Low T3 syndrome III: Inflammation Strikes Again

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This article is part of a special report on Thyroid Disorders. To see the other articles in this series, click here.

In the last article in this series we discussed some common myths and misconceptions about Low T3 Syndrome. In this article, we’re going to look at causes and mechanisms.

As I mentioned briefly before, researchers now believe that the fall in T3 seen in acute and chronic illness is most likely due to either impaired production of T3 in the thyroid (due to a change in the hypothalamic-pituitary-thyroid axis) or to a decrease in thyroid binding proteins. Both of these changes are caused by inflammation.

The thyroid set point

There’s been a lot of discussion recently in the blogosphere about the body fat set point, which is the complex neurobiological system that regulates weight. However, there is also a set point of the hypothalamic-pituitary-thyroid (HPT) axis that regulates the production of endocrine hormones, including TSH, T4 and T3.

It seems that the low TSH associated with illness, or the failure of TSH to rise in response to low T4 and T3, is caused by alterations in the set point of the HPT axis. There’s a set of neurons in the paraventricular nucleus (PVN) of the hypothalamus that is responsible for promoting TSH synthesis in the pituitary and regulating thyroid hormone synthesis.(1)

Post-mortem samples from patients who died after prolonged illness show a decrease of thyrotropin-releasing hormone (TRH) gene expression in the PVN.(2) Moreover, administering TRH and growth-hormone (GH) secretogogues to patients with prolonged illness at least partially restores TSH, T4 and T3 levels.(3) Both of these lines of evidence suggest that a change in the HPT axis is involved in the Low T3 Syndrome.

While there are multiple causes of such changes in the HPT axis, two of the more clinically relevant ones are inflammation and either a decline in serum leptin levels or leptin resistance.

Inflammatory cytokines released in the acute phase response (the inflammatory process) suppress the production of TRH in the PVN.(4) I’ll discuss the role of inflammation in more detail below.

Fasting or diminished calorie intake due to prolonged illness leads to decreased T3 levels, and this is thought to be mediated by a decrease in circulating leptin. Leptin prevents certain neurons (NPY/AgRP) from inhibiting TRH gene expression.(5)

Although I haven’t seen any studies on this specifically, it’s entirely conceivable that leptin resistance (which characterizes obesity) could have the same T3 decreasing effect. Most people are aware that poor thyroid function contributes to weight gain, but this mechanism suggests that it may also work in reverse: leptin resistance associated with overweight and obesity may contribute to poor thyroid function.

Thyroid binding proteins

When thyroid hormone is produced and released into the circulation by the thyroid gland, it’s bound (reversibly) to thyroxine-binding globulin (TBG), transthyretin and albumin. TBG is the major binding protein in humans, and under normal circumstances, less than 0.05% of thyroid hormone is unbound (“free”) in the blood.

It’s thought that only this tiny fraction of “free” thyroid hormone is able to enter the cell and perform the biological actions of thyroid hormone. This means that the concentration of total T4 and T3 (produced by the thyroid gland) is heavily dependent on the concentration of these binding proteins, while the free hormone concentrations are largely independent of them.

In Low T3 Syndrome, the concentration of thyroid binding proteins decreases as a consequence of the “acute phase response” (a.k.a. inflammation). For example, TBG levels decrease by as much as 60 percent in the 12 hours following bypass surgery.(6) In rodents, inflammation leads to a significant decrease in transthyretin, which is the major plasma thyroid hormone binding-protein in that species.(7) The fall in these binding proteins is probably what accounts for the decrease in total (protein-bound) T4 and T3 levels in acute and chronic illness.

Inflammation strikes again

Pro-inflammatory cytokines, which are chemical messengers involved in the inflammatory response, have been shown to contribute to Low T3 Syndrome in multiple ways.

Interleukin-6 (IL-6) is positively correlated with reverse T3 (an inactive form of T3) and negatively correlated with free T3.(8) In other words, the more IL-6 that is circulating in your blood, the less active thyroid hormone you’ll have available to your cells and tissues.

Administration of tumor necrosis factor alpha (TNF-alpha) to healthy individuals produces changes in thyroid hormones characteristic of Low T3 Syndrome.(9)

Administration of interferon alfa (IFN) to normal volunteers results in a decrease in T3 and TSH and a rise in reverse T3.(10)

Other studies have shown that lipopolysaccharide (LPS), a bacterial endotoxin, can downregulate TSH, T4 and T3 levels.(11) This explains the link between chronic bacterial infections and the Low T3 Syndrome, and it’s yet another connection between gut health and the thyroid (since many people with poor gut health have gut infections).

The takeaway of this article is that the primary mechanisms of Low T3 Syndrome are mediated by inflammation. That inflammation could be caused by an infection, autoimmune disease, obesity, diabetes or other chronic illness. Just about any disease you can think of is characterized by inflammation, so the list here is quite long.

In the next article I’ll discuss how – and if – Low T3 Syndrome should be treated.

Articles in this series:

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Comments Join the Conversation

  1. says

    Hi Chris,

    This is a really interesting series. I haven’t looked at these papers myself, so perhaps you have a good answer for this.

    In the last section, you provide compelling evidence that inflammatory markers actually decrease the total pool of T3 by making less of it available for use, either by increasing conversion to reverse T3 or decreasing initial production of T4 and T3.

    However, is it not possible that in the case of acute illness, we are witnessing an increased utilization of T3? If the illness lowers binding proteins, shouldn’t that make more of it available as free? We have to remember that when we take a serum sample we are looking at a snapshot that was taken of a process in motion. What is the serum half life of free versus bound T3? If free T3 quickly enters the cell (which seems the view you are presenting), then it seems likely that once T3 is freed it will not stay in the blood very long. Thus, if more free T3 is mobilized from the binding protein and makes it into the cell, the “snapshot” may be a large decrease in bound T3 and no change in free T3.

    In other words, say you are filling up your gas tank. Free T3 is analogous to the gasoline passing through the nozzle at any given point. The cell is the car’s gas tank and the binding protein is the gas station’s total reserve. If you were able to monitor the gasoline in all three compartments as you filled up your tank, you would watch it rise in your car’s gas tank, fall in the station’s reserve, but you would see no change in the amount flowing through the nozzle (free T3).

    So my question is this: is it possible that the acute phase response is quite different from what we see in chronic inflammation? Is there an effort to utilize more T3 in the fight against illness?

    Chris

  2. Chris Kresser says

    Great question, Chris. I do think the changes that happen in the acute phase response are different than those that occur in chronic inflammation. In some patients with chronic illness, a desialylated form of TBG is synthesized by the liver that has only 10% of the affinity for thyroid hormone of normal TBG. This causes a similar fall in circulating total thyroid hormones in chronic illness to what is seen in the acute phase response.

    My understanding from what I’ve read is that free thyroid hormone levels do change in acute NTIS, but the changes are much more modest than those seen in total thyroid hormone levels (d/t the decline in TBG) – especially when more reliable methods for testing FT4 and FT3 are used, as I pointed out in the last post.

    Then there’s THR function to consider. It appears that THR expression is decreased in acute illness, but increased in chronic illness. That adds another wrinkle to the mix, because of course thyroid hormone action is largely dependent upon binding to THRs. If the gas cap is still on, no free T3 can get into the tank! This argues against the idea that the body is attempting to utilize more T3 in the fight against acute illness, but may do so in the case of chronic illness.

    It starts to get pretty complex, and I don’t feel like I fully grasp all of the nuances and connections yet.

  3. Chris Kresser says

    BTW, another interesting mechanism that I’m going to cover in the next post is autoimmune hypopituitarism. This occurs in up to 40% (!!) of Hashimoto’s patients and causes damage to the pituitary, which in turn leads to deficiencies in ACTH, TSH, FSH/LH, GH and prolactin. One of the hallmarks of this condition is atrophy of the gonads, adrenals and thyroid glands, because if the pituitary isn’t stimulating them, they shrink under the lesser workload. I think this may explain, at least in part, why people with Hashimoto’s tend to have adrenal and other hormone imbalances.

    • says

      I know someone with autoimmune hypopituitarism and I wouldn’t want to be in their situation – it is devastating having to replace and balance so many hormones manually.

  4. David says

    If autoimmune hypopituitarism and inflammatory cytokines like IL-6 are involved in low T3 syndrome, do you think that a therapy like low-dose naltrexone would be helpful in getting things back on the right track, given how beta-endorphins can down-regulate cytokines like IL-6, as well as balance out the Th1/Th2 response?

  5. KenG says

    Hi Chris,

    How can the systemic inflammatory ‘load’, for lack of a better phrase, be measured? I am a general dentist with a particular interest in endodontics (root canals). We know that teeth with necrotic pulps, or inflammed pulps, create some level of inflammatory challenge. How does this measure up quantitatively to “dietary” inflammation? To inflammation in the gut for instance? Much is made of the inflammatory component of gum diseases as well. Again, what I struggle to understand is the relative measure of these inflammatory burdens. In other words, are the dental concerns, such as a low grade chronically inflamed single tooth, or a very mild gingivitis, creating a larger systemic burden than dietary choices? Or is it likely the other way around, where inflammatory gut and vascular loads are by far of greater significance? Any comment appreciated.
    Thanks,
    Ken

    • says

      kenG you can order highly sensitive crp, serum ferritin level to globally assess inflammation. Another moremindirect way is to look at the patients last chemistry panel and look at the CO2 level. When it is below 24 this signifies more oxidation at the mitochondrial level assuming there is no massive acid base issues present. Its not a great individual test but sometimes helps fill out the clinical picture when you see bad thyroid numbers, low vitamin d levels, and low dhea s and sex steroids too.

      • KenG says

        Thanks Jack. I wonder if anyone has attempted to correlate those tests with periodontal and endodontic status of patients. Would be very interesting. Right now, some dentists use the correlation to imply causation and patients con often misunderstand the implications. Truth is, as dentists, we really don’t have a clear picture of the relative importance of dentally related inflammation compared to other sources of systemic inflammation.
        Thanks for the reply.

  6. says

    Hi Chris -
    I have the antibodies for Hashimoto’s but seem to have discovered the primal/paleo lifestyle before too much damage has been done. I am gluten-free and have realized that I probably need to be casein-free as well and have added that. I blog about all of this and many women come to my site for Hashimoto’s support.
    Would you be open to putting together a primer of steps for someone who was trying to work their way out of Hashimoto’s symptoms? (If you haven’t already. If you have, please refer me to where to go on your site…) It is tough for many (myself included at times) to know all that should be done and what the best order is for tackling things.
    I love this intricate science stuff, but I also appreciate just knowing the simple steps laid out for me.
    Thanks! PS – Enjoy your blog! :)

    • says

      If you have not already heard of Sarah Wilson, I have included a link to her blog – she does a whole special section on Hashi’s b/c she has it! I have learned some very practical tips from reading her articles (i.e.How I handle crappy/thyroidy days and similar posts). The biggest tip I took away that has helped my Hashi’s is to stop pushing and go into recovery mode as soon as I start to feel bad, instead of waiting to bottom out. Now, I can usually turn it around in a day or so, where it used to be a week. She has recently started to shift a bit from from WAP to Paleo, which is also nice to see. All the best to you!

      http://www.sarahwilson.com.au/category/autoimmune/

    • says

      Chris -

      Thanks for your recent podcast where you detailed a step-by-step for individuals trying to deal with Hashimoto’s. I know it is a complex problem, but you did a great job highlighting a path for people to get started…

  7. Adam says

    Chris,

    Would you classify low T3, high rT3, normal T4 and normal TSH brought about by VLC as Low T3 Syndrome?

    Thanks,

    Adam.

  8. says

    Chris I thought you might be interested in this article considering the questions raised by Chris Masterjohn. I also think the leptin receptor neurons in the PVN and Arcutate nucleus (described by Dr Myers) have major effects on the neuroplasticity of these circuits and direct control over them I might add. I touched on them in my central leptin series. Here is the paper you might like as you develop your series. I am enjoying seeing you get into the brain in this series.

    Astapova I, Vella KR, Ramadoss P, et al. The Nuclear Receptor Corepressor (NCoR) Controls Thyroid Hormone Sensitivity and the Set Point of the Hypothalamic-Pituitary-Thyroid Axis. Mol Endocrinol:me.2010-0462. The Nuclear Receptor Corepressor (NCoR) Controls Thyroid Hormone Sensitivity and the Set Point of the Hypothalamic-Pituitary-Thyroid Axis — Astapova et al., 10.1210/me.2010-0462 — Molecular Endocrinology

    The role of nuclear receptor corepressor (NCoR) in thyroid hormone (TH) action has been difficult to discern because global deletion of NCoR is embryonic lethal. To circumvent this, we developed mice that globally express a modified NCoR protein (NCoR{Delta}ID) that cannot be recruited to the thyroid hormone receptor (TR). These mice present with low serum T4 and T3 concentrations accompanied by normal TSH levels, suggesting central hypothyroidism. However, they grow normally and have increased energy expenditure and normal or elevated TR-target gene expression across multiple tissues, which is not consistent with hypothyroidism. Although these findings imply an increased peripheral sensitivity to TH, the hypothalamic-pituitary-thyroid axis is not more sensitive to acute changes in TH concentrations but appears to be reset to recognize the reduced TH levels as normal. Furthermore, the thyroid gland itself, although normal in size, has reduced levels of nonthyroglobulin-bound T4 and T3 and demonstrates decreased responsiveness to TSH. Thus, the TR-NCoR interaction controls systemic TH sensitivity as well as the set point at all levels of the hypothalamic-pituitary-thyroid axis. These findings suggest that NCoR levels could alter cell-specific TH action that would not be reflected by the serum TSH.

  9. Richard Furr says

    I’m definitely looking forward to some practical HOW TO FIX information that ACTUALLY WORKS. All this theory is cool, but basically useless unless it can be effectively implemented to achieve results.

    • Chris Kresser says

      Richard, it sure would be nice if I could give simple, practical information about treating a vastly complex, multi-systems condition like Low T3 Syndrome. Unfortunately, that is not possible because of the nature of the disease. It’s caused by inflammation, and inflammation itself could have any number of causes – ranging from autoimmune disease to gut infections. The human body is complex, and so is chronic illness.

  10. Mario Iwakura says

    Hi Chris,

    Some toughts.

    First, I think that we have to distinguish between cause and effect: is chronic low inflammation a cause or simple a body healing process? Of course, if inflammation goes out of control it could be a secondary cause of disease.

    Second, the low T3, high rT3 syndrome seen in chronic infections and some diseases could be a body healling process too. When you are sick, your appetite is generally supressed, leading to starvation, which helps the body to heal. The same could be occurring in low T3 syndrome: starvation mode.

  11. William Trumbower MD says

    In my practice, I use the freeT3/reverse T3 ratio to help determine the metabolic state. 20 is ideal, but I rarely see levels of 15 or greater and often see levels less than 10. Most of these people have some evidence of chronic systemic inflamatory change and/or malnutrition.

    • says

      This phenomena is very common but when you aremfaced with good complete thyroid panels and a low hs crp and ferritin and the ration is sub 20 the two best options are to maximize their leptin reset with behaviors to cause neuroplastic changes that get the ratio ideal over time. In my experience, it takes 1-3 yrs of using the leptin reset strategy to do so. The other way to skin this cat, that has a lower margin of safety is to tinker with the patients T3 level with dose and frequency of dosing changes. I have chosen to use the leptin reset 95% of the time over tinkering with the T3 method. The key is the patient’s patience with the time needed for the hypothalamus to reset but it always does. The tougher cases are the morbidly obese or the patients with hypothalamic amenorhea who want results in a year. That is a common patient with a difficult want.

  12. Lilian says

    Thank you for this incredibly interesting and helpful series! I may be missing something here, but I still don’t see a clear reason for my low fT3- levels. I have for a long time (10+ years) had overt symptoms of GI-infection/dysbiosis (actually I think I’ve finally figured that part out and am feeling much better in that’s regard).

    However, my TSH has been “normal” (now on the lower end of the reference range with 2 grains of Naturethroid), and even though I’ve gained some inexplicable pounds (not due to overeating or lack of physical activity) I’m in the normal-weight range. The only potentially contributing factor I’m aware of is low Pg/high E2. (Addressing that). So inflammation, probably, but not lowered TSH, and no obesity. What gives? Are there any current theories whee this picture fits?
    Sincerely,
    Lilian

    ibuting factor I’m aware
    of is a high E2/low Pg (addressing that through DIM and bio-identical

  13. Tierney says

    So it seems to me like the TOTAL T3 and T4 tests are more informative then, since the body can make use of bound thyroid as it needs? I’ve always been confused as to why the FREE tests are thought to be superior. Wouldn’t you want to know how much is actually bound and ready for use? It seems like that would give a more complete picture.

    • Chris Kresser says

      This is a common misconception. There is no “better” or “worse” test; they provide different information. Total T4 tells you how much hormone the thyroid gland is producing. Total T3 tells you how much T4 is being converted into T3. Free T4 & free T3 tell you how much thyroid hormone is available to the cells and tissues. All useful information.

  14. annalisse says

    GREAT SITE, AND SO SMART THIS DOCTOR CHRIS KRESSER! i will get and appointmnent with you , i live in Houston Texas, and i have been really sick for many years, i have a degree in holistic nutrition, i used to dance,no now because the totally lack of energy and the daily excrutiniating pain in my whole body , i have Hashimotos,with high antibodies, but i am underweight, really strange ah? with this condition. I need to eat every two hours to sustain only small amount of energy, 3 years ago my weight was 110pounds, now even eating healthy, organic and gluten free ect food i coudn’t increase any pound. they did tons of thyroid test but my problem is my body don’t tolerate, any thyroid hormone, none sintetic,none coumpounded, everytime i tried those my body goes into a crash, my muscles get in so much pain, i can’t walk, my energy go down, so is almost i can’t function, some doctors say oh is adrenal problem ,but i have been in so many good adrenal supplements, vitamins, minerals,herbs,ect, for almost 3 years without any reasults, also my adreanl tests show that my body is producing cortisol, i am using bio identical progesterone 20mgs,but nobody can tell me why i can,t accept the thyroid , which i need it,now my TSH IS NOT HIGH, 3.5 and my free T3 is2.8,my freeT4 is1.2,and myTPO are 439 and Thyroglobulin antibodies 130. Please tell me if you can help me to resolve this mistery, why my body act like an immune reaction when i take the medication …i really thank you so much for reading this letter, i am a women in my 50,and my husband and i we both are suffering a lot because, i can’t function anymore, even for almost 3 years i coudn’t go to any store, because the so much pain , and visited like 20 doctors, without any answer….thank you again! god bless you for your answer!! ANNALISE

  15. Beth says

    Mr Kessler I’ve seen a few of your post and was wondering if you could explain a few things reguarding hypothyroid testing I have tons of symptoms that point in hypo direction had tsh of 3.5 extreme fatigue pain in feet legs and back numbness tingling insulin resistant only on occasion according to my ups and downs I do have some depression my hair is brittle nails just peel extremely dry skin wired or summer feet are always cold but I’m tod I’m fine why do I eel like they are missing something I do have hypo and hyper in the family but I’ve struggled with my weight my whole life also gained 30 lbs in the last 3 months without changing anything when I was working out I gained weight cortisol level was good neuro says I may have ms what are your thoughts

  16. Leslie says

    So is there a co-relation between slightly elevated ESR (23 mm/hr) and low T3 (73 ng/dl) with rest of the thyroid function in the normal range?

  17. Anita says

    Hello, I am very new to any of this! I went to the doctor a few weeks ago because I get sick often or at least feel sick. This year, I had a hysterectomy because I bled non stop for two months straight and had a 1.5lb fibroid removed, uterus and cervix. Never had any children and I am 37. That was in February. I felt great for two months after my recovery month. My productivity at work doubled! Then all of the sudden, I felt fatigued, and sick again and I could barely make my stats at work. Then I couldn’t get rid of a bad sore throat that lasted for another month and a half. Saw a ENT doctor who diagnosed me with Acid Reflux. Eventually sore throat went away with strong meds and I just have a remaining slight cough and a little hoarse now and then. But I still felt sick and very tired so I went to my primary care doctor and she tested my Thyroid and Antibodies. She said I should be re-vaccinated for Phenomena and something else (I forgot what that was). My Vitamin D was below normal range, I have small nodule goiters and she put me on Synthroid 50mcg and Rx Vitamin D. Then referred me to an Endocrinologist. The Endo took me off the Synthroid and yesterday I went through a long test called ACTH. I really do not like the idea of having chemicals injected in me and I’m irritated why one doctor would give me a medication, then a week later, another doctor would take me off the meds. My initial thyroid test results without any thyroid medication were T3 Free 2.7, T4 Free .9 and TSH .47. The Endo noticed my hyper pigmentation on my face ( look like I have a lot of freckles that I cover with makeup the best I can) and noticed that my hysterectomy scars were also a dark brown. I have been experiencing more headaches lately and pain in my neck and for a couple weeks it was my entire back. The back pain went away but the headaches persist. What are they looking for with an ACTH test?

    Thanks,
    Anita

  18. Anita says

    Oh, and I also saw a GI doctor and after being put under and three biopsies, he said I have Gastritis. Then I found out that the Acid Reflux eroded a tooth, so I had to have that filled. That tooth is still sensitive and its been over a week. After my ACTH test, I went home and slept for 3 hours. I am not very overweight, I could loose but I am 150lb and 5’4″. I mostly eat out of nervousness most of the time, I am not really hungry which I know is probably not helping. What is going on in my body?

  19. Trish says

    I am writing for a friend who has diabetes and has been seeing an endocrinologist for 7 months. I work in the medical industry and have gone with her to some of her appointments. I have been unimpressed with her treatment plan. (My friend was adopted, so she does not know her family medical history. however, her twin sister was also diagnosed with hypothyroidism). The PA ran several thyroid tests and all were normal except the first TSH test which was .9 higher than normal range. Based on that test, she was given synthroid 75 mg. which was subsequently increased to 88 mg. She has been taking the 88mg for a month and the lab results taken yesterday show normal T4 free, TSH, T4, thyroid uptake and Thyroxine Index Free T7. The only abnormal result was the T3 which is now low. It was never low until she started the synthroid. She is going to see a new endocrinologist and after reading your article, I am wondering if you think we need to raise the Low T3 syndrome with him. Any advice would be greatly appreciated. Thanks.

  20. sarah says

    Hi, I think I have a unique situation and I’m not sure where to go from here. We have a 11 wk old baby with a benign brain tumor. It is about the size of a golf ball and inoperable. I have been giving her fucoydon, which is limu moui. She is on seizure meds trileptal. The drs told me that her thyroid levels coming from her brain are a little high but the levels in her blood are slightly low. They want to put her on generic synthroid. I dont want to put her on more meds if its not necessary or going to fix the problem. Any insight and advice would be greatly appreciated! Thanks sarah.
    Ps if you want to email me that would be fine

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