What the Snapshot Misses
The Cause That Isn’t Destiny - Part 4
This is Part 4 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, Part 2 here, and Part 3 here in case you missed them.
Very few people have never heard of cholesterol, and most associate it with something bad. Unfortunately, this is partly based on a misunderstanding, since cholesterol is one of the body’s most important building materials. Yet this is the message we in the medical profession have managed to sow among those who are not specialists in the field.
We often have a particular image in mind when we think about cholesterol and heart disease. Many of us picture thick, yellow cholesterol chunks clogging arteries like sludge in a pipe, but that's far from the truth. Arteries are living tissue, constantly responding to their environment and to signals from the endocrine and nervous systems. Atherogenic lipoprotein particles (those containing ApoB) often move out of the blood and into the artery wall. Most simply leave again, but not all. It's the ones that stay behind that tend to cause trouble. Once inside the arterial wall, the particle can get caught there. Proteoglycan molecules bind to its surface, rather like a burr catching in wool, leaving the particle trapped within the wall.
Today it’s pretty well established that ApoB particles retained in the vessel wall are a key event in the initiation of the atherosclerotic process. Once retained, the particles undergo chemical changes such as oxidation. White blood cells called monocytes are then drawn to the area, and once inside the vessel wall, they become macrophages that take up the altered lipoprotein particles. Over time these cells accumulate large amounts of the cholesterol the particles carry, since ferrying cholesterol through the bloodstream is one of the particles’ main functions. Under these conditions, the macrophages take on a distinctive appearance and are called foam cells.
This process isn’t particularly controversial today. The question that burns on my lips, though, is why it advances rapidly in one person and barely at all in another, sometimes even between two people from the same family. What drives this process forward, and what holds it back?
To understand this, we need to look at our most important metabolic organ, the liver, and at research two young scientists in Texas began more than fifty years ago.
In the early 1970s, two young scientists, Michael Brown and Joseph Goldstein, were working at the University of Texas Southwestern. They had noticed a small group of patients with extraordinarily high LDL cholesterol, almost as if it were a typo: 600 or 700 mg/dL, roughly 15.5 to 18 mmol/L, many times higher than most doctors ever see in daily practice. These patients often had cholesterol deposits in the skin, tendons, and around the eyes. Some developed coronary artery disease at a very young age, and many did not live to adulthood.
The condition was named familial hypercholesterolemia, or FH, since it turned out to involve a very strong genetic component. Brown and Goldstein wanted to know what lay behind it: what caused these high LDL cholesterol values that seemed to be the key to severe, early-onset arterial disease. Their findings changed our understanding of cholesterol metabolism.
On the surface of our cells are proteins that capture and bind LDL particles traveling through the bloodstream and ensure they enter the cell. Proteins of this kind are called receptors. Brown and Goldstein isolated and characterized the LDL receptor, which turned out to be a key factor in the regulation of blood cholesterol.
Liver cells play a central role in this work. LDL particles bind to receptors on liver cells and are thereby removed from the circulation. The cholesterol they carried is used, stored, or processed further, while the particle itself is cleared from the bloodstream.
This is an important point to keep in mind, because we have traditionally been taught that diet is the biggest factor that determines blood cholesterol levels. In fact, it is determined mainly by how efficiently the liver removes LDL particles from the blood, and the LDL receptor plays a key role in that process.
In patients with FH, liver cells have impaired LDL-clearing capacity because LDL receptors are absent, too few, or not functioning properly. There are two main forms of the disease. In homozygous FH, both inherited copies involved in the LDL receptor pathway are defective, and LDL cholesterol is usually extraordinarily high from birth. Signs of atherosclerosis are often detected as early as childhood, and it can progress rapidly during adolescence, leading to serious coronary disease from the early twenties onward unless lipid-lowering treatment is started. The heterozygous form of the disease is far more common, found in roughly 1 in every 250 to 500 people. Here, only one mutated gene is present, and LDL cholesterol usually falls in the range of 200–400 mg/dL (5.2–10.3 mmol/L), though individual variation is considerable.
In both forms, the liver removes fewer LDL particles from the blood than it should. These particles accumulate in the blood, and with them the LDL cholesterol level rises, which is, after all, the number we’ve always decided to focus on. The result is that artery walls are exposed to a greatly increased number of LDL particles from birth onward.
Brown and Goldstein received the Nobel Prize in 1985. Their research showed how the body regulates the number of LDL particles in our blood, and what can happen when this critical clearance system fails. They left it to others to answer why particles that continue circulating in the bloodstream sometimes become trapped in the artery wall, and why some people can live their entire lives with a high number of LDL particles without ever developing arterial disease.
FH gives us fairly strong evidence that a high number of LDL particles from birth is likely to cause severe coronary disease at an early age, and in the most severe cases the connection is striking.
But as so often happens, nature surprises us here too. Not all people with FH are alike, and some develop far less atherosclerosis than others. Although the endothelium’s exposure to LDL particles is a key factor, other things matter too: endothelial function, blood pressure, smoking, metabolism, and inflammation all strongly influence whether arterial disease actually develops.
Most people with high LDL cholesterol don’t have a single, easily identifiable genetic defect. For many, it’s a matter of a complex combination of common genetic variants together with environmental factors such as diet, exercise, metabolism, and other influences.
Professional advice is directed mostly at this much larger group. “You need to change your diet” is usually the first thing said to someone with high LDL cholesterol, and it’s worth asking what evidence actually stands behind that instruction. Let’s consider two questions. The first: what diet should we adopt to lower LDL cholesterol? The second: will such a reduction actually slow atherosclerosis and lower the risk of cardiovascular disease?
It's clear that dietary composition affects LDL cholesterol. Replacing saturated fat with unsaturated fat lowers it. So do things like fiber, plant sterols, and weight loss in people carrying excess weight.
These are two entirely different questions, but they are unfortunately often conflated, which creates a great deal of misunderstanding, since people frequently aren’t even talking about the same thing. It is, however, quite clear that diet is a tool that can be used to influence LDL cholesterol, and everyone has access to it. The same cannot be said of a genetic mutation determined at conception. That will never change.
That a dietary change lowers LDL cholesterol is one finding. Whether that particular dietary change actually prevents heart attacks, strokes, or death is an entirely different matter, and a hugely important question in its own right. I won't try to answer it here — I'll set it aside for later.
It's no wonder people are afraid of high numbers, given what we've taught them over the years. Say we're sitting across from someone with high LDL cholesterol and have to explain what's behind it and whether it matters. The main thing, though, is to grasp right away that the number can reflect many different underlying factors, and it doesn't mean the same thing for everyone. Sometimes the number is mainly signaling genetic influence. In other cases, we're seeing the effects of lifestyle, diet, exercise, and metabolism. Often the result is a mix of both.
Let's now revisit the woman from Chapter 1 and her brother. We don't know what her LDL receptors are doing. LDL cholesterol above 200 mg/dL (5.2 mmol/L) may be consistent with heterozygous FH, polygenic hypercholesterolemia, or other metabolic or LDL clearance abnormalities. Nor do we know what her LDL cholesterol was at twenty, forty, or sixty. Even if we had access to results from repeated measurements over decades, they would still only give us an approximation of her arterial wall's total exposure to LDL. Nor would these measurements tell us anything about whether these LDL particles had actually entered the artery wall and become lodged there. The imaging studies she underwent, however, showed no signs of atherosclerosis, which suggests that LDL particles did not lead to the development of coronary disease.
Turning to her brother: the LDL cholesterol value we gave him in this story is a single value at a single point in a life that ended at fifty-two. It can’t tell us much about his LDL exposure in the years before that, though it is a clue of its own kind.
It’s very important for us to understand the difference between a single LDL cholesterol reading and our arteries’ exposure to a high or low number of LDL particles over a long period. The number printed on the lab report doesn’t tell the whole story. The artery wall has to experience particles arriving, leaving, or becoming trapped, day after day, year after year. In patients with FH, this may be obvious, since the exposure begins early in life and lasts a long time. For the rest of us, the overall picture is far less clear.
The story of the receptor does, of course, strengthen the case that LDL is involved in atherosclerosis. But it also tells us that a single LDL cholesterol measurement says little or nothing about what has happened inside a person’s artery walls over decades.
I'm not claiming that the number that appears on the lab report is useless. It is, however, just one moment in a long process, and should be interpreted as such.
FH has taught us that time is the key factor. How long the artery wall has been exposed to a high number of LDL particles is often what matters most. What FH cannot explain is why two people with seemingly similar exposure over an equally long time can sometimes end up with very different arteries.
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