In my search to learn more about what the heck the relationship is between ketosis and the stratospheric increases in both Total Cholesterol and LDL that seem to occur in so many people (myself included), I came across this case presentation and write up by Dr. Thomas Dayspring, who is a renowned lipidologist.
I carefully went through this paper and did my best to digest, simplify, and summarize it… mainly for myself, but I figured I might as well share it with you guys too.
It took me a couple read-throughs to process it all since things can get a bit complex. I also didn’t realize how hard it can be to read single spaced paper like this.
Of course I encourage all of you to give it a read yourself.
Ketosis and High Cholesterol
Dr. Dayspring discusses a case in which a post-menopausal female went low carb paleo and in the span of a few months developed super high Total Cholesterol (TC) and LDL-C.
TC: 196 -> 323
LDL-C: 105 -> 230
HDL-C: 75 -> 83
Triglycerides (TG): 78 -> 49
Total LDL-P: 2643
In this 14 page, single-spaced case discussion, Dr. Dayspring explores what it means for patients who go low carb and demonstrate tremendous improvements in insulin sensitivity including loss of weight, decreased waist size, improved TG and HDL-C, and decreased inflammatory markers… BUT develop an increased TC, LDL-C, ApoB and LDL-P.
“I and other lipidologists and many patients themselves are starting to see that the above lipid response to a high fat diet as not being very rare response in people who abandon carbs and replace it with saturated fat, especially so in those doing extreme carb restriction to achieve nutritional ketosis.”
“The true incidence remains to be determined but experienced colleagues who have a lot of patients on low carb diets advise it is about 1/3 of patients”
In all the literature that he’s reviewed, the most important coronary heart disease (CHD) risk factor aside from smoking and age, is having a high LDL-P.
He emphasizes that there is a lot of misinformation (according to him) on the internet saying that atherosclerosis is a disease of too-much-inflammation and not of too-much-cholesterol.
The truth (again, according to him) is that atherosclerosis is a disease of EITHER too-much-inflammation OR too-much-cholesterol.
- People without inflammation can still have atherosclerotic plaque.
- People with low cholesterol (TC and LDL-C) can also have atherosclerotic plaque.
Atherosclerotic plaques are composed of cholesterol that has infiltrated the arterial wall. Cholesterol enters the wall via LDL, and the amount of cholesterol that enters the wall is correlated with the LDL particle number (LDL-P) not LDL concentration (LDL-C).
The Difference Between LDL-C and LDL-P
Let’s take a moment to review the difference. I’ll begin by saying that this example is a tremendous oversimplification, and this simplification is not a part of the paper. I included this part only to give you a better understanding of what he’s talking about (if someone has a better way of explaining this, please let me know).
LDL-C stands for the concentration of LDL cholesterol, or rather the amount of cholesterol carried by all LDL lipoprotein complexes.
LDL-P stands for the amount of LDL particles, or rather the amount of LDL lipoprotein complexes that are present.
Now let’s say there are 10 cholesterol molecules.
Let’s say these 10 cholesterol molecules are packaged into 1 LDL lipoprotein complex.
What’s the LDL-C? 10, because the CONCENTRATION is 10 cholesterol molecules.
What’s the LDL-P? 1, because there is only one LDL lipoprotein complex.
Now let’s say these 10 cholesterol molecules are packaged into 5 different LDL lipoprotein complexes, each containing 2 cholesterol molecules each.
What’s the LDL-C? 10 still, because the concentration is still the same: 10 cholesterol molecules.
What’s the LDL-P? 5, because there are now 5 separate LDL lipoprotein complexes.
Now back to the paper
Ok, getting back to the atherosclerotic plaque. After LDL particle number, the most important factor in developing atherosclerotic plaques is the integrity of the arterial endothelium (cells lining the arterial wall). If they are inflamed, they will develop gaps that will allow LDL to enter.
Obviously the worst-case scenario is to have both high inflammation AND high LDL-P.
Dr. Dayspring cautions: “But make no mistake the driving force of atherogenesis is entry of apoB particles and that force is driven primarily by particle number not arterial wall inflammation.”
He provides a reference (which I plan on reading in the future):
Ira Tabas, Kevin Jon Williams, Jan Borén. Subendothelial Lipoprotein Retention as the Initiating Process in Atherosclerosis Update and Therapeutic Implications Circulation. 2007;116:1832-1844.
He next goes over the biochemistry and absorption of cholesterol. I won’t go over it too much here except for some of the highlights:
“Ingestion and small intestinal absorption of saturated fatty acids in some patients can lead to a hypersynthesis of cholesterol.”
“In those on low carb diets, fewer carbohydrates are available for energy, and that energy (adenosine triphosphate or ATP) must then come from fatty acids which are broken down by an catabolic (oxidative: oxidation = burning) process.”
Basically what happens with fatty acid metabolism is that when fatty acids are metabolized for energy, they are eventually broken down by the mitochondria into a molecule called HMG-CoA, which can basically do two things: it can either be converted into cholesterol OR into ketone bodies (which occurs when not enough glucose around).
When there are too many ketone bodies around, as in nutritional ketosis, the ketone bodies can be converted BACK into HMG-CoA which is then converted to cholesterol.
It’s through this mechanism that women with anorexia nervosa develop high cholesterol! This was a fact that I was surprised to learn.
When the liver is hyper-synthesizing LDL, biomarkers like lathosterol and desmosterol will be high, AND because in this situation the amount of cholesterol in the liver is high, the liver will DECREASE the expression of LDL receptors, which function to clear LDL from the blood, leading to a further increase in LDL-C and LDL-P.
“The classic study of the Framingham Offspring Study done by Bill Cromwell showed clearly that risk trafficked better with LDL-P, than LDL-C. In persons with elevated or reduced LDL-C, risk was pretty much related to LDL-P, meaning there are patients with high LDL-C who had excellent survival because there LDL-P was not elevated. Also those with lower levels of LDL-C but elevated levels of LDL-P did have CV risk.”
The most common response Dr. Dayspring hears about this from low carb advocates is that, “Framingham offspring is not a study of those on a low carb or paleo diet and thus does not necessarily apply to them.”
“The big question right now really is: Are there persons who do not get atherosclerosis with apoB-cholesterol/lipoprotein levels greater than the above posted concentrations who do not get atherosclerosis?”
“…It seems for a small percentage of people that is true, but using existing trial evidence (which looked at folks on no specific diets or standard AHA low fat, low cholesterol type diets) they are rare exceptions, not the rule.”
The patient was informed of all of the above and was given the option of altering the diet without returning to carbohydrates or using an LDL-P lowering medication, specifically a statin. The dietary advice was to cut back on saturated fat and use more MUFA and PUFA without increasing carbs
After doing just that for a few months the patient reports: “The only modifications I’ve made because of my high lipids are eating steel cut oats regularly, adding chia seeds to my diet, and eating apples regularly (to increase fiber levels); cutting out most dairy; and watching my saturated fat intake a little more closely–all aimed at getting my high LDL-P down.” Weight has remained stable.
TC: 196 -> 323 -> 178
LDL-C: 105 -> 230 -> 92
HDL-C: 75 -> 83 -> 82
Triglycerides (TG): 78 -> 49 -> 21
Total LDL-P: 2643 -> 948
Cholesterol Synthesis Markers:
Lathosterol/TC: 31 (low), synthesis marker
Campesterol/TC: 217 (normal), absorption marker
Beta-sitosterol/TC: 231 (high), absorption marker
He notes that these numbers are specified as a ratio in relation to total cholesterol.
He wished the patient had these tests done prior to the intervention because he hypothesizes that in light of the elevated LDL-C and LDL-P, the patients cholesterol synthesis was probably high.
After the patient reduced her saturated fat intake, this normalized her cholesterol synthesis and thus her elevated LDL-P.
With regard to these markers, he cautions that:
“Another key point regarding absorption synthesis markers is that these change in response to nutrition, drugs, aging, other morbidities and they are not ever too be used as a onetime assessment. In at risk persons, like lipid and lipoprotein and other biomarkers, they need to be repeated with each and every blood draw.”
For people who want to control their LDL-P while at the same time remaining in ketosis, Dr. Dayspring proposes three options:
- Do nothing and hope for the best.
- Decrease intake of saturated fat
- Start a statin and/or ezetimibe (depending on absorption/synthesis markers).
He also says that sometimes the combination of 2 and 3 need to be employed.