The Number We Trust Too Much

The Cause That Isn’t Destiny - Part 3

This is Part 3 of The Cause That Isn’t Destiny, an eight-part series on cholesterol, causality, and the limits of any single measurement to predict an individual’s future.

You can find Part 1 here and Part 2 here in case you missed them.

Let me start by telling you something many people don’t realize when they get their blood lipid results back: LDL cholesterol, which many consider the most important value, is usually not measured directly but is instead based on a guess. The guess is certainly built on professional grounds, so we might want to call it an estimate, but let me be bold and call it what it is: a guess. The sources of error are many. I know this may sound ridiculous, but that’s how it is.

Most laboratories measure total cholesterol, HDL cholesterol, and triglyceride levels in the blood. Then a formula is used that a scientist named William Friedewald put together in 1972. Some laboratories have moved on from Friedewald in recent years and used newer formulas such as Martin-Hopkins and Sampson. These are designed to work better when the original tends to fail. I also have to mention that direct assays that measure LDL cholesterol are available. They are used in some laboratories when triglycerides are very high or when precision is considered important. However, most routine lipid panels still rely on a calculated number, one reason being that it is much less expensive.

The Friedewald formula assumes that the ratio of triglycerides to the cholesterol traveling in so-called VLDL particles is always the same: 5/1 if mg/dL is used, as in the United States, or 2.2/1 if mmol/L is used, as in most other countries.

Most of the time this is a perfectly usable method, and the formula gives a good idea of the amount of LDL cholesterol in the blood. The weakness of the formula reveals itself, however, in individuals who have high levels of triglycerides. At that point, the above ratios can no longer be assumed. If triglycerides are higher than 400 mg/dL (4.5 mmol/L), the formula simply gives up, and most laboratories do not report an LDL cholesterol value under these circumstances.

The formula, in other words, starts to mislead us slowly but surely as triglycerides rise, until it becomes essentially unusable. The weaknesses come out most clearly in individuals with insulin resistance, metabolic syndrome, and type 2 diabetes. This is because high triglyceride levels are most likely to be present in this group, and, as it turns out, so is a mismatch between what the LDL cholesterol number says and what’s actually going on.

It troubles me to say it, but under certain circumstances the LDL cholesterol number we get may be further from reality than most patients, and perhaps some doctors, realize. This becomes even more troubling given that most studies on the effects of lipid-lowering drugs have been based on LDL cholesterol values. I am not thereby saying that all these studies are useless (they certainly are not), but it is unpleasant to think that a better variable was not used as the reference point.

LDL cholesterol tells us how much cholesterol is being carried by LDL particles in the blood. It does not tell us how many particles are handling the transport, only the total amount of cholesterol bound within these particles. This may sound like an insignificant detail, but it is not. It turns out the number of LDL particles matters more for the development and progression of vascular disease than the amount of cholesterol those particles happen to be carrying.

Let’s imagine trucks. One is large and makes a single trip with a full load. The other is a fleet of a hundred smaller vehicles, each carrying a small load. The total cargo may be the same, but there are many more vehicles on the road, and therefore many more opportunities for one of them to end up where it shouldn’t.

Cholesterol particles work in much the same way. A person can have large LDL particles that carry a large amount of cholesterol, or many smaller particles that carry a small amount of cholesterol. The LDL cholesterol value is the same.

Small-dense LDL particles tend to show up in people with insulin resistance, metabolic syndrome, and type 2 diabetes, usually going undetected on a standard blood lipid test — which tells us that the LDL cholesterol value is most likely to mislead us precisely in the patients who have more particles than their LDL cholesterol indicates. It isn’t only that there are more of them, either. Small-dense particles are also individually more dangerous — they bind less readily to the liver’s LDL receptors, which keeps them circulating longer, and they seem to slip into the artery wall more easily than their larger, cholesterol-rich cousins.

There is also something else worth keeping in mind: LDL is not the only lipoprotein that carries cholesterol in the blood. There are others too: HDL, IDL, VLDL, and lipoprotein(a). HDL does not tend to make its way into the vessel wall and promote vascular disease, but the other three all, along with LDL, tend to do exactly that. This is why LDL, IDL, VLDL, and lipoprotein(a) are called atherogenic lipoproteins, but not HDL.

One way to capture the total amount of cholesterol in atherogenic lipoproteins, and not just LDL, is to calculate what is called non-HDL cholesterol. This is done by subtracting HDL cholesterol from total cholesterol. The number we get is the amount of cholesterol traveling in atherogenic lipoproteins (LDL, IDL, VLDL, and lipoprotein(a)). Non-HDL cholesterol turns out to predict cardiovascular disease better than LDL cholesterol, probably because it captures the cholesterol carried by all of these particles, not just the one we’ve been fixated on.

This inevitably raises the question of why HDL is not atherogenic while the other lipoproteins are. The main difference between these particles is that the atherogenic lipoproteins each contain one molecule of a protein called apolipoprotein B (ApoB), while HDL does not. In other words, atherogenic lipoproteins carry a specific marker that can be identified and measured, allowing us to count them.

Hence, we do, in fact, have a way to count the trucks instead of estimating the amount of cargo. Measuring ApoB indicates the number of all atherogenic particles but tells us little about the amount of cholesterol. Of the measures we’ve looked at so far, ApoB is the one with the strongest track record for predicting who develops cardiovascular disease and how it progresses.

ApoB is admittedly not standard equipment at most laboratories, which is a shame, because in patients where LDL cholesterol and particle number disagree (a phenomenon called discordance), it is usually ApoB that turns out to have told the truth.

There is one more character in this play whom we haven’t properly introduced yet. When triglyceride-rich lipoproteins circulating in the blood are broken down by an enzyme called lipoprotein lipase, acting out in the tissues rather than in the liver, they don’t disappear all at once. They shrink into much smaller leftovers, particles very rich in cholesterol, which the liver then clears from circulation. The amount of cholesterol in these can be calculated from a standard lipid panel: total cholesterol minus HDL cholesterol minus LDL cholesterol. That LDL cholesterol, of course, is usually the same calculated, Friedewald-derived number we’ve already spent this chapter picking apart, so this calculation inherits exactly the same weakness.

What remains is often called remnant cholesterol and reflects the amount of cholesterol bound in IDL and VLDL. For a long time, this type of particle wasn’t thought to matter much and was often seen as some kind of background noise. They were just a byproduct of triglyceride metabolism. We later learned that this was completely wrong. Particles carrying remnant cholesterol appear to be an independent risk factor that can matter a great deal, even though we almost never see this value in our blood test results.

Taking all of this into account, it is somewhat strange that we have focused on LDL cholesterol for as long as we have. This is, after all, the value that is often flagged in red, the one the patient photographs and brings home worried, the one we have used to decide whether drug treatment is justified or not.

I am not saying we should throw out this number and disregard it. We do, however, need to know its weaknesses, and the fact that there are other blood lipid values that say much more about a patient’s risk and prognosis.

Measurements of LDL cholesterol have, after all, driven fifty years of research that has saved countless lives. One cannot help but wonder, though, where we would be, and what our knowledge would look like, if we had used more reliable measurements from the start.

There is reason, in other words, to stop treating LDL cholesterol like a photograph of the truth and start treating it as what it is: estimated by a mathematical equation, sometimes useful, sometimes misleading, and sometimes simply nonsense.

Let’s return, one more time, to the woman from the first chapter, the one with the very high LDL cholesterol and the very clean coronary arteries, and to her brother. What is their LDL cholesterol telling us? Much less than we think, and clearly only a small part of the story. This number should never have had to carry the weight it has been made to carry.

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Part 4 - What the Snapshot Misses