This article is part of a special report on Thyroid Disorders. To see the other articles in this series, click here.
In Low T3 Syndrome I, I introduced the Low T3 Syndrome (a.k.a. Euthyroid Sick Syndrome, Non-Thyroidal Illness Syndrome), provided some background on thyroid physiology and metabolism, and emphasized the fact that Low T3 Syndrome is not caused by a problem in the thyroid gland itself.
In this article we’re going to discuss common myths and misconceptions about Low T3 Syndrome and problems diagnosing it in a clinical setting.
This is important because there’s a lot of chatter around the internet these days about this condition. I’m getting a lot of questions about it and I see a lot of people diagnosing themselves with Euthyroid Sick Syndrome on the basis of what I feel is pretty sketchy evidence.
Early Theories on Low T3 Syndrome
The typically accepted view in the scientific literature until quite recently was that the conversion of T4 to T3 is impaired in illness because of a decrease in the activity of D1 & D2 thyroid deoidinases (enzymes responsible for activation of thyroid hormone) in the liver, kidney, skeletal muscles and other peripheral tissues. (1)
The trigger for these changes was thought to be an increase in cortisol and pro-inflammatory cytokines, both of which typically occur in chronic illness.
Recently, however, this theory has been challenged.
This is supported by studies on D1, D2 and D3 knockout mice subjected to treatment with lipopolysaccharide (LPS), an pro-inflammatory endotoxin. These mice, which don’t have any thyroid deiodinase activity, experienced the same decrease in T4 and T3 as wild-type mice. (3)
Also, when wild-type mice are injected with LPS, the fall in T4 and T3 precedes the decline in deiodinase activity (4), and in humans it has been shown that decreased D2 activity doesn’t contribute to Low T3 Syndrome in either prolonged or acute illness. In fact, D2 expression increases two- to three-fold in chronic illness states. (5)
However, evidence now suggests that the fall in T3 found in acute illness is more likely to be caused by impaired production of T3 in the thyroid gland (in turn caused by decreased hypothalamic production of TRH and pituitary production of TSH), and the reduction in thyroid horomone-binding proteins in the serum. (6) We’ll discuss these mechanisms in more detail in the next article.
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Problems with Testing and Diagnosis
First, it’s often the case that only total T4 and T3 are tested, rather than free T4 and free T3. While total T4 and T3 give us important information about what the thyroid gland itself is producing, free T4 and T3 tell us how much thyroid hormone is actually available at the cellular level to exert its metabolic effects.
But even when free T4 and T3 are tested, the results are often inaccurate because of the methods used. Although it is often claimed that free T4 is low in patients with Low T3 Syndrome, when the proper methodology is used, free T4 is rarely low—and is often normal or even high. (7)
In fact, is studies using reliable assays for free T4, around 50 percent of patients had low total T4 but only 2 percent had low free T4! (8)
The situation is even more problematic, in some ways, with the measurement of free T3—especially because the free T3 level is fundamental to the diagnosis of Low T3 Syndrome.
It is unequivocal in the literature that total T3 falls during illness, and that the degree of the fall is directly proportional to the severity of the illness. And most routine methods used to measure free T3 commercially and even in research settings tend to show that it drops right along with total T3.
However, results from two studies that have used an improved method for free T3 analysis have found that illness results only in a modest fall in free T3. In fact, free T3 levels were only 10 percent lower in sick patients than in healthy controls. (9)
Another study using this method found that while 70 to 80 percent of sick patients had low total T3, only 27 percent of them had low free T3. (10)
Why does this matter? Two reasons:
- First, a lot of people diagnosed with Low T3 Syndrome may not actually have low free thyroid hormones. This is a concern because some people are supplementing with T4 and/or T3 under the false impression that their hormones are low.
- Second, it implies that the significant changes seen in total T4 and T3 in Low T3 Syndrome are largely due to changes in the serum binding capacity for thyroid hormones.
We’ll discuss each of these points in more detail in the posts to follow.
Articles in this series:
- Low T3 Syndrome I: It’s Not About The Thyroid!
- 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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Can you explain the situation when a person has no Thyroid. I had a total Thyroidectomy because of relapsing Graves disease ( over 15 years) Between episodes of thyrotoxicosis, I went Hypothyroid. I had both Graves and Hashi antibodies. I m on 125mg Levothyroxine.
I would so value your opinion. I have Hashimotos – health declining rapidly in the last few years.. Fatigue, depression unable to work, digestive problems bloating, wind.
Liver under functioning according to acupuncturist. weight gain healthy eating.
Should I start taking T3/ T4 not receiving any help from my doctor.
LDL high 4.2 mmol range from lab is 2.00 – 5.00mmol/L
Serum ferritin 67ug/L – range13.00 – 150.00ug/L
TSH 1.50mlU.L 0.30 – 3.94MlU/L
FREE T4 14.1 PMOL/L 12.30 – 20.20PMOL/L
FREE T3 3.6PMOL/L 3.70 – 6.70PMOL/L
Cortisol morning 651 nmol/L 193.00 – 690.00 NMOL/L
I would be most grateful for any advise.
Hello. I am wondering if you could give me an opinion on treatment options. I have been struggling with thyroid issues for over 7 years. I have seen countless endo’s, holistic and integrative doctors. My main concern is an ABSOLUTE inability to lose weight and just gaining and gaining. I eat impeccably and have tried EVERYTHING. Low carb, low carb/high fat, high protein, low protein, low fat, high carb. Cut my calories drastically, to no avail. I have always been very fit and active but have had an extremely difficult time looking like it. My husband is a weight lifter and has been flabbergasted at my inability to lose fat and gain definition. Even though I can lift incredibly heavy amounts. I have other symptoms: low blood pressure, low body temp, hives, moodiness, headaches, etc. But the most concerning is the weight gain. I have been on Cytomel, Synthroid, Armour, WP, and now I am on Thyroid S. I was referred to this site by a doc who works with HCG. In the past, HCG is the only thing that reduces the weight. I still lose slower than most, but at least I lose. But in this last round, it’s not even working. I am desperate to figure out this weight issue. Lab #’s:
Free T4 : .9 (.6-1.8 ng/dL)
TSH: 1.48 (.35-5.5 uIU/mL)
Free T3: 1.65 (2.3-4.2 pg/mL)
Free T4 : 11 (12-22 pmol/1)
TSH: .27 (.27-4.2 mIU/1)
Free T4 : 14 (12-22 pmol/1)
TSH: 1.82 (.27-4.2 mIU/1)
Free T3: 2.6 (3.1-6.8 pmol/1)
Can anyone help me??
Hopefully you found answers by now, if not, read The Plan by Lyn genet Recitas. Food sensitivity can affect weight loss and thyroid. I also felt terrible and COULD not lose weight. With The Plan and a food sensitivity test (MRT-Oxford labs) I’ve lost 55 pounds.
I have been reading your posts and I was wondering what you think about my labs. TSH 0.463 range 0.450-4.500
free t4 1.29 range 0.82- 1.77
t4 9.0 range 4.5-12.0
t3 73 range 71-180
free t3 2.1 range 2.0-4.4
I have hashimotos disease taking 88 mcg levothroxine was having shortness of breath and hair not growing and breaking off.. just added 5mcg cytomel. Dr said I was sub clinical . Its only been 2 days with the cytomel added. Just worried cause my TSH is at the bottom. Any suggestions??
Hi, interesting info, thank you.
My doctor has told me I can take Thyroxin to help my symptoms of low thyroid function.
I have so many times asked for that to be tested and so it has now been shown to be low. After having read a whole lot more and speaking to many who don’t feel better, I am not sure Synthetic Thyroxin will help me fix the problem, as you say, and there must be another solution to help the body correct its own regulation somehow?
I have read too about natural Thyroxin therapy….what do you think of this rather than synthetic, re better for bone density and symptom improvement some have said?
How do you think that the adrenals and long term Adrenal Stress or Insufficiency and long term allergy could affect pituitary/liver and body’s ability to regulate thyroid??
How could one go about correcting that best? (beside healthy nutrition and moderate exercise which I already do as well as avoiding stimulants like caffeine most of the time)
I have studied Nutrition and Fitness and worked helping others improve and often get rid of lifestyle diseases, teaching classes and training people……despite a very active lifestyle……….my weight does not budge one bit…..I simply gain lean mass and was still experiencing long term fatigue which I was used to ignoring.
first sorry for my english
and this is my lab tests:
total t4:5.6 microg/dl
free t4:16.5 ng/dl
total t3:0.6 ng/dl
free t3: 1.37
t3 uptake: 24 percent
free t4 index:1.3
and im diagnosed by my endo to be hypo by this lab tests plus i have many related
symptoms and he got me on t4 only medication!
but i dont know what to do about it should i take medication or not…
chris,whats your perscription for this?what shall i do?
thanks for your wonderfull website… and again sorry for my english im in iran…
im waiting for your response to see whats my real problem
I am desperate for help. I have been suffering with chronic insomnia for 2 years. I have enlarged thyroid OR nudules as I’m not sure which definition defines the growths. My reports say nodules. My blood work has come back normal as per 4 different doctors – 2 being Endos, one was a gyno and one was ENT DRSo apparently my thyroid is functioning normally. The ENT Dr put me on Armour but I had heart palpitations and was reved up at night even more than normal. So he told me to discontinue.y I am luck if I get 2 hours of sleep a night. Sometimes I don’t even get that and I’m not sure how I manage to function. I am tired but feel keyed up all the time even through the night. I had a partial hysterectomy 6 years ago but I still have my ovaries. How might this be connected? I have an appointemnt at end of month with a NP that has hormonal treatemnt in their practice. Any advice for me? Could the thyroid cause my insomina even if the blood work shows a normal?
Excellent series Chris and extremely relevant in the Paleosphere right now given the amount of VLCers who are turning up with elevated LDL that appears to have been caused by low T3 and high rT3. I’d be very interested in your take on the situation as detailed at http://perfecthealthdiet.com/?p=4457
I’m assuming that your views would pretty much mirror Paul’s in that once the underlying problem is addressed then the situation should rectify itself and that supplementing T3 to reduce LDL is premature.
The reason this is such a big topic in the “Paleosphere” is that 1/2 of the people overtrain and under-eat in their desperate effort to get the cover-modelish look everybody is striving for, these days…
^ long known, high RT3 = simple adaptation (which by the way happens in men, as well, even if we do not lose our fertility as fast as the ladies)
Great topic. Can’t wait!
Studies that support t3 treatment is beneficial for the depressed is all the evidence you need to support the idea that low t3 benefit from t3. Also wilson’s work proves there are patients whose t3 to reverse t3 production is simply “stuck” and the ratio will remain corrected even after t4 is reintroduced to the body proving that there is no protective mechanism in these instances.
What studies? I’d like to see them.
I have only looked at in passing, but I believe that T3 has been used to augment the treatment of refractive depression and other mental states – two examples from Pubmed. I don’t think patients had low T3 to start with though.
my t3 is 3.7 so i get sick more often. this is aproblem for me
any suggeston s to bring it up .. t4 and tsh are fine
Hi Chris — I’d also appreciate if you could touch on the reverse T3 issue a bit. Thanks!
I have the opposite problem. My T3 levels are on the high side. I can not take any supplements with iodine in them, or I notice my heart racing and I have trouble sleeping. It would be nice if you could cover the opposite end of the spectrum, because I think there is often too much emphasis on just hypothyroidism. And of course we live in a culture where more is supposed to be better, but it doesn’t seem to work that way with hormones. I have intermittent troubles with depression. My acupuncturist thinks this is either related to liver function or adrenal function. I’m just wondering how it all affects my T3 being on the high end.
Anyone know if soy has any effect on thyroid?
I’ve read that fermented soy (natto, miso) is the way to go if you eat soy, but I haven’t read much about tofu. I assume tofu is a bit more processed, and therefore probably loses some of it’s fermented goodness, but perhaps it should be avoided all together?
(Incidentally, I’m asking because I’m looking towards shirataki noodles / spaghetti squash as a pasta substitute, that won’t negatively affect my thyroid!)
Sorry to be a bother, but I was just wondering I supplementing under false pretenses would cause permanent negative effects or, instead, provide a beneficial source of hormesis? I ask because I’ve read of certain people at weight loss plateus experimenting with t3( no idea how they got the prescription)and obtaining positive results( weight loss, more energy..etc)
I am very interested in this series as I have just been diagnosed with thyroid problems. My free t4 is at the upper end of the range. My free t3 is in the very lowest end of the range. My reverse t3 is extremely high. My ratio of free t3 to reverse t3 is 3.4. My doctor is kind of puzzled at the moment because my body temperatures average around 98.2, but she thought it would be lower considering thyroid numbers. Extreme fatigue and depression are my main symptoms. Chris, I am not expecting any kind of diagnosis, etc., but do you have any recommendations of other material that I could read while I am wainting on your future posts? I also would love to hear comments from others that have experienced anything similiar.
I have low total T3 and in range free T3 and reverse T3. However, references like this site say the ratio of free T3 to reverse T3 should be more than 20, and mine is 10.
The site’s recommended treatment for someone like me is T3 supplementation. Do you see any validity to checking reverse T3 and and calculating the ratio of free T3 to reverse T3? What is the link between Euthyroid Sick Syndrome and Thyroid Resistance Syndrome?
I’d love to see the references supporting the claims made by sites like that. So far in my research I’ve found no evidence to support the idea that supplementing with T3 in Low T3 Syndrome provides significant benefit at the population level, especially if FT3 and rT3 are in range. I’m not saying people don’t improve by doing it, I’m just saying I haven’t seen any studies supporting that. I will discuss the clinical significance of Low T3 Syndrome and whether T3 replacement is warranted or not in a future article.
OK hold on. “You’re not saying people don’t improve by doing it, but then in the same breath saying no studies support that.” Is not that why medicine is an art and a science? Many times things are done without level one evidence and they still work. Is there level one data on how its best to remove a nail from your finger? Most chemotherapy is delivered in off label fashion. In fact, my chemotherapy was off label by MD Anderson specialists and I got better real fast. I spent time at an academic research hospital in LA and their peer reviewed approach did nothing for me. I want my doctors or surgeons to have a lot of “real world experience”. I think the purpose of seeing a health care professional is partly what is peer reviewed published and their clinical expertise. (level 3 data) I’m not so sure I am like that brand of thinking here. Most of the statin data is peer reviewed and is dead wrong. I think the person who is “the clinical expert” is the critical point here. If they are CW and dogmatic, I think your implications maybe correct. If they are a real expert who has a lot of clinical experience with a particular issue, I’m not so sure patients will follow some peer reviewed journal article if their life/health depends upon it. I know I did not for my own cancer and subsequent hormone troubles. This argument only holds water when your doctor is asleep at the wheel. I think if we patients do our own due diligence we can mesh the best of both worlds for great success. A research paper does not always contain the correct answers in my opinion.
I agree with the general sentiment of your comment, but you’re missing a key point here: the first goal in medicine should always be “do no harm”. If T3 levels are low because the body lowered them on purpose (as an adaptation to chronic disease, to preserve energy and resources), then giving someone T3 could actually make them worse. A classic example of this is anemia of chronic disease, where hemoglobin, red blood cells and hematocrit are all very low – indicating anemia – but ferritin is high. This suggests the body is sequestering iron to keep it away from a pathogen or cancer. If a clinician gave this patient iron (based on the “appearance” of iron deficiency anemia), he/she could die.
Many researchers and physicians do believe that Low T3 Syndrome is an adaptation, and not a disease, and that the underlying problem should be treated rather than giving T3. I think each case needs to be looked at individually.
I really appreciate hearing this differing viewpoint on FT3 level and treating. I had normal TSH and low normal FT4 & low normal FT3 (at the low end of normal range) with hypothyroid symptoms. I wanted thyroid to be the answer to my metabolism problems. I sought out a doctor who treated with Armour and after a slew of tests she started me on meds. My symptoms never really got better, in fact, after titrating my dose up to a very high 3 grains, I was really feeling worse. But my labs were now “optimized”. Optimized according to a few websites and online forums anyways. Well, I knew I wasn’t optimized, I felt horrible and had actually gained at least 25 pounds.
I sought out a new doctor, did more tests and found my adrenals had tanked, literally a flatline from morning until night. New doc insisted I should have never been on thyroid from the beginning and it actually contributed to the adrenal insufficiency. It took three years to dig out of that hole and have been off thyroid meds for well over a year. I know there are others out there that want to label their metabolic problems on their thyroid and think that taking thyroid meds will fix them. What I have learned over the past three years is it isn’t always that simple. What you said above: “If T3 levels are low because the body lowered them on purpose (as an adaptation to chronic disease, to preserve energy and resources), then giving someone T3 could actually make them worse.”
Looking forward reading more in this series!
THanks for all the great information! If you have low free T3 (e.g. 1.8), can supplementing with that hormone actually cure you, or is it just palliative and you can assume you will have the same problem in the future?
Evidence suggests it may either do nothing at all, or even cause harm. Low T3 in chronic illness states may be an adaptive response to conserve energy and resources, and raising it back up may not be a good idea. I’m open to the possibility that it can help, but haven’t seen evidence of it in the literature.
Would you categorize obesity as a chronic debilitating illness in the presence of low free T3?
There are patients that cannot loose the weight and you test their free T3 and it’s low. Treating during short term with T3 will kick start weight loss. Is there any evidence that you know of about this being harmful?
An important question is what I want to be done if I was in hospital with heart failure and my T3 was low. Do I ask (if I am able) to have my T3 levels restored to some sort of normal. Or, do I assume that the low T3 is my body adapting to its weakened state. I would ask for the T3 myself. Here are some papers that make me think this way:
What would you do?
Acute heart failure is one of the few cases where there’s some evidence to support T3 replacement in Non-thyroidal Illness Syndrome. I’ll discuss this in a future post.
“First, it’s often the case that only total T4 and T3 are tested, rather than free T4 and free T4.” Correct your typo? xoxo
Thank you for writing this series. As a thyroid patient for 20+ years who has felt no relief of symptoms since the first six months of treatment, I may not understand it all, but I do need to know these things.