at once in the same locus, for the father and mother, is a very unlikely event.

By the way, despite what many are led to believe based on fictional characters in movies and series like the X-Men and Hulk, mutations in functional genes usually lead to harmful traits. In our evolutionary past, those traits would have been largely removed from the gene pool by selection, making them rare or nonexistent in modern humans. Today we have modern medicine; a double-edged sword.

Mutations leading to super-human traits are very, very unlikely. The myostatin gene, for example, suppresses muscle growth. And yet the mutations that lead to little or no secretion of the related myostatin protein are very uncommon. Obviously they have not been favored by selection, even though their holders are very muscular – e.g., Germany’s “Incredible Hulky” ().

Okay, back to FH. Xanthelasmas are relatively common among those who suffer from FH (see photo below, from Globalskinatlas.com). They are skin deposits of cholesterol, have a genetic basis, and are NOT always associated with FH. This is important – several people have xanthelasmas but not FH.

FH is a fairly rare disease, even in its heterozygous form, with an overall incidence of approximately 0.2 percent. That is, about 1 in 500 people in the general population will have it. Genetically related groups will see a much higher or lower rate of incidence, as the disease is strongly influenced by a genetic mutation. This genetic mutation is apparently in the LDL receptor gene, located on the short arm of chromosome 19.

The table below, from a study by Miltiadous and colleagues (), paints a broad picture of the differences one would typically see between heterozygous FH sufferers and non-FH controls.

The main difference is in total cholesterol and in the relatively large contribution of LDL to total cholesterol. A large difference is also seen in Apolipoprotein B (indicated as "Apo B"), which acts as a LDL transporter (not to be confused with a LDL receptor). The LDL cholesterol shown on the table is calculated through the Friedewald equation, which is notoriously imprecise at low triglyceride levels ().

Looking at the total cholesterol row on the table, and assuming that the numbers after the plus/minus signs are standard deviations, we can conclude that: (a) a little more than two-thirds of the heterozygous FH sufferers had total cholesterol levels falling in between 280 and 446; and (b) a little more than two-thirds of the non-FH controls had total cholesterol levels falling in between 135 and 225.

Keep in mind that about 13.5 percent {calculated as: (95-68)/2} of the non-FH controls had total cholesterol levels between 225 and 270. This is a nontrivial percentage; i.e., these may be a minority but are not rare individuals. Heterozygous FH sufferers are rare, at 0.2 percent of the general population. Moreover, about 2 percent of the non-FH controls had non-pathological total cholesterol levels between 270 and 315. That is not so rare either, amounting to an “incidence” 10 times higher than heterozygous FH.

What would happen if people with heterozygous FH were to replace refined carbohydrates and sugars with saturated fat and cholesterol in their diets? Very likely their already high total cholesterol would go up higher, in part because their HDL cholesterol would go up (). Still, how could they be sure that CVD progression would accelerate if they did that?

According to some studies, the higher HDL cholesterol would either be generally protective or associated with protective factors, even among those with FH (). One of those protective factors may be a more nutrient-dense diet, as many foods rich in cholesterol are very nutrient-dense – e.g., eggs, organ meats, and seafood.

This brings me to my main point in this post. It is mainstream practice to diagnose people with FH based on total and/or LDL cholesterol levels. But the main problem with FH is that it leads to early onset of CVD, which can be measured more directly through simple tests, such as intima-media thickness and related ultrasound plaque tests (). These are noninvasive tests, done in 5 minutes or so, and often covered by insurance.

Even if simple direct tests are not perfect, it seems utterly nonsensical to rely on cholesterol measures to diagnose and treat FH, given the possible overlap between pathological and non-pathological high total cholesterol levels.

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.