Transcription
Good morning. So, my name is Dr. Paul Mason, and I'm a sports and exercise medicine physician from Sydney. And today, I'm going to talk about cholesterol. What it is, what makes it good, what makes it bad, and more importantly, how to interpret a cholesterol blood test to see whether there's any cause for concern. And we're going to finish our talk by looking at the Feldman protocol, where people have been shown to be able to dramatically drop their LDL levels simply by following a high-fat diet for three days. But please note, this lecture is purely educational and in no way constitutes any personal medical advice.
So, I'd like to start by sharing a story about one of my patients. It was a 48-year-old male, and when he walked in, I did a double-take. I really didn't know why he was there. I mean, he looked ripped. But as it turns out, he had a rather unique problem. You see, he had recently applied for health insurance, income protection insurance, and he had received this letter from the insurance company. Apparently, they felt that he was high risk.
This is a recent photo, not a "what if" scenario. He's 48 years old, people. This is his DEXA scan. The blue areas represent lean tissue, the red areas represent fat. So, why did his insurance company refuse to insure him? Why did they think he was a bad risk? Well, it was his cholesterol levels. They were high. This is his test result, and the insurer based their decision based on this test. So, down the right-hand side, you can see what we call the reference ranges, with a lower and an upper value. And if a result falls outside of this reference range, it's considered abnormal. And what I've done here is I've highlighted three of his results which fell outside this range: his total cholesterol, his HDL, which stands for high-density lipoprotein, and his LDL, which stands for low-density lipoprotein. But if I was his insurer, based on this result, I would have signed him up right away. And to understand why, let's take a closer look at exactly what we're looking at when we look at these numbers.
So, the term cholesterol is very loosely, but incorrectly, used to refer to a number of different particles in our blood that carry fat around their body. And there's five major classes of these particles, and their correct name is lipoprotein. Now, a little bit confusingly, one of the fats that these carry around the body is actually cholesterol. But to call these lipoproteins cholesterol is a bit like mistaking a horse float for a horse. It just really doesn't make any sense. And we can differentiate between these lipoproteins based on their size and their density. And the lipoprotein on the bottom left, the big one, that's the least dense, the biggest, that's formed after we eat. But by the time we do a fasting blood test, the chylomicrons have basically disappeared from our blood. So, we don't need to focus on chylomicrons anymore.
Now, in yellow, you can see three lipoproteins which are linked by arrows: VLDL, IDL, and LDL. This stands for very low-density lipoprotein, intermediate-density lipoprotein, and low-density lipoprotein. And the reason I've linked them by arrows is to demonstrate that they are essentially the same particle. So, they all start out as the big one, the VLDL. And then, as it circulates around our body, it donates some of its cargo to tissues. That's what they're meant to do. And as it offloads its cargo, they shrink, they get a little bit smaller. It's like a deflating balloon, but they're still the same particle. And finally, up on the top right here, you can see HDL, which is closely known as "good cholesterol," with higher levels generally considered favorable.
Now, you've also probably heard of LDL referred to as "bad cholesterol." But the LDL we're looking at here, in fact, is not deleterious in any way. I'd be quite happy to have a bunch of that in my circulation, and I do. But not all LDL is good. It can turn bad if it mixes with the wrong crowd. And that wrong crowd is sugar, or more specifically, glucose. If we expose LDL to glucose, it can be damaged in a process called glycation. And that then leads that damaged particle to be vulnerable to a process called oxidation. And both of these damaging steps make the particle fractionally smaller. You've probably heard of small, dense LDL before. That's what it is. It's been damaged. And that damage, as a consequence of exposure to sugar. This damaged LDL is what leads to heart disease, not the other stuff.
So, now we know what the different types of lipoproteins are. Let's have another look at my patient's cholesterol panel. Now, you'll notice one thing where it says cholesterol 8.8, and this is in millimoles per liter. This is the unit that we use in Australia and the UK. Now, the breakdown of the cholesterol underneath that doesn't add up to the total cholesterol. And there's a very good reason for this, because this panel is missing some of the lipoproteins that we just saw, which we know exist. And the reason they're missing is because they're not actually measured on a standard blood test. You see, centrifuging the blood to spin it down so that you can actually measure the particles is a time-consuming and expensive procedure, so it's usually not done. So, instead, some values are calculated, which is really a euphemistic term for saying "guessed." So, VLDL, we know exists, but it's actually not listed here, but it's actually estimated as part of the calculation for LDL. Estimated IDL, here, in actual fact, is assumed to be absent. Makes it a bit easier to do the calculations if we pretend that's not there. Right. So, then we use these assumed values to calculate LDL. So, I said, any wonder that accuracy is not always guaranteed. At least the HDL is measured.
Now, one alternative to all of this guesswork would be to centrifuge the sample and actually measure these particles individually. And that's what I often do. So, what we do, we get the sample and we place it in a gel, and then we spin the gel down. And as we spin it, the particles sink into the gel at different rates and different depths, depending on how big they are and what density they are. And you can see here, the dark spots represent peaks of the different LDL populations. And the results are presented something like this. And you can see that the peaks actually correlate with the dark spots in the gel. So, we can actually measure this.
Now, I just want to focus for a moment where it says LDL, when we've divided it into seven sections. And I just want you to have a look at the peak. It's a nice, smooth peak. There's only one peak. And this is because it represents a healthy population of LDL. The fact that there's only one peak means that there's not been any change in size due to damage of the LDL. They've not been glycated, they've not been oxidized. And this is what we call a Pattern A LDL. This is healthy. If the particles were damaged, I would expect to see more than one peak.
So, let's have a closer look at what happens with the LDL when it does hang out with the wrong crowd and when it does get damaged. First of all, it gets exposed to sugar, glucose, and that causes glycation, shrinks a little bit. And then that makes it very vulnerable to oxidation. And interestingly, this oxidative process has been shown to be significantly accelerated when we have an excess of omega-6 fats, the kind found in vegetable and seed oils. There is a connection.
So, let's come back to this graph here. And up the top, we'll now add to our single LDL, let's add the two damaged populations. Let's see if we put that sample into a gel tube and spun it down, what would it look like? So, have a look at the middle blob where the LDL is represented. And now you can see it spread out, and you can see in this example, two distinct populations of LDL. And down the bottom, not of the sample here, but another one of my patients, just for illustrative purposes, you can see here in the LDL, you have three distinct peaks. This is Pattern B LDL. This is the dangerous LDL. And you need to understand, it doesn't occur because of saturated fats. It occurs because it's damaged by sugar, it's damaged by blood glucose levels.
So, to understand why it's so damaging and can lead to blockage of our blood vessels, let's have a look at the normal life cycle of VLDL once it's created from the liver. So, as it donates its cargo, it shrinks in size through the intermediate stage and finally ends up at low-density lipoprotein. And then the low-density lipoproteins are able to be taken back up by the liver or by cells in the peripheral tissues. And they use something which I've shown here in blue, which is called an LDL receptor. And these LDL receptors are able to specifically recognize the LDL particles. And that's because there's a special protein on the LDL particles, which we call ApoB100. And you can think of this like a security swipe card. If you don't have a security swipe card, or if you've snapped it in two, it's broken, you can't get in that door.
So, if we have a look at an LDL in green here, there's the ApoB100 protein. There's a very important point here. There's only one of these proteins for every LDL molecule. There is no redundancy. If you break it, it does not work. There's no backup. And if it's working properly, this is the security swipe card that will allow the LDL receptors to recognize it and take it out of circulation. Now, the problem is, the sugar damage actually targets the proteins. It actually targets this. That means the LDL receptor won't be able to recognize this particle. "I don't know who you are. You're not welcome here." Persona non grata. Go away.
So, what happens in that situation? Well, the LDL is coming out of the liver, converted to IDL, LDL. And then the LDL gets damaged. So, that means it's not recognized at these receptors. So, then what happens? It begins to accumulate. Their numbers then increase in the circulation. And this is when we see what's called a high LDL particle count. One thing you need to know, because at the end of their journey, they've donated most of their cargo, so they're quite small. So, the absolute volume of LDL is not necessarily going to be that high, but the number of particles is. And this is why the LDL particle count has quite useful predictive value for heart disease, because it reflects these damaged, small, dense particles that are small and can't be taken out of the circulation.
So, if they can't be taken out of the circulation in a normal, healthy way, what happens to them? Well, they end up here. They line the inside of our arteries. You can see on top of the deposit there, you've got a thin layer of cells. That layer on top is just one cell thick. It's called the endothelium. And this fatty deposit occurs underneath that layer. And we can see from this graph here, so in yellow here, we're graphing oxidized LDL in the circulation. And you can see that an increase in oxidized LDL is what actually precedes the development of this atheroma inside the blood vessel, which we can see in red. As you take the oxidized LDL out of circulation, it ends up deposited in the lining of the blood vessels.
So, how does the LDL actually get through this layer that's one cell thick? Well, oxidized LDL has the effect of increasing the permeability of this layer. That's been shown in a lot of scientific articles. So, if you have oxidized LDL, this membrane becomes a little bit leaky or porous, and the LDL particles are able to travel to the underside of it. And then, once they're underneath, they come in contact with a cell called a macrophage. So, remember how the LDL receptors would only recognize healthy LDL? Well, these macrophages have a receptor called a scavenger receptor that only recognizes damaged LDL. It's quite convenient. They have a very strong affinity for it. So, what they do, the LDL particle binds with the scavenger receptor and it engulfs it, a little bit like Pac-Man. And then eventually, these macrophages end up so full of LDL that we call them foam cells. And here you can see a foam cell with all the lipid droplets inside. And this is the way in which damaged LDL ends up lining the inside of our blood vessels. And this is the end result. This artery here is called the left anterior descending artery. It's the main artery supplying the heart muscle. And it's been injected with dye, so you can see the internal lumen, the diameter of the lumen. And you can see here that's a significant narrowing. And that is caused by LDL that's been damaged by sugar.
And that's why HbA1c is such a brilliant blood test for predicting heart disease, because HbA1c looks at how sugar damages or attaches to the red blood cells. It correlates with high blood glucose levels. And we know that high blood glucose levels are what will also damage our LDL. And that's why diabetics have a significantly higher rate of heart attacks.
Now, for the good news. We can often tell if you're Pattern A or Pattern B based on the standard blood test. Despite the limitations of it and the inherent inaccuracies within it, we still get a lot of very important information. And we often might not need to do any further testing. So, we're going to look at two things. And the first thing we're going to look at is called the triglycerides. So, in this patient here, you can see they've got an abnormal triglyceride, an abnormally low triglyceride, which makes me question the reference ranges. But they've got a high total cholesterol. So, let's have a look at how triglycerides relate to Pattern A and Pattern B.
So, in this paper here, you can see the green line represents Pattern A, and the red line represents Pattern B. The higher the green line, the more likely it is to be a Pattern A cholesterol. The higher the red line, more likely it is to be Pattern B. And along the bottom, you can see the triglyceride levels. In yellow are the units for the UK and Australia, and in blue, they're the units used in the US and in Europe. Now, we can see, if we're looking at the red line, that if our triglycerides are less than 0.5 millimoles per liter, then you're almost certainly going to have a Pattern A phenotype. But if we go down the other side, if your triglycerides are over 2, your chances of having a bad phenotype are very, very high. And remember, in this example we just looked at, they had a level of 0.4. So, they're going to be very, very comfortable.
The other factor that's really useful on this blood test is the HDL level. This is another patient, high total cholesterol and a high HDL cholesterol. Let's have a look at a similar kind of graph for this patient. So, again, we have the good phenotype in green and the Pattern B in red. Except this time, as the number goes higher, it looks better. So, we can see that if your HDL cholesterol, and I use the term loosely, is less than about 0.4, 0.5, you're almost certainly going to have a bad profile. However, if you have over 1.5, you're singing easy. And the one example we just saw, 2.6, doesn't even register on this scale. That's what a ketogenic diet can do.
So, let's have a look at my patient who was denied insurance. And let's have a look at his results on each of these and see how informative that can be. So, his triglycerides is 0.9. That's certainly down the good end. But would you sign off on it? I don't know. There's a gray area. But have a look at his HDL, 1.7. Clearly in the green zone. I didn't need to do any further testing on him. I wasn't worried about his cholesterol levels. Even without doing a sub-fraction, I was confident that he was Pattern A.
Now, there's one more metric that we can use to assess for Pattern A and B, and that's when we use the power of triglyceride and HDL together. And that's when we calculate what's called the triglyceride to HDL ratio. We divide the triglyceride by the HDL. Now, in his case, millimoles per liter, his came out at 0.53. So, let's see where this fits on a similar kind of graph. So, in green, in yellow, remember the Australian units, if it's under 0.8, it's good. So, if his is 0.5, again, he can rest easy. If it was over 1.8, then we would almost certainly have had a Pattern B. And if it's in the intermediate zone, well, that's when we need to think a little bit harder.
So, just for the benefit of some of our international audience, these are very conservative numbers. These are how I interpret the data. And I'm sure there's a lot of other people who could interpret it slightly differently. And I'm probably a bit more conservative than most people. I don't like to leave a lot of room for doubt. But in Australia, if you're under 0.8 in terms of millimoles per liter, well, in the US, if you're under 1.8 with milligrams, then you can probably rest easy.
So, if I'm interpreting a blood test, I'll usually look at the triglycerides. If they're good, happy days. If not, try the HDL. If that's good, excellent. If not, we move on to the triglyceride to HDL ratio. And almost every one of my patients who has been on a ketogenic diet for a sustained period of time will end up having at least one of those figures, usually two or three, looking excellent. And if it's not, then we have to have a bit of a think. And that's an independent, individual decision. Do we do an HbA1c? Do we do a coronary artery calcium score? Do we do lipid sub-fraction? There's a lot of other tests we can do, inflammatory markers, which are also very predictive. And we look at the whole picture. But what you do next should be discussed with your doctor.
Now, we've all heard about the Feldman protocol. So, essentially, what happens is, if you have a very high LDL level on a ketogenic diet, it's been demonstrated quite nicely that if you go on a very high-fat diet for about three days and have a blood test at the end of it, your LDL levels will significantly drop, some would even say plummet. And this is why it comes down to these LDL receptors. Now, these LDL receptors are what actually takes healthy LDL out of the bloodstream. It doesn't work for damaged LDL, remember. It only works for the healthy LDL. And the amount of LDL in the blood has an inverse relationship to the number of receptors. If we have more receptors that are able to take the LDL out of the circulation, then we're going to have less in our circulation. It's only logical.
And interestingly, increasing the amount of calories in our diet, which increases our insulin, actually increases the genetic expression of these LDL receptors. In actual fact, rather than doing a high-fat diet, as with the Feldman protocol, a lesser amount of carbohydrates would probably do exactly the same thing because of a much stronger insulin response. Now, why does it take three days? Well, just because you increase the expression of a gene doesn't mean that you get an instant effect. There's a lot of steps that you need to go through before you end up with the final product, which in this case, is the LDL receptors. And it's this process between genetic upregulation and the final protein synthesis that likely delay explains the three-day delay between when you increase the amount of energy in the diet and the LDL actually falls.
In addition to increasing the number of LDL receptors, insulin also increases the affinity that each of these receptors has for each LDL particle. So, it's an extra benefit. And the reverse of this is also true. We see LDL receptor expression reduced with fasting because it lowers your insulin levels. And this explains why so many people have an elevated LDL compared to normal if they fast for longer than the usual eight or ten hours before their blood test. Fasting will increase your LDL level because your insulin levels will drop, and the number of LDL receptors taking LDL out of the circulation will also drop. That's how it works.
Now, as a little aside, one of the mechanisms of statins, those medications which lower your cholesterol, they actually increase the expression of LDL receptors. And that's something a lot of people don't know about. And that's one of the major mechanisms by which they actually reduce the amount of LDL particles in the circulation. And it's probably understated.
So, to finish, I'd like to conclude a few things. Having a high LDL is not always a bad thing. Having damaged LDL is. And remember, it's not damaged by fat, it's damaged by sugar. High carbohydrate diets and having a high blood glucose level is what will lead to these pathogenic, damaging LDL particles. You can use your triglycerides or you could use HDL to evaluate a blood test to estimate whether it's likely to be Pattern A or Pattern B. And if you have Pattern A, then it's not, it doesn't have any significant association with any increases in cardiovascular risk. And finally, as far as my patient was concerned, if I were the insurance company, I'd sign him up. He looks fantastic. Thank you. [Applause]