In the last article in this series, I explained that LDL particle number (LDL-P) is a much more accurate predictor of cardiovascular disease risk than either LDL or total cholesterol. In this article, I’m going to briefly outline the five primary causes of elevated LDL-P.
Conventional medicine is primarily focused on suppressing symptoms. If your blood pressure is high, you take a medication to lower it. If your blood sugar is high, you take a medication to lower it. If your cholesterol is high, you take a medication to lower it. In most cases there is rarely any investigation into why these markers are high in the first place, with the possible exception of some basic (but often incorrect) counseling on diet and exercise.
On the other hand, functional medicine focuses on treating the underlying cause of health problems instead of just suppressing symptoms. If your blood sugar, blood pressure or cholesterol are high, the first question a functional medicine practitioner will ask is “why?” If we can identify the root cause of the problem, and address it at that level, medication is often unnecessary.
To use a simple analogy, if you have weeds in your garden, what happens if you just cut the weeds from the top? They grow right back—and sometimes faster than before! If you really want to get rid of them once and for all, you have to pull them up by their roots.
With this in mind, let’s look at some of the potential causes of elevated LDL particle number. If your LDL-P is high, it makes sense to test for and treat any of the conditions below (with the exception of the last, which is genetic and thus can’t be treated) before—or at least along with—taking pharmaceutical drugs.
Insulin resistance and metabolic syndrome
LDL particles don’t just carry cholesterol; they also carry triglycerides, fat-soluble vitamins and antioxidants. You can think of LDL as a taxi service that delivers important nutrients to the cells and tissues of the body.
As you might expect, there’s a limit to how much “stuff” that each LDL particle can carry. Each LDL particle has a certain number of cholesterol molecules and a certain number of triglycerides. As the number of triglycerides increases, the amount of cholesterol it can carry decreases, and the liver will have to make more LDL particles to carry a given amount of cholesterol around the body. This person will end up with a higher number of LDL particles.
Consider two hypothetical people. Both have an LDL cholesterol level of 130 mg/dL, but one has high triglycerides and the other has low triglycerides. The one with the high triglyceride level will need more LDL particles to transport that same amount of cholesterol around the body than the one with a low triglyceride level.
Numerous studies have found an association between increased LDL particle number, and metabolic syndrome. One study measured ApoB, a marker for LDL particle number, in a group of 1,400 young Finns with no established disease. The participants with the highest LDL particle number were 2.8 times more likely to have metabolic syndrome than those with the lowest levels of LDL-P. (1) A much larger study of over 300,000 men also found a strong association between LDL-P and metabolic syndrome and its components (i.e. insulin resistance, abdominal obesity, high blood pressure, etc.). (2)
Poor thyroid function
Poor thyroid function is another potential cause of elevated particle number. Thyroid hormone has multiple effects on the regulation of lipid production, absorption, and metabolism. It stimulates the expression of HMG-CoA reductase, which is an enzyme in the liver involved in the production of cholesterol. (As a side note, one way that statins work is by inhibiting the HMG-CoA reductase enzyme.) Thyroid hormone also increases the expression of LDL receptors on the surface of cells in the liver and in other tissues. In hypothyroidism, the number of receptors for LDL on cells will be decreased. This leads to reduced clearance of LDL from the blood and thus higher LDL levels. Hypothyroidism may also lead to higher cholesterol by acting on Niemann-Pick C1-like 1 protein, which plays a critical role in the intestinal absorption of cholesterol. (3, 4)
Studies show that LDL particle number is higher even in subclinical hypothyroidism (high TSH with normal T4 and T3), and that LDL particle number will decrease after treatment with thyroid hormone. (5)
Another cause of high cholesterol profile is infection. Multiple studies have shown associations between bacterial infections like Chlamydia pneumoniae and H. pylori, which is the bacterium causes duodenal ulcers, and viral infections like herpes and cytomegalovirus and elevated lipids. (6) For example, H. pylori leads to elevated levels of total cholesterol, LDL cholesterol, lipoprotein (a), ApoB or LDL particle number, and triglyceride concentrations as well as decreased levels of HDL. (7)
Several mechanisms have been proposed to explain the association between infections and elevated blood lipids. Some evidence suggests that viral and bacterial infections directly alter the lipid metabolism of infected cells, and other evidence suggests that lipids increase as a result of the body’s attempt to fight off infection. Other evidence suggests that LDL has antimicrobial properties and is directly involved in inactivating microbial pathogens. This has been confirmed by studies showing that mice with defective LDL receptors—and thus very high levels of LDL—are protected against infection by gram-negative bacteria like H. pylori. (8)
One of the primary functions of the intestinal barrier is to make sure that stuff that belongs in the gut stays in the gut. When this barrier fails, endotoxins such as lipopolysaccharide (LPS) produced by certain species of gut bacteria can enter the bloodstream and provoke an immune response. Part of that immune response involves LDL particles, which as I mentioned above, have an anti-microbial effect. A protein called LPS-binding protein, which circulates with LDL particles, has been shown to reduce the toxic properties of LPS by directly binding to it and removing it from the circulation. (9) Studies have also shown significant increases in LPS-binding protein (and thus LDL particles) in cases of endotoxemia—a condition caused by large amounts of circulating endotoxins. (10)
Though more research is needed in this area, the studies above suggest that a leaky gut could increase the level of LPS and other endotoxins in the blood, and thus increase LDL particle number as a result. I have seen this in my practice. I recently had a patient with high LDL-P and no other risk factors. I tested his gut and discovered H. pylori and small intestine bacterial overgrowth (SIBO). After treating his gut, his LDL-P came down to normal levels.
The final cause of elevated LDL-P is genetics. Familial hypercholesterolemia, or FH, involves a mutation of a gene that codes for the LDL receptor or the gene that codes for apolipoprotein B (ApoB). The LDL receptor sits on the outside of cells; the LDL particle has to attach to the LDL receptor in order to deliver the nutrients it’s carrying and be removed from the circulation. ApoB is the part of the LDL particle that binds to the receptor. If we use a door lock as an analogy, apolipoprotein B would be the key, and the LDL receptor is the lock. They both need to be working properly for LDL to deliver its cargo and to be removed from the bloodstream.
Homozygous carriers of FH have two copies of the mutated gene. This condition is very rare. It affects approximately 1 in a million people. And people that are homozygous for this mutation have extremely high total cholesterol levels, often as high as 1000 mg/dL. And unfortunately they usually die from severe atherosclerosis and heart disease before the age of 25.
Heterozygous carriers, however, only have a single copy of the mutated gene, and the other copy is functioning normally. This is much more common. The prevalence is between 1 in 300 to 1 in 500 people, depending on which study you look at. These heterozygous carriers of FH have total cholesterol levels that often range between 350 and 550 mg/dL, along with very high LDL particle number. They have about three times higher risk of death from heart disease than people without FH if it goes untreated.
It’s important to note that people with FH have primarily large, buoyant LDL particles, and yet are still at much higher risk for cardiovascular disease. While it’s true that small, dense, oxidized LDL particles are more likely to cause atherosclerosis, large, buoyant particles can also be harmful when their concentration is high enough. This is one reason why LDL particle number is a superior marker to LDL particle size.