Table of Contents
Thyroid Physiology | Mechanisms of Low T3 Syndrome | Low T3 Syndrome in Acute and Chronic Illness
This article is part of a special report on Thyroid Disorders. To see a comprehensive eBook on thyroid health, click here.
Hypothyroidism involves high levels of thyroid stimulating hormone (TSH) and low levels of the thyroid hormones T4 and T3.
However, in my clinical practice I frequently see people with low levels of T3 with normal T4 and either low or normal TSH. This condition has been reported on in the medical literature for years, and there is a growing realization among conventional medical practitioners that it’s an important issue. (1) However, many conventional practitioners aren’t sure how to address the condition, which leads to patients who don’t have a clear understanding of what’s causing their illness.
This particular pattern goes by three different names in the medical literature: Euthyroid Sick Syndrome (ESS), Non-thyroidal Illness Syndrome (NTIS), and Low T3 Syndrome.
NTIS has become the term of choice in the literature. However, I’m going to use Low T3 Syndrome in these articles because it’s more descriptive and accessible to the layperson.
What’s most important to understand about this condition is that, although it does involve low levels of T3 (the most active form of thyroid hormone), it is not caused by a problem with the thyroid gland. This is a crucial distinction and it’s what distinguishes Low T3 Syndrome from “garden-variety” hypothyroidism.
In this series we’re going to discuss:
- What causes Low T3 Syndrome
- Its clinical significance
- If it should be treated, and if so, how
But first we need to lay the foundation with a little basic thyroid physiology.
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Basic Thyroid Physiology
In order to understand Low T3 Syndrome, you’ll need a basic understanding of thyroid physiology. Regulation of thyroid metabolism can be broken down into the following five steps:
- The hypothalamus (a pea-sized gland in the brain) monitors the levels of thyroid hormone in the body and produces thyrotropin releasing hormone (TRH).
- TRH acts on the anterior pituitary (directly below the hypothalamus, but outside of the blood-brain barrier) to produce thyrotropin, a.k.a. thyroid stimulating hormone (TSH).
- TSH acts on the thyroid gland, which produces thyroxine (T4) and triiodothyronine (T3), the primary circulating thyroid hormones. The thyroid produces T4 in significantly greater quantities (in a ratio of 17:1) than T3, which is approximately 5x more biologically active than T4. (2)
- T4 is converted into the more active T3 by the deiodinase system (D1, D2, D3) in multiple tissues and organs, but especially in the liver, gut, skeletal muscle, brain and the thyroid gland itself. D3 converts T3 into an inactive form of thyroid hormone in the liver.
- Transport proteins produced by the liver—thyroid binding globulin (TBG), transthretin and albumin—carry T4 and T3 to the tissues, where they are cleaved from their protein-carriers to become free T4 and free T3 and bind to thyroid hormone receptors (THRs) and exert their metabolic effect.
Mechanisms of Low T3 Syndrome
As you can see, the production, distribution and activation of thyroid hormone is complex and involves several other organs and tissues other than the thyroid gland itself.
Hypothyroidism is a defect in step #3, because it typically involves a dysfunction of the thyroid gland itself—most often caused by autoimmune disease (Hashimoto’s, Ord’s, Graves’) and/or iodine deficiency.
However, in Low T3 Syndrome, the problem generally occurs in steps #1, #2, #4 and #5. None of those steps are directly related to the function of the thyroid gland itself.
More specifically, Low T3 Syndrome can include the following mechanisms: (3)
- Modifications to the hypothalamic-pituitary axis
- Altered binding of thyroid hormone to carrier proteins
- Modified entry of thyroid hormone into tissue
- Changes in thyroid hormone metabolism due to modified expression of the deiodinases
- Changes in thyroid hormone receptor (THR) expression or function
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Low T3 Syndrome in Acute and Chronic Illness
Most of the studies on Low T3 Syndrome have been done on people suffering from acute, life-threatening illness. In the intensive care unit, the prevalence of abnormal thyroid function tests is remarkably high. More than 70 percent of patients show low T3 and around 50 percent have low T4. (4)
Many of these studies have indicated a direct relationship between Low T3 Syndrome and the severity and both short- and long-term outcome of disease. (5) The lower the T3 level in critically ill patients, the worse the outcome tends to be.
However, studies examining thyroid hormone replacement in these situations have shown mixed results. In most cases—with the exception of cardiovascular disease—taking thyroid hormone did not improve outcomes. (6) We’ll discuss this in more detail later.
Recently, more attention has been given to Low T3 Syndrome in non-critical, chronic illness. Specifically, the question on everyone’s mind (including mine) is whether thyroid hormone replacement is useful in this situation, or if—as some have suggested—it could even be harmful.
On the other hand, in those suffering from long-term chronic illness, Low T3 Syndrome may be more reflective of pathology than adaptation, and this group may benefit from T4 or T3 supplementation.
We’ll explore all of these questions in more detail in the articles to follow, and I’ll also share some of my observations from my clinical practice. Stay tuned!
Articles in this series:
- Low T3 Syndrome II: Myths and Misconceptions
- Low T3 syndrome III: Inflammation Strikes Again
- Low T3 Syndrome IV: An Autoimmune Disease You’ve Never Heard Of?
- Low T3 syndrome V: Should It Be Treated With Thyroid Hormone?
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Thanks for posting this. I enjoyed reading this and the second part that you wrote as well.
yep, you are right: correlation doesn’t equal causation. But I didn’t rush back to carbs, only after a year after the symptoms started and after gaining those 15kgs I increased some carbs and subjectively I feel better. Also I haven’t put on weight since adding carbs. I also read the post written by Paul Jaminet (http://perfecthealthdiet.com/?p=4383) and I get even a stronger feeling that I shouldn’t go zero carb. But, time will tell, I guess. Since no one else will… 😉
Hope you’re getting better, Paul!
I’m SO looking forward to the rest of the series since this might directly fit to my case… Been on a thyroid medication now for six months (recently switched from T4 to Thyroid) but I suspect this kind of scenario talked about this post might be the case. It’s subclinical but the symptoms are obvious. It’s not autoimmune either and my other blood work is really quite excellent (including ferritin, B12).
So please, please get the next ones out soon! I’m feeling hopeful 🙂
Ps. About the carbs&thyroid issue; I read Nora Gedgaudas’ book Primal Body Primal Mind in February 2010 after which I ditched the rest of my already low carb diet’s carbs. She really recommends like a zero carb, just leafy greens and “the less insulin we secrete the longer and healthier we live”. Well, that didn’t seem to do me any good (also started eating with just three times a day and did IF regularly). My problems started couple of months after and they’ve only now, over a year later started to get a bit better with the mentioned thyroid medication, adding carbs (berries, fruit, a little sweet potato – still very, very moderate since it’s not easy to go from a almost zero carb to eating more carbs, mentally) and some other stuff like herbal support.
Anyway, just received Nora’s new version of Primal body primal mind and skimmed trough it; it still recommends a very low carb diet and I’m just wondering whether it’s me or is it really the best thing for everybody… Don’t really know what to do. I just do a lot better eating more often, a bit more carbs, no IF.
My T3 crashed too after going low carb. But, was it less carbs, more protein or more fat? Is rushing back to carbs the best approach – I did and I gained weight. I have upped my T4 and T3 and am trying vlc again – checking T3 later this month.
I’ve found that correcting digestive problems 1st corrects many thyroid problems.
Honora it’s Paul Jaminet’s site.
Oh, yeah. Found it through John Stanton. Cheers.
I’ve been following a discussion on low-carb/low T3 levels on John Stanton’s site too.
Very much looking forward to the rest of the series.
Chris, How does one know what kind of Hypothyroid autoimmune disease they have (Hashimoto’s, Ord’s, Graves’) and/or iodine deficiency)? I was diagnosed a year after I gave birth to my one and only child was born, in Dec. 1983, (my was then age 36). I was put on Synthyroid & never felt normal until I asked my Dr. to prescribe me ARMOR in Nov. 2010 & also started eating Paleo Diet Feb. 2011, now I finally feel the most normal for me since I was in my mid 20’s. I am looking forward to learning more about this topic! Thank you so much for expanding on thyroid disease.
You get your thyroid antibodies tested: thyroid peroxidase (TPO) & thyroglobulin (TG) if you suspect Hashimoto’s or Ord’s and Thyroid Stimulating Immunoglobulins (TSI) if you suspect Graves’
My antibody tests all came back satisfactory; however I have a host of the symptoms for Hashimoto’s.
The antibody tests are not 100% accurate. If my patients have signs and symptoms of Hashimoto’s, I treat them as if they do have it and watch how they respond.
I am also on Plaquenil 200 2/d. Could carbs make my T3 drop? Will it hurt if my T3 is low when the other thyroid markers are ok?
Chris, graves causeshyperthyroidism, not hypo. Sheila
Initially, Graves is related to hyperthyroidism. However, after medication treatment, many of us end up hypothyroid with the FT4 and FT3 looking “normal” but being too low to feel good, and the TSH on they very low end. Unfortunately the doctors look at the TSH and label us as hyper, when in fact you are hypo if you look at the thyroid hormones. I’m finding it next to impossible to find a doctor who is really knowledgeable about treating Graves.
Chris, it might be helpful if you quantify what you consider low, normal, and high for TSH, T3, T4, and rT3. Thanks.
Thank you for this informative article. I’d like to know what lab value do you consider as low T3?
My question exactly!!!
I’m wondering about this question too on what’s considered high and low for TSH, T3, T4, and rT3, thanks.
The rT3 that you bring up very popular subject at the moment especially in regards to leptin resistance. If you have high rT3 usually marker for leptin resistant (as per Dr Kruse). Hopefully you address leptin when talking about rT3. High rT3 from calorie restriction.
Thank you for addressing T3 issue. I have been diagnosed with “Reverse T3 Dominance”, and I hope you will be addressing this as well, especially how keep in in check/ preventing reoccurances.
The problem for a lot of people – including myself – is in taking thyroid medication with any T4 in it whatsoever. Those with a poor free T3/reverse T3 ratio need to be on T3-only medication. Many cannot simply add T3 to their T4 regimen or take dessicated thyroid as it will make their problem worse due to the T4 converting to reverse T3 instead of T3 and thereby blocking the thyroid hormone receptors. They are then hypothyroid on a cellular level.
All doctors should be running a free T3 along with a reverse T3 test and understanding what to do with the resulting ratio of free T3 to reverse T3. It will catch many with thyroid hormone resistance that will never be diagnosed through the TSH, free T4 and free T3 alone.
Excellent comment. I wish every doctor would test Rev T3. But it’s hard enough to get T3 and T4, along with TSH, tested.
You can get your own reverse T3 tested if you are having trouble finding a doctor who will order it. There are online labs you can pay for, print out the lab order, and take the sheet to your nearest lab for a blood draw.
Also, I would fire a doctor that refuses to order it and find one who will. Even if he/she isn’t sure how to interpret it. Unfortunately, most doctors do not order the reverse T3 as part of the standard thyroid panel as, surprisingly, they are not up-to-date on thyroid disease diagnosis, testing, and treatment. The free T3/reverse T3 ratio is key to have done if you have any chronic health issues. The TSH indicates thyroid hormone levels in the pituitary, but does not indicate whether one has hypothyroidism in the rest of the bodies’ tissues and is therefore quite far from a gold standard test. Free T3 and Free T4 alone do not show what is going on in the tissue level. People with fibromyalgia, chronic fatigue syndrome, leptin/insulin resistance, depression, dieting, obesity, and other chronic health issues should be checking this ratio. If the ratio is off, one will need T3 only treatment in most cases. Even Armour will not cut it, as the T4 will convert to too much reverse T3 and block the thyroid hormone receptors, keeping one hypothyroid.
great information thankyou so much. I have suffered with depression,severe fatigue ,trouble sleeping, muscles aches ect. im on synthroid and think thats what is making me sick. what do u think about natural hormones. I will know check with my Dr abut mt t-3 level is and make sure a reverse t3 was done. what ussually is the cause of depresssion and sever fatique ,any ideas. thank you so very much andrea
T3 is key in depression and muscle aches. When I got off T4 and went onto dessicated thyroid, the muscles in my neck and back that had been stiff released within a day. There are also more and more studies to say that brain fog is cleared by T3 therapy. Look into dessicated or synthetic T4/T3 therapy.
I am 56 and had hashimoto’s as well as papillary thyroid cancer with follicular and small area of tall cell variant.
My thyroidectomy was in 2011. I am on synthroid 137 mcg and atenolol 50 mg. i recently started on cymbalta. I went on it a few months after my thyroidectomy and then went off and two months ago back on 30 mg. i had never in the past suffered depression although i woukd have periods of anxiousness. When i get the low feelings, my sense of smell gets incredibly heightened.
I also have leg and muscle cramps. My tsh was last 0.13 total t4 11.4 free t4 3.2. T3 total 123. T3 uptake 28. Thyroglobulin <0.2
Are these labs a bit off. Would i feel better if my t3 were higher?
I am startimg with a new doc at cleveland clinic and looked at the lab orders and he is not even requesting t3
I want to feel normal, lose 15 pounds and stop having muscle spasms and cramps. Calcium and magnesium have always been normal as have K levels
At the end of your article you bring up rT3, which is most interesting. I have been looking into rT3 dominance and its ability to shut down even normal levels of T3. The point about stress is very important, as we are talking about emotional, as well as physical stress. I have read that even a lack of exercise – strenuous exercise – can also apparently result in higher rT3 levels.
Looking forward to your future articles.
excellently clear description of the various places “thyroid” problems can happen! i look forward to the rest of this series!
Awe…..way to leave us hanging!!! I am extremely interested in this topic because I have been on Armour Thyroid for 2 years after my alternative healthcare practitioner found my Triiodothyronine, Free Serum levels to be at 2.5pg.mL. The “lab limits” were 2.3-4.2 but she said the level was low and could be causing some of the nervous system disturbances I was experiencing. This view concurred with a very informative article by Dr. Joe Mercola in which he promoted the use of Amour Thyroid for low T3. However, I later went to an ND who wasn’t thrilled to know I was taking it. So now I’m confused and waiting on the edge of my seat for the rest of this article!
My T3 was tested twice and I reported 2.6 and 3.0, with lab ranges from 2.0-4.4. (My TSH is between 0.5-0.8, and T4 1.1-1.7. Never tested me for Rev T3, even though I show very obvious clinical hypothyroid symptoms). I didn’t realize these number could be interpreted as “low”. Just curious, what kind of nervous system disturbance are you experiencing?
Looking forward to learning more. BTW, I am a hypothyroid whose T3 dropped badly (with TSH <1) when I switched to low-carb approach. I have remained substantially low-carb, but have increased my T4 & T3.
I am interested in the Broda Barnes / William McK Jefferies view that the conversion of T4 to T3 and the uptake of the T3 in the cell is, to some extent, dependent on adequate cortisol levels – levels of which can become depressed in a chronically un(nder)treated hypothyroid.
I have noticed some papers showing some benefit from supplemental T3 in heart failure patients. The most recent (a review) being: Thyroid Replacement Therapy and Heart Failure http://bit.ly/rsAaNN
I would encourage you to check out Peat’s stuff (www.raypeat.com) he is particular into the carb (sugar) thyroid relation and although I do not agree with him on everything I think that he is onto something when he says that “no sugar = metabolic shutdown”
Thanks, I will check it out.
please expand on your peat ideas. i cant figure out wat to believe and wat to toss out with it
INTERESTING SERIES…LOOKING FORWARD TO IT!
I would also love to know the relationship with iron. The STTM group says low iron will make you unable to tolerate Armour or any synthetic T3. In my experience, Synthroid gets me to about 90% of where I want to be. When I add in T3, I have some issues and have to go super slow (but it’s the only thing that will budge my weight.) My iron is very low (although I am never anemic) and I’ve been taking so much iron for almost a year now, but my iron levels hardly move. To give you an idea, I take about 200 mg iron bisglycinate and 10 mg ferritin each day and my ferritin has gone from a 22 to a 36. Why would it be so hard to raise iron? I want to take my T3! Thanks so much for this series!
B-12 shots have kept my iron at a normal level. Without them my iron goes way down. Drs believe I have connective tissue autoimmune disorder. T3 is half of what it should be, but others ok with 88 mg levothyroxine daily.
Wow, It seems like you are talking about me. I was given by my doctor some T3 pills. I have to admit i did not take my iron for whole month and now it has been very hard to make it go up. I cut the T3 dosis in half just because of my schedule, could it be possible that it also affects the iron in your body? Scary. I am losing weight with all the treatment the doctor gave me.
Just another thing: Are you familiar with Ray Peats perspective on the whole thyroid issue? If not, start out reading here – > http://raypeat.com/articles/articles/thyroid.shtml almost all his articles are somehow related to the thyroid estrogen serotonin connection. Some interesting, some dump and certainly a lot of controversial hypothesis from this “extraordinary” blogger 😉
Thanks for this article, Chris! This is exactly the problem I have been facing. Even with T3 supplementation in addition to Armour, my T3 levels continue to go down and my TSH is below range. I have been working on eliminating candida and healing my gut in hope that my thyroid function will improve. Do you know how iron plays into this as I have difficulty getting my iron levels where they need to be. Thanks!
Iron needs adequate thyroid hormone in order to “hold/stick”, and the thyroid needs adequate iron so it can be taken into the cells, versus pooling in the blood. Armour contains T4 and it may be that you have a reverse T3 issue blocking thyroid hormone from getting into the receptors and need to be on a T3-only medication should there be too much T4 being converted into reverse T3. It may be that you would do better “ramping up” iron and T3 together, slowly. Candida should greatly improve once your body temp comes up to normal (ie, you are treating your hypothyroidism adequately). Candida thrives in a low-temp body and will be hard to eliminate while actively hypothyroid.
I too have this exact same issue! Cant keep my iron levels up and have been healing my gut through SCD.
Always enjoy your articles, Chris and am already looking forward to this one, although my own research into this topic tells me that we (or rather the pharma-financed medical research) knows nothing about NTIS beyond its clinical manifestation in really critically ill patients – part of the establishment even still deny its existence and exacerbate the problem of hundredthousands of patients by propagating T4 treatment and TSH diagnostics as the treatment and diagnosis techniques of choice.
Would hyroyroid T-3 be beneficial if thyroid has been removed.??