Genes, LDL-Cholesterol Levels, and the Central Role of LDL Receptor Activity In Heart Disease

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Are high concentrations of LDL-cholesterol a major cause of heart disease?  If we are a proponent of the “lipid hypothesis,” we say yes.  If we are a “cholesterol skeptic,” we say no — total cholesterol, LDL-cholesterol, LDL particles, triglycerides, and other blood lipids have little or nothing to do with heart disease.

I believe both of these positions are wrong.

I think the evidence for the central role of the of the LDL particle in the development of atherosclerosis is overwhelming.  However, I believe the evidence is very strong that the LDL particle is a victim rather than a perpetrator in the process, and that it is the oxidative destruction of the particle itself rather than the concentration of cholesterol within it that is the culprit.  In this post, we will explore some important pieces of this evidence, and consider whether measuring blood cholesterol is meaningful.  In the next post in this series, I will consider the possibility that leptin signaling and thyroid hormone are central governors of the risk of heart disease.

Let's consider for a moment this graph from the Framingham Study (1).

The dotted line represents the people who developed coronary heart disease, while the solid line represents those who remained heart disease-free.  There are several legitimate points we could make about this graph on either side of the “lipid hypothesis” argument.
If we are a “cholesterol skeptic,” we might point out that the dotted line is only shifted to the right marginally, meaning that people who developed heart disease only had slightly higher cholesterol, on average, than people who did not.  We might also point out that the vast area in the middle is shared by both those with and without heart disease.  In fact, the solid line represents about seven times as many people as the dotted line. That means that the vast majority of people who developed heart disease developed it with cholesterol levels similar to those of seven times as many people who remained free of heart disease.
But let's look a little more closely at the graph.  What else can we learn from it?  Over to the right, we see a hump in the dotted line where everyone has heart disease.  On the left, we see an area below 150 mg/dL where no one has heart disease.

Who are these people?  And can they teach us anything about the cause of heart disease?The Genetic Evidence — LDL Receptor Activity

Many of the people in the hump on the right are undoubtedly people with familial hypercholesterolemia.  Familial hypercholesterolemia results from a genetic defect in the LDL receptor, which is the receptor required to bring the LDL particle into cells.  It can come in two forms.  People who inherited only one defective copy of the gene from either their father or mother are heterozygous for the disease, while people who inherited a defective copy from both parents are homozygous for the disease.
People who are homozygous for familial hypercholesterolemia can develop atherosclerosis and coronary heart attacks in infancy (23).

In the third edition of The Metabolic Basis of Inherited Disease (1972), Fredrickson and Levy reported a South African child with the homozygous form of this disease who died of a heart attack when only 18 months old.  The oldest survivor in their case series died at age 27 after his third heart attack.

Thus, while most people become at risk for heart disease after the age of 60, people with two defective copies of the LDL receptor gene have this risk shifted back to the ages of 0-30 and are pretty much guaranteed to die from atherosclerosis or related complications early in life.

People who have only one copy of the defective gene have the risk of heart disease shifted instead to the 30-60 age range, and their age- and sex-adjusted risk of heart disease is dramatically increased (4).


If we amass groups of people who have one copy of any number of different mutations that result in a defective LDL receptor and compare them as a group to their unaffected relatives, adjusting for age and sex, those with a mutation that decreases the effectiveness of the receptor have a four-fold elevated risk of heart disease, while those who have a mutation that eliminates the gene's ability to code for an LDL receptor entirely have a six-fold elevated risk.

But if we specifically match each person with a defect to their own relatives so that we control for any other genetic and environmental factors they share in common, those with a copy of a partially defective gene have an eight-fold increase in risk and those with a completely defective gene have a more than ten-fold increase in risk.

Now, who might those people be on the other side of the Framingham graph who have low cholesterol levels and zero incidence of heart disease?  Perhaps some of them have a genetic defect in the PCSK9 gene, which codes for the enzyme that degrades the LDL receptor.  These people have a genetic defect that increases LDL receptor activity instead of decreasing it.  This is essentially the opposite of familial hypercholesterolemia.
Those who have a “nonsense” mutation that deletes the enzyme have a whopping 88 percent reduction in the risk of heart disease (5)!  That's virtual abolition!
Thus if we look at the genetic evidence, we see a dose-response effect of LDL receptor activity.  Mutations that increase its effectiveness virtually abolish the risk of heart disease.  One copy of a mutation that decreases its effectiveness pushes the risk back from the over-60 age range to the 30-60 age range and raises the risk eight- to ten-fold.  Having two copies of a defective gene pushes the risk back to the 0-30 age range, virtually guarantees an early death, and can produce heart attacks in infancy.
Can these genetic mutations tell us anything about what causes heart disease in the rest of us?
I would argue that this is incredibly powerful evidence that we can and should use to learn about the cause of heart disease in people without these mutations, so long as other forms of evidence from mutation-free populations are consistent with and supportive of the hypothesis we develop.
Why?  Mutations in single genes that affect single traits are the closest form of evidence we have to a lifelong experiment.
Genetic mutations, however they develop, are randomly sorted and distributed to the sex cells that eventually form new human beings.  Thus, this type of evidence, although observational, is much closer to a “natural” randomized experiment than a typical observational study, and it's the only form of such evidence that can be carried out over a lifetime. 

Sometimes genetic variants can be linked to variants in other genes nearby on the chromosome.  However, this cannot possibly account for the genetic evidence presented here thus far, because the study referenced above included people with nine independent mutations in the LDL receptor, four of which were present in substantial numbers, and the PCSK9 gene isn't even on the same chromosome!Furthermore, the fact that adjusting for family ties increased rather than decreased the risk estimate for heart disease among people with familial hypercholesterolemia in the above study provides further confirmation that the increase in risk is due specifically to the LDL receptor mutations.

Thus, the genetic evidence suggests that LDL receptor activity plays a central role in governing the risk of heart disease.
While it would be wrong to consider this genetic evidence separately from other forms of evidence without trying to synthesize the totality of the evidence into a coherent theory, it would likewise be wrong to assume that the findings of these genetic studies transfer to humans without these mutations.  It is possible that the range of LDL receptor activity in “normal” people just isn't broad enough to impact heart disease risk, or even that there is some type of funny-shaped risk curve that looks like this:

Can we find evidence supporting a role for LDL receptor activity among those who do not have these mutations?  If so, this would allow us to synthesize these different forms of evidence into a coherent theory about the importance of LDL receptor activity.

Modest Evidence From Drug Trials Suggests That Increasing LDL Receptor Activity Lowers CHD Risk
As it turns out, we already have evidence from randomized, controlled drug trials showing that drugs that increase LDL receptor activity decrease the risk of heart disease.  Both cholestyramine and statins lower blood levels of LDL-cholesterol by increasing LDL receptor activity (6).
Here are two slides from my most recent Wise Traditions lecture, “Heart Disease and Molecular Degeneration: The New Paradigm,” showing how this occurs.  You can click on them to enlarge them if necessary.
Cholestyramine binds bile acids and causes their excretion.  As a result, the liver makes more bile acids from cholesterol.  The level of free cholesterol in the liver thus declines, and the liver increases its expression of the LDL receptor in order to take in more cholesterol from the blood.
Statins target cholesterol synthesis in the liver.  By inhibiting cholesterol synthesis, they decrease the level of free cholesterol in the liver just like cholestryamine.  Consequently, the liver increases its expression of the LDL receptor in order to take in more cholesterol from the blood.
As I pointed out recently in my post, “Conflating the Lipid Hypothesis With the Diet-Heart Hypothesis Led to the Public Condemnation of Bacon, Butter, and Eggs,”  the Coronary Primary Prevention Trial (CPPT) provided very convincing evidence that cholestyramine reduces the risk of heart disease, with strong, though perhaps not definitive, evidence for a dose-response.
Virtually everyone agrees, cholesterol skeptic or lipid hypothesis proponent, that statins reduce the risk of heart disease and related mortality at least in certain specific well-studied populations, such as middle-aged white males with established heart disease, but the evidence that would be relevant here, and comparable to the Coronary Primary Prevention Trial with cholestyramine, is whether they prevent heart disease in people who are initially heart disease-free.
A recent Cochrane Review pooled the results of nine statin trials conducted in people without established heart disease and found a 28 percent reduction in the relative risk of cardiac events (7).
The authors also warned, however, that most of the trials did not report adverse effects at all, that in some trials the investigators may have exaggerated their effects by stopping the trial short when the results looked good, that Big Pharma sponsored all of the trials except one, that the populations tended to be white, male, and middle-aged, that investigators have downplayed potential side effects such as diabetes and avoided even looking for others such as cognitive impairment, that the reporting of details was so poor that the data were ultimately “impossible to disentangle,” and that if they had loosened their criteria of  which trials to include their analysis could have shown no benefit at all.
Thus the evidence from statins is somewhat supportive, but should probably be taken with a grain of salt.
Unfortunately, it is currently impossible to provide a single, definitive test of whether increasing LDL receptor activity in members of the general population can reduce their risk of heart disease.  Not only are statin trials usually too short (one to five years, compared to 7-10 year followup in the CPPT), but all of these drugs increase LDL receptor activity indirectly and without complete specificity.
Statins inhibit the synthesis of mevalonate, a compound that eventually, far down in the biochemical pathway, gets converted to cholesterol.  But our cells use mevalonate for many other things, and thus statins have many “pleiotropic” effects.  One such effect is to decrease the activation of a little enzyme called Rho, an enzyme that is part of the stress response and almost certainly contributes to both atherosclerosis and thrombosis.  On the other hand, statins also decrease the synthesis of coenzyme Q10, a compound that likely protects against heart disease.  Thus, statins are likely to have opposing effects on the risk of heart disease through different mechanisms.
All of these effects result from the inhibition of mevalonate synthesis, meaning they should all correlate with one another.  Thus, the question of whether the effect of statins on mortality correlates with their effect on cholesterol levels is meaningless.

Cholestyramine's effect on LDL receptor activity is more specific than the effect of statins, and the results of the CPPT are more convincing than those of the statin trials, but cholestyramine's effect is still indirect.  There is no way to definitively separate its effect on the LDL receptor from its effect on many other parameters, such as the amount of cholesterol degraded and excreted from the body, or potential effects on the absorption of other compounds from the gut.As I will discuss in a future post, thyroid hormone is the other central governor of LDL receptor activity besides the cholesterol level within the cell.  While the cell regulates its expression of the LDL receptor for the sake of maintaining its own constant state of free cholesterol, thyroid hormone communicates to the cell that the organism is in a state of abundance and can dispose of that cholesterol by making bile acids and reproductive hormones, which enhance digestion, strength, and fertility.

Yet can we conduct a specific test of the hypothesis that LDL receptor activity is a central governor of heart disease risk by conducting a randomized, controlled trial using thyroid hormone or using natural means of normalizing thyroid hormone status?  Of course not.  Thyroid hormone has all kinds of metabolic effects and is far less specific to LDL receptor activity than cholestyramine, and even less specific than statins.  Of course, normalizing thyroid hormone status would improve digestion, cognitive impairment, and other parameters that may be impaired by cholesterol-lowering drugs, but it cannot constitute a specific test of the hypothesis.

Thus, there is no evidence from clinical trials that can definitively support or falsify the hypothesis that LDL receptor activity governs heart disease risk in the general population, but the current evidence from randomized trials is about as supportive as we might expect assuming the hypothesis is true.Support From Animal Experiments

Given the impossibility of specifically testing the hypothesis in humans, we must turn to experimental evidence in animals and cell culture.
The cholesterol-fed rabbit model is often dismissed by “cholesterol skeptics” because it supposedly does not produce human-like atherosclerosis and because it supposedly cannot be reproduced in animals that are not naturally vegetarians.  The first claim is simply false.  The second claim is another case of mistaking the diet-heart hypothesis for the lipid hypothesis
Although the effect of dietary cholesterol is not necessarily generalizable from rabbits to other species, investigators have shown the effect of elevated cholesterol levels in the blood called hypercholesterolemia to be generalizable to many other species including the baboon, cat, chicken, chimpanzee, dog, goat, guinea pig, hamster, monkey, mouse, parrot, pig, pigeon, rabbit, and rat (8).  I will cover the collective animal evidence in more detail in a future post.
Anitschkov's drawings of the arterial plaques in his cholesterol-fed rabbit looked very much like those found in human atherosclerosis (9):
Image hosted on the Journal of Lipid Research web site.
Anitschkov observed first fatty streaks populated by cells from the immune system that we now call “foam cells,” which developed as the disease progressed into a plaque with a necrotic core (a core full of death, or dead cells) containing crystals of cholesterol and calcium deposits, covered by a fibrous cap of smooth muscle cells, just as occurs in humans.Anitschkov and those who reproduced his model were also able to produce a range of severity that mimics what is found in humans.  Feeding massive quantities of cholesterol produced a disease state similar to familial hypercholesterolemia, where atherosclerosis develops rapidly and the various internal organs develop deposits of cholesterol.  Feeding cholesterol-containing foods such as milk or egg yolks produced a much milder elevation of blood cholesterol levels and atherosclerosis that developed slowly and  without abundant cholesterol deposits in the internal organs, as occurs in the general population.Anitschkov also observed that inflammation, high blood pressure, and local arterial injury accelerated this process, while sex hormones, thyroid hormone, and iodine proved protective.  He suggested that infection and disturbances of the nervous system were also likely to accelerate the process.

He developed two theories to explain this.  The first was his infiltration theory, which corresponds to the lipid hypothesis as defined by Ahrens, Steinberg, and other major figures in the history of the lipid hypothesis.  He considered hypercholesterolemia the necessary pre-requisite for human-like atherosclerosis and summarized this view with his dictum that atherosclerosis never develops without cholesterin.” The second was his combination theory,  which held that many other factors determine the final fate of the animal with the disease.

Animal models of atherosclerosis almost never produce a true heart attack, which requires the thinning of the fibrous cap and the release of clotting factors from the lipid-rich necrotic core into the blood, and subsequent formation of a clot that blocks a coronary artery.  This may be because rabbits and most other animals synthesize their own vitamin C and are therefore able to continually synthesize collagen even as the inflammatory process degrades it.

In any case, this further supports Anitschkov's combination theory, and suggests that while atherosclerosis may be necessary to produce a true heart attack (of course there are other forms of heart disease and not all are strictly dependent on atherosclerosis), additional factors must also be present.  Thus, while elevated levels of cholesterol (in Anitschkov's “infiltrative” view, which I will argue below is wrong) may be necessary to cause atherosclerosis, a multitude of other factors intervene to determine the rate at which atherosclerosis develops and whether it ultimately produces a heart attack.

This is very consistent with the genetic evidence from humans in three important ways.

First, the rabbits seem to develop atherosclerosis when the amount of LDL and related lipoproteins in the blood greatly exceeds the capacity of LDL receptors to clear it.  Rabbits with genetically defective LDL receptors develop a very similar presentation (6).

Second, thyroid hormone was able to reverse the disease, and thyroid hormone governs the activity of the LDL receptor.  Likewise, dietary cholesterol does not produce atherosclerosis in dogs unless the researchers also inhibit thyroid hormone, suggesting that species that have adapted to eating cholesterol have done so in part by acquiring means of revving up the activity of their LDL receptors.

Third, it is very consistent with the suggestion of human genetic evidence that poor LDL receptor activity is required but not sufficient to produce heart disease.  I reviewed evidence above that the PCSK9 mutation increases LDL receptor activity and results in an 88 percent reduction in the risk of heart disease.  This suggests, conversely, that the lower LDL receptor activity seen in the general population is virtually required for heart disease to develop.

Alternatively, while those with homozygous familial hypercholesterolemia are essentially guaranteed a very early death, many people with heterozygous familial hypercholesterolemia live to old age without developing heart disease severe enough to be diagnosed.  Here's a survival chart from the genetic study I cited above (4):


As can be seen above, heart disease begins developing much earlier, around 30, but still by age 40 virtually everyone is still heart disease-free.  As the most vulnerable people with familial hypercholesterolemia die off and the people without the disease all start developing atherosclerosis, the slope of the line starts to become similar. By the time these people are in their 70s or 80s, there are far fewer people left without heart disease among those with familial hypercholesterolemia as a result of all of the heart disease that occurred at earlier ages.  Nevertheless, even by age 70 or 80, there are people with familial hypercholesterolemia who survive heart disease-free.

Thus, the principle that insufficient LDL receptor activity is necessary but not sufficient to cause heart disease seems generalizable across many species, which makes it very unlikely that humans without specific mutations in the receptor are the sole exception.

So is it true, then, as the proponents of the “lipid hypothesis” suggest, that high cholesterol causes heart disease?  No.  I believe the evidence suggests that it does not.Cholesterol Does Not Cause Heart Disease 

The cholesterol-fed rabbit model provided the striking revelation that high levels of cholesterol in the blood do not cause heart disease.

Here's a slide from my Wise Traditions lecture, Heart Disease and Molecular Degeneration: The New Paradigm, showing how.


If they fed rabbits cholesterol, they developed atherosclerosis.  If they injected rabbits with cholesterol, they did not.  If they fed rabbits cholesterol, isolated the lipoproteins from their blood that were carrying that cholesterol, and injected those lipoproteins into other rabbits, those other rabbits did develop atherosclerosis.

Thus, it was not the presence of high cholesterol in the blood that caused atherosclerosis, but rather the presence of high amounts of lipoproteins.

Or was it?

Researchers in the late 1970s and early 1980s found that when they incubated LDL particles with endothelial cells, which are the types of cells that make up the inner lining of the blood vessel, something in that LDL changed.  It became toxic to those cells.  More recent research has continued to confirmed this (10).

Incubating the LDL with those cells for a long period of time approximated the condition of the LDL particle spending a long time in the blood, with the exception that immune cells and many other cell types that would be present in the blood of an organism were absent.

Researchers began calling this “endothelial-cell modified LDL,” but in June of 1984, just three months after Time Magazine hailed the Coronary Primary Prevention Trial (CPPT) as proving that the American Heart Association had been right all along since it first started recommending we replace animal fats with vegetable oils in 1961, Daniel Steinberg's group published a paper in the Proceedings of the National Academy of the Sciences showing that this “modification” was the oxidative destruction of the polyunsaturated fatty acids in the membrane of the LDL particle (11). 

This was ironic for several reasons.  First, Steinberg was the chair of the CPPT planning committee.  Second, polyunsaturated fatty acids are found in the vegetable oils that Time was praising.  Third, Steinberg's group had already provided evidence the preceding year suggesting that this oxdiative “modification” of LDL, and not its concentration, promoted heart disease (12):

As the line moves upward, immune cells called macrophages have taken up a larger absolute amount of LDL. This is what causes them to morph into the “foam cells” that populate atherosclerotic plaques. As the line moves to the right, the concentration of LDL is increased.  The white circles represent fresh LDL and the black circles represent “endothelial-cell modified” (oxidized) LDL.

As we can see, moving from the left side of the graph to the right, the concentration increases five-fold but in the case of the white circles the line stays pretty much flat.  This suggests that the concentration of LDL has virtually no effect on the amount that macrophages gobble up.  By contrast, oxidation can increase uptake three-fold, five-fold, or more, depending on the concentration.

Later research showed that oxidation occurs in several stages (13).  First, polyunsaturated fatty acids in the membrane begin to oxidize.  If these products come into contact with the endothelial cells that line the blood, the endothelial cells will produce “adhesion molecules” that attract immune system cells such as monocytes.  As the fatty acids continue to oxidize, they eventually destroy the protein in the membrane and prevent its interaction with the LDL receptor, while at the same time facilitating its interaction with the “scavenger receptors” that the monocyte expresses.

Once in the monocyte, the most abundant components of oxidized LDL that are capable of initiating changes in gene expression that turn the monocyte into a macrophage and then into a foam cell are oxidized derivatives of linoleic acid (14), which in the diet are found most abundantly in vegetable oils.

Thus, what we see in this collective evidence is that oxidative destruction of polyunsaturated fatty acids in the membrane of the LDL particle causes it to become toxic to the cells that line blood vessels, and they then send out “help signals” calling on the immune system to clean up the toxic mess, and the immune system then creates an atherosclerotic plaque as an alternative to the greater harm of letting the cells that line the blood vessels die.

Thus, the proximate cause of the development of atherosclerosis is not poor LDL receptor activity, but LDL oxidation.  Yet, it is quite clear from the genetic evidence in humans and from animal experiments that insufficient LDL receptor activity is at least one of the major ultimate causes that can lead to LDL oxidation and thus to atherosclerosis.

How?  By allowing the LDL particle to spend too long a time in the blood.  Unlike the cell, the LDL particle has no vast database of genes nor vast enzymatic machinery to access that genetic information in order to produce antioxidants like glutathione or coenzyme Q10.  The liver packages the lipoprotein with a store of antioxidants that will be sufficient if the LDL transports nutrients rather quickly, but if LDL receptor activity is poor, this nutrient transport is compromised, the oxidants within blood deplete the particle of its antioxidants, and oxidation ensues.

The Intrinsic Elusiveness of Biological Truth
Given the complexity of any biological phenomenon, it will be in most cases impossible to
provide a single, definitive demonstration of its truth.
Even the event of LDL oxidation is elusive because cells quickly take oxidized LDL out of the blood in order to protect the blood vessels.  There is no specific intervention we can use to increase or decrease LDL receptor activity without having other unintended consequences, whether good or bad.  There is likewise nothing we can do to specifically prevent LDL oxidation, since no antioxidants are specific to LDL and since supplementing with single antioxidants can as easily disturb the antioxidant network as it can support it.
Thus, there will certainly be dietary strategies that can minimize LDL oxidation, but none that can do so specifically enough to provide a definitive test of the hypothesis.
I nevertheless believe that the role of lipoproteins in heart disease is one of the most extensively supported biological hypotheses in existence, especially in the realm of human health.  The problem is that proponents have so often mistaken this evidence for indicting the concentration of LDL-cholesterol rather than the oxidative degeneration of the LDL membrane that they have misconstrued high LDL-cholesterol as the “cause” or at least a cause of heart disease.
This then brings us to the question of whether we should even pay attention to cholesterol levels or just ignore them.

Do Cholesterol or LDL-Cholesterol Levels Matter?

Although cholesterol levels do not determine our risk for heart disease, they may indeed be a marker for poor LDL receptor activity and related metabolic problems and they should therefore not be ignored.

First, let's dispense with the false notion that cholesterol levels determine our risk for heart disease.

The Framingham data I opened this post with is intriguing, but rather deceptive because of its small sample size, and many people have misused it to suggest that if cholesterol levels are low enough, you simply can't get heart disease.

For example, Caldwell Esselstyn, in his book Prevent and Reverse Heart Disease (see my review here), writes the following:

This is it: if you follow a plant-based nutrition program to reduce your total cholesterol level to below 150 mg/dL and the LDL level to less than 80 mg/dL, you cannot deposit fat and cholesterol into your coronary arteries. Period.

Likwise, in The New Evolution Diet (see my review here), Arthur De Vany refers to an LDL-cholesterol level under 100 as “the no-risk level” as if it is impossible to develop heart disease with cholesterol that low.

Although the Framingham data indicated that everyone with a total cholesterol under 150 mg/dL remained free of heart disease, nine people who underwent screening for the MR FIT trial and had cholesterol levels under 140 mg/dL died of heart disease (15).

Likewise, the single man with a PCSK9 nonsense mutation in the study I cited above who developed heart disease died of a heart attack at the age of 68, but had an LDL-cholesterol level of only 53 mg/dl, well below the supposed “no risk” level.  He was obese, smoked, and had high blood pressure.  This supports Anitschkov's “combination theory” but flatly contradicts his “infiltration theory,” in which it is the amount of cholesterol rather than the oxidation of 
lipoproteins that matters.

Nevertheless, levels of blood lipids, when interpreted in the appropriate context, may be important indicators of metabolic problems, including low LDL receptor activity.

If LDL receptor activity is poor, LDL particles and related lipoproteins will stay in the blood for a longer period of time.  The longer they are in the blood, the more they are exposed to cholesterol ester transfer protein, which causes LDL to give triglycerides to HDL in exchange for cholesterol.  This will increase LDL-cholesterol and decrease HDL-cholesterol.  Furthermore, since cholesterol is more dense than triglycerides, this causes the LDL particles to become small and dense.

At the same time, this causes LDL to continuously encounter oxidants.  As its antioxidants become depleted, it begins to oxidize, which makes it even more dense.

The total-to-HDL cholesterol level is a well-established predictor of heart disease risk.  This is virtually the same thing as the ratio of LDL-cholesterol to HDL-cholesterol because most cholesterol that is not carried in HDL is carried in LDL.

A recent meta-analysis pooled together the results of 68 prospective studies including over 302,000 participants and found that LDL-cholesterol, HDL-cholesterol, and triglycerides were all capable of predicting the risk of heart disease.  When they combined them in a statistical model, however, triglycerides lost their predictive power and only LDL-cholesterol and HDL-cholesterol remained predictive (16):


Clicking on the picture will enlarge it.  The circles show the unadjusted correlations while the squares show the adjusted correlations.

Likewise, a meta-analysis published in 2007 pooled together the results of 61 studies with almost 900,000 participants (17).  These authors were not interested in triglycerides, which allowed them to include some larger studies that didn't measure them.  They came to similar conclusions about the predictive power of LDL-cholesterol and HDL-cholesterol, but also concluded that these two factors are independent of one another, so that the total-to-HDL cholesterol ratio provides the most information:


They found that the relative risk of a high ratio decreases with age, but that the absolute risk of a high ratio actually increases with age because so many more people develop heart disease and die from it in old age.

In a future post, I will treat individual studies more thoroughly to examine the nuances.  It is quite clear that triglycerides, for example, are not meaningless, because they can be a marker for insulin resistance.  Nevertheless, the results of these meta-analyses represent the most consistently powerful blood lipid predictors in the general population.

In a future post, I will also consider other tests that may be useful, such as LDL particle size, emerging tests for oxidized LDL, and others.  My point here is simply that the most comprehensively studied, best-established markers do predict heart disease risk and can be seen as markers for poor LDL receptor activity.

Nevertheless, these markers do not determine the risk of heart disease.  Therefore, they must be considered clues to look for the real metabolic issues lying behind them.

In the next post in this series, I will consider the possibility that abnormal blood lipids may be markers of poor leptin and thyroid status.  I will also take a look at the fact that the natives whose diets we always want to emulate always have “healthy” cholesterol levels.

However, seemingly “bad” changes in blood lipids could also indicate positive healing processes.  As I pointed out in a post recently, “Why Is My Cholesterol So High On This Diet?” an increase in cholesterol or triglycerides following a dietary change could indicate that the diet is curing fatty liver, or that the cells are faced with a new abundance of energy that they can use for productive processes, both of which are good things.  They may also accompany weight loss, which emphasizes the need to measure blood lipids after a period of stable diet and weight.  And finally, a number of factors may increase cholesterol synthesis or decrease the oxidation of VLDL and LDL particles either before they are sent from the liver or once they are in the blood, both of which could  raise blood lipids.

Thus, these markers, in my view, should neither be ignored nor interpreted out of context.

Interpreting that context may be difficult and nuanced, and I will consider these nuances in future posts in this series.


1. Kannel WB, Castelli WP, Gordon T.  Cholesterol in the prediction of atherosclerotic disease.  New Perspectives Based on the Framingham Study.  Ann Intern Med. 1979;90(1):85-91.

2. Rose V, Wilson G, Steiner G. Familial hypercholesterolemia: Report of coronary death at age 3 in a homozygous child and prenatal diagnosis in a heterozygous sibling.  J Pediatr. 1982;100(5):757-9
3. Fredrickson DS, Levy RI. Familial Hyperlipoproteinemia. In: Stanbury JB, Wyngaarden JB, Fredrickson DS, eds.  The Metabolic Basis of Inherited Disease. New York, NY: McGraw-Hill (1972). pp. 531-544.
4. Umans-Eckenhausen MA, Sijbrands EJ, Kastelein JJ, Defesche JC. Low-density lipoprotein receptor gene mutations and cardiovascular risk in a large genetic cascade screening population. Circulation. 2002;106(24);3031-6.
5. Cohen JC, Boerwinkle E, Mosley TH Jr, Hobbs HH. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med. 2006;354(12):1264-72.

6. As reviewed in Goldstein JL, Kita T, Brown MS. Defective lipoprotein receptors and atherosclerosis. Lessons from an animal counterpart of familial hypercholesterolemia. N Engl J Med. 1983;309(5):288-96.7. Taylor F, Ward K, Moore TH, Burke M, Davey Smith G, Casas JP, Ebrahim S. Statins for the primary prevention of cardiovascular disease. Cochrane Database Syst Rev. 2011;19(1):CD004816.

8. Steinberg D.  The Cholesterol Wars: The Skeptics vs. the Preponderance of the Evidence.  San Diego, CA: Academic Press (2007).

9.  Anitschkow N. Experimental Arteriosclerosis in Animals. In: Cowdry EV. Arteriosclerosis: A Survey of the Problem. New York: Macmillan (1933).

10.  Sata M, Walsh K.  Endothelial Cell Apoptosis Induced by Oxidized LDL is Associated with the Down-regulation of the Cellular Caspase Inhibitor FLIP. J Biol Cehm. 1998;273(50):3303-6.
11. Steinbrecher UP, Parthasarathy S, Leake DS, Witztum JL, Steinberg D. Modification of low density lipoprotein by endothelial cells involves lipid peroxidation and degradation of low density lipoprotein phospholipids. Proc Natl Acad Sci USA. 1984;81(12):3883-7.
12. Henrisksen T, Mahoney EM, Steinberg D.  Enhanced macrophage degradation of biologically modified low density lipoprotein.  Arterioscelrosis.  1983;3(2):149-59

13. Watson AD, Leitinger N, Navab M, Faull KF, Horkko S, Witzum JL, et al.  Structural Identification by Mass Spectrometry of Oxidized Phospholipids in Minimally Oxidized Low Density Lipoprotein That Induce Monocyte/Endothelial Interactions and Evidence for Their Presence in Vivo.  J Biol Chem. 1997;272(21):13597-13607.

14. Nagy L, Tontonoz P, Alvarez JG, Chen H, Evans RM.  Oxidized LDL regulates macrophage gene expression through ligand activation of PPARgamma.  Cell. 1998;93(2):229-40.

15.  Iso H, Jacobs DR, Wentworth D, Neaton JD, Cohen JD.  Serum cholesterol levels and six-year mortality from stroke in 350,977 men screened for the multiple risk factor intervention trial.  New Engl J Med.  1989 Apr 6;320(14):904-10.

16. Emerging Risk Factors Collaboration, Di Angelantonio E, Sarwar N, Perry P, Kaptoge S, Ray KK, Thompson A, Wood AM, Lewington S, Sattar N, Packard CJ, Collins R, Thompson SG, Danesh J.  Major lipids, apolipoproteins, and risk of vascular disease.  JAMA 2009;302(18):1993-2000.

17. Prospective Studies Collaboration, Lewington S, Whitlock G, Clarke R, Sherliker P, Emberson J, Halsey J, Qizilbash N, Peto R, Collins R. Blood cholesterol and vascular mortality by age-sex, and blood pressure: a meta-analysis of individual data from 61 prospective studies with 55,000 vascular deaths. Lancet. 2007;370(9602):1829-39.

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  1. Chris, if rabbits are naturally strict herbivores, how do they have the ability to absorb and package cholesterol and then distribute the packaged cholesterol through their bloodstreams.

  2. Chris- Just finding your blog after hearing you on Jimmy Moore. I've been on a low carb/paleo"ish" diet (no processed food, just dairy) for 3 months and lost 23lbs (with 6 pounds left to lose). I recently got a VAP panel done and had a total cholesterol of 307, LDL 232, HDL 48, and TG 95. TSH and T4 in normal range. I'm totally freaked out and nervous that I'm going to have to give up my diet I have grown to love (fat and all)! Any suggestions? Is a statin in my future. I'm only 34 and wondering if familial hypercholesterolemia is a possibility.


  3. Hi Chris,

    If I recall correctly, you have claimed that LDL becomes small and dense due to spending a large amount of time in the blood. I have also heard (and it seems to be true for me) that one can get an idea of the relative skew towards sdLDL by looking at the TG/HDL ratio — the more HDL relative to the TG, the lower the amount of amount of sdLDL.

    This would imply that people with high HDL and low TG have LDL that spends a relatively short time in the blood.

    My question is: do you have a reference for the amount of sdLDL itself (as opposed to oxLDL or disease states) relative to the amount of time the LDL particle spends in the blood (and/or relative to the number of LDL receptors)? In other words, how certain is it that the concentration of sdLDL is caused by low numbers of LDL receptors instead of some other factor?

    Thanks, Beth

    1. Hi Beth,

      It is not a specific marker of time spent in the blood. However, it is not a specific marker of heart disease risk either. What I have suggested is the portion of variation in sdLDL that accounts for risk is roughly equivalent to the portion of variation that is accounted for by poor LDL receptor activity. It may be more complicated than that, but since poor LDL receptor activity has the most evidence behind it out of all putative causes of atherosclerosis, I think it is prudent to invoke it to explain the epidemiological correlations whenever it is plausible and sufficient to explain them.

      Let me know if that needs more clarification.

      Take care,

    2. I was just wondering if there were any experiments that looked at time in the blood vs amount of sdLDL directly. If both sdLDL and oxLDL happen together, then there is also a question of which causes the other or if they both have a common cause. These may be hard or uninteresting experiments to do though.

      I think you have answered my question.

      Thanks, Beth

  4. Chris, this is very interesting approach. I always felt skeptical and a bit suspicions about both extreme theories, of cholesterol causing heart disease and cholesterol having nothing to do with heart disease. The truth is there is much more factors to consider. Cholesterol levels being rather an implication of metabolic problems than a cause of heart disease sounds very persuasive and logical.

  5. Hi Chris:
    What do you think of the PCSK9 inhibitor drugs currently under development? What could be potential drawbacks of this treatment strategy?

    I enjoy the blog, and just watched your AHS video. Great job.

    1. Hi Scott,

      They seem to have some promise, particularly for people with familial hypercholesterolemia, but a potential drawback is that PCSK9 plays an important role in homeostasis and an inhibitor could throw the homeostasis off. I guess we'll see what happens in the clinical trials.


  6. Hi Chris,
    Thank you very much for your reply. Yes, I heard that the hormones should be very carefully handled. I keep wolking a lot and use to some sport 2-3 times a week. I eat and fiber and lots of vegetables and fruits.
    I read a lot about its support for the thyroid hormones. Here are interesting articles by Ray Peat.

    I want to ask whether it would be appropriate to add the coconut oil?

    1. Hi Anonymous,

      I think coconut oil is good, but with FH you probably don't want to overdo it. Coconut oil will tend to raise total cholesterol but HDL-C the most, which I think generally reflects that it is good, but in FH there is a backup of cholesterol metabolism so I don't think dietary modifications should be made if they seem to produce large increases in total cholesterol in that specific condition. Perhaps follow Peat's recommendation for a low-fat diet that uses coconut oil as its major fat but in only modest amounts.


  7. Hi Anonymous,

    If you increase your thyroid hormone, I would do it under strict medical supervision — it is a viable option if you increase very slowly, not too high, and under supervision. There are side effects so I would not do it without careful and knowledgeable supervision.

    You could try experimenting with dietary fibers and exercise, if these things seem to help and not hurt your health.

    With FH, you will probably never totally normalize your lipids. So you should focus on optimizing the things you can fix, like inflammation, clotting, and antioxidant status.


  8. Hi Chris and John,

    Im reading your blog a articles regulary for one year and I like them. I have problem that you described in discussion.
    I'm woman and I have diagnosis isolated FH and autoimunitnu hypothyreozu , detected 17 years ago. I have 2000 antidote units. I used Euthyroxu 25 ug for a long period and I have now 200 units. My thyroid is now ok with fluent structure without damage.

    My values from last measurement are TSH – 4,2 pmol/l, FT3 – 4,52 pmol/l, FT4 – 13,68 pmol/l. I
    My total cholesterol level is 17 years in interval 7,9 – 9,5 mmol/l.
    My current values :
    Weight:54 Height: 164 BMI:20.8
    Total cholesterol: 8,800 mmol/l
    HDL-C: 1,460 mmol/l
    LDL-C: 6,699 mmol/l
    Apo-B: 1,980 mmol/l
    Apo-AI: 1,690 mmol/l
    RI1: 4,588
    RI2: 1,172
    TG: 1,410mmol/l

    I have issue with my LDL cholesterol value. Value is bad. Nothing else.
    I would like to ask, if is possible to lower my cholesterol level with bigger amount of Euthyrox ? One expert recommend me to icrease Euthyrox to 50 ug, to speed up cholesterol metabolism. What is your opinion on this ? And do you have any other solution?

  9. This is a very informative article. People must be encouraged to check their cholesterol levels daily in order to know the status of their health and body. Being able to monitor your cholesterol levels will definitely help you learn what you may be at risk for, as well as what you need to do to lessen those risks.

  10. continued – due to length..

    My biggest problem with your otherwise excellent analysis here is that not a one of the studies you cite includes people eating ancestral or paleo or high fat/LC diets. The total C/HDL ratio should therefore be considered neither reassuring or necessarily alarming unless you are a SAD eater, IMO.

    What do you make of the Kitavans having little heart disease but having very low HDL as reported by Lindeberg?

    I tend to agree with Peter that we should regard these lipoprotein numbers, including the newest fad of sdLDL, as markers for type of diet, and not as causative agents or parameters to adjust for their own sake.

    And although I agree that total C can be elevated due to hypoT, I still think that the best lipid is one that you never measure, and one should diagnose thyroid issues with clinical assesment and thyroid tests.

    There is simply nothing to be gained -a priori -by testing for total C, HDL, LDL or even CRP. Unless you want to have to lie when you apply for health insurance (they often ask if you have high cholesterol but don't demand that you get tested – I've had that experience twice) or you want to incur the expense of following up with NMR.

    There is no evidence that treating a single one of these numbers, beyond eating a whole food diet low in PUFA, etc, does anything at all to reduce your risk. Even if they actually mean something on your paleo type or WAPF diet, which I have just argued they might not…

    If you really want to know your personal risk of heart disease, get a calcium score or CIMT. For the same price as VAP or NMR lipoprofile, you will get information that actually means something.

  11. @Chris

    Very nice discussion.

    I agree with your thinking on most of this, especially regarding the significance of LDL receptor expression. The major implication I see is that for just about everyone, the major way to decrease risk of atherosclerosis is to limit oxidized LDL species, then after that perhaps decreasing their dwell time in the circulation may be of benefit.

    I also think that the most likely strategy to decrease risk in those with hetFH is to "paradoxically", eat in the way that results in the highest LDL mesurements – high sat fat, very low PUFA, no fish oil diet. Strive for pattern A – LDL-C will be high, but particle counts will not, and lack of atherogenic particles of oxLDL will mitigate damage more than half-assed pleiotropic attempts at getting LDL-C lower, as the cholesterol mass per se is not the cause of the pathology.

    Same goes for ApoE4 people, they are supposed to worry about being "sensitive" to a high sat fat, yet they have the genotype more common in those with less agricultural history – they need to eat high fat LC more than the rest of us do.


    "Feeding massive quantities of cholesterol produced a disease state similar to familial hypercholesterolemia, where atherosclerosis develops rapidly and the various internal organs develop deposits of cholesterol."

    I am actually not sure how similar the atherosclerosis of FH is to the conventional variety. The distribution of vascular lesions and the association with unrestrained cholesterol production intracellularly – producing the cholesterol deposit stigmata plain old vasculopaths on the SAD never have – argue that the end-points are similar but the pathologic process is not completely the same.

    It is not likely just a shifting in the curve to earlier ages.

    There are likely more than a few varieties of atherosclerosis, with overlap on patholgy slides, but differences in genesis. For example, the small vessel disease seen in diabetes afffects vessels usually spared in non-diabetics, even those with severe coronary disease.

    I think we should entertain the idea that fatty streaks come and go and that a certain senile form of repair atherosclerosis that may not have anything to do with heart attacks is completely normal in old age, no matter what our diets are. Unless we believe Loren Cordain is right that eskimo mummies had pathologic atherosclerosis cause by palmitic acid and only fish oil saved them : )

  12. Hello – I appreciate your posts very much. I’m concerned about my son who is in his 30’s and is on the paleo diet. I asked him to send me his diet and exercise regimen which I’ve pasted below what I’m writing. His HDL is 57; his LDL is 233 – but fluffy. My father had a massive heart attack at age 37 so I’m worried about my son and am wondering if he should take statins. The average doctor who is not interested in paleo diets would say he should. In fact, he went to a paleo-friendly doctor who was concerned about his LDL even though it is fluffy. His C-reactive protein was 0.1 which isn’t bad at all. If it isn’t too much to ask, would you mind reviewing his diet and exercise regimen below and let me know whether I should be worried. I know that he takes your posts very seriously, though he would never write to ask himself. Thank you in advance.

    Concerned mother.

    * 2 oz. of cow liver every morning, lightly sautéed in onions and butter/coconut oil
    * salad — usually cabbage and scallions with lemon juice, flavored vinegar and copious olive/macadamia oil, a little salt and pepper, sometimes carrots.
    * homemade stock with lots of salt and some pepper–made from cow bones, allium, carrots, celery, lemon juice/apple cider vinegar, the occasional kombu for iodine. this is ideally every day, but i sometimes skip entire weeks of not making stock; I need a more reliable source of bones.
    * ~.8-1.2 lbs. of meat or fish–lamb/beef/pork 6 days a week, wild alaskan sockeye with skin 1 day a week. meat is almost always sautéed in copious butter or coconut oil. fish is poached in water, wine, melted butter, lemon wedges and thyme. i boil down the poaching liquid after taking the salmon out, then use it as a butter sauce. i squeeze lemon on it.
    * sometimes sauteed veggies, perhaps 3-4x/week–brussels sprouts, kale, occasional broccoli. maybe .25-.33 lb., sautéed in copious coconut oil/butter.
    * usually i eat all this at a single meal, usually in the evening. lately i've been feeling more like having either 1) two meals a day, or 2) an earlier large meal, like late afternoon
    * almost everything is organic. almost all the meat i eat is grass-fed, pastured, organic–the only exception is when i get caught away from home and have to buy a rotisserie chicken or eat at Chipotle.


    * i hope to experiment with replacing 60% (by weight) of the meat with traditionally prepared gluten-free grains/legumes, mostly to save money, but also for variety of taste.
    * i hope to add more fermented and cultured vegetables–kim chee, sauerkraut, pickles, pickled vegetables.
    * i hope to experiment with raw egg yolks every morning along with my liver (cooked liver), like Chris Masterjohn does.
    * i may add another half pound of fish every week, and break the 1.5 lbs. of weekly fish into three separate meals (separate days)
    * more herbs–I've been sometimes adding (1x/week) turmeric/curry powder to my sautéed meat. already getting lots of pepper; garlic powder in my burgers; thyme in my salmon.
    * as stated before, more consistent broth/soup.
    * maybe more starch, besides the traditional grains experiment–squash and sweet potatoes, which i've been neglecting because it takes so long to prepare.

    Almost as important as my diet is my exercise regimen:

    * HIIT two times a week–currently, Mark Sisson's 15-minute HIIT workout. kind of a prison-style, bodyweight-only circuit training workout, which I do at home.
    * Kettlebells two times a week–I've just started doing this. I do it at the park so I don't drop a kettlebell on my floor. Multi-joint, core-intensive weightlifting, as guided by various YouTube videos and the book "Enter The Kettlebell."
    * daily meditation, currently 45 minutes, in the morning.
    * Intermittent sprints once a week–10 seconds on, 30 seconds off, for 15 minutes.

  13. Thank you for a very well written and easy to understand post. Also like your layout which makes a difficult subject easier to read. Looking forward to the sequel.

  14. Chris,

    Loved your post and I very much look forward to reading more of your posts on this topic.

    I have FHC myself so that this topic is near and dear to my heart (no pun intended).

    I liked how you explained that, "The liver packages the lipoprotein with a store of antioxidants that will be sufficient if the LDL transports nutrients rather quickly, but if LDL receptor activity is poor, this nutrient transport is compromised, the oxidants within blood deplete the particle of its antioxidants, and oxidation ensues."

    I was wondering if supplementing with tocotrienols would be of any benefit for people that have slow clearance of LDL like people with FHC? It is my understanding that tocotrienols have a 40-60 times greater antioxidant potency than tocopherols. I also read that, "Tocotrienols have a shorter tail with double bonds (farnesyl) that renders them more flexible and better equipped to cover a large surface area of cell membrane."*.

    It seems to me that tocotrienols might help better protect these slow clearing LDL particles from oxidation. Any thoughts you might have about this would be greatly appreciated.


    John M.


  15. This does not confuse me John/Jack K/Dr K. I mean… I definitely did not see that coming! But it's nice to connect things up. Nice dialogue here. See ya on PH Doc.

  16. To confuse you more Jack Kronk….I am a Jack K too. Given name is John, but no one goes there with me. And I am the same Dr. K from paleohacks. So now you know who I am and I am not trying to take your moniker away here or anyother place!

  17. Chris thank you so much for this information. Could I ask your advice with regard to my grandmother? Her cardiologist found a 98% blockage in a coronary artery that cannot be stented. She has been taking statins for a few years to help minimize her risks due to this but appears to be suffering from cognitive trouble because of them and has chosen to discontinue taking them. Is Slo-Niacin going to help upregulate LDL receptors as effectively as her statin has? Do you have any advice? I have been unable to convince her to alter her sugar/flour/Omega-6 heavy diet. Thanks for any words of wisdom you can share.

  18. Chris,

    Thanks for the advice on supplementing with antioxidants. Here are the details of the Spectrox test, from the provider.

    1. A mixture of lymphocytes is isolated from the blood.

    2. These cells are grown in a defined culture medium containing optimal levels of nutrients necessary to sustain their growth in cell culture.

    3. The T-lymphocytes are stimulated to grow with a mitogen (phytohemagglutinin) and growth is measured by the incorporation of titriated (radioactive) thymidien in the DNA of the cells.

    4. The patient's cells are grown in the optimal media, stimulated to grow, and then increasing amounts of a free radical generating system (H2O2) are added. The cell's ability to resist oxidative damage is determined. The increasing levels of peroxide will result in diminished growth rates in those patients with poor antioxidant function capacity.

    5. In the tests for individual antioxidants, it is determined which specific antioxidants may be deficient and thus affecting the antioxidant function result. For these tests, the patient's cells are preincubated with one of the nutrient antioxidants, i.e. selenium, and then the Spectrox test is repeated to determine if the addition of selenium improves the patient's antioxidant function. This process is repeated for each individual antioxidant: glutathione, cysteine, coenzyme-q10, selenium, vitamin E and alpha lipoic acid.

    I hope this is enough for you to have an opinion on whethet the results from such a test would be useful.

    Cheers, Jeremy

  19. Chirs,

    Hilarious about Jack and John. I didn't know that.

    I see what you're saying about not wanting to wait, especially given the importance of the topic.

    My concern is just basically cautionary in nature…. that we may be trying to correct something that doesn't need correcting. Since we are more sure of the other factors (like trigs/HDL/VLDL… etc), it seems odd if many people score very well in those areas yet 'fail' miserably in the LDL. To me, all that does it immediately put up a red flag that there are definitely some mysterious elements to the way our bodies handle LDL and I wonder if jumping into copper/iodine supps and the like is the right approach.

    At any rate, this is why I am so thankful for people like you and the Jaminets (and others too) who are digging deeper into the LDL issue.

    Jack K (but you can call me John)

  20. I'll go for a VAP in a couple of weeks, my first one ever.

    I'm still perplexed by the rapid switch in my numbers. Low TC to High TC. Low LDL to pretty damned high. Moderate triglycerides to low. All in a matter of weeks. I'm telling you, that's just crazy, man.

    Pulse is up and BP is up too.

    Do I feel like I'm anywhere near a heart event? Nope, not by any stretch. However, I bet that there are millions who have said the same thing before and been disappointed by the surprising news.

  21. Jack Kronk,

    Sorry for the confusion. Some people with the given name John often go by Jack:


    Jack is a male given name, although in very rare cases it can be used as a female given name,[1] and sometimes as a surname. In English it is traditionally used as the diminutive form of the name John (and less commonly Jacob), though it is also often given as a proper name in its own right.

    The "john" posting here posts as Jack on my facebook page, with his last name attached. I know who he is.

    I agree with you that we would want to see the predictive power separated by population. However, there are lots of things we cand o to assess metabolic health now, so I think it is reasonable to suggest someone with a total-to-HDL-C ratio through the roof to take a look at some of those metabolic parameters and esnure all signs are good. I think it's reasonable not to wait several decades before we have solid information on predictive power specific to people on the paleo diet, if such data is ever obtained at all.

    Stephan noted those exact limitations of the survey — I don't think that was "some people" who were heckling it. He noted even further ones, such as the fact that ~50% responded, which is likely to further introduce bias since people with noteworthy results may have been more likely to respond. The survey will be very interesting, but like he said, useful only for generating hypotheses and not for testing any — useful as a lead, and not for making conclusions, similar to the value of looking at someone's LDL-C.


  22. Chris,

    You must be seeing some weird stuff that we don't see. You keep addressing (Dr?) John as Jack. I have only made one comment on this article. That was that I hadn't made a comment.

    So all of your "Jack" references in your comments are really for "John" incase anyone is confused by that.

    Also, I don’t think the anonymous (es) are part of the problem. It seems that it’s just when Richard Nokely comments (I gather). Anyway I promise I am not trying to pester. I will let you handle it from this point forward. Just wanted to let you know.

    As for the real discussion, you guys are both off your rockers. Reading the exchange between the two of you is like watching Donnie Yen battle Jet Li.

    Chris, the scenario you reference about someone who measures up very well in all areas, save for one, LDL count, is pretty common among Paleo folk. I think this is what John is referring to as far as what he's personally seen.

    Before we can know if a high LDL in combination with all the other factors in order is something to fret about, shouldn't we want to see a group of pure Paleo eaters (or some variation of a quality high fat, mod protein, mod safe carb diet) tracked for all these numbers. Imagine if a high majority of them have "high" LDL (by currently observed standards), yet the group as a whole have a very low rate of CVD and very low rate of other health issues. Wouldn’t that be pretty telling?

    Stephan G did that GFJ survey and some people ‘complained’ that the results will be lopsided, since most of his readers are already eating close to what he advocates. Well, I think it’s brilliant. And it’s about time! We desperately need studies from groups of ONLY healthy eaters. A "Paleo type" diet (whatever that means nowadays) is very different from other ways of eating. If we are comparing numbers with studies done of people who are almost certainly not eating a healthy diet, then I think it's unfair to draw conclusions from numbers of pure whole food high fat eaters when we don't yet know if the same issues will occur with that group as they do with your folks on SAD or any other type of diet.

    Does that make sense? Do you know if there's a study like this in the works?

    Thanks so much Chris,

    jack kronk

  23. Hello..

    Heart disease can be caused by a number of factors but High cholesterol levels can greatly increase the risk of heart disease.To lowering cholesterol can have many positive effects and reduce risk.

  24. Jack, my point is that while insulin resistance and even excessive de novo lipogenesis may contribute to these problems, the evidence that it is mediated by palmitate is weak because the plausibility that the effects of free palmitate in studies of cell culture, direct infusion to the brain, or oral gavage of non-food can be reproduced in a truly physiological context is doubtful. Possible, certainly, but I wouldn't say we "know" much about the role of palmitate in this mess yet.


  25. Chris to get fatty liver from SAD we have the perfect storm….high TG from carbs and high omega six levels and topped off glycogen in the liver and peripheral leptin resistance of muscles that further worse the situation in the hepatocyte to drive more palmitic acid to shut down leptin signaling by trashing SOC3. Once we get cerebral leptin issues the process becomes almost impossible to stop. Unless you know how to alter biochemistry with timing and diet to get it back. The more visceral fat the more Il-6 TNFa leading to activation of NF kappa beta and cancer and disease. The link of insulin resistance and cancer propagation is clear now in literature and medicine……but the bigger issue is that leptin resistance is required before one becomes insulin resistant and eventually adrenally resistant……and if it contuinues we wind up with complete metabolic failure which is the clinical condition called fibromyalgia.

  26. Jeremy,

    What was the "total antioxidant capability" measured with? ORAC? FRAP? A different test? This makes a big difference. These tests might just be silliness, although testing them in blood is much less stupid than testing them in food. But really, if, for example it was FRAP, it could just mean your uric acid is low from not eating sugar. Do they just test cysteine or do they test the cysteine/cystine redox status? This is a sensitive marker of oxidative stress and aging. I think supplementing with a broad spectrum of antioxidants is unlikely to be harmful, but I would make sure if you supplement with vitamin E it contains gamma tocopherol, and I would avoid more than 100 mcg selenium/day, and opt for selenocysteine instead of selenomethionine.

    Travis, good thoughts. And also, as per my latest post, too much meat could be a problem, perhaps with anti-thyroid effects of homocysteine.


    At the moment, no I do not have any clear thoughts on this but thank you for the information and I will try to incorporate it into my thinking.

    Jack Kronk, sorry about that. Maybe I should prevent anonymous posting? Anonymous(es) would you stop posting if I did?

    Anonymous, thanks! I'm glad you're learning. And yeah, my grandfather is in his mid going on late 80s and he has said "if I were young, I would rigorously read ingredient lists and never buy anything with high fructose corn syrup. But, I'm in my 80s." So I get it. 🙂

    Jack, thanks for the references. Neither of these look like physiologically relevant interventions, though, so I think it is rather premature to indict de novo lipogenesis (DNL). The first reference notes that palmitoleate and oleate are protective, and these are also products of DNL. Palmitate may be the first product, but it is subsequently modified in substantial amounts to palmitoleate, stearate, and oleate. I think in most circumstances, modest DNL is very unlikely to increase free palmitate in the brain and in fact its unlikely to make a huge increase in free palmitate anywhere. It will increase TG though, and Bill Banks has done some studies suggesting that if blood TG reach high enough, they will impair BBB transport of leptin. His studies are probably not quite definitive, but intriguing. In any case, carbohydrate will increase DNL but this is mostly relevant in insulin resistance, IMO, where DNL response to carbohydrate is greatly increased. Thanks for th references!


  27. Jack (john) and Anonymous,

    Let me try to sort this out. First, I agree with Jack that someone who's LDL is high, but has been exhaustively tested for thyroid and sex hormone profiles, hepatic triglycerides, inflammation, homocysteine and vascular health and shown to be clean on all counts probably has nothing to worry about. HOWEVER, the average person when they go to the doctor does not go to Jack. Thus, they do not get all the cutting-edge tests. Despite the fact that some 70-100 million Americans probably have fatty liver and that this is vastly superior predictor of heart disease risk compared to many other standard tests, the average person is not screened with magnetic resonance spetroscopy for heaptic triglycerides even if they are overweight. The average person gets a TSH test and their doctor thinks he just tested their thyroid health because he is living in an alternate universe. *But* this typical person *will* get their total and HDL cholesterol checked and at least get a mathematical estimate of their LDL-C. The total-to-HDL-cholesterol ratio is an extensively investigated and repeatedly confirmed predictor of heart disease risk, and as I say here, likely a marker of poor LDL receptor activity.

    Thus, for the average person who finds out their ratio is "high-risk" and goes to a blog bashing the lipid hypothesis as being the most evil thing since sliced bread, my take-away message is that they should not panic but they should also not buy this idea that these measures have no relevance, and they should instead use this as a potential clue to pursue further testing of metabolic health.

    My view of this is slightly different than Jack's, despite being mostly in agreement. In a comparison to insulin signaling, I think LDL would be analogous to glucose rather than insulin, and that perhaps we could consider thyroid hormone analogous to insulin (sort of). I do not think the evidence is "damning" of small, dense LDL. As I noted above, I think it could simply be a marker of poor LDL receptor activity. Confusing correlation with causation led to torcetrapib. Perhaps it killed people left and right because of "off-target toxicity," or perhaps CETP inhibitors kill people because CETP plays a critical role in mediating the passage of vitamin E from LDL to HDL to endothelial cells, as I have hypothesized in the American Heart Journal. In any case, the predictive value of HDL-C does not mean that intervention to increase HDL-C will reduce risk, and the same is true of small, dense LDL. That it is more vulnerable to oxidation is an interesting hypothesis, but it has less evidence than reverse cholesterol transport, and the one test in humans of reverse cholesterol transport (torcetrapib) so far has failed.

  28. Responses to Kulimai, Jim, Jack, Anonymous, Jeremy, Soiltosustenance, Jack Kronk, and Jack again.


    There are a number of things that could raise LDL-cholesterol indefinitely and would still be good things. For example, coconut oil will do this, but it will tend to increase HDL-cholesterol much more, so that the total-to-HDL-cholesterol ratio actually decreases. Also, in about 30% of people eggs will do this, but they will tend to increase HDL-cholesterol proportionately so that the ratio doesn't change, and they will tend to shift LDL particle size toward the "good" "pattern A." There are other good things that will increase LDL-cholesterol levels and I will elaborate on them in the future.

    However, I would think that in general the total-to-HDL-C ratio should stay at least *decent* in these cases. And indigenous people on native diets all have "good" cholesterol. Islanders that eat tons of coconut may max out around a population mean of 180 total cholesterol or so, so I find it difficult to believe that much higher levels are ideal for Americans of mixed heritage. But again, I'll address this more thoroughly soon.

    Jim, exactly — oxidation.

    Anonymous, yes it is possible, but like I said cholesterol out of whack should be used as a clue to look for true metabolic abnormalities, and not a reason for panic.

  29. Chris here are the links to peripheral and central leptin signaling. The bibliography on both are great too.

    1. THE JOURNAL OF BIOLOGICAL CHEMISTRY VOL. 285, NO. 45, pp. 34371–34381, November 5, 2010
    © 2010 by The American Society for Biochemistry and Molecular Biology, Inc. Palmitate-induced Down-regulation of Sortilin and Impaired
    GLUT4 Trafficking in C2C12 Myotubes

    2. Palmitic acid mediates hypothalamic insulin
    resistance by altering PKC-θ subcellular
    localization in rodents in J. Clin. Invest. 119:2577–2589 (2009). doi:10.1172/JCI36714.

    Chris you can also get with me on FB as you know. I am quite happy that this is an area you want to go. This is an area that will play a central role in my own book whose goal is to open physicians eyes to the dietary factors that are tied to health and longevity from a spine perspective.

  30. Chris,

    Great post! I learn so much bio-chem at this blog–new and refresher course.

    The only cholesterol that concerns me is HDL. Even that, I haven't tested for about five years and will probably wait another five or ten years. At sixty, I am on borrowed time so I would rather go back-county skiing than spend time in a Lab or in a doctors office. I will continue to eat a quasi-paleo, moderate carb diet because I feel better on it even if it raises my LDL. When it is my time to go, I would rather die of heart disease than cancer.

  31. Hi Chris,

    Once again, the comment high above about "your specific recommendations" is not from me. It seems that there is some kind of oddball glitch when Richard Nokely comments here.

    Anyway… that aside, this is a fascinating article. I admit that my brain hurts a bit from reading it, but I gathered what I could. Thanks Chris. And tell that Melissa of yours thanks for letting me change that subject question on PaleoHacks! lol.

    -The Real Jack Kronk

  32. Hi everyone,

    I'm not ignoring any questions here but will answer them later today.

    In the mean time, John, could you post what you consider the most compelling reference(s) for the role of palmitic acid in leptin signaling? Also, are you referring to palmitate itself, or are you considering it simply a marker for de novo lipogenesis, and considering the increased blood TG that results the actual culprit (as in the hypothesis that TG decreases BBB transport of leptin)?


  33. Hi, John. Thanks for indulging my admittedly ignorant posts.

    By the way, I am not the same anon who posted the link to Richards. (I really should use a name here to avoid the confusion.)

    I'm one of those high LDL, high HDL, low triglyceride guys. I'm not convinced that this makes for a healthier heart than when I was a low LDL, HDL, TC guy with moderate triglyceride levels. I'm not particularly unconvinced either.

    I do certainly see that Chris is talking about receptors, but it seems to me that it remains unanswered whether, as Kulimai points out above, high LDL signals the receptor issue that leads to potential trouble some of the time, part of the time or none of the time.

    I'm not willing to assume that since I have high HDL and low triglycerides that my high LDL doesn't trigger these receptor concerns. I've seen a lot of talk that this situation makes for good heart health, but I haven't seen anything that I believe is particularly compelling.

    Again, thanks for indulging me. I do indeed feel ignorant and inadequate in explaining myself here, so I appreciate the conversation.

  34. I wonder if high cholesterol with a paleo diet might be the result of an iodine and/or selenium deficiency. The iodine deficiency would result in a decrease in T4, while a selenium deficiency would decrease T3. These would then result in lowered LDL receptor activity. Additionally, selenium deficiency would result in a decrease in sex hormones, which would be an obvious thing for the body to convert the cholesterol into. It's quite easy to eat strict paleo and have these deficiencies if one doesn't eat seaweed and organ meats/shellfish.

  35. actually I phrased my question carefully above, precisely to avoid the (otherwise important but not really novel) debate that developed in this connection between john and anonymous.

    I asked if there could be a connection between high LDL and LDL receptor downregulation on paleo for some. (a) This does not equate LDL and LDL receptor (b) this does not imply that high LDL is harmful or the sign of something else that is harmful in this population

    Clearly (b) is a further question. Logically allowing the answers (i) never (ii) sometimes (iii) always (in this population) Only under (ii) and (iii) are we faced with the still further distinct question of what to do about it.

    (See also dr Davies hit and run post (eg. KGH's perinent questions barely answered) about high sdLDL in some high HDL low TG people and also some of the apo E4 literature on genotype – diet lipid type interactions)

    Any (however partial) clarification of these issues would I guess be both theoretically and practically most helpful

  36. increased production of palmitic acid causes leptin resistance peripherally and centrally…..once you are centrally leptin resistant the hypothalamus is blind to energy stores and to run the machine…so it perceives that the human is starving. Once uncoupled from leptin the thyroid is down regulated because of the central loss of signalling of leptin. That set the thyroid metabolic rate to low. Moreover, cells are blind to leptin as well peripherally so they cant utilize the energy sources so it stays in the blood longer allowing oxidation of the LDL particles……and there is where the action begins. VLDL and IDL get shunted to the liver and the rest gets packed in viscera. This also causes adipocytes to begin to divide again…..ironically something plastic surgeons dont believe happens. I guess that is how they sell liposuction to fat folks? Moreover, High blood sdLDL is very very sensitive to ROS and becomes oxLDL. That is how I understand thyroid and leptin signalling in 3/2011 and how thyroid and cholesterol dance in our bodies.

  37. Chris, You have been clear about the dangers of supplementing with isolated antioxidants. I got a test from SpectraCell (Spectrox) about antioxidant function and I came out deficient in the total antioxidant capability of my blood, although I was not deficient in glutathione, cysteine, coenzyme q10, selenium, vitamin E, alpha lipoic acid, and vitamin C. Do you feel consuming a broad spectrum of supplemental antioxidants (like those in this list) would be harmful? Jeremy

  38. and anon Richards initially points out in his blog you linked how great it is to have "bricks" of cholesterol in part one yet then he praises lowering LDL in steps two? TC and LDL walk a tandem walk. You cant have it both ways. Richards methods cant explain why paleo works. My paleo patients have skinny wastes low cardiac crp's and MRI's of the livers devoid of fat……yet he says they should have NAFLD……Why? Cause he is wrong on it. I like the guy a lot because his book on leptin is a great primer but he is more interested in downing western MDs than really thinking thru what he is saying. He really is lost on the biochemistry of de novo lipogensis and palmitic acid. And that bothers me huge. Why? Because he more than anyone should know where palmitic acid comes from and how it effects the hypothalamus and muscle leptin signaling……and its not mentioned once in any of his books. Epic failure. I bet he pulls an update ala Cordain and does not explain it…..until others point it out.

  39. I disagree because insulin is different than a receptor for it……leptin is different than a receptot for it……….and LDL is different that the receptor for it. That is how I look at because that is how science and medicine look at the lock and key of ligands and receptors.

  40. "Chris is talking receptors and Paleo guys are talking blood levels of LDL."

    Chris talks all about LDL and here's a quote from the article above:

    "Although cholesterol levels do not determine our risk for heart disease, they may indeed be a marker for poor LDL receptor activity and related metabolic problems and they should therefore not be ignored."

    So in a roundabout way, if you want to look at it as such, it's right in the middle of the discussion.

    More from this article:

    "A recent meta-analysis pooled together the results of 68 prospective studies including over 302,000 participants and found that LDL-cholesterol, HDL-cholesterol, and triglycerides were all capable of predicting the risk of heart disease."

    There's much more. To fall back on saying it's not directly and exactly what he's talking about is to talk around it. (in my humble opinion)

  41. @ Anonymous…..your last post. LDL levels and receptor resistance are two totally different issues. Chris is talking receptors and Paleo guys are talking blood levels of LDL. Moreover, they really are not concerned with total LDL levels. They are concerned with their VAP, specifically the sdLDL and not the ILDL or VLDL that make up the total LDL. The data is pretty damning that sdLDL are the LDL particles that are most easily oxidized and are the ones that humans have to avoid. They come from carbs not proteins or fats that paleodieters eat. I know……I take care of hundreds of them and their TG's HDL and sdLDL fractions are ridiculously good and all have pristine cardiac CRP scores……and most importantly their their calcium index scores are outstanding. They wont be getting heart disease because 99% of western medicine thinks total LDL blood levels mean something bad……… does not. You need context. That is why our cholesterol edicts are flawed beyond belief.

  42. Hey John,

    Here are some references I just took off the slides from my Heart Disease and Molecular Degeneration lecture from this fall's Wise Traditions that cover the topic.

    Glagov S, et al. Compensatory Enlargement of Human Atherosclerotic Coronary Arteries. NEJM. 1987. 316:1371-5.

    Burke AP, et al. Healed Plaque Ruptures and Sudden Coronary Death: Evidence That Subclinical Rupture Has a Role in Plaque Progression. Circulation. 2001;103:934-40.

    Peter Libby's reviews are usually useful resources. For example:

    Libby P. The molecular mechanisms of the thrombotic complications of atherosclerosis. J Intern Med. 2008;263(5):517-27.

    Libby P and Theroux P. Pathophysiology of Coronary Artery Disease. Circulation .2005;111:3481-8.

    Hope that helps,

  43. @Chris….you said, "the history of collagen breakdown can be visualized with proper staining and imaging techniques, and these studies in humans so far have produced evidence that collagen breakdown occurs primarily after atherosclerosis has progressed to a stage of about 40% stenosis." Can you give me some links about where you got this information? I could use it big time. Jack.

  44. @Tierney the cheapest test of leptin resistance is a mirror. But there are a small subset of patients who are not overweight who are still leptin resistant. And one part of this group was uncovered by amgen's failed trials on their synthetic leptin drug, namely those who are post serious weight loss naturally or via gastric bypass. Reverse T3 should be as low as possible if youre leptin sensitive. Infact we now know that what makes us leptin resistant peripherally and centrally is the same intermediate. That is palmitic acid from de nove lipogenesis. It has been shown to be the signal transducer in the muscles at UCP3 and in the hyprothalamus. If you understand biochemistry you'll understand why this makes sense. Its from overflow carbohydrates that build the 16 carbon backbone after the muscles are shut down from burning sugar, same thing with the liver, and the livers glycogen levels are full. It also explain why Kitivans dont get leptin resistant eating 90% carbs from tubers. Because they dont eat fructose and omega sixes that drive the formation of palmitic acid.

    J. Clin. Invest. 119:2577–2589 (2009). doi:10.1172/JCI36714. central leptin signalling.

    THE JOURNAL OF BIOLOGICAL CHEMISTRY VOL. 285, NO. 45, pp. 34371–34381, November 5, 2010
    Peripheral leptin signalling

  45. "Come to think of it, I cannot offhand recall any contribution stating initial high LDL on paleo that subsequently normalized."


    Which means POSSIBLY that the paleo diet is setting people up for heart disease. We have to be open-minded enough to see this, particularly in light of Chris's post here.

    It's just troubling seeing all of us paleo guys run around from blog to blog, trying to find evidence that our elevated LDL is not going to lead us to troubles down the road. I see some of the people latching on like pit bulls to ANYTHING posted that tells them that they're ok, despite the elevated LDL, due to this ratio or that number.

  46. Roger,

    This is a piece of what I would at best call "non-evidence" for any of the questions addressed in this post. The data do not "contradict the conventional view," but instead contradicts the prospective data. In other words, the studies showing who develops heart disease in the future according to lipid levels at baseline show something different than this study, which addressed an entirely different question of what lipid levels look like upon hospitalization for CHD.


  47. Chris, have you seen this study of lipid levels in 136,905 patients hospitalized with coronary artery disease?

    In this study, *lower* LDL levels were associated with a *higher* incidence of CAD, contradicting the conventional view. (The study strongly confirmed the conventional view that higher HDL is associated with lower incidence of CAD, however.)

    The study compared LDL and total cholesterol levels in CAD patients with the rest of the population and found that the CAD patients on average had *lower* LDL and total cholesterol levels, again contradicting the conventional view.

    The authors somehow concluded, strangely, that the solution is to shoot for even lower levels of LDL.

  48. Lately I've come to the conclusion that thinking that high cholesterol causes atherosclerosis is like thinking that buildings are caused by bricks.

    Something is causing the cholesterol to form plaques just like something is causing the bricks to form walls.

  49. John,
    do you look at the rT3 range or the fT3/rT3 ratio? I ask because my ratio was something like 8, but the rT3 was mid-range, and the doctor said it was ok… but I wonder.

    Also, once you confirm a rT3 problem and leptin resistance, what treatment do you use?

  50. me too, really looking forward to reading the rest of the story…

    For anonymous 110 to 215 LDL there are a number of hypotheses around from the healing fatty liver to healing vascular damage (Jaminet) and others. However many typical commenters with high LDL on paleo but unremarkable before, stay that way for years on end (see eg. the recent thread "answer day…" on the Perfect Health Diet for numerous examples and many others on PaNu and Mark's Daily),–suggesting some additional factor. Could this be connected perhaps to LDL receptor downregulation for these cases on this diet? (Come to think of it, I cannot offhand recall any contribution stating initial high LDL on paleo that subsequently normalized)

  51. Thank you for this article.

    I'm a guy who went from 110 LDL to 215 LDL within less than 8 weeks when converting from a vegan way of eating to Robb Wolf's paleo recommendations. (All of the other lipid numbers changed dramatically as well, though the other markers changed for the better.)

    I am VERY MUCH looking forward to your dietary (and supplement) recommendations.

    I greatly appreciate your work.

  52. Hi Jack, Erin, and Anonymous — thanks! And I'll be addressing the recommendations, causes of thyroid illness, and so on eventually.

    Eric, while I find this theory interesting and believe that it might have some minor role somewhere, it is completely implausible to give it a major role for a number of reasons.

    First, athersclerosis develops in animals that do not produce their own vitamin C.

    Second, it is not speculation but well demonstrated down to the molecular pathways that inflammation promotes collagen degradation.

    Third, the atherosclerotic process is marked by increased collagen as a protective reaction to accumulation of oxidized lipids in its initial phases.

    Fourth, there is substantial evidence that the pattern of blood flow mediates the localization of plaques because of the positive effect of shear stress due to blood flow parallel to vessels, which is diminished in areas of conflicting blood flow. While it is possible, perhaps, that this leads to collagen breakdown, I think it would be difficult to show this is from physical force itself because there is a good deal of evidence showing that the absence of shear stress in these areas makes the endothelium more permeable to LDL particles and that nitric oxide status is compromised, each of which in tandem lead to oxidative stress and inflammation, which itself should lead to collagen degradation.

    Finally, the history of collagen breakdown can be visualized with proper staining and imaging techniques, and these studies in humans so far have produced evidence that collagen breakdown occurs primarily after atherosclerosis has progressed to a stage of about 40% stenosis. Up to that point, plaques grow primarily outward into the muscular portion of the vessel, but after that point the accumulation of oxidized lipids, necrosis, and so on, lead to sufficient inflammation to produce sufficient collagen breakdown to actually break through the fibrous cap. This leads to successive clotting and the growth of the plaque inward into the lumen.

    While this does not exclude a role for more moderate levels of collagen earlier in the process, I do think it contradicts the idea that collagen is the overwhelming dominant force through the process. I think it is clear that the oxidation of lipid is the dominant force at the beginning of the process and that collagen breakdown becomes more dominant in the latter part of the process.


  53. Great post, Chris!
    @John- don't forget a thyroid antibodies panel (which is usually not part of a regular thyroid panel) because more and more thyroid disease is of the autoimmune variety and blood tests may look normal, otherwise.
    I'd also like to mention that it's important to evaluate the panels according to functional medicine ranges rather than standard ranges, or people may go undiagnosed.
    Dr. Kharrazian's book is stellar and outlines 7 patterns and 22 sub-patterns of thyroid disfunction.

  54. I echo the thought about specific recommendations, in particular dietary strategies. Would be interested in your take on this article, "The Five Key Things You Can Do to Lower LDL Cholesterol Healthfully," which appears to deal with lowering LDL by addressing the reasons it is elevated, including thyroid and liver issues.

  55. I couldn't help but notice your remark:

    "Animal models of atherosclerosis almost never produce a true heart attack … this may be because rabbits and most other animals synthesize their own vitamin C and are therefore able to continually synthesize collagen even as the inflammatory process degrades it."

    In this connection, are you aware of the work of researchers like Thomas Levy (book: "Stop America's #1 Killer"), Steve Hickey and Hilary Roberts (book: "Ascorbate: The Science of Vitamin C") or Matthias Rath (see his websites)? They all claim more or less that the "inflammatory process" you refer to is not the cause of collagen degradation but rather a result of it–it is the body's attempt to martial resources to repair the collagen in order to avoid hemorrhaging–and that the actual cause of collagen degradation is normal wear and tear coupled with a subclinical lack of vitamin C to enable its restoration and maintenance. For example, Rath likes to point out that atherosclerosis never appears in veins but only in arteries, and especially in the coronary artery right next to the heart, and claims that this is due to a) the higher blood pressure in arteries, respectively b) the mechanical force incurred on the coronary arteries due to the pumping action of the heart, causing a greater rate of collagen breakdown. Consequently these researchers claim that vitamin C or lack thereof is the cause and cure of essentially all atherosclerotic heart disease. Please have a look especially at the two books mentioned above as I believe you will find them well-researched with sizable bibliographies and therefore susceptible to your style of evaluation. I for one would much appreciate hearing it.

  56. Actually Norman, the evidence you cite is entirely supportive of my point and you're making me wishing I included it to drive my point home further. The mutation among blacks is a nonsense mutation, meaning it simply deletes the gene product. The mutation in whites is a sequence variation within unknown molecular consequences, except that it somehow reduces LDL-C. The mutation in blacks leads to a greater, not a lesser, reduction in LDL-C and a proportionately greater decrease in the risk of heart disease.

    John, thanks for all the great information. I'll try to incorporate it into my thyroid post.


  57. One last point…..reverse T3 is the best biochemical test for leptin resistance we have……it is never part of a regular thyroid panel and has to be special ordered. And when it is the labs very rarely get the test done unless the doctor calls them directly. I know because I order the test all the time.

  58. If you are one of the people with high cholesterol levels but you have not yet been diagnosed with a thyroid condition, how can you tell if you are hypothyroid?

    First, start by doing the Thyroid Neck Check, which is located at the AACE website.
    Second, fill out the Hypothyroidism Symptoms Checklist
    Third, ask your doctor to run a Thyroid Stimulating Hormone (TSH) test to evaluate your thyroid levels. You really need a full panel done and a doc who knows how to intrepret them.
    Fourth, if your TSH levels are normal but you still suspect hypothyroidism, be aware that there are different ways to interpret the test results that might have an impact on your diagnosis.

    Here is a list of symptoms.

    •Weight gain, or inability to lose weight

    •Fatigue, exhaustion

    •Feeling run down and sluggish

    •Depression, anxiety, mood swings


    •Menstrual irregularities, including more frequent or heavier periods

    •Dry, coarse and/or itchy skin

    •Dry, coarse and thinning hair

    •Feeling cold, especially in the extremities

    •Muscle cramps, joint pain, carpal tunnel or tendonitis

    If you look at old textbooks of internal medicine the link between low thyroid levels and cholesterol was well known and treated. Since 1980 this information appears to be non existant in medical textbooks and heavily weighted to just treating with a statin first if the TC is above 200. Insanity really.

  59. Chris thyroid function is intimately tied to leptin sensitivity for sure. We also know inflammation is critical to the thyroid receptors. First, inflammation (which is characteristic of all autoimmune diseases, and Hashimoto’s is no exception) causes a decrease in thyroid receptor site sensitivity. We also know the sex steroid hormones have huge effects on the TBG's in both sexes and leptin directly exerts control over the production of sex steroid hormones. We also know people who are leptin resistant are also are bad converters of T4 to T3. It is also very important to know that the brain has its own control of thyroid hormone levels so peripherally their can be thyroid issues while centrally the brain does not. This is a critical difference between the heart and brain with respect to thyroid hormone receptors and production. Moreover, several medications that alter the absorption or activity of T4. These include commonly prescribed drugs like antibiotics & antifungals (i.e. sulfonamides, rifampin, keoconazole), anti-diabetics (Orinase, Diabinese), diuretics (Lasix), stimulants (amphetamines), cholesterol lowering medications (Colestid, Atromid, LoCholest, Questran, etc.), anti-arrhythmia medications (Cordarone, Inderal, Propanolol, Regitine, etc.), hormone replacement (Premarin, anabolic steroids, growth hormone, etc.), pain medication (morphine, Kadian, MS Contin, and oxycontin etc.), antacids (aluminum hydroxides like Mylanta, etc.) and psychoactive medications (Lithium, Thorazine, etc.).
    In January 2010, as part of Thyroid Awareness Month, the American Association of Clinical Endocrinologists (AACE)released the results of a new survey on the thyroid-cholesterol connection, looking at the connection between undiagnosed hypothyroidism and high cholesterol.

    The National Cholesterol Education Program and the Food and Drug Administration recommend thyroid testing in patients with high cholesterol levels. The prescribing information for the popular cholesterol-lowering drugs also recommends that patients be tested for thyroid disease before beginning cholesterol-lowering drug therapy. Few doctors even know this data.

  60. Hmm, looking a bit further into the article, the white people they studied had a different set of mutations, which produce a lower decrease in cholesterol. So I guess if you want to focus only on the more powerful mutations, that's fair enough.

  61. Uh, looking up your reference, that 88% reduction in heart disease for PCSK9 mutations is only for black people. For whites, it's a 47% reduction. Also, due to the low number of people with the mutation, the confidence intervals are rather wide.

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