What Causes Elevated LDL Particle Number? | Chris Kresser

What Causes Elevated LDL Particle Number?

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To read more about heart disease and cholesterol, check out this eBook on the Diet–Heart Myth.

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—which is what I practice—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 heart health 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.

5 common causes of elevated LDL particle number that can increase your risk of heart disease.Tweet This

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)

Infections

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)

Leaky Gut

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.

Genetics

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.

In the next article in this series, I will debunk the myth that statins extend lifespan in healthy people with no pre-existing heart disease.

240 Comments

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  1. What are all of the cardiology tests that one should ask a physician to do? I am inferring from this discussion:

    Triglycerides
    Total-C
    HDL-P
    HDL-C
    LDL-P (the one I know about is LipoScience NMR LipoProfile test)
    LDL-C (does anyone have an opinion on the Berkeley Heartlab test to graph different LDL particle sizes versus something like the VAP test?)

  2. Hi

    Great article. You are right about all doctors treating symptoms and not root cause.
    I have been having rash/hives recurring issues and saw about 8 doctors (PCP and dermatologists) with no results. Irecently identified a high LDL of 196 which I never had. I used to take niacin and i stopped for 6 months as part of the elimination strategy but I do not think that my LDL goes from 140 to 196 just because of niacin.

    I think i have internal bacerial infection that no one has been able to diagnose.

    Are you local in Reston, Virginia area and if not can you recommend any doctor who does the functional medicine.

    many Thanks,

  3. Great article! After dealing with chronic and intermittent upper abdominal pain for well over six months, my new doctor gave me a battery of blood tests. My SED was 36, my Vitamin D was 16, and my LDL was 127. We are still waiting on the ultrasound results.

    After reading this article, I am intrigued (albeit a smidgen worried) to find out what could be going on. My father had a history of high cholesterol as well.

    Thanks for a great read!

  4. What if the LDL is High, and the non HDL, but overall is not, nor are trglycerides…all Thyroid is normal EXCEPT T3 which is very high…Eosinophls high too. I recently cut all meat, flour and have been raw juicing for at least three months (along with salads, some soups and protein drinks etc)…so I was shocked my bad cholesterol is up. I had EKG, and stress test…heart function looks fine. What do you think of high LDL number in this scenario?

  5. My 21yo daughter who is extremely physically active, within normal weight (135), has very low blood pressure and the diet of an athlete, was just informed that for the second year in a row, her triglycerides and LDL are unusually high. There is no family history of early onset metabolic syndrome. She has had a nodule on her thryoid scanned once (benign) and she currently take Zoloft (150mg) and Birth Control Pills. I had hyperthyroid when I was pregnant with her. Any thoughts ???

  6. Today I listened to your third podcast on high LDL where you discuss the role of the thryoid in LDL uptake (I think) and the impact of low Iodine and Selenium. I have been on a low carb high fat diet since October last year. As it happens I have concentrated on cruciferous veggies AND at the same time have changed from iodised salt to Himalayan rock salt (OK because it was pink and came in a scrunchy shaker – this was not all science). My LDLs are really high at 239 mg/dl (The lab report marked that as ‘measured’). I also had my apo-A1 and apo-B measured which are also high.(1.56 and 1.66 respectively).

    In his ‘straight dope on cholesterol’ series Peter Attia highlights high LDL as a predictor of atherosclerosis so I need to take this seriously. I have not read your response to this but intend to read more of your site in the future.

    I have lost 6 kgs on this diet and am feeling more energy than I have for decades.

    My strategy is to ramp up my iodine slowly as you suggest in the podcast, as well as selenium. I will measure again in two months (all going well) and will then consider the impact of the low carb jolt to which I have subjected my body. I suspect in the long term I will go for a more balanced paleo menu.

    I appreciate the information you are making available here. Medicine for the 21st century indeed!

  7. 1) The “elevated LDL” may not even be elevated, just calculated wrong: “In patients with low serum triglyceride and undesirably high total cholesterol levels, Friedewald equation may overestimate LDL” – http://www.ncbi.nlm.nih.gov/pubmed/18426324

    Friedewald equation: Total – (HDL + [Trigs/5]) = LDL

    There is a newer equation, called the Iranian Equation, that does a better job of calculating LDL when trigs are below 100. That equation is: (Total/1.19) + (Trig/1.9) – (HDL/1.1) -38 = LDL

    2) Having triglycerides under 100 is correlated with Pattern A LDL particle size (the healthier pattern), which also often lead to high measured LDL. – http://www.ncbi.nlm.nih.gov/pubmed/1420088

    3) A paleo-based diet results in low serum triglyceride and high total cholesterol levels, but what matters is the ratio of triglycerides to HDL-cholesterol is what shows strongest association with the extent of coronary disease. – http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2664115/

    • Your post has been helpful. I have been on a paleolithic diet for 8 months now and my ldl is up to 190. So discouraged till I recalculated. It is only 163. My triglycerides are down from 127 to 81. Lost 30 lbs this year.

  8. Chris–

    Although I have not been tested for a genetic cause for my hyperlipidemia, I am almost certain it is genetic in nature, as I fit most of the characteristics (low triglycerides, large LDL particle size but immeasurably high particle number, dad died of second heart attack at the age of 50.) I eat almost entirely paleo and stay very active. It would appear saturated fat intact actually drives my numbers up even higher. What are the treatment options for someone in my situation? Am I one of the unfortunate individuals who might have to resort to statin use?

  9. Interesting that you mention family history as the last one–I bet Bill Clinton would’ve benefited more from this post than the statins, bypasses, and vegetarian diet doctors put him on! Now, he looks like his head is too big for his body because he’s lost so much weight in muscle mass.

    Question concerning thyroid hormones: I told my doctor to test me for thyroid problems because I was freezing to death in a 70 degree room–menopause had come home to roost. She tested me, and said the usual “nothing’s wrong.” What kind of specific test should I have asked her to run besides the usual TSH, T-3 and T-4 tests? Is this something a GP can do, or do I have to see an actual endocrinologist?

  10. I wanted to confirm that LDL-P is not the same thing as Lp(a) which was what was elevated in my cholesterol profile (I don’t see an LDL-P).
    Thanks!

  11. 1.7% of population (119 millions people) have homozygous APOE mutation (4/4) which seriously affects fat metabolism. It is still not clear what would the optimal Paleo version in regards to overall macronutient ratios, fats, sat. fats, and cholesterol foods for these people in order to get high HDL, low LDL and good particle numbers. It would be sooooooooooooooo enlightening to read a detailed science-based post with practical recommendations on this topic!

    • I’m a 3/4. I’m reading an essay by MIT Sr. Research Scientist Stephanie Seneff. http://people.csail.mit.edu/seneff/alzheimers_statins.html. Only IDL contains ApoE but LDL can bind to ApoE and the cell can access its nutrients. People that carry the defect tend to have higher cholesterol levels at a younger age. Her theory is that since there is a defect in the IDL connection LDL will be higher to ensure enough nutrients (fats, cholesterol, etc) are getting to the brain. Maybe LDL is higher and there are more particles to ensure there is enough in the bloodstream for ApoE to grab onto and use. There’s one thing I can say about going Primal. I never thought I would be reading and thoroughly enjoying biochemistry.

  12. I come from a genetic predisposition of diabetes and heart disease on the paternal side. My husbands parents both died of heart attacks at 63 and 62. I found out that my son had high cholesterol at the age of 9 and took the necessary steps with regard to diet. However, both the LDL and HDL lowered with in the same ratio…..the LDL being higer. That did not change. Am I to understand that the particle number is the only thing he should test for to determine his risk of atherosclerosis? Anyone may answer. Thanks!
    BTW my son is now early thirties, healthy on the outside, however, underweight. Tall, very small boned, 71 inches at about 135. Paleo/organic diet for the most part and not much interested in food….same as his Dad.

    • Caette, Chris explains that “…particle number (LDL-P) is a much more accurate predictor of cardiovascular disease risk than either LDL or total cholesterol.” What he is saying is that when LDL-P is measured, studies have correlated the reading with the occurrence of some manifestation of cardiovascular disease. We would have to see the studies to know exactly what the correlation is based on. What matters, I think, is that LDL-P might be measured today and then a problem may show up tomorrow, but it might show up years from now. LDL-P is being used as a leading indicator, to give some warning ahead of time, before the atherosclerosis or other problem shows up, just as you used the “cholesterol” measurements when your son was only 9, and when he probably had no symptoms, to change his diet to try to head off a problem.

      One thing I have already suggest on this series of articles by Chris is to use a different measurement: digital pulsewave analysis. Your son is over 30. Actual signs of damage could be showing up in his circulatory system at this age. It is possible to precisely detect these, including inflexibility, plaque, slow responses to rises in blood pressure – all signs of atherosclerosis. I would say it is more important, if one is actually possibly suffering the symptoms of atherosclerosis, to determine the degree of progression of the disease, rather than to just be testing for a “marker” like LDL, The “marker” has relevance when the disease is not present, because it can give an early warning. But it doesn’t at all measure the disease or the progression of the disease! It only measures an assumed tendency toward the disease.

      It is time now to measure if there is any atherosclerosis. And if there isn’t, to get a baseline measurement of cardiovascular health to measure against if the disease should show up down the road.

      This is all done with a digital pulsewave analysis. It’s very simple, is done with inexpensive equipment, and gives several invaluable measurements in just minutes.

      Here is a video on one manufacturer’s equipment that was reviewed by the news media several years ago:

      http://www.youtube.com/watch?v=Jeh1s-820Pk There are other videos on this on the same page.

      Here is a very complete description of the technology:

      http://sterlinghart.com/?page_id=452

      Good luck with helping your son toward better health.

      • Thank you so much for that valuable info! I forgot to mention too that my father had aortic stenosis and was type one diabetic, beginning heart disease at age 47 and died of a heart attack at 56. His father had his first heart attack at age 40 but lived to 72 at which time he had another. I am very concerned about my son so your note was very much appreciated!

  13. Hi
    can you recommend any books on diet and fitness as i want to lose some weight. I think your website is very informative and cuts through the cr*p.
    i wish you all the best and keep up the good work

  14. I had an ApoB of 1.2 and I’m on a paleo type diet, so started taking 1500 mg of niacin daily.
    ApoB now 0.8 and I’m happy with that.

  15. “Niemann-Pick C1-like 1 protein, which plays a critical role in the intestinal absorption of cholesterol. (3,”

    Your reference “3” links directly to the Apple Home Page. Should I be scared or reassured Apple may have something to say about nutrition? :p

  16. This is great information!

    I do have high LDL particle number -> 2000 and my PCP advised me to start Statins -?? I am not even sure if Statins even address LDL-P.

    However, after reading this, I wonder if its the dormant herpis that is causing this. During winter, pretty every year, I get blisters in my nose, and my PCP said it was herpis and advised acyclovir to treat it.

    Otherwise, I don’t have metabolic syndrome, or any family history of cholesterol. I exercise everyday and on a healthy diet.

    Would to love to see what you think.

    Regards

  17. Hi Chris,
    My son suffered arrhythmia when around 15 with unknown cause. It developed to Sick Sinus Syndrome. He was treated with drug Sotalol for a few years and the he was cleared and drug stopped when he was around 20 years. He is now 34 and leads a normal life. However being slightly obese he is on statins off and on under medical advice.
    Should I presume the statins he takes are superfluous? Would appreciate your comments.

  18. Chris – You mention LDL particles not only carry cholesterol but also trigs, fat soluble vitamins and antioxidants. As the amount of trigs increases this decreases the amount of cholesterol the LDL particle can carry and therefore the production of LDL particles increases. Would high amounts of fat soluble vitamins or antioxidants also reduce the amount of cholesterol an LDL particle could carry and therefore also increase their production?
    Eric

  19. Chris,
    If you had RA and type 1.5 diabetes and had cholesterol of 193, HDL of 60, LDL of 119, and TG of 79, would you consent to taking a statin as my GP and endo doc want me to do? I’ve never had heart issues. 62, 138 lbs, 5’9″, exercise 5 days per week, eat paleo. Have reduced HBA1c from 7.4 to 6.0 and heading south from that based on my daily readings. I plan to get the particle number test. Is red rice yeast a good or bad idea (take methotrexate and Enbrel for RA – read that red yeast rice can be not so good for the liver as a combo with those two).

    Thanks,
    Mark

    • Mark — Both of your conditions are autoimmune in nature. You sound like a very proactive patient (the kind many docs don’t appreciate). I’m not a medical professional but I’m familiar with dealing with them! Do yourself a favor — make up your mind that you want a partner in your health care, and find a doctor, ARNP, or naturopath who specializes in reversing autoimmune diseases. Remember, your body wants to get well — we just have to get out of the way!

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