✅Evidence-Based: written by a Board-Certified Endocrinologist
In Comments and Controversies on Hormones Demystified, I laid out the case for why I needed to write this series of posts about T3. In this and future articles about the topic, I will address the myriad claims and questions that have come up over the years in the Comments section of T3 Or Not T3 – Exploring The Controversy. Per my current Comment policy, I will aggressively moderate reader-generated content that doesn’t meet the standard. I would also ask you to restrict your thoughts, questions, and theories about T3 to the narrow subject of each post in the T3 Controversies Series. I believe this will make the reader experience better for everyone, allowing people to more easily find the information they need. Let’s get started on today’s subject!
Claim: Not all tissues have deiodinase enzyme activity1. Therefore, these tissues are unable to take levothyroxine (T4) and use it to make their own T3. Because of this fact, hypothyroid patients with persistent symptoms should always be treated with escalating doses of T3 until symptoms resolve.
HD: Partly True but Misleading. I’ve already covered this ground to some extent in T3 Or Not T3 – Exploring The Controversy, and I discussed the impact of the much-talked about Thr92Ala polymorphism in the D2 (Type 2 deiodinase) gene in Is TSH the Best Test? I also touched on this topic in Everything You Never Needed to Know About Reverse T3. So, I will limit the discussion here to the question of whether tissues without deiodinase activity could suffer in the setting of impaired T4-to-T3 conversion.
It is true that not all tissues have deiodinase activity. It’s possible that one could infer from things I’ve written in prior posts that every tissue can produce its own T3, which is not true. I apologize for that implication, which occurred because of my intention to keep a complex topic from becoming overwhelmingly dense.
In the interest of clarifying the topic, but at the risk of hitting you with too much…the Type 1 deiodinase (D1) enzyme is found in the liver, kidney, and thyroid, and it is believed to be largely responsible for plasma levels of T3. In other words, the conversion of T4 to T3 by D1 leads not only to the production of T3 that can be used by liver, kidney, and thyroid, but also by tissues throughout the body.
While not every part of the human body has D1, D2, or D3 activity, most of the major players do:
- D1 activity: liver, kidney, thyroid
- D2 activity: brain/CNS, pituitary, muscle, heart, brown adipose tissue
- D3 activity: fetal tissues, adult brain tissue, re-expressed in critical illness/certain cancers
In the setting of what I will call “total” primary hypothyroidism (surgically absent thyroid or completely nonfunctional thyroid), tissues that do not have the ability to produce their own T3 will get just about all their T3 from D1-mediated conversion of T4 to T3 in other tissues2. This begs the questions: can D1 activity be impaired, and what happens if that’s the case?
It turns out that the answer to questions of this nature is always extraordinarily complicated and not completely understood. For example, take the case of what happens in the setting of iodine deficiency3. Iodine deficiency leads to decreased D1-mediated T4-to-T3 conversion. In an attempt to compensate for this, D2-mediated efficiency of T4-to-T3 conversion increases. Also, neuronal D3 expression decreases, which means that the local half-life of T3 increases (remember that D3 inactivates T4 and T3, so inhibiting the enzyme that inactivates T4 and T3 will lead to a longer half-life of T4 and T3). And, if you happen to have a thyroid, the thyroid will increase T3 production in an attempt to compensate for iodine deficiency.
In addition to all of the above, remember that there are other mechanisms along the pathway of thyroid hormone production, conversion, transport, and action. These mechanisms can serve to maintain/defend T3 levels/action by increasing transport of T3 into the cell and increasing binding of T3 to its nuclear receptors.
There are other things (endocrine-disrupting chemicals, drugs, D1 polymorphisms, etc) that certainly have the potential to impair D1 activity4. However, it is misleading to state that people with conversion problems must take T3. First, given that the vast majority of people with hypothyroidism do fine on T4 (levothyroxine) alone, it is likely that people treated with T4 alone who also have conversion problems are able to fully compensate as described in the preceding paragraphs. Second, there isn’t a reliable way to diagnose impaired conversion (serum T3 levels are usually not helpful for that purpose). That doesn’t mean we can’t do a therapeutic trial of liothyronine as an add-on to levothyroxine, as discussed in my first T3 post. But, appropriate expectations need to be set, given that these trials often fail – presumably because the residual “hypothyroid” symptoms are actually due to something other than hypothyroidism.
Now, high-dose T3 proponents claim that the reason why T3 trials often fail is because the dose has not been pushed high enough. They advocate doses that achieve supraphysiologic T3 levels in the blood in order to provide symptom relief. This claim is usually tacked on to the end of all other claims about why T3 therapy is needed, so I believe it deserves its own post. Therefore, I’m not going to cover this ground today – but stay tuned.
- Most tissues have deiodinase activity and can use T4 to make their own T3.
- In hypothyroid people, those tissues that lack deiodinase enzymes will still be exposed to T3 because of D1 activity in other tissues that contributes to T3 plasma levels.
- There isn’t a reliable way to diagnose T4-to-T3 conversion problems, impaired thyroid hormone transport into cells, or impaired thyroid hormone action inside cells5.
- In the presence of residual “hypothyroid” symptoms, despite a normal/optimized TSH, it is reasonable to do a trial of liothyronine added on to levothyroxine.
- When initiating a trial of liothyronine add-on therapy, keep expectations reasonable, and be open to the concept that some residual symptoms might not actually be due to hypothyroidism.
By reading this site and interacting with me and others in the Comments, you agree to abide by my Disclaimer. As a reminder, please restrict your comments and questions to the narrow topic at hand. There will be plenty of opportunities to discuss other claims and controversies in future posts.
Image Credit: Photo by Dario Valenzuela on Unsplash
- For the purpose of this discussion, think of deiodinase enzymes as being responsible for the conversion of T4 to T3. Remember that T3 is the active form of thyroid hormone that gets the job done. Also note that deiodinases regulate thyroid hormone action locally, in addition to other responsibilities, but that is outside the scope of this discussion. [↩]
- I’ve invented the term “total primary hypothyroidism” to distinguish people with zero thyroid function from people who have a damaged thyroid that is still capable of producing at least some T3 on its own. [↩]
- I plan to address iodine deficiency in more detail later in the T3 Controversies series. For now, I’m simply bringing it up to illustrate a point about how it might affect T3 levels. [↩]
- I covered EDCs in detail in T3 Controversies: Can Impaired Thyroid Hormone Action be Treated with T3? As for D1 polymorphisms, I’m not going to cover those in detail, because human clinical research thus far has not shown a consistent impact of any D1 polymorphism on the well-being of hypothyroid patients. [↩]
- For the gajillionth time, T3 levels in the blood are usually not helpful for any of these scenarios. [↩]
19 Replies to “T3 Controversies: What About Tissues That Can’t Make T3?”
When would testing T3 be appropriate? Thanks again for writing on this topic.
If I narrow the focus of your question to, “When is T3 testing appropriate in the management of hypothyroidism,” then the answer would be, “Very rarely.” Since I do sometimes use liothyronine as an adjunct to levothyroxine for my patients, I will occasionally check a FT3 to see what the peak is 2-4 hours post-dose. But since I don’t use high doses of liothyronine, the FT3 levels are rarely high. All the level really does is reassure my patient that their T3 level isn’t “low,” which is often their concern. But as I have discussed previously, the FT3 level does not correlate with what’s happening in the tissues, so it isn’t terribly useful.
Leslie DeGroot, MD (for those that don’t know him
recommends T3 be within normal range on thyroxine replacement therapy. One would assume that he would have tested for it. Given his stature and contributions to the field, why isn’t this an universal accepted practice?
Dee, you’re correct that Dr. DeGroot was a giant in the field of thyroidology. The link you provided to Thyroid Manager is to a flow diagram about how to dose levothyroxine. At the bottom of the diagram, there is a caption that states: “The author (Leslie DeGroot, MD), believes that patients feel best on replacement therapy when TSH is at the lower end of the normal range, at which time FTE is usually just above normal, and T3 is in the normal range.” That statement is almost certainly based more on his clinical experience and opinion – as opposed to convincing data – given that the data don’t consistently show that to be the case.
I’ll ask you to table this thread for now, as I’m currently working on a post about this very question of “should T3 levels be normal when treating hypothyroidism?”
Thank you, that’s very helpful! Looking forward to the next article.
The problem with T3: patients often have adherence issues, because they need to take it more than once a day. What we often see is a rapid and significant suppression of TSH if patients take a dose that is slightly too high and/or take T3 once a day.. Suppression of the thyroid function in the absence of TSH can lead to apoptosis of the thyroid cells [HD: I’d like to see a reference for this statement, as I’m not sure this is true], which means further loss of functional cell mass. T3 overdose not only Leads to TSH suppression, but often to a reduction of free T4.
Thank you so much HD for embarking on this T3 series. As a medical student we don’t get much of this and I have found it extremely helpful when discussing with patients, or quacky family members.
You’re doing the Lords work.
Interesting about iodine deficiency. My THS is above the reference range, the free T4 is at below the range but free T3 is at 90% of the reference range.
Thyroid patients have been conditioned to our awful symptoms by painful experience. In the case of Hashimoto’s, other autoimmune diseases may become comorbid and present precisely the same symptoms.
The most frequent of these is a condition few docs believe exists–hypocortisolism. Not Addison’s, just enough hypo- to feel terrible. An awful lot of endos look at the labs rather than listening to the patient.
The lab at my local hospital uses a reference range for 6-8am cortisol of 138-690 nmol/L. Such an enormous range has a patient feeling terrible at either end of the spectrum. 300-400 is said to be ideal but how can a doc help a patient achieve that goal and become functional again?
Some turn to T3. Sometimes it works. How else?
Respectfully, I’m not going to address this in detail in the comments section of this particular post. It is off-topic. I will simply say that there is no good evidence that this “mild hypocortisolism” is a real entity. I strongly disagree with any assertion that it is real. For more information, check out my post about the made-up diagnosis of adrenal fatigue, under the adrenal section of this site: Adrenal Fatigue – A Fraud Perpetrated On Unsuspecting Patients
One thing I’ve noticed over the past few years on T4 treatment (and maybe related to the discussion) is some parts of my body seem happy while other parts do not. Could this mean some parts need more T3 than others? Or some parts don’t handle it correctly? Not sure. I also think my levels are constantly going up and down depending on stress and such. I’ll have a string of good days followed by a string of bad days. That being said, my TSH is kind of on the bubble at 2.47…so maybe a small change from stress pushes it up a bit and then I start to feel bad again.
Mike, although I can’t speak to your situation, I think people need to ask themselves: does it make sense for symptoms that cycle on and then off for days at a time to be related to differential T4-to-T3 conversion? If one really had a problem with type 1 or type 2 deiodinases, wouldn’t that tend to be a more consistent problem on a consistent basis, leading to consistent symptoms? Would it not make more sense for there to be other issues like poor quality sleep or increased stress that would be responsible for a few days of feeling lousy, when one feels perfectly well on other days (assuming all other health conditions are stable)?
I think you are correct that stress and sleep are culprits. But I think these cause direct impact on thyroid levels. The level of impact poor sleep and stress has now is MUCH MUCH more than I used to have (prior to being on medication and diagnosis). A year before diagnosis I played on a dart team and sometimes was out until 2am. Getting up for work later that morning at 6:30. Was I tired the next day, sure. But it didn’t impact me half as much as it does now. For me stress is the biggest impact on my health. And I actually live a relatively low stress life. Stress and trauma is what I feel accelerated my hashimotos into full steam. I’m sure I had this going on (at a lessor level) for many years or decades. But it accelerated quickly after trauma and stress events. What I think doctors may not realize (unless they have this issue) is the direct impact on thyroid levels. A high stress day at work usually sets me back a few days. My stools get poor, my energy gets low (and not a normal low), I get colder, etc. However, this has gotten less strong the better my thyroid levels have become. But unfortunately it’s still occurring. My personal observation is I feel I’m on the edge of good numbers (TSH 2.47)…so anything stressful, bad sleep, less exercise puts me probably above that and I feel bad. My set point maybe somewhere around 1-2. This is one example article talks to this: https://pubmed.ncbi.nlm.nih.gov/17192582-the-role-of-stress-in-the-clinical-expression-of-thyroid-autoimmunity/
Another observation on these situations where I have stress and I feel it impacts my thyroid levels. My voice get horse and the pitch changes. My wife will ask “are you extra tired today, because your voice sounds different”. It’s very interesting.
Thank you for posting these details. Very helpful. I don’t have a Thyroid. I have read in research papers that the heart does not make its own T3 so relies on free T3 – if I understood correctly. If that’s correct I assume it’s a good idea to check free T3 levels, yes?
I take 5mg of T3 daily and when I miss taking it I consistently notice an increase (10 to 20 beats per minute)in my heart rate when exercising- I wear an Apple Watch for tracking.
The heart has D2 activity, so it can make T3. The question of whether to check FT3 will be addressed in the next post.
Very interesting article! I’m especially interested in the iodine deficiency comparison that you made. I had Graves when I was 8 and spent the next 7 years trying to control it. During that time, my endo told me not to use iodized salt. Out of habit, I just never went back to iodized salt even after I had RAI at 15 years old.
I’d be interested in an article about idione deficiency, especially in patients who have had a thyroidectomy or RAI. Should we resume taking iodized salt, or does it not matter? I always assumed that it didn’t matter, but if it can cause a decrease in conversion, I’m not so sure anymore!
I have MTHFR gene and hashimot’s, I am always hypo, I am taking Levothyroxine only I believe I have histamine intolerance and allergy to sulfa. What am I missing that I could take to help? I have tried t3 to help convert this, as I am not converting to t3. Thanks for any advice .
Thanks for the great articles and for the suggestions for how to broach T3 supplementation with an endocrinologist. I am currently trying to get a referral to an endocrinologist but the wheels of medicine move slowly. In the meantime any input you can give me would be greatly appreciated.
I have a 30 year history of hypothyroidism (TSH >20 at diagnosis). On levothyroxine 75mcg I am euthyroid (TSH in the lower half of the normal range) with symptoms well controlled EXCEPT for longstanding (decades) cardiac signs (bradycardia [usually 30-45bpm at rest] and PVCs/PACs). Echocardiogram shows that my heart is normal for my age (69), I don’t have cardiovascular disease (CT calcium score of 0), my cholesterol and LDL-cholesterol are borderline and my HDL cholesterol is high. In contrast to the typical hypothyroid picture, I have never struggled with weight gain but have always been thin. I don’t suffer from anxiety.
My current problem is that my bradycardia has become symptomatic within the past year (dizziness at rest, and dyspnea with exercise, each about once or twice weekly) and my cardiac pauses have become longer…these are now mostly 1-3 seconds but a couple were 5 seconds). My cardiologist has recommended a pacemaker but I would like to trial supplemental T3. I have two questions:
1) Based on the science, is T3 a reasonable option for persisting bradycardia in hypothyroidism otherwise controlled with levothyroxine?
2) How long of a trial of T3 would be needed to see if it resolves my bradycardia and its symptoms?
Thank you again for the work you do.