Keto and ME/CFS (part II): the cholesterol hyper-responders

When I set out to write this piece, I thought it would be just that: one piece. I have been in the cholesterol rabbit hole for five months now and have concluded that this complex topic will require several posts to cover it adequately. There are many threads I attempt to weave together, including how both the ketogenic diet and myalgic encephalomyelitis (ME, also called ME/CFS) influence cholesterol homeostasis. There is very little written on cholesterol and ME yet it appears that many people with this disease have abnormal lipid levels. I hope my cholesterol journey will help others better understand their risk for cardiovascular disease and treatment options.

The cholesterol hyper-responders

Many cardiologists will tell you that diet has little bearing on cholesterol. When pressed, they may concede that patients can reduce cholesterol through diet, but only by about 30%. Even so, this is often insufficient to address the risk of high cholesterol. Instead, they are likely to suggest a statin.”Why suffer from a restrictive diet when all you have to do is pop a tiny pill each day?”, they might add. Some people cannot take statins and need to find alternative ways of lowering their cholesterol, including diet.

The truth is that around 20% of the population experiences a hyper-response to dietary cholesterol and fats. Hyper-absorbers see their cholesterol go up when they eat foods high in cholesterol, such as eggs and shrimp. Normally, only about 25% of our cholesterol comes from dietary sources with the remaining 75% made by our cells. However, some people have genetic abnormalities that increase cholesterol uptake from dietary sources.

Hyper-responders, in contrast, see a rise in cholesterol with increased consumption of dietary fat. Approximately 25% of people who go on the ketogenic diet, especially one heavy in saturated fat, experience a spike in cholesterol. In some cases, such as mine, it can be quite dramatic.

When cholesterol goes up there are three likely explanations: 1) more cholesterol is being absorbed through diet, 2) more cholesterol is being synthesized, and/or 3) less cholesterol is being cleared from the body. Another controversial hypothesis is that a rise in cholesterol could result from the heightened demand for lipid transport and delivery in lean people who burn fat (vs. glucose) for fuel. Or, could high cholesterol have something to do with the disease process in ME?

Most GPs and cardiologists will not dig deep enough to understand why cholesterol has gone up in their patients because prescribing a statin will likely bring their numbers down, regardless of the mechanism. However, if you have a complicated health picture, as I do with ME, some digging may be necessary.

In this piece, I discuss a complication that many people experience when they start the ketogenic diet: a dramatic rise in LDL cholesterol. I also give a brief tutorial on how to navigate the standard cholesterol (lipid) panel.

Future pieces will include:

Keto and ME/CFS (part III): I expand on competing lipid hypotheses and how they relate to cardiovascular health, including one promoted by keto enthusiasts.

Keto and ME/CFS (part IV): I explore whether ME contributes to elevated cholesterol (dyslipidemia) and why statins might not be a great option for those of us with this disease.

Keto and ME/CFS (part V): In the final piece, I discuss how to assess cardiovascular risk when LDL cholesterol is high and explore treatment options for those hoping to avoid statins.

Cholesterol by the numbers

As part of a workup with my new ME physician last fall, I had a fasting cholesterol panel done. The last one I had done was way back in 2006. I had known my total cholesterol was near the top of the range back then but figured it was not a big deal given that my HDL cholesterol was good and my LDL cholesterol (LDL-C) wasn’t too high. This past August, my total cholesterol came back at 322 mg/dL (the top of the normal range is 200 mg/dL). My doctor told me to get it checked out.

I finally got around to it in March 2019 and soon discovered that my total cholesterol had risen to 450 mg/dL (!) in the intervening months. My cardiologist insisted that the numbers were an error and had only seen values this high a few times. She sent me away to get the test redone and told me that if the numbers were real she would not be able to help due to my complex health situation. She said my results point to familial hypercholesterolemia (FH), which was news to me given that heart disease and cholesterol are not part of my family history.

Sure enough, the test was correct, which I already knew based on my numbers last August. I told her that I had recently started the ketogenic diet and asked if that might have something to do with my dramatic rise in LDL cholesterol? She said that diet has nothing to do with it. Categorically.

Table 1. My various lipid panels over the past year. Values in bold are above the reference range. The August 2018 test was pre-keto and the dramatic drop from March to May occurred after reducing saturated fat intake down to <25 g/day. Units are in mg/dL (values in parentheses are in mmol/dL). * My first test after starting the ketogenic diet.

Marker Reference 8/29/18 3/6/19* 3/21/19 5/8/19 5/10/19
TC 100 – 199
mg/dL
322
(8.37)
450
(11.64)
413
(10.68)
354
(9.15)
327
(8.46)
Trigs 0 – 139
mg/dL
114
(1.29)
103
(1.16)
162
(1.83)
97
(1.10)
135
(1.52)
HDL >39
mg/dL
111
(2.87)
94
(2.43)
85
(2.20)
94
(2.43)
81
(2.09)
VLDL 5 – 40
mg/dL
23
(0.59)
21
(0.54)
32
(0.83)
   
LDL 0 – 99
mg/dL
188
(4.86)
335
(8.66)
296
(7.66)
238
(6.16)
219
(5.66)

My dietary experiment

Despite what doctors say about diet and cholesterol, I decided to lower saturated fat to see if I could bring down my LDL-C to more acceptable levels. When I started keto I let some high-fat dairy (mmm…butter, whipped cream) slip back into my diet and was eating fatty meats and mainlining MCT oil. Using an app called Cronometer, I set out to eat fewer than 25 grams of saturated fat per day but held fat consumption constant at 130-140 g/day. I ate a lot of macadamia nuts, avocados, and olive oil! This allowed me to stick with keto and only change one variable at a time. I did not change my intake of dietary cholesterol in hopes of teasing apart whether I am a hyper-responder vs. a hyper-absorber.

Within 6 weeks I had my answer: my LDL-C dropped over 100 points (35%). I am clearly a hyper-responder but is there more to the story? My numbers are still unacceptable but they were before going on keto, suggesting that factors in addition to dietary fat (and keto) are a problem. To answer this question I needed to do a deep dive into cholesterol, starting with understanding what my numbers on the standard cholesterol (lipid) panel truly indicate.

Understanding the standard cholesterol panel

What do the various results on a lipid panel mean and how do they map on to cardiovascular health? There are a lot of misconceptions about cholesterol, including ones perpetuated by physicians, in an attempt to keep things simple (this is me being charitable). Cholesterol homeostasis is a nuanced and complex topic, but a basic understanding of the standard lipid panel is an important starting place when assessing the risk of high cholesterol.

It is important to mention upfront that leading cardiologists often require more sophisticated testing to assess risk, a topic I pick up in a future blog.

Cholesterol is essential to cell membranes and is the precursor for steroid hormones, bile salts, and vitamin D. Each cell makes all of the cholesterol it needs. Only specialized cells, such as those producing hormones, require additional cholesterol. Cholesterol tests measure the cholesterol found in lipoproteins (defined below), not cell membranes.

Cholesterol molecule – unesterified, meaning there is a hydroxyl group – OH – at carbon position #3. Image credit: https://en.wikipedia.org/wiki/Hypercholesterolemia.

Total cholesterol refers to the total amount of cholesterol found in all lipoproteins. It is also referred to as serum cholesterol. It does not measure the cholesterol found in cell membranes. The units are in mg/dL in the USA and mmol/dL in most other parts of the world. Most cardiologists view it as a fairly useless measure because it, alone, is not predictive of cardiovascular disease.

Cholesterol, a lipid, is not water-soluble and will not move through the blood on its own. Instead, it hitches a ride in proteins that circulate in the bloodstream called Lipoproteins.

Lipoproteins are spheres with a phospholipid membrane with embedded apolipoproteins forming the surface coat and cholesterol and triglycerides in the lipid core. I pick up apolipoproteins in a future blog. They often are compared to boats, as they transport cargo such as triglycerides to muscles for energy, deliver phospholipids to cells, collect excess cholesterol from cells for clearance in the liver or gut, and to deliver cholesterol to cells where it is needed.

Lipoproteins are spheres with phospholipids and embedded apolipoproteins (an important topic I explore in a future piece) on the outer surface and cholesterol and triglycerides in the core. Image credit: https://commons.wikimedia.org/wiki/File:Structure_of_a_Lipoprotein.png.
Lipoprotein “lineages”. Chylomicrons are lipoproteins that originate from the liver and carry huge triglyceride loads. In contrast, the VLDL line originates in the liver. VLDLs (very low-density lipoproteins) and IDLs (intermediate density lipoproteins) carry both triglycerides and cholesterol, whereas LDLs (low-density lipoproteins) carry cholesterol only. LDLs are also produced de novo in the liver, as are HDLs (high-density lipoproteins), without coming from a VLDL. Image is based on one by Dave Feldman from Cholesterol.com.

The primary function of “chylos” and VLDLs (see above) is to deliver energy to cells that either store (i.e. fat cells) or use triglycerides for energy (i.e. muscle cells). When VLDLs dump their triglyceride-rich loads and become smaller they can become low-density lipoproteins, also known as LDLs. However, about 40% of LDLs are produced directly by the liver and do not come from a VLDL. This becomes an important point when evaluating competing lipid hypotheses – the topic of my next blog.

LDL-C is often referred to as the “bad” cholesterol and HDL-cholesterol (HDL-C) as the “good” cholesterol, which is pretty absurd considering the cholesterol in both types of lipoproteins is the same! Cholesterol is only bad if it ends up on the inside of your artery wall. When doctors speak imprecisely about cholesterol it suggests they do not have a very good understanding of the subject.

HDL-C is often referred to as the good cholesterol because it can pick up excess cholesterol from cells and help eliminate it from the body. Cell membranes need cholesterol but too much of a good thing will kill a cell. After picking up cholesterol from cells that have too much, HDLs can be cleared by the liver and dumped into the intestine where they can then be eliminated (or their cholesterol reabsorbed). They can also get cleared directly in the intestine by a mechanism called trans-intestinal cholesterol efflux (TICE). HDLs also play an important role in immune modulation.

It is worth asking why we have LDLs in the first place if they are such a nuisance and harmful to health. They tend to stick around in the bloodstream for a long time (LDL residence time is a day vs minutes with VLDLs or seconds with chylos), which increases the chances that they become oxidized inside of an artery wall. Do they serve any purpose?

This is where the whole good vs bad cholesterol thing breaks down a bit. HDLs have a special protein that allows them to transfer the cholesterol they have picked up from cells to an LDL particle, where it can then be cleared by the liver. So, who is the good or bad lipoprotein at this point? Besides, HDLs remnants can be pathologic in people with metabolic syndrome and type-2 diabetes (T2D). It is better to think of good vs. bad cholesterol pathways vs. good vs. bad lipoproteins.

HDL transferring cholesterol to an LDL via the cholesterol ester transfer protein (CETP). The cholesterol in the LDL is cleared from the liver via the LDL-receptor (LDL-R). Image credit: https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/reverse-cholesterol-transport.

Triglycerides, or trigs, are a type of fat found in VLDLs and chylomicrons. The body converts excess calories to trigs, which are then stored in fat cells until needed. In general, high LDL-C is more worrisome when trigs are high and HDL-C is low because it usually is an indication of hyperinsulinemia (insulin resistance) and possibly metabolic syndrome – something I drill into in my next piece.

Trigs are sensitive to fasting time, making it all that much more important to fast for 12 hrs (but not more) when doing a lipid panel. Trigs also can be sensitive to the cafestol found in coffee, caffeinated or otherwise, so best to skip it for a day or two before testing if you are not happy with your results. Some say you should stop coffee for a week before testing.

It is important to recognize these tests don’t help with understanding risk. However, for now, it is fair to say LDL-C serves as a proxy for risk in many cases, but not always. To truly assess risk requires an LDL particle analysis, and an apolipoprotien B and lipoprotein(a) count in the very least. It is also important to place lipid results in the context with other aspects of metabolic health, such as insulin sensitivity, inflammation, coagulation levels, and blood glucose levels. Sadly, most people will receive no further testing beyond the standard lipid panel before being prescribed a statin. However, if you have health complications – especially ME – it is essential to understand what your true risk factors are for cardiovascular disease.

Up next, I explore two lipid models – the lipid model of atherogenesis and the lipid energy model – to better understand if and when high LDL-C is a problem. Coming soon!

Acknowledgments. I owe a lot to Drs. Peter Attia and Tom Dayspring for providing some excellent resources that allowed me to dial in the complex world of lipids fairly quickly. It is a field that requires an appetite for biochemistry and takes decades to master. I have only been at it for five months (and am far from mastery!) and cannot imagine how long it would have taken to get to where I am without their materials.

I highly recommend Attia’s Straight Dope on Cholesterol blog series and the many interviews he has done with prominent lipidologists, cardiologists, and physicians who truly understand the ketogenic diet. They are highly technical, but so worth exploring if you have dyslipidemia. Here is a selection of my favorites that are relevant to this piece. I will include other links in my coming blogs as well.

#03 – Ron Krauss, M.D.: a deep dive into heart disease

#20 – Tom Dayspring, M.D., FACP, FNLA = Part I of V: and introduction to lipidology

Peter Attia’s cholesterol blog series

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