Insight into molecular determinants of T3 vs. T4 recognition from mutations in thyroid hormone receptor alpha and beta

[helvella]

Sometimes a paper is way above my head in some ways - and this is one. Nonetheless, it is of considerable interest that it describes a fundamental reason for T3 being the active hormone. It also explains why a genetic mutation can make T3 considerably less effective and is a basis for one form of Resistance to Thyroid Hormone.

Obviously this is rare, probably genuinely so, but the mere fact that it exists should be absorbed by all endocrinologists to be brought to the fore before dismissing the patient in front of them. Oddities can and do occur and must not be missed and ignored simply because they are infrequent.

J Clin Endocrinol Metab. 2019 Feb 28. pii: jc.2018-02794. doi: 10.1210/jc.2018-02794. [Epub ahead of print]

Insight into molecular determinants of T3 vs. T4 recognition from mutations in thyroid hormone receptor alpha and beta.

Wejaphikul K1,2, Groeneweg S1, Hilhorst-Hofstee Y3, Chatterjee VK4, Peeters RP1, Meima ME1, Visser WE1.

Author information

1 Erasmus MC, Department of Internal Medicine, Academic Center for Thyroid diseases, Rotterdam, the Netherlands.

2 Department of Pediatrics, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.

3 Department of Clinical Genetics, Leiden University Medical Center, Leiden, the Netherlands.

4 Wellcome-MRC Institute of Metabolic Science, University of Cambridge, United Kingdom.

Abstract

CONTEXT:

The two major forms of circulating thyroid hormones (THs) are tri-iodothyronine (T3) and tetra-iodothyronine (T4). T3 is regarded as the biologically active hormone since it binds to thyroid hormone receptors (TRs) with greater affinity than T4. However, it is currently unclear what structural mechanisms underlie this difference in affinity.

OBJECTIVE:

Prompted by the identification of a novel M256T mutation in a resistance to thyroid hormone alpha (RTHα) patient, we investigated Met256 in TRα1 and the corresponding residue (Met310) in TRβ1, residues previously predicted by crystallographic studies in discrimination of T3 versus T4.

METHODS:

Clinical characterization of the RTHα patient and molecular studies (in silico protein modeling, radioligand binding, transactivation and receptor-cofactor studies) were performed.

RESULTS:

Structural modeling of the TRα1-M256T mutant showed that distortion of the hydrophobic niche to accommodate the outer ring of ligand was more pronounced for T3 than T4, suggesting that this substitution has little impact on the affinity for T4. In agreement with the model, TRα1-M256T selectively reduced the affinity for T3. Also, unlike other naturally occurring TRα mutations, TRα1-M256T had a differential impact on T3- versus T4-dependent transcriptional activation. TRα1-M256A and TRβ1-M310T mutants exhibited similar discordance for T3 versus T4.

CONCLUSIONS:

Met256-TRα1/Met310-TRβ1 strongly potentiates the affinity of TRs for T3, thereby largely determining that T3 is the bioactive hormone rather than T4. These observations provide insight into the molecular basis for underlying the different affinity of TRs for T3 versus T4, delineating a fundamental principle of thyroid hormone signaling.

Copyright © 2019 Endocrine Society.

PMID: 30817817

DOI: 10.1210/jc.2018-02794

ncbi.nlm.nih.gov/pubmed/308...

[jgelliss]

Helvella , Thank You for bringing this interesting and informative Amazing Report . Will this convince thyroid patients on T4 only to perhaps add some T3 ? Most of all will Dr's be more willing and convinced to give scripts for T3/NDT for thyroid patients ???

[helvella Administrator Thyroid UK in reply to jgelliss]

Honest answer? No, it won't.

It just might help some people who seem to take enormous doses of T3 to offer one suggestion as to why they can do so without being over-medicated.

[jgelliss in reply to helvella]

Does it make any sense honestly there are so many proofs and studies and still Dr's are not prescribing T3/NDT . What does it take how much more proofs do we need to show ???

If I'm not mistaking Helvella respectfully are you on T4 only ?

[helvella Administrator Thyroid UK in reply to jgelliss]

I am on T4 only.

But I am completely convinced that T3 is necessary for many.

It is very tempting to try some T3 but I tend to the "if it ain't broke..." camp. How silly to change as I seem to do quite well on my T4 only regime.

Now, if there were some well-proved way of determining, in advance, whether a little T3 would be a good idea...

[jgelliss in reply to helvella]

Thank you for your very kind and *Spot On* response . I was dosed with T4 only after my TT . At first it was great . With time symptoms just kept popping up . Palpitations high BP , weight issues , Insomnia , Jaundice , anxiety , panic attacks etc. Adding a small dose of NDT for my T3 mix made a such a Huge difference . Since then I learned I am not a good converter T4 to T3 and the T3 in the NDT is helping me with that + Nutrients .

It would be nice if thyroid patients would be able to get T3 NDT without having to fight for T3/NDT and Dr's would be on the same page as thyroid patients .

[helvella Administrator Thyroid UK in reply to jgelliss]

At first it was great .

That statement, worded in many different ways, is such a regular feature of this forum. There simply has to be some underlying reason for so many people doing well, sometimes for many years, then not. (Actually, I'd be happy to believe there are many reasons!)

[TSH110 in reply to helvella]

Very interesting post. I like a challenge...but if you find the article tough to comprehend I have no chance - not being able to read the full article is a shame but I doubt I would understand it anyway.

I wonder if this is relevant to bipolar patients who took large doses of T3 but tolerated it well with a goodly number getjng relief from their bipolar symptoms in the STAR*D study.

Do you think our bodies twig the stuff we take is foreign and starts rejecting it?

[TSH110 in reply to helvella]

The proof of the pudding is in the eating!

A relative who feels well on Levothyroxine tried my NDT and did get some improvements, but clearly not enough to keep on it, they soon reverted back to T4. I don’t think it caused any problems once stopped. I know some people seem to get messed up by trying different hormone therapies, but I like to know for myself. I find T3 interesting (4mcg addition to my NDT so quite tame). I have a clearer mind and feel less anxious generally but oddly I am more mercurial which seems a contradiction. I am close to what I once was but it is different. I remember when I got diagnosed thinking with dismay that I was nothing more than a bunch of hormones - they determined everything I was. It is probably more complicated than that...but I do wonder. I think I could have been a medical maverick, they were always experimenting on themselves according to Michael Mosley - it was a great series.

[DippyDame]

Thank you.....been looking for more info that suggests a T3/DIO2 homozygous/poorconversion/RTH connection.

Posted about a possible connection yesterday

healthunlocked.com/thyroidu...

healthunlocked.com/thyroidu...

I'm on 100mcg T3-only...and possibly rising.

Self medicating and much improved

After a year spent "digging", titrating and trial and error I now conclude RTH is the cause of what has been decades of declining health

Will read tomorrow

Best...

DD

[crimple]

Thanks for posting Helvella. Plenty to think about. I am still on my journey of adding in T3 to my 100mcg levo. started on 6.25mcg and then had to buy Thybon Henning, so now on half of 20mcg tablet per day and suspecting I need a bit more. Bloods will confirm. I tend to the view that everyone should have some T3 since that is what a normal healthy thyroid would produce!

[helvella Administrator Thyroid UK in reply to crimple]

My reservations are based on the fact that taking thyroid hormone orally, once a day, is already considerably different to how healthy bodies work.

The best approach might be to add some T3, but quite how? A small addition of T3 once a day could conceivably be no better than T4 monotherapy for at least some of us.

I don't want to fall into the trap of it appearing sensible (which it does) but actually possibly being worse for some of us.

[crimple in reply to helvella]

I agree Helvella and I'm sure that's why diabetics with insulin pumps would appear to be better than those who inject several times per day. Our bodies are constantly producing hormones according to our needs not by the clock. Just something else the medics should but won't grapple with! All too difficult!

[DippyDame in reply to crimple]

By saying, "everyone should have some T3" do you mean everyone, regardless of state of health, should add T3?

I'm afraid I cannot agree if that is what you imply.

T3 is a very potent hormone and should be added only once it , and how it works, is understood. Very careful monitoring of heart rate and temperature are amongst the precautions required.

Do you convert well?

Are your nutrients at optimal levels in order to support conversion?

I have only read the abstract so far but as I understand it this paper refers to a patient with resistance to thyroid hormone (RTH) and the involvement of alpha and beta receptors in the absorption of T3 into the cells. This is a (pehaps) rare genetic condition not to be confused with hypothyroidism. Some suggest it is more prevalent than is recognised.

Patients with RTH can tolerate supraphysiological levels of T3 that would vastly overmedicate someone with hypothyroidism. This large dose is required to ensure adequate T3 reaches cellular level - an action that is impaired by RTH with resultant low T3 and ensuing symptoms.

I gather much is still unknown about RTH

We are all vastly different with vastly differing needs...so many medics fail to understand this. They look at numbers on a scale and forget about clinical assessment!

They also forget that once thyroid hormones are added test results, particularly TSH, can be problematic/misleading

I'm not a medic and these are my own views. I'm just someone who has spent more than a year trying to work out why, over more than 40 years, my health declined very slowly to the point where I could barely function. My doctors had no answers so desperation led me to "hit the books" with much advice and support from fellow members here.

Hope things go well for you

DD

[penny]

I’m on 200mcg of T3 once per day. I once took 500mcg of T3 by mistake and didn’t feel any worse (or better). In fact, other than worrying that this would have an adverse effect, I didn’t feel any different to ‘normal’.

[helvella Administrator Thyroid UK in reply to penny]

Beautiful example of how different we all are.

I don't like being a few micrograms over on levothyroxine. Even thinking about 500 micrograms of T3 gets me sweating and increases my heart rate!

[penny in reply to helvella]

On the contrary, it did not get me in a sweat. It is inevitable that medication is a broad-brush approach, as you say, we are all different, but it would be good if the medical profession would acknowledge this and adjust treatments accordingly. It is very much ‘one size fits all’.

[crimple]

In spite of optimum levels of vits etc my T4 never got above 16 (range 12-22) and T3 has always only just been in lower end of range. Since taking T3 my T3 levels have gone up, but still room to improve (going by how I feel). As I have said before if a healthy thyroid produces enough T4 and T3 then an unhealthy, in my case atrophied thyroid will never produce enough of anything. Add into the mix TPO and TgAb antibodies, which I didn't have when first diagnosed hypo, I am not surprised that I never felt right.