What Causes Elevated LDL Particle Number? | Chris Kresser

What Causes Elevated LDL Particle Number?

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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. Hi, I am interested if anyone has gotten their questions replied to? I am doing research on my own challenge which is LDL of 166. Plus, I recently found out I have H. Pylori, so I am on a 14 day antibiotic treatment to try and kill it. Like all you, I strongly want to get my LDL under 100. I am going after my diet and the doc finally convinced me to take Crestor. I am not sure I like the latter. If the administrators of this website know of any studies and/or trials I can look into joining, please respnd. Thank You.

    • I had Cancer, a Heart Attack, and Poly Cystic Kidney Disease.
      The Doctor put me on Metoprolol, Atorvastatin, and Lycenipril. I took the lipo profile test, and it showed that my Genetics causes high production of small dense LDL Particles.
      I found out by the internet how harmful my prescribed medicines are. I decided on my own, without a Doctor, to take high dose Niacin,
      2500-3000 MG a day. I was able to slowly quit all prescribed Medicines, and my Blood pressure is better now than before,
      My Cholesterol readings and ratios are also better than before. My LDL-P has gone down to 827. The Doctors have been giving me bad advice, it’s that simple.

      • Thanks for you information! I am so against taking statins except last resort. Many future issues, nerve damage, etc. possible. I have also started the Niacin (1600 mg/day) and Cholestoff (Plant sterols) twice a day. Numbers came down and doc said to keep up the good work! Thinking raising the Niacin, but was concerned about liver damage. Doc did a liver function and was great. So will begin to raise to +/- 2400 mg/day. Testing again in 3 months.

        • You may be missing the point… cholesterol is not a disease but has natural function/s! To reduce it has been part of a largely refuted theory that high levels cause or associate with heart disease. I have read repeatedly that the only group showing a significant correlation between high cholesterol and heart disease is for middle aged men who had had a previous heart attack!

          Something else is more important than cholesterol at predicting and preventing heart disease and death from it!!

          Research has indicated that CHD is a disease of hardened arteries/ veins and that newer theories and treatments are emerging which promise more significant and effective strategies.

          Taking cholesterol lowering agents misses the point of the CAUSE of ‘high’ levels and as a treatment of only reducing high levels relying only on this protocol ( of lowering High levels of cholesterol) MUST be leaving vulnerability somewhere else in the body.

          • Are you saying that cholesterol, no matter how high is not related to CHD?

            I see all kinds of blogs and articles saying high cholesterol is OK. But they don’t give numbers.

            When I tell one of these guys my LDL went from 100 to 300 when I switched to a high fat/ very low carb diet, then admit that it too high.

  2. Thank you for such great information. I agree that LDL levels are part of the bigger picture when it comes to cardiovascular risk factors.

  3. Hi,

    I’m trying to understand more the link between thyroid function and elevated LDL (and high blood pressure). I know someone whose thyroid was 90% removed after hyperthyroid graves disease, as was the commen practice back then. That person needs to take thyroxin. So, in someone who effectively has no thyroid, is it the t4 or t3 or something else that is required to keep LDL low? Can iodine still help in such a case?

    Also, trying to understand which comes first, high blood pressure, or artherosclerosis. I had logically assumed artherosclerosis came first, causing hardening, and hence inflexible vessels which caused high blood pressure, but some regular health sites seem to say something contradictory to this. I have read about pomegranate being great for reversing artherosclerosis, and I had thought then this might fix high blood pressure, but perhaps not.

    Any insight or suggestions to other links appreciated….
    Helen

    • Hey I had papillary carcinoma in 2007 VA medical facility was my primary doctor after our AI 135. They treated me with 175MCG levothyroxine – I felt horrible for a few years recently moved insurance companies been working on a full work up for the past two years and like VA was saying I’ve got lupus- right after my thyroid was taken out I was hypothyroid and they said my gallbladder was bad so they took that out now my TSH is 9.5 and I say I’ve got lupus- in ANA- six more months to my first daughters graduation I’m just so close- My youngest daughters graduation is two years away I have to make. The doctors don’t know what they’re doing I tell them to look at my T3 and T4 but they won’t listen I’ve changed so many times everybody just starts from the beginning- I was such a strong person before they took my thyroid out sometimes I think they lied about me having cancer- but that’s a bad TSH level talking- having a bit of a tough day but I’ll cheer up tomorrow

      • Oh and the reason why am here my LDL is off the norm- two hi all sorts of weird LDL markers were high- just got a call for blood in urine – hummm

  4. I am 46 y/o. My mothers side of the family (9) siblings; only 2 made it past 60 due to heart or stroke. I am 5’7″ and I am approx 150 lbs. I work out frequently, yoga, bike, etc. Blood work in 2012 shows good “reg” cholesterol #’s, but LDL particle # 1262. May 2014 “reg” cholesterol not great and LDL particle #1697. So I behaved and ate better/exercised more. 9/4/2014 “reg” numbers back great but LDL particle #1761. It went up! The small particle number went from 452 in May to 837. What am I doing wrong? My doctor just wants to put me on a statin and I don’t want that. Please help!!

    • Try High dose Vitamin B3 (Niacin); 2.5 to 3 grams a day, not the slow release kind, and not the no flush kind, Take the kind that causes a Flush. I did and it really works!! You should start out slow, like 50-100 mg tablets, 2-3 times a day and work your tolerance up to 2500 mg to 3000 mg a day. Improves HDL, Cholesterol, Triglycerides, LDL-P, LDL Cholesterol, Blood Pressure. It’ll also help your hair grow, LOL. Also, cut down on Carbs, 50-150 gms a day.

      • Hi i finally found a positive post. thanks i just got back some test and my LDL-p is 1300, and my cholesterol is 245……. BUT MY SMALL LDL-P IS 913 AND THE NORMAL IS 527 AND THIS SCARES ME BECAUSE I DO NOT KNOW WHAT TO DO TO BRING THIS DOWN AND WHAT CAUSED IT WITHIN 5 MONTHS. MY LAST BLOOD WORK NOTHING WAS HIGH OR LOW…

  5. Hello! I just read your article and I do have one question. What happens when HDL is good (74 mg/dl), triglycerides are low (52 mg/dl), lipid levels are low as well, but LDL is high (above 200 mg/dl)? I feel like that LDL level is from another movie, really! Very frustrating because I don’t know if I should worry or not!

  6. Does Apo b automatically rise as woman get older?

    How can I lower my levels and how long does it take with proper nutrition and exercise protocol?

    If I ate high carbs lately (hummus),can it affect Apo b level?

  7. Great info! I’m struggling and seeking guidance regarding my recent cholesterol #’s. I am a 51 y/o menopausal female who is slim, exercises vigorously @3-4x/wk, vegan with little to no sugar or processed food intake, drinks water and green tea only. My trigylcerides are 58 (excellent), HDL is 67 (good) with LDL of 132 (border high). Past 3 years all #s the same except LDL been rising slowly. MD prescribed Rx. I dont take any prescriptions and question this option. If this is genetics I’m not sure what are my options? Any info or suggestions is greatly welcomed

  8. I had a blood test last week and my triglycerides were 62 mg/DL.
    My particle count was 1802.
    Your article states that a high Trigl. will equate to a high LDL-P. Is that true?
    How do I verify the cause of the High LDL-P? If caused by the thyroid, what test is needed?
    Is my only hope of lowering my LDL-P through medication?

  9. My wife dealt with many bouts of sinus infections and was given may doses of antibiotics. She then began having serious gut issues. She switched to a pure paleo eating meats, veggies, butter, coconut oil, etc. things got worse and she eventually was diagnosed with ulcerative colitis earlier this year. They wanted to start here on steroids but she decided to go with a GERD diet with bone broth, cooked carrots and broccoli coconut oils and other GERD foods. She has stopped all grains, sugar, hi carb foods. Trying to stick with It’s been 3-4 months and she has improved greatly. Also her achy hands and feet have stopped aching. Her allergies were gone too. She lost weight and overall the colitis symptoms (mucus and runny stools) and began having regular stools and everything seems to be working right. She has always had higher cholesterol thinking it’s due to FH. Like above the 200’s. she is 49 years old 5’2 120 lbs her BP is like 100/60 and pulse is usually in the 60’s. she is in great shape. She recently had here blood work done so we could see if she had the big fluffy partials. We got the results back and we were very shock.
    Here are the results
    Lipids
    Total 398
    LDL-C 290
    HDL-C 104
    TRI 58
    Non-HDL-C 294

    Particle
    Apo B 198
    LDL-p 3150
    sdLDL-C 65
    SDldl-c 23
    Apo A-1 170
    HDL-P 48.4
    HDL2-C 50
    Apo B:Apo A-1 ratio 1:16
    Lp (a) 22

    Inflamation
    Hs-CRP 0.4
    Lp-PLA 303

    Metabolis
    All were optimal except
    Her free fatty acids were 1.40

    Thyroids
    TSH 1.96
    T4 7.1
    T4 free 1.27
    T3 88

    Were kinda super concerned now.
    I read this article and were thinking its FH and leaky gut
    Could it also be SIBO and or H. pylori.???
    I know you cant answer personal questions but we need some help here and be directed to who we can talk to in the Portland Oregon area.
    HELP!

  10. I am reading my recent labs and have a LDL-P of 2262 and LDL (calculated) 152
    Cholesterol 233
    Small LDL-P 897
    I do have hypo thyroid
    will get tested for h pylori (have had in past) also SIBO will test for
    Heard that it is important to know if you are pattern A or B??
    What are the risks for either or with conjunction to these levels.
    I have never had such high markers in prior labs.
    Thank you!!
    Renee’

    • @Renee

      You should read this

      http://www.lecturepad.org/dayspring/lipidaholics/pdf/LipidaholicsCase291.pdf

      ““Let’s get rid of the nonsense seen all over the internet that atherosclerosis is an inflammatory disease, not a cholesterol disease. That is baloney-with the reality being that it is both. One cannot have atherosclerosis without sterols, predominantly cholesterol being in the artery wall: No cholesterol in arteries – no atherosclerosis. Plenty of folks have no systemic vascular inflammation and have atherosclerotic plaque. However clinicians have no test that measures cholesterol within the plaque – it is measured in the plasma. It is assumed, that if total or LDL-C or non-HDL-C levels are elevated the odds are good that some of that cholesterol will find its way into the arteries, and for sure there, are many studies correlating those measurements with CHD risk. Yet, we have lots of patients with very low TC and LDL-C who get horrific atherosclerosis. We now recognize that the cholesterol usually gains arterial entry as a passenger inside of an apoB-containing lipoprotein (the vast majority of which are LDLs) and the primary factor driving LDL entry into the artery is particle number (LDL-P), not particle cholesterol content (LDL-C). Because the core lipid content of each and every LDL differs (how many cholesterol molecules it traffics) it takes different numbers of LDLs to traffic a given number of cholesterol molecules: the more depleted an LDL is of cholesterol, the more particles (LDL-P) it will take to carry a given cholesterol mass (LDL-C). The usual causes of cholesterol depleted particles are that the particles are small or they are TG-rich and thus have less room to carry cholesterol molecules. Who has small LDLs or TG-rich LDL’s? – insulin resistant patients! After particle number endothelial integrity is certainly related to atherogenic particle entry: inflamed endothelia have inter-cellular gaps and express receptors that facilitate apoB-particle entry. So the worse scenario is to have both high apoB andan inflamed dysfunctional endothelium. Is it better to have no inflammation in the endothelium – of course! But make no mistake the driving force of atherogenesis is entry of apoB particles and that force is driven primarily by particle number not arterial wall inflammation.”

  11. Charles…read the Dr. Davis blog….seems like a very common sense physician. Thanks.

  12. @david gary

    What was your LP-IR score on the NMR test?

    As to niacin – Dr William Davis – Track Your Plaque – is a big believer in SloNiacin at doses of 500-1500mgs/day – you might do some research on that

    Aspirin for LP(a) has some validity

    http://www.clinchem.org/content/48/9/1454.full

    I would combine both of your doctors advice – they both have some good points

    Here’s a post by Dr Davis on Treating Lipoprotein(a)
    http://www.healthcentral.com/heart-disease/c/1435/44295/lipoprotein/

    Have you had a thyroid panel done?
    Have you have your Vit D levels checked?

  13. @david gary

    IMHO – your lipid profile is excellent with the exception of the high lp(a) which is genetic in nature – did your doctor give you a valid reason for switching to paleo which will probably elevate very lipid marker you have?

    The only suggestion I can make is to investigate the Pauling Protocol

    http://www.drlam.com/opinion/Lp%28a%29.asp

    • Thanks for your comment Charles. The mixed result physician says because I restrict my fats to 10-15 percent per the Ornish theory, I eat too many carbs which raises my LP(a).
      He feels I need more fats and a lot less carbs. He feels these LP(a) particles are a serious problem. BTW… my insulin level was reported as optimal on the NMR, my A1C was 5.4, my fasting blood sugar was 86, and all my inflammation and cardiac stress markers were reported as optimal. I lost 50+ pounds over 2 years using the Ornish model and greatly improved my lipid results and am reluctant to alter my methods.

        • Charles….

          Thanks again for your comment. I will certainly read the links you provided.

          My PCP has told me that the LP(a) is mostly genetic, but did have me start using an 81 mg aspirin a day as one study showed it affected LP(a) to a 20% degree. He believes the best way for me to manage my risk is to keep the LDL_C low and the particle number low and do what we can on the LP(a). He is not a big believer in Niacin use due to side effects especially so in my case because my overall lipid profile was in his words “excellent” and I have modified lifestyle factors considerably over 2 years. My other doc feels more should be attempted to lower the LP(a) such as niacin use and increasing fats which he says may favorably impact the LP(a). It has gotten a little confusing honestly as I am just a layman, trying to be as wise/informed as I can in making choices.

      • NMR Lipoprofile does not measure insulin levels?

        Remember you can have a very good A1C level and be very insulin resistant and have persistently high insulin levels. Cardiac disease risk tracks to the high insulin levels, and those are never measured in a time series except during a glucose-insulin challenge test.

        • Thanks for the comment Pone. I am not as well versed as many who post here. Relative to insulin my NMR test reported an insulin test result of 7 with an optimal range being 3-9. Perhaps I do not understand what that means. I have not done a challenge, but will raise that issue with my PCP.

          • David, it gets complicated.

            First, it looks like the good people at NMR Lipoprofile created their own proprietary metric, and very inappropriately called it the LP-IR. In fact they never measured insulin at all. It looks like they are simply inferring that the reason for a bad LDL-P reading is because you are insulin resistant. But that’s patently false. There are many other reasons you can have high LDL-P, such as familial hypercholesterolemia or bacteria or viruses. I wish they would not have named their internal metric by insulin resistance, because it isn’t a direct measure of that.

            Regarding your one-time reading of insulin at 7, unfortunately that doesn’t mean anything. When you are in a fasted state, insulin travels up and down in patterns that resemble big sine waves. Taking one static reading doesn’t tell us much.

            What’s more useful is to see how your insulin responds to a glucose challenge. Can you ask your doctor for a “glucose-insulin challenge test” and make sure you tell him “I do NOT want just a glucose challenge. I want them to record both the glucose and the insulin reading together, at each point during the test.”

            The above test would show more clearly if you have a very large insulin response to glucose that your body doesn’t respond to appropriately (insulin resistance).

            • Thanks for the explanation. You have a great point. I will ask my PCP about the glucose-insulin challenge. I am learning day by day.

  14. Just had NMR… TC 121, LDL 59, TG 100, HDL 42, Particle number 832, APOB/APOA ratio .39, CRP .5, LP(a) was high 161—one doc says excellent another says very mixed….have been on Ornish program for 2 years….mixe doc says it is not a good program…prefers Paleo…Thoughts?

  15. Anthony.

    I am kind of like you same build and age . My LDL- p is 1883 ans as you also I didn’t fast before blood work

  16. What if the patient is prediabetic, insulin resistant, but has low triglycerides? Would low triglycerides alone rule out metabolic syndrome as the cause for high LDL particle counts?

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