Cholesterol
It took me a long time to finally give the Ketogenic diet a try. I have already documented many of the reasons for this on prior blog posts. Another reason was my fear of cholesterol. High cholesterol has been vilified as a cause of heart disease and stroke and overall mortality for decades. There has been recent science suggesting cholesterol does not deserve this bad rap, but I have never researched the studies myself until now.
Did the Keto diet raise my cholesterol levels?
I got an extensive blood test about 1 week into the Keto diet and then a more detailed cholesterol only test after 4 weeks and I was anxious to find out what my results were. The bottom line is all of my labs are absolutely perfect, except my cholesterol levels are way above normal. I shouldn’t have been, but I was actually shocked at my cholesterol numbers and started to get worried about it. My doctor also expressed concern about my numbers and recommended I try a low fat diet and increase exercise to bring my numbers down with follow up in one year.
My Labs on 5/1/2019
Fasting Glucose - 82 (Normal is 70-100, but 80-85 is ideal
Hemoglobin A1C - 4.9 (Normal is under 5.6. This means I am not insulin resistant)
C-Reactive Protein - 0.38 (Normal is under 2.99, so this is a fantastic number that indicates there is almost no inflammation occurring in my body at this time)
Testosterone - 581 (Normal 23-854)
Vitamin D - 27.9 (Normal 30-70. I started taking a Vitamin D supplement after these labs were drawn so I should be well within the normal range now. But this low value confirms that Vitamin D supplementation is important for me)
Vitamin B12 - 520 (Normal 220-600)
Folate - >20 (Normal is >3)
TSH - 1.65 (Normal 0.4-4.6)
My basic metabolic panel and chemistry panel are all within normal limits. I have no concerns with any of those numbers.
My cholesterol labs
For reference purposes, I will list my labs taken during my National Guard PHA in April 2018 first
Total Cholesterol - 152 (Normal <200)
LDL Cholesterol - 90 (Normal <100)
HDL Cholesterol - 44 (Normal >40)
Triglycerides - 88 (Normal <150)
Labs drawn on 5/1/2019
Total Cholesterol - 200 (Normal <200)
LDL Cholesterol - 131 (Normal <100)
HDL Cholesterol - 58 (Normal >40)
Triglycerides - 66 (Normal <150)
Labs drawn on 5/23/2019
Total Cholesterol - 191 (Normal <200)
LDL Cholesterol - 158 (Normal <100)
HDL Cholesterol - 55 (Normal >40)
Triglycerides - 45 (Normal <150)
Apoliprotein A1 - 139 (Normal 101-178)
Apoliprotein B - 111 (Normal <90)
Apo B/Apo A Ratio - 0.8 (Normal 0.0-0.7)
Analysis of my cholesterol numbers
I had a dramatic increase in all of my cholesterol labs compared to my normal baseline from one year earlier. Total cholesterol is not a good indicator for cardiovascular disease because that number alone does not tell me whether it is high because of good cholesterol or bad cholesterol. Although it is much more complex than this, the first thing to know is that LDL is the “bad” cholesterol and HDL is the “good” cholesterol. Both my LDL and HDL increased on the Keto diet. It is also interesting to note that my triglycerides were normal 1 year ago, but significantly improved while on Keto. So which of these numbers is the most important? Do the improvements in my HDL and triglyceride levels counteract the significant worsening of my LDL numbers? Here are a few additional ways to evaluate my numbers.
The ratio of Total Cholesterol to HDL is felt by some to be more important than total numbers. My ratio was 3.455 in April 2018. My ratio was 3.448 on May 1, 2019. And my ratio was 3.473 on May 23, 2019. So essentially no change over the past year.
Triglyceride to HDL ratio may be another helpful indicator of my risk for CVD with <2.0 being ideal. My ratio was 2.0 in April 2018. It was 1.14 on May 1. And it was 0.82 on May 23. This would indicate my risk of CVD is lower.
Apoliprotein A1 plays a role in cholesterol transport and should be above 120 in men (>140 in women). My number is normal at 139.
Apoliprotein B is the protein component of LDL. Although the reported range at the lab shows me as high with a number of 111, the Bulletproof blog reports that this number should be less than 130.
hsCRP is an inflammatory marker and according to the Bulletproof blog, this number should be below 1.0. My number is 0.38.
The cholesterol debate
There is an ongoing heated debate about the role cholesterol plays as a cardiovascular risk factor. Cholesterol is essential for life. There are a number of functions in our body that require cholesterol including hormone production and bi-layer cell membrane production. But all tissues in the body have the ability to create their own cholesterol with endogenous cholesterol production (meaning what we are producing in our body) much greater than the exogenous cholesterol intake from our diet. The liver synthesizes a lot of our cholesterol and the gut regulates our cholesterol levels.
HDL cholesterol
Knowing that LDL is “bad” and HDL is “good” is just the beginning.
HDL (High Density Lipoprotein) activates anti-inflammatory pathways and is protective for cardiovascular disease. This is because HDL takes cholesterol from the arteries and sends it to the liver for reprocessing or excretion. The most important thing to know about HDL is that low HDL is a stronger predictor of heart disease than is high LDL.
Nutritional and lifestyle changes can have a beneficial affect on HDL, while HDL raising drugs have not proven to be beneficial.
The different types of LDL cholesterol
LDL (Low Density Lipoprotein) is more complicated. It is true that LDL is overall lower in density than HDL, but there is also wide variability in how dense LDL particles are. And it is the particle composition of our LDL that is probably the most important factor in regards to our cholesterol contributing risk of cardiovascular disease.
There are two “patterns” in regards to the composition of our LDL particles. Pattern A = predominantly larger and more buoyant LDL particles that are probably not harmful and can be used metabolically. Pattern B = smaller and more dense LDL particles that are correlated with heart disease.
LDL-C is the number reported on blood tests. This measures the concentration of LDL cholesterol in the blood as a summation of the range of small and compact LDL particles to large and buoyant LDL particles. Blood levels of LDL-C measure all of these but do not differentiate between the different types of particle composition. Therefore, if two people have the same LDL-C number, a person who is predominantly Pattern A will have fewer cholesterol particles because they are larger while a person who is predominantly Pattern B will have an increase in the number of cholesterol particles because it takes more of these smaller particles to have the same overall concentration of LDL in the blood.
Lipoproteins
It is common practice to call HDL and LDL cholestero, but this is actually false. HDL and LDL and VLDL are actually lipoproteins, which are transport molecules consisting of part lipid and part protein. These transport molecules are used to carry cholesterol, triglycerides, and phospholipids and that is why people think these are types of cholesterol. LDL should be carrying predominantly cholesterol. VLDL should be carrying predominantly triglycerides. When there is excess triglyceride, we make more transport molecules, which may also be an important factor.
How does cholesterol contribute to atherosclerosis?
Atherosclerosis is not a lipid-mediated disease. It is a lipoprotein-mediated disease. Atherosclerosis occurs when the lipoprotein gets trapped in the endothelial cell layer on the periphery of our arteries. Pattern A type of LDL particles are larger and more buoyant and therefore are not easily trapped in the endothelial cells. The Pattern B type of LDL particles, however, are smaller and more dense so they have a greater tendency to end up at the endothelium. They are also stickier and are more easily oxidized.
When an LDL particle contributes cholesterol to a cell, the receptor that is now free can be occupied by an endotoxin that is circulating in the blood due to chronic stress. This endotoxin containing lipoprotein can get trapped in the endothelium. This causes an inflammatory reaction as the cell recruits macrophages to get rid of this intruding endotoxin containing lipoprotein that isn’t supposed to be there. Macrophages function to digest cellular debris and are sent to the endothelial cells to remove the lipoprotein. After the macrophages have ingested the oxidized LDL, they are known as foam cells. However, the presence of this foam cell in the endothelium actually makes it more likely for additional LDL particles to get trapped. This results in a spiraling effect with increasing inflammation leading to plaque formation in our arterial walls.
Decrease in size of the LDL particles also decreases the ability of the receptor to be exposed and removed from the blood stream. So these small LDL particles also hang around in the blood longer and therefore have more opportunity to get stuck in an endothelial cell. This is called the residence time of LDL particles.
Number of lipoprotein particles
Understanding this process highlights the importance of the size and density of our LDL particles as well as the importance of the number of LDL particles. The more LDL particles we have floating in our blood, the more likely it is to get trapped in the endothelial cells. LDL-P is a measure of the number of particles. This can be measured directly with the NMR LDL-P test. It can also be measured indirectly. Every Lipoprotein has one Apolipoprotein on it’s periphery. In particular, every molecule of LDL has only one Apolipoprotein B on it’s surface. So measuring the ApoB in our blood is a surrogate for LDL-P. The higher the LDL-P, the higher the risk of cardiovascular disease may be.
One study that was performed showed that High Fructose Corn Syrup caused the biggest change in ApoB levels when compared to fructose and glucose. Another reason to avoid High Fructose Corn Syrup.
Lipoprotein(a)
Lipoprotein(a), also known as LP(a), is an LDL particle with an extra protein attached to it that cause it to invade arterial walls aggressively This leads to plaque formation and increased risk of cardiovascular disease, peripheral artery disease, and aortic stenosis. The typical scenario with this disease is a middle aged man with no apparent risk factors for heart disease who has a heart attack. Lipoprotein(a) is the most common inherited risk factor for early heart disease but it cannot be detected in normal cholesterol panels. And we do not routinely test for it in the general population unless you have a first degree relative who has a heart attack at a young age (before age 55 for men, before age 65 for women) despite a normal LDL. Or unless you have heart disease despite normal untreated cholesterol levels. There is no targeted intervention for this genetic abnormality other than aggressive reduction of other risk factors. There are also other well known genetic disorders that cause significantly elevated cholesterol levels, but this will be detected on routine cholesterol blood panels.
What about VLDL?
VLDL (Very Low Density Lipoprotein) is the lipoprotein produced by the liver. It is the molecule primarily responsible for transporting triglycerides, taking them to muscle cells to be used as energy or taking them to adipose cells to be stored as fat. LDL is a byproduct of VLDL, with different forms of VLDL becoming different forms of LDL. When we have high triglyceride levels, the liver makes more VLDL to deal with it resulting in higher numbers of LDL. Eating low carb is the best diet to significantly reduce triglyceride levels. (A to Z trial in 2007. Workplace Diet Trial in 2008.)
Causes of atherogenic dyslipidemia
High levels of small, dense LDL cholesterol.
Low levels of HDL cholesterol.
High levels of triglyceride rich lipoproteins.
Other possible tests to indicate risk of cardiovascular disease
The best marker of inflammation in the endothelium is Lipoprotein-associated phospholipase A2 (Lp-PLA2). This is a specialized test that may be beneficial to monitor your risk of inflammation and atherosclerosis. A Coronary Artery Calcium score, obtained with a CT scan, is another screening tool that can be used to evaluate the presence of any calcified plaque formation in coronary arteries. This is not a perfect test because it cannot detect non-calcified plaque, but is another tool that can be used. There is also a Carotid Intima-Media Thickness (CIMT) test that measures the thickness of the inner layers of your carotid artery.
Drug treatment for high cholesterol
Statins are a class of drugs that effectively inhibit the enzyme HMG-CoA reductase resulting in decreased LDL cholesterol by as much as 30-40%. Controlled trials have shown that statins have a positive effect on overall mortality in regards to heart disease. It is unproven, however, that it is the Statin’s effect on lowering LDL cholesterol that provides that improvement in mortality. Many other drugs that effectively decrease cholesterol have not had the same impact on mortality as statin drugs so it is possible that there is another mechanism of action in play that improves mortality. We don’t know for sure. Studies have also indicated that Statin drugs work primarily on lowering the larger LDL particles instead of the more dangerous smaller LDL particles, which may decrease their effectiveness in improving heart disease.
The class of Statin drugs are not benign. They have significant side affects. It is important, therefore, that physicians do not treat patients with statin drugs based on Total Cholesterol and LDL levels alone. A more advanced cholesterol panel is necessary to determine if statin drugs are really indicated. But if I have a cardiovascular event or if the totality of my risk factors indicate I am at significant risk of a cardiovascular event, I would want to be on a statin drug to mitigate that risk as much as possible.
Lifestyle treatment for high cholesterol
The classic lifestyle intervention is a low fat diet with a particular focus on reducing saturated fat intake in conjunction with an increase in exercise. A low fat diet is obviously the opposite of what I have been doing recently with my Ketogenic and now low carb diet. And the big problem with a low fat diet is the calories have to come from somewhere and therefore you end up eating a high carb diet, with most people increasing their simple sugar and processed food consumption.
What should I do about my high cholesterol?
My dad started having chest pain a couple years before his cancer diagnosis which resulted in the placement of 2 cardiac stents so I do have a significant family history of heart disease. So what do I do about these high cholesterol numbers? All of my other cardiovascular risk markers are perfect so even if this elevated LDL increases my relative risk of heart disease 3 fold, which sounds like a lot, this would still keep my absolute risk of heart disease extremely low. It is also important to remember that my ratio of Total Cholesterol to HDL has not changed and all my other labs look great, including the inflammatory markers. So taking my entire metabolic health into account, I am not very worried about my high LDL numbers. They are certainly not high enough to even consider drug treatment. And I do not think it is necessary to switch to a low fat diet just to try and improve my LDL number, particularly since my low carb diet has improved everything else in my health profile. I might decrease my saturated fat intake a little bit, but will continue to eat a low carb diet. If I had metabolic syndrome or insulin resistance or was in a state of chronic inflammation for another reason, I would feel differently. But in my current health situation, I will continue to watch my cholesterol levels with annual or semi-annual lab work.
Hyper-Responder
Hyper-responder is a term used in the low carb community for those individuals who have a significant increase in cholesterol levels after adopting a low carb diet. I meet this criteria with my 26% increase in total cholesterol, 25% increase in HDL, and 76% increase in LDL after 4 weeks on a Ketogenic diet. The LDL cholesterol number that is usually used is 170 or higher, however, and I do not meet the criteria based upon that. It is estimated that between 5% and 33% of people in the low carb community are hyper-responders, so this is not a problem for everyone who adopts this lifestyle.
The important question is whether being a hyper-responder is dangerous or not and the data is not clear. Dave Feldman, of cholesterolcode.com has become a de-facto expert regarding this question, performing research and experiments on himself to try and figure this out. His LDL numbers have been as high as 380 but he has undergone all the extra tests including CIMT, echo, cardiac ct, etc. with no change in his level of atherosclerosis. In his research, he has seen a pattern emerge of Lean Mass Hyper Responders, who are typically thin and athletic individuals. This is because the body is using the fat you are eating for energy and these triglycerides have to be carried to the cells by VLDL particles and therefore the liver ramps up production of these VLDL carrier molecules. And as previously discussed, VLDL becomes LDL. The typical lab pattern in this Lean Mass Hyper Responder scenario is high LDL-C and very low triglycerides (exactly what I experienced with my triglycerides decreasing from an already low 88 all the way to 45). This means my body revved up my VLDL and LDL transport molecules to use all this extra fat I am eating. Other possible ok clinical scenarios to explain an increase in LDL is if my body were healing from an injury or infection, but this does not fit my clinical scenario.
His research has also revealed that your measured cholesterol levels are highly dependent on how much fat you ate in the 3 days prior, but it is an inverse relationship. Contrary to what you would expect, the more fat you ate, the lower the cholesterol number is. And if you are fasting for those 3 days, the cholesterol number may jump really high. (This is how he got his LDL-C as high as 380).
LDL-P is again probably the more important number. I wish that would have been a part of my labs, but I will specifically request this the next time I have labs drawn. But assuming I also have a high LDL-P, most physicians would encourage me to try and decrease that number. The counter argument is that no cholesterol numbers matter unless I am in a state of inflammation, which is typically remedied through a low carb high fat diet.
There are other possible contributions to consider.
Familial Hypercholesterolemia. This is unlikely because my cholesterol labs should have been abnormal 1 year ago with this genetic disorder.
Copies of the ApoE4 gene. This is identified with an increased risk of higher cholesterol and is a possibility for me. I would need genetic testing to determine this.
Hypothyroidism. Unlikely given my normal thyroid labs and absence of hypothyroid symptoms.
Insulin resistance. This is not me given my body habitus and otherwise normal labs.
Dave Feldman’s bottom line is that LDL alone does have a weak association with heart disease. But in the setting of high HDL and low triglycerides, high LDL does not matter.