Saturday, August 27, 2011

The Central Role of Thyroid Hormone in Governing LDL Receptor Activity and the Risk of Heart Disease

by Chris Masterjohn

In "Genes, LDL-Cholesterol Levels, and the Central Role of LDL Receptor Activity in Heart Disease," as well as my most recent presentations at Wise Traditions and AHS, I described the overwhelming genetic evidence for the theory that LDL receptor activity centrally governs the risk of heart disease and the large amount of other evidence from human and animal experiments that offers further support for this theory.

If we look at the factors that govern how many LDL recpetors our cells make, we immediately begin to suspect that thyroid hormone may play a central role in providing immunity to heart disease.



Here is a diagram of the promoter region for the gene that codes the LDL receptor (1):


 
Figure taken from Lopez D, Abisambra Scarras JF, Bedi M, Ness GC.  Activation of the hepatic LDL receptor promoter by thyroid hormone.  Biochim Biophys Acta. 2007;1771(9):1216-25.

If you would like to enlarge the picture, you can do so by clicking on it.

This is a diagram of the promoter region of the rat gene, but the human gene is structured similarly (2).  The arrows point to two parts of the promoter marked "TRE," circled in red.  "TRE" stands for "thyroid response element" and is the name we give to sections of DNA where thyroid hormone and its receptor bind.

In between the two thyroid response elements, we also see a section marked "SRE."  This is a "sterol regulatory element."  It's role is to respond to the level of free cholesterol in the cell.

We can thus see that the cell regulates its expression of the LDL receptor for two reasons.  It cares about its own needs for cholesterol, and it cares about the body's need for bile acids, sex hormones, and other things made from cholesterol.  

If the cell doesn't have enough of its own cholesterol, it communicates this through the sterol regulatory element (SRE).  Once the cell activates this section of DNA, its gene expression machinery will descend upon the gene and begin making LDL receptors.  These will bring cholesterol-rich LDL particles in from the blood and restore the cell's level of cholesterol.

Thyroid hormone, by contrast, is an endocrine hormone. It's job is long-range communication.  Through the brain and some closely related glands, the well-fed body determines that it is in a state of abundance and communicates this to cells using thyroid hormone.  Even if a liver cell or adrenal cell has plenty of cholesterol, thyroid hormone comes with trumpets and fanfare announcing that it's time to collect even more cholesterol so the cell can ramp up its production of bile acids, sex hormones and other goodies.  It binds to its receptor, activates the thyroid response element (TRE), and once again the cell's gene expression machinery descends upon the gene and begins making LDL receptors.

Many cholesterol-lowering drugs such as cholestyramine and the statins work their black magic by lowering the level of free cholesterol in the cell.  The cell reacts to this deficiency by increasing its production of the LDL receptor through the SRE.  More LDL receptors means more LDL-cholesterol will be cleared from the blood in a shorter amount of time, and this will help prevent the oxidation of those LDL particles, which will in turn reduce the burden of atherosclerosis, all things being equal.  But these drugs do nothing to ramp up the level of cholesterol-made goodies to promote strength, proper digestion, virility and fertility.  It is the vocation of thyroid hormone, by contrast, to do both.

Cholestyramine and statins have some nasty side effects, some of which can actually promote heart disease.  Since I've already sold out to the USDA (I hope my overlords don't find this), I don't want anyone to think I'm actually pushing these drugs!

In any case, we could use our map of the LDL receptor promoter region to predict that correcting thyroid hormone deficiency would protect against heart disease.  In fact, decades before we knew anything about the LDL receptor, a physician and medical professor by the name of William Kountz published a clinical trial showing that correcting thyroid hormone deficiency nearly abolished the risk of heart disease (3).

Kountz selected three groups of people with a low basal metabolic rate.  The first group consisted of just under 50 business men with an average age of 55; the second group consisted of just under 200 office patients, some men and some women, with an average age of 61; the third group consisted of poor elderly people with an average age of 67, all of whom were confined to an infirmary and had advanced heart disease. 

Kountz gave all his patients B vitamins, but he gave some of them thyroid extract and let others serve as controls.  He advised both the thyroid-treated patients and the controls to quit smoking and to be "moderate" in their consumption of food and alcohol.  He gave the treated patients just enough thyroid extract to normalize each individual's basal metabolic rate.

Thyroid treatment proved ineffective in the poor elderly infirmary patients with advanced vascular degeneration, but here are the results in the other two groups with less advanced disease:



Thyroid extract reduced the incidence of heart attacks by four-fold in the older office patients and by seven-fold in the younger business men.  Stated another way, it reduced the incidence of heart attacks by 76% among the older office patients and by 85% in the younger business men.  This effect is much more powerful than that seen with any drugs that are currently on the market and suggests that correcting thyroid deficiency may be able to nearly abolish the risk of heart disease if done so early enough.

Kountz published his results in 1951, over two decades before Brown and Goldstein discovered the LDL recpetor pathway.  Thus, Kountz had no way of knowing the role of thyroid hormone in regulating the expression of this receptor, and no way of knowing the critical role of this receptor in governing the risk of heart disease.  He suggested that thyroid hormone was especially protective against degeneration of the media, the layer of the blood vessel that lies behind the intima, where atherosclerosis takes place.  

Thyroid hormone may indeed protect the media from degeneration, but it is difficult not to view his experiments in light of the role we now know thyroid hormone plays in regulating production of the LDL receptor, thus protecting LDL particles from oxidation and thereby preventing the development of intimal atherosclerosis.

Nikolai Anitschkov had identified thyroid hormone as a protective factor decades earlier based on his experience with the cholesterol-fed rabbit model, and this was one of several protective factors he listed in his combination theory of atherosclerosis.   I discussed this theory in my post "The Origin of the Lipid Hypothesis — And Proposal of a New Term."  Anitschkov was truly a man ahead of his time.

It would appear from Kountz's results that thyroid hormone is a central governor of heart disease risk in patients with a low basal metabolic rate.  It also seems that the basal metabolic rate is a good test for identifying people whose risk of heart disease can be nearly abolished merely by boosting thyroid status.  I would then say that in a large sector of the population, the degeneration of lipids in the blood is caused by a form of miscommunication, where the body is in a state of abundance, but it is unable to communicate that message to its cells.  

Read more about the author, Chris Masterjohn, PhD, here.

26 comments:

  1. Your "3" link leads to the Kountz clinical trial Amazon page with a price of $0.01--I got the only one though.

    What is going on in calorie restricted animals? I think they have low temperature and thyroid (and sex) hormones, but their metabolic rate per unit mass is high, and I recall from one study their heat production per cell being high?

    Do obese animals typically have high or low blood thyroid levels?

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  2. You Said, "I would then say that in a large sector of the population, the degeneration of lipids in the blood is caused by a form of miscommunication, where the body is in a state of abundance, but it is unable to communicate that abundance to its cells." Sounds a lot like Leptin resistance. Moreover in the hormone cascade in the body when we have LR we see elevations of reverse T3 ironically. Reverse T is a competitive inhibitor of T3. It also blocks the conversion peripherally of T4 to T3 and completely abolishes the utilization of glucose in a normal fashion. This is also seen in diabetes another disease with huge heart disease risk. This was a good blog Chris and mirrored your discussion at the end of your AHS talk, but I am still wondering out loud why you might think a statin is not a bad idea for someone with FH given this information? I think the critical points need to be maintence of thyroid function to support a good T3 to T4 ratio and absolute control over your HDL levels to improve endocytosis in the portal circulation and thereby decrease the oxidation potential of the general circulation. Clinically, our problem as clinicians is that it is quite risky to try to optimize thyroid function in the face of an elevated T3 with huge amounts of thyroid hormone. It is far better to reverse the high T3 and focus on raising the HDL. Good job at AHS and nice job on this blog. It is a blog every PCP should read but sadly wont. Maximizing HDL also is a topic that needs to be reviewed by most clinicians because the most common ones wont help a patient with FH. The more aggressive options clearly do.....if you know about them. Optimization of Vitamin D, the sex steroid hormones and using a ketogenic diet high in MCT is a start. But making sure the gut microbiome is solid is a huge issue that can be followed by ones trending HDL level. Dr. Kruse

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  3. Do you think a high serum LDL level indicates poor LDL receptor function?

    I ask because I am hypothyroid and have what my doctor regards as a frighteningly high LDL of 217. (That's an estimated value, and since my triglycerides are only 39, I suspect the real value is somewhat lower, but I'm sure still elevated in my doctor's eyes. For what it's worth, my HDL is off the charts high at 157.)

    My longstanding hypothyroidism is treated, but as you know there is controversy about the best way to treat this condition, and I wonder if my lipids indicate the treatment may be suboptimal.

    On the other hand, it seems that LDL and other lipoproteins have multiple functions, including important immune roles, so I wonder if it's really possible to infer what's going on with LDL receptors simply from their levels. Perhaps my high lipids indicate infection, autoimmunity, or something else entirely. Perhaps they mean I will live forever!

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  4. Dr Broda Barnes's book "Hypothyroidism - The Unsuspected Illness" talks quite a lot about how appropriate thyroid levels are protective against heart disease. Dr Barnes died in 1988, so his observations are not confounded by the increased junk carbs in the modern sad. Interestingly, Dr Barnes recommended a high fat diet for weight loss and that dietary protein increased the need for supplemental thyroid hormone in hypothyroid patients.

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  5. Hi Chris,

    How did Kountz determine whether the patients had a low BMR? I'm curious what his method and cutoff were, and what percent of the people he tested were considered to have a low BMR based on his criteria.

    Measuring BMR and normalizing it correctly is not easy.

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  6. Chris,
    Thanks for the great post. Are there any studies showing lower heart disease rates in people with naturally high BMR?

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  7. Hi Chris,

    Thanks for the great post!

    How should we boost our thyroid funcition, and improve the output of thyroid hormone?

    Do we need to go the doctor to get blood work done? Or get specialized tests? I know that my doctor doesn't like asking for more than just TSH. And only if that is abnormal, would he check other stuff like T3 and T4.

    So can you write a followup, or let me know in comments what we should do to improve Thyroid function?

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  9. Chris, I am the FH individual plus Framingham Heart study who attended your session at AHS. Since your session, and at the suggestion of Dr. Kruse, I have tested my thyroid function fully, including negative T3 TSH and antibodies and salivary cortisol. All were well within normal range or negative. My question for you is, given that thyroid function is so important should I walk the line to pushing myself toward hyperthyroidism? I have max'd out my HDL at 80-91 (www.tripleyourhdl.com) and had a 0 CAC score at the age of 45 two years ago. I am happy to experiment with my doctor's supervision, if the risks are low. Any thoughts on what I might suggest?

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  10. The study used thyroid extracts. One of the constituents is calcitonin. Calcitonin reduces blood calcium. Lots of heart disease patients have calcium deposits in their arteries. Could this be a factor?

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  11. http://uk.reuters.com/article/2011/08/26/us-cholesterol-idUKTRE77P53O20110826


    check out this new drug...thoughts?

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  12. Hi Chris: I would echo Stephans comment on what constitutes a low BMR? Also, what would constitute a problem thyroid? My TSH was 1.7, Free t4 1.24(range .89-1.76), and Free T3 2.6(range of 2.3-4.2).
    Appreciate your thoughts

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  13. Chris, a lot of your links from older articles to Weston Price are broken. I hate for people to not be able to find some of those great articles.
    You probably know about the broken links, I'm just bugging you to fix them :)

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  14. I'd also like to know what is considered a low BMR.

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  15. What about having a drop of 2% lugol's solution iodine everyday in a glass of water? Doesn't that make the thyroid run more smoothly?

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  16. Hi everyone,

    Replies are coming soon. In the mean time, this is from Jack Kronk, who had trouble posting here and posted this over at Mother Nature Obeyed.

    =================
    Chris – Jack Kronk here. (from PaleoHacks) Thanks for this write up… a topic I’m quite interested in, obviously. It seems likely that I suffer from poor LDL receptor activity. Could it be that’s what’s causing my HDL to be so low at 40, or is it the reverse of that… that my HDL being so low contributes to the cause of the poor LDL receptor activity, causing mostly small dense LDL?

    Also, what’s the best way for me to test for proper/poor thyroid function? I am finding that testing for certain things is not readily available and it’s pretty frustrating. I live in San Diego so I’d guess that I probably have several good options available to me. Do you know of a certian lab that can test me for Thyroid health? Should I also test for ApoE?

    Thanks Chris!

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  17. Jack Kronk,
    What is your LDL level?
    Knowing your TSH and serum levels of T4 and T3 can be helpfull. The tests for free T4 and T3 are rubbish.
    But you can very easily see if you are hypothyroid or not without doing any tests. Common symptoms of hypothyroidism are low pulse rate (< 70), low temperature, cold hands and feet, orange spots on your palms, and problems with your sleep. Of course, your mood and motivation also depend on thyroid function.
    Hope that helps!

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  18. Hi everyone, first of all, a commenter named Vladimir brought it to my attention on Facebook that in fact Kountz's third group did benefit from thyroid treatment even though it was dramatically less effective in this group. He is right, so I'm going to revise my graph, hopefully tomorrow.

    Now for a few individual responses -- my sincere apologies for the delay.

    Responses to John, Dr. Kruse, Anonymous, Tibbles, Stephan, Jeff, Michael, Gregory, JCarey, Anand, Derian, Steve, d, and Anonymous

    John, I will change the reference tomorrow to a Google Books link or something like that since it is not available on Amazon; thank you for letting me know. There are a lot of adaptations going on with calorie restriction and obesity. For example, in obesity you have a compensatory reaction from the leptin-thyroid axis that attempts to minimize the excess fat accumulation but does so insufficiently to prevent obesity. I'm not sure about caloric restriction, I'd have to look, but in general when you have a flood of free fatty acids, which maybe you have in caloric restriction -- I'm not sure at the moment -- you have inhibition of thyroid hormone at the level of the nuclear receptor but nevertheless an up regulation of UCP in the mitochondria that leads to increased heat production. I'll take a look when I can.

    Dr. Kruse, I agree that leptin resistance and reverse T3 is involved, though I think there are other aspects, for example FFA interfering with T3 binding nuclear receptor. I'm not opposed to a statin for FH; I just think that alternatives should be investigated because there are obvious downsides to statins. On the whole, I think FH is serious enough that it has to be treated even if the treatment is suboptimal, but I'd like to see clinicians push the envelope safely with alternatives. I think to "optimize thyroid function" doesn't necessarily mean to supplement more T4 or T3 or thyroid extract. Removing the interfering signal is the best thing in most cases. Thanks for your comments.

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  19. Anonymous, I think high LDL-C can indicate poor LDL receptor function, especially if accompanied by low HDL-C, but there are too many things that can increase LDL-C to say definitively. I would look into whether you have familial hypercholesterolemia. If not, I doubt your thyroid is being treated properly. Are you on T4? If so, you might want to try adding a small amount of T3 (e.g. cytomel) or switching to a thyroid extract like Armour or Nature-Thryoid, etc.

    Hi Tibbles, thank you for the book reference. Both that book and Solved: The Riddle of Heart Attacks were written in 1976, so Barnes was unable to see the connection to the LDL receptor, but his clinical experience is very valuable and I will write about it in the future.

    Hi Stephan, Kountz used closed circuit measurement of oxygen consumption, and unfortunately his cutoff appears to be "-10" which I believe means 10% lower than a "normal" reference value. If there is a major drawback to this report it is the lack of clarity in some instances, including this one, and including how he divided his subjects. I want to assume he randomly allocated them, but he doesn't state it explicitly. Regardless of how precise his method of identifying low basal metabolic rate and normalizing it, it nevertheless appears that either a) his method was rather superb at identifying people whose risk of heart disease could be nearly abolished by thyroid treatment and his dosing was sufficient to secure this abolition or b) his methods are so faulty they are irrelevant and everyone should be treated with thyroid extract. I'm inclined to believe the former. I'll try to uncover more on Kountz's methodology and other clinical results for future blog posts.

    Hi Jeff, this would be complicated in comparing to Kountz's work because of the methods Kountz used as I just described to Stephan, but it is an interesting question. Of course, it would be greatly confounded by the fact that obesity up regulates metabolism as a compensatory response, but obesity clearly predisposes to CVD. I'll try to look into this for future posts.

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  20. Michael, you're welcome, and thanks! I will address how to optimize thyroid function in future posts. I would get TSH, T3, T4, rT3, thyroid antibodies, and even look at basal temperature a la Barnes's technique. I will definitely followup.

    Hi Gregory, you're welcome. thanks for your suggestions. I will get to these in future blog posts.

    Hi JCarey, it was good meeting you and good to hear from you again. I'm somewhat averse to the idea of experimenting with hyperthyroidism if everything else you can test suggests minimal atherosclerotic burden. I'd rather people in your situation attack clotting, inflammation, and oxidative stress. However, I will say in case you do go this route that the older experiments used, without any knowledge of FH, 1/4 to 2 grains thyroid extract. Deaths were produced in people with 8 or more grains, which was reckless use, and there was no evidence that using up to 2 grains was not safe, to my knowledge, but Barnes suggested working up very slowly for 1/4 grain. Again, I do not think this is advisable if there is no evidence that your high lipid levels are leading to an oxidative burden.

    Anand, I don't know if that is quantitatively important, but it's certainly an interesting point and may be. I will consider that confounder in the future.

    Derian, I don't think we know enough about the PCSK9 mutations to be able to predict potential adverse effects. It seems this might provide an interesting possibility for FH treatment but in virtually all other cases I'd rather see attempts to get at the root of the problem and remove the signals interfering with proper LDL receptor function.

    Hi Steve, Good questions. I'll try to address diagnostics for hypothyroidism in the future. I do not think they can be judged on these tests alone, though they are important.

    d, thank you, I will try to get to those soon. The transition to the new WAPF site was quite a mess.

    Anonymous, that will help if you are deficient in iodine or have a suboptimal intake for your situation.

    Chris

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  21. Oops, I forgot to respond to Jack Kronk!

    Jack,

    Low HDL-C is more likely the result than the cause of poor LDL-R activity. However, there are too many confounding factors so it is not possible to identify a particular cause without verifying it. Worthwhile tests for thyroid function include TSH, free and total T3 and T4, thyroid antibodies, and basal temperature a la Barne's test, but none of these are specific. It may be worth testing free fatty acids. You may want to check healthcheckusa.com if you can't get these tests in other ways. You'd have to test your basal temperature yourself. There are no perfect tests for thyroid function.

    Any other lipid-related tests would of course provide potential reasons for low HDL-C. High CETP activity could be a cause. Many things that would cause low HDL-C would also cause small, dense LDL -- one of the reasons it is mostly redundant to test particle size.

    Chris

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  22. Chris, can you think of any evolutionary reason why high intakes of palmitic acid only suppress LDL receptor activity (ie raise serum LDL-C) when consumed along with a low intake of linoleic acid but they don't do so when linoleic acid intake is above a certain threshold?

    http://apjcn.nhri.org.tw/server/APJCN/Volume11/vol11sup5/S401.pdf

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  23. Quick sketch: 45 y.o. without major medical issues, eating paleodiet for 6 months, VLC x 1 month (mostly meat, fish, butter, eggs, coconut oil, occasional cream, dark chocolate, no grain, no sugar, some veggies and fruit occasionally, but very little carbs overall < 50 grams.

    Good: weight down 185ish to 165ish, body composition much improved, mental health better, sleep better, I feel good!

    LABS: TGs 58, HDL 55, DHEA 5.8, HS-CRP 2.2, cortisol normal, CBC, CMP, TSH all normal, Vitamin D 39.

    What I'm scared about: LDLp increased from 1587 to 3076, sLDLp increased 534 to 869, total cholesterol shot up from 224 to 343, and LDL went from 153 to 276. This change is over 6 months.

    I'm nervous about my LDL and TC. I'm not asking you for specific medical advice, but with someone with labs like this change something?

    Copper problem? Apo E test? Thyroid?

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  24. Dan,

    As a reader of many blogs, I think you may find the advice for your condition (increased LDL) at Perfect Health Diet worthy. In sum, you may be low in copper or too low in carbs (below 50-100 grams net per day and your thyroid levels drop to the point of being unable to clear out LDL, as Masterjohn here shows).

    http://perfecthealthdiet.com/?p=4457

    I had this same phenomenon myself when I went Paleo Atkins for several months (HDLc went from 70 to 90, LDLc went from 70 to 140, trigs 50 to 25). I then added 100 grams carbs from potatoes and/or fruit to my diet, added some kelp supps and now my HDLc is still 90, but my LDLc is now back to about 70. Not as dramatic as you, but I'm young and exercise a lot.

    My personal rec would be to NOT take thyroid hormone until you add back in 50-100 grams of carbs from fruit and or clean starches (white rice, potatoes; not wheat) and make sure your copper intake is 2-4 mg per day (use nutritiondata.com as a guide). For copper, you could supplement desiccated liver if your diet isn't high enough: http://www.radiantlifecatalog.com/product/Radiant-Life-Desiccated-Liver-Capsules/superfoods-supplements. This liver supp will add other good nutrients too, like choline and vitamin A.

    I think you probably are low in copper since, unless you're getting organ meats in your diet, meats and fats are nearly void of it. Your diet also looks likely low in iodine, so add in some kelp supps (200-400 mcg daily).

    If Cu, Iodine, and adding some carbs back in on a daily basis doesn't lower your LDL (concentration and particle number) after a few months, then definitely get your thyroid antibodies and t3, rt3, etc. checked out.

    Just my thoughts, since Chris and others haven't responded.

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  25. Chris
    Listened to your podcast with Chris K and I have read a lot of his and your stuff. I have some basic question about thyroid. If one has had their thyroid removed and has been taking levoxl for the past 15 years, how does that affect t3/t4 conversion. The only number from the doctor is the TSH which is 1.38.
    This leads to a second question about the interaction between thyroid and cholesterol. Actually it is not the total cholesterol 203.
    Hld 58 trig 43 ldl 136
    The problem is small ldl_p 935 which as near as I can tell is the 95th percentile. I am told the numbers are discordant.
    The numbers have been going up for the past five years and I have gradually been getting worse.
    My father who is 88 has had three bypass surgeries since he was 58 (every fifteen years.) Trying to understand what to do

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  26. I have never thought that hyperactive thyroid would also lead to heart problem. This blog really provided me some important information regarding thyroid hormone, thanks for this!

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