Low T3 Syndrome III: Inflammation Strikes Again | Chris Kresser
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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 percent 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:

  1. What do you folks think?
    Is it possible that a Histamine Intolerance cause low T3?
    Too much histamine causes inflammation (cytokines), so I thought probably this could cause low T3 (beside other factors).

    • I wonder if too much histamine, in my case from food allergies, can cause high reverse T3 as well. When I cut wheat and other gluten grains out of my diet, my TSH came down and stayed more consistently in the 1’s. Before, it would sometimes be in the 2’s or even the 3’s. I have a wheat allergy but tested negative for celiac disease and Hashimoto’s. Also, my TSH was high at the same time I had extremely elevated eosinophils. It turned out that a reaction to flaxseed was the culprit. When I cut the flaxseed, my eosinophil levels and TSH dropped back down to normal.

  2. I am 56 years old and had my 25 year old silicone breast implants explanted two months ago ~ thus my body has been fighting this foreign object for 25 years. 🙁 Other than that, my health has been good and I take no meds. I’m just a little fatigued post surgery (or maybe age is contributing to this as well). I had blood tests taken post surgery and my cholesterol has skyrocketed. Total Cholesterol 269, HDL Cholesterol 87, Triglycerides 46 and LDL Cholesterol 173. Those are down abit from the first post-surgery test and I am working hard to bring those numbers down further with strict diet and exercise. I am also upping my carbohydrate intake as I did a ketogenic diet from March – July. I’m concerned about my thyroid numbers though: My TSH was 1.81, Total T4 was 6.30, Total T3 was 70, and Free T3 was 2.60. It looks like everything is ok, except my T3 counts, which are abit low. Also, I saw mention of C02 above, and mine is 23. Not sure where to go from here and would appreciate any guidance you can provide.

  3. Adopted young adult daughter is ultra rapid cycler (bipolar) /suffers from anxiety. Have always suspected pituitary/thyroid issue. Low TSH, Low FT3, Low FT4. (Never fat/heavy and always active.) As a child, she had eczema…and always complained of stomach ache. These test results are prior to mood disorder treatment (not the result of prescription meds)
    Tests: (1) TSH (3120)
    TSH 1.19 uIU/mL 0.50-4.30

    Tests: (2) FREE T3 (3140)
    FREE T3 [L] 2.65 pg/mL 2.90-4.60

    Have read that high dose thyroid hormone may be way to go. Am sure doc will not be receptive. Can you recommend treatment/doc? Thank you.

    • Have you gotten her progesterone levels checked? Slow thyroid means lowered production of calming homones including progesterone.

      • That’s interesting. Thank you. She also gets her period 2x per month which i see can be low progesterone

  4. You stated that Low T3 Syndrome is mediated by inflammation, which can have a number of different causes. If a person gets their High Sensitivity CRP tested, and it comes back extremely low (almost zero), is that information enough to rule out Low T3 Syndrome in the presence of normal TSH, low-normal FT4, and low FT3?

  5. Wow, GREAT stuff here Dr. Chris! Where are you? I need a doctor with your insight and desire to actual understand the thyroid and all the dysfunctions it can cause.
    I read a comment on one of the articles stating..”why don’t doctor’s offices take your temp. anymore?” Good point!
    Also, I would add another ‘why not?’…Why is a person’s blood type nonexistent in carrying any clues to health needs???
    Example…I am the rare blood type O Negative. My mother was as well but my father was positive. I have text book problems associated with the battleground womb I was provided. I nearly died at age 5…complete autoimmune..then again at age 13 and again problems at age 45…I’m 50 now and I have 6 children. Even the sound of 6 kids to many can make them tired. So tired and needing a nap myself has been a norm for me BUT as of lately the body that has been so good to me, that has been so extremely fit and could run a 7 minute mile, 10 mile a day, can’t even run faster than an 8o year old person …and we live in Florida so we have lots of the old folks around. I am also FREEZING. ..summers here feel great. …people, actually everyone, can tell somethings wrong, except my doctor. ….she says I’m fine.
    I was able to convince her to do an ultrasound, because I am self medicating with tons of supplements, iodine etc….my report came back , my thyroid is over twice the size of normal, (I googled a norm one 🙂 ) and I have 2 cysts and the entire T is abnormal (heterogeneous)….the only specialist in my insurance group is over 3 1/2 hours away and she a 1 1/2 star doc…I have found stars matter… lol
    So they sent me to an ENT who found that not only is my T enlarge but the reason I can’t breathe and have trouble swallowing is because my esophagus is COMPLETELY swollen shut. And I am oxygen deprived and suffering all the symptoms of that as well.
    Long story short, so to speak,:) it is very complicated and in a way, a small way, I see why my family doctor is ‘afraid’ to help.
    I just want to be able to make it through the day without feeling like I’m going to collapse.
    I am trying to keep my focus on how good I am going to feel when I ONE DAY get this all resolved and healed…because it is a miracle that I am able to do all that I do with 6 kids , and a 40lbs puppy, when I’m being chocked 24/7 by my own thyroid and esophagus, together…lol! (Thanks guys!)
    Chris, any words of advice or can I give you my doctors email, you could send her some stuff…lol! JK
    Blessing, Dana

  6. As an older woman who was recently diagnosed with partially empty sella of the pituitary, I am also dealing with hypothyroidism, low T3 levels, and atherosclerosis. Plus, I was diagnosed with Epstein Barr in my teens and multiple sclerosis in my late 30s. I take no other meds except 60 mg of N P Thyroid. My T3 levels have been 1.2 for years, but recently raised to 2.1 — I was thrilled! Perhaps it’s because I started taking Astaxanthin, a natural anti-inflammatory?
    I wonder, could the partially empty sella be causing some of these issues, and can anything be done to correct this? Thank you so much for your reply…your articles are a lifeline to those of us who are desperate for help.

  7. 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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