✅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.
- 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.