Differences in hypothalamic type 2 deiodinase ubiquitination explain localized sensitivity to thyroxine

[helvella]

helvella here! Desperately hoping that diogenes will respond with some explanation of this.

My initial take is that if the hypothalamus has greater sensitivity to T4 (than do other cells), then its onward signalling will be affected more by T4. As part of the role of the hypothalamus affects conversion of T4 to T3 elsewhere, this greater sensitivity to T4 could reduce the T4 to T3 conversion downstream when there actually is still not enough T3.

Please tell me if that seems wrong!

J Clin Invest. 2015 Jan 2. pii: 77588. doi: 10.1172/JCI77588. [Epub ahead of print]

Differences in hypothalamic type 2 deiodinase ubiquitination explain localized sensitivity to thyroxine.

Werneck de Castro JP, Fonseca TL, Ueta CB, McAninch EA, Abdalla S, Wittmann G, Lechan RM, Gereben B, Bianco AC.

Abstract

The current treatment for patients with hypothyroidism is levothyroxine (L-T4) along with normalization of serum thyroid-stimulating hormone (TSH). However, normalization of serum TSH with L-T4 monotherapy results in relatively low serum 3,5,3'-triiodothyronine (T3) and high serum thyroxine/T3 (T4/T3) ratio. In the hypothalamus-pituitary dyad as well as the rest of the brain, the majority of T3 present is generated locally by T4 deiodination via the type 2 deiodinase (D2); this pathway is self-limited by ubiquitination of D2 by the ubiquitin ligase WSB-1. Here, we determined that tissue-specific differences in D2 ubiquitination account for the high T4/T3 serum ratio in adult thyroidectomized (Tx) rats chronically implanted with subcutaneous L-T4 pellets. While L-T4 administration decreased whole-body D2-dependent T4 conversion to T3, D2 activity in the hypothalamus was only minimally affected by L-T4. In vivo studies in mice harboring an astrocyte-specific Wsb1 deletion as well as in vitro analysis of D2 ubiquitination driven by different tissue extracts indicated that D2 ubiquitination in the hypothalamus is relatively less. As a result, in contrast to other D2-expressing tissues, the hypothalamus is wired to have increased sensitivity to T4. These studies reveal that tissue-specific differences in D2 ubiquitination are an inherent property of the TRH/TSH feedback mechanism and indicate that only constant delivery of L-T4 and L-T3 fully normalizes T3-dependent metabolic markers and gene expression profiles in Tx rats.

PMID:

25555216

ncbi.nlm.nih.gov/pubmed/255...

Wiki page about ubiquitin:

en.wikipedia.org/wiki/Ubiqu...

Rod

PS: I have always wondered at the technology of implanted medicines, whether by diffusion from a solid or gel, or using a micro-pump. Have continued to wonder why no-one seems to be attempting to use those technologies for thyroid hormone - but regular as anything for depo provera and such like.

[PR4NOW]

Rod, full article PDF here. Dr. Bianco's work again, maybe there is some intelligence in the profession of endocrinology after all.

jci.org/articles/view/77588

"However, patients on L-T4 monotherapy exhibit a relatively higher serum T4/T3 ratio (3), with unknown long-term consequences to thyroid hormone signaling and general health. This is particularly relevant given that clinical studies indicate that 5%–10% of L-T4–treated hypothyroid patients with normal serum TSH have persistent symptoms that can be related to the disease "

I don't agree with the 5-10%, I think that is vastly understated. PR

"These observations that a lower serum T3 and higher serum T4 could independently dampen thyroid hormone signaling support a modified approach to treatment of hypothyroidism that includes combination therapy with L-T4 and liothyronine (L-T3), through administration of either L-T4 plus L-T3 or desiccated thyroid extracts, which inherently contain both compounds."

"Only combined therapy with constant delivery of both L-T4 and L-T3 fully normalized T3-dependent metabolic markers and gene expression in Tx rats. These findings have important implications that may support the role of combination therapy in the treatment strategy for humans with hypothyroidism and thus may drive the need for development of improved pharmacologic modes for L-T3 administration and for high-quality randomized controlled trials in humans."

"Avoiding a higher serum T4/T3 ratio through chronic combination therapy with L-T4 and L-T3 through slow-release subcutaneous pellets was key to normalize thyroid hormone–dependent biological parameters in the brain, liver, and skeletal muscle."

[helvella Administrator in reply to PR4NOW]

All my ability to find anything, especially new papers, seems to have disappeared recently!

Thanks.

Rod

[PR4NOW in reply to helvella]

Rod, Holy Cow, this is a major finding, I can't wait till you read the whole paper. PR

[shaws in reply to PR4NOW]

This is an excerpt from an Endocrinology Meeting in April in 2002. So 13 years later we're no further forwards and certainly it hasn't come full circle. Why do we have abstracts, etc. that no-one seems to take notice of.

AD Toft

Endocrine Clinic, Royal Infirmary, Edinburgh, UK. Excerpt

However, a significant minority of patients only achieve the desired sense of well-being if serum TSH is suppressed. Furthermore, patients rendered hypothyroid following treatment of thyrotoxicosis and taking a dose of T4 which maintains a normal TSH, gain more weight than those who do not become hypothyroid. Studies in hypothyroid rats suggest that it is only possible to restore universal tissue euthyroidism using a combination of T3and T4. In patients in whom long-term T4 therapy was substituted by the equivalent combination of T3 and T4 scored better in a variety of neuropsychological tests. It would appear that the treatment of hypothyroidism is about to come full circle.

thyroiduk.org.uk/tuk/resear...

[PR4NOW in reply to shaws]

shaws, endocrinology is 50 years behind what patients have had to learn to survive the inferior standard of treatment we are subjected to but this paper is an important milestone in their catching up to reality. PR

[shaws in reply to PR4NOW]

If they take notice and not just file it away somewhere, never to see the light of day again.

I certainly hope it changes attitudes in this New Year.

Happy New Year by the way.

[PR4NOW in reply to shaws]

And a Happy New Year to you also. PR

[helvella Administrator in reply to shaws]

shaws,

Are you, or is everyone else here, going to LET THEM file it away and forget it? The effort you put in to spread the word is a powerful weapon. And you are not going to stop now, are you?

The building of patient understanding, the growth of communication among patients, is simply not going to allow it to be ignored.

I note this quote:

In other words, a high serum T4/T3 ratio in L-T4–treated patients could actually reduce thyroid hormone signaling in D2-expressing tissues such as brain and BAT.

And ask the question: Why do so many people appear to feel worse when their Free T4 appears fine?

Of course, we can only know T4/T3 ratios if we have T4 and T3 tests. That might be the first challenge for many.

Rod

[Spareribs in reply to helvella]

but we're tired...

in the trenches...

[shaws in reply to helvella]

I think when there is any injustice it really riles.

What should be a relatively easy way to treat humans adequately with whatever thyroid hormones suits in this day and age, that the guidelines restrict the doctors from prescribing and it just doesn't make sense trying to 'fit' a person into a nonsense range or medication that makes you worse with far more symptoms than you presented before being diagnosed. Also that their knowledge of what appears to be a 'common' disease is appalling.

At present, I don't want any blood tests as I am in a good stage and don't want any interference in my dose if my bloods are 'out' or 'in'. On reflection that's how it used to be, i.e. medicate patients until well (if they are diagnosed at all nowadays). As we know thousands aren't and the sorry stories of many of our members prove this.

The biggest surprise/shock to me was that I remained undiagnosed with not one person even remotely thinking of the possibility of maybe a 'thyroid' condition. Even in desperation saying to the GP 'I want to pay for a full body scan' there's something far wrong and given yet another full range of blood tests which came back as 'absolutely fine'. By now heart playing up and Cardiac Dept discharge you with 'probably viral with high cholesterol'. No red flags whatsoever popped up. Thank God a first aider suggested thyroid gland. The fact that not one medical person even thought of the possibility shows that the gland is not even remotely considered. I also saw two ENT specialists - wrong diagnosis given.

And the poor Irish Mother of 3 who drowned herself leaving a bereft husband and children and more sorry stories we have read here. It's criminal.

[PR4NOW]

Rod, after taking some time to digest the study I believe this is one of the most important studies you have posted. PR

[helvella Administrator in reply to PR4NOW]

Afraid I *still* have not read it all. But it does appear to be one of those "giant leap for mankind" papers. The suggestion that we need to find some way of delivering both T4 and T3, continuously, is precisely what I (and surely many others) thought would be the obvious direction to follow. The idea that once-a-day dosing might be sufficient was surprising - and, if indeed adequate, would have been wonderful for its simplicity.

And now, at last, a possible explanation for some of the apparent inconsistencies and oddities. Or a step towards that.