Paper showing how the body/thyroid interraction responds to the failing thyroid

[diogenes]

We also have a paper in the European Journal of Clinical Investigation accepted today as well. It will be available soon. It shows that, as the thyroid function declines, the whole system of body and thyroid whips up T4-T3 conversion to try to maintain FT3 in the body as close to normal as possible in the face of a reducing T4 supply. When thyroid function is getting very close to zero, the frenzy suddenly collapses and a new situation arises where the relation between T3 and T4 becomes very unstable. This leads to quite different needs for control of treatment for those who have some thyroid function left as opposed to those who have none.

[jimh111]

Thank-you for your work. This is an area I'm very interested in as although it is generally accepted that type-2 deiodinase (D2: T4 to T3 conversion) is upregulated when fT4 falls there is also evidence that elevated TSH also upregulates D2, at least in the thyroid and brown fat. I believe TSH upregulates D2 in the brain but I’m not aware of any studies demonstrating this.

This is very important as we see many patients on this forum with a normal TSH and low normal fT3 and fT4. Their thyrotrope has not responded adequately to combined low fT3, fT4 indicating a down-regulated axis. These patients often have quite substantial symptoms such that they cannot lead a normal life.

A key factor of D2 is that it is responsible for local T3 regulation as well as being the prime source of serum T3. Patients with reduced D2 activity will be hypothyroid in D2 regulated tissues, even if serum T3 is restored to normal levels. This might explain why so many patients on liothyronine require above average fT3 levels to feel well. Higher fT3 levels are needed to restore local fT3 levels in these D2 regulated tissues such as the brain.

[Polly91 in reply to jimh111]

Very interesting jimh111

Can you explain to me what D2 does- is it responsible for conversion of FT4 to FT3 ?

Also are you saying it goes up when FT4 is low?

How do you find out about your D2?

Thank you

Polly

[jimh111 in reply to Polly91]

Polly, there are three deiodinase enzymes D1, D2, D3. The subject is very complex and challenging, even for the expert researchers in the field. Very crudely: -

D1 takes over when thyroid hormone levels are high, it converts T4 to equal amounts of T3 and reverse T3 (rT3 inhibits the action of T3). It also converts rT3 to T2. D1 seems to be a mechanism for preserving iodine and preventing thyrotoxicosis.

D2 activity increases when thyroid hormone levels are low, it converts T4 to T3. D2 activity is also stimulated by TSH in some tissues. As well as contributing to serum T3 levels D2 is responsible for maintaining local levels of T3 in organs such as the brain.

D3 converts T3 to T2 and T4 to rT3, thus it lowers the levels of T3. D3 activity increases when hormone levels are high.

So generally T3 levels are maintained by D2 and D3 working together. If you start to get high levels of hormone, due to hyperthyroidism or taking high doses of thyroid hormone D1 increases in an attempt to prevent thyrotoxicosis.

There is no way you can measure your D2 activity. You can get a rough idea by looking at your fT3, fT4 levels to see if they look normal. In this respect you need to look at fT3 when your fT4 is around average. I don't believe in using an fT3 / fT4 ratio because this ratio changes as hormone levels go up or down. It is useful when hormone levels are averaging but it's in danger of giving a false sense of precision.

As diogenes points out the body reacts to falling thyroid hormone levels to preserve T3 levels but there comes a point when stepping up D2 doesn't work because there just isn't enough T4 to convert. His comments also suggest there are other mechanisms involved which are revealed in his new study.

This document ncbi.nlm.nih.gov/books/NBK2... gives a good description of the deiodinases. You have to register (for free) to view it. It is a difficult subject but Fig 2 has a useful diagram. Tony Bianco is the leading expert in this field, his website deiodinase.org/ is a great resource. Again the subject matter is difficult to understand, not helped by the tiny print!

[Polly91 in reply to jimh111]

Gosh you guys really know your stuff. Thank you for explaining it in layman’s terms for me. What a complex area. No wonder GPs don’t really understand it.

Thank you

P x

[trelemorele]

Do you have informal link to that paper?

Thanks

[diogenes Remembering in reply to trelemorele]

Not until it gets an official doi number.

[linda96]

Thank you Diogenes, looking forward to seeing this paper. Would it also apply to patients who's thyroid gland is destroyed for one reason or another?

[diogenes Remembering in reply to linda96]

The difference is whether you've got any working thyroid left or not. How this happens isn't important compared with the drastic difference between having any kind of thyroid and none at all.

[TSH110 in reply to diogenes]

Is there any way to determine this? I was told mine had shrivelled up, was very small indeed and highly unlikely to have any function (ultrasound), but I know the thyroid tissue can regenerate.

[diogenes Remembering in reply to TSH110]

The general idea is that, until the thyroid is lost, FT3 (no therapy) does not decline very much owing to compensation. On total loss, FT3 will plummet as of course does T4.

[Hidden in reply to diogenes]

If FT3 level is maintained via compensation how do symptoms develop? I've seen quite a few people on here (no therapy) with almost identical FT3 levels across a series of tests. So the compensation mechanism seems to be in operation as FT3 almost identical between subsequent test results. TSH may have risen from say 2.5 up to 8 to increase conversion of T4-T3 but they are very much more symptomatic. Feeling much, much worse. Yet FT3, as you say, is compensated and maintained. Their test results prove this. So how do symptoms develop at all since T3 is the active hormone and it's being maintained at the same level? Does reverse T3 come into play to down-regulate metabolism and save energy? Then symptoms become worse.

[diogenes Remembering in reply to Hidden]

I ought to say that FT3 remains within its reference range whilst the thyroid is dying. But the actual FT3 might not be high enough for someone to have a level adequate for them.

[Hidden in reply to diogenes]

Thanks for clarifying that key point. So when I mention FT3 being consistent between subsequent tests the fact remains that FT3 is more than likely too low for the person to feel well. Most people don't get thyroid panels done when they feel well so would have no idea what their FT3 was when they were well. I have no clue what mine was in health.

Something that often worries (and puzzles) me as a T3 only taker - If the body pulls out all of the stops to maintain a consistent FT3 level, how does taking T3 (whether in mono or combination therapy) affect this? It seems wholly unnatural to have FT3 peaks and troughs. That doesn't seem to be how mother nature intended, in fact quite the opposite. What will the body do to compensate for varying FT3 levels? Modulate T3 at the cellular level?

[diogenes Remembering in reply to Hidden]

I've come round to thinking that we shouldn't merely regard the FT3 levels as "instantaneously dangerous" when they peak after swallowing T3 tablets. The T3 will take time to stimulate whatever biochemical events happen in the cells, so that the actual effects of the blip in T3 might be considerably smoothed out because of this. It isn't perfect of course, but possibly the actual responses are more muted than appears from the T3 spikes.

[Hidden in reply to diogenes]

That makes sense thanks.

[jimh111 in reply to diogenes]

Thyroid hormone receptors need to be saturate in T3 for several hours before DNA transcription takes place. Although total T3 levels will increase substantially after ingesting liothyronine (or NDT) the free fraction varies less (if I remember correctly). Free T3 is actively transported into the cell nucleus by cellular transport proteins and made available to receptors. This takes time. Also deiodinase activity works to stabilize T3 levels. Even after DNA transcription the proteins released take considerable time to take effect, e.g. T3 lowering cholesterol levels or raising the resting heart rate.

All these mechanisms buffer the variability of T3 so the variations in total or free T3 are of much less consequence than long term T3 levels. In technical jargon it is the pharmacodynamics that matter not the pharmamokinetics.

[TSH110 in reply to jimh111]

Very interesting and why I don’t feel as high as a kite after ingesting my daily NDT, in fact if I ever forget it to take it I still feel ok that day - clever thing the body!

[jgelliss in reply to diogenes]

Diogenes

Thank you for your very interesting and very valuable information's that you present to our Great Forum . I am wondering when I was going thru an ailing thyroid my heart would go thru palpitations . Would that be high T3 or high T4 trying to compensate for the ailing thyroid gland ? Or is it a lack of optimal thyroid hormones and the adrenals kicking in to compensate for the loss of thyroid hormones ?

[diogenes Remembering in reply to jgelliss]

It will arise from a FT3 inappropriate for you, probably slightly lowered from your healthy level, which the heart is sensitive to.

[jgelliss in reply to diogenes]

Diogenes

Thank You so much for clarifying It . Great and Very Valuable Information as Always . I'm Very Amazed and Very Appreciative to all the Great information's you so very kindly provide us .

Being Dosed on T4 Only after my TT caused me Much palpitations . Ironically I do well with higher T4 with just a small dose of T3 . It's a Very Fine Line and Balancing Act .

[TSH110 in reply to diogenes]

I wonder if this explains how I kept going for so long. I had lots of symptoms (felt like I was in the artic for 30 years) all treated as individual problems as no one saw any pattern to it all, despite my suggestions it could be thyroid related (my mother and grandmother had thyroid problems then a sister) . I started really going off the rails only in the last few months before diagnosis getting long bouts of hypo peppered with short intense hyperthyroid phases where I’d go completely crazy. I was so bad by the time I got diagnosed the whole caboose must have shut down. It was really horrendous when I think back. Oddly the worst time of all was once I got Levothyroxine and the long horrible fight to try and get better. Only NDT really gave me proper quality of life. I have that DIO2 thing giving me poor conversion of T4 to T3.

[UrsaP in reply to TSH110]

It is possible isn't it to have both Hyperthyroidism and Hypothyroidism? I used to think the high to low, which could happen within minutes. hours/days or weeks ...very erratic, was due to the nature of Hashimoto's but although my records show antibodies in 1982, I can't see them showing since. Never quite got to the bottom of the cause of my condition. I saw a specialist for about 18 mths around '82-84, there were intermittent positive bloods - positive for what I wouldn't know, records do not make clear, but was dismissed by specialist without treatment. GP put Acquired Hypo down in 1992 when they finally gave me a diagnosis.

There is more HypEr in family, two older sisters, Aunt, lots I can see - as yet undiagnosed, both HypEr and HypO. Mam had two types of TC.

All I know is that a further 20 years of T4 made me more and more ill and left me unable to work, CFS, Fibro and constant migraines. Dropping T4 for T3 was like heaven, within days these symptoms dissipated. Only to return every time I started back on T4! Hence T3 only for the last 8 years.

Got my DNA earlier this year, and heterogeneous for DIO2.

So in theory I should be able to convert some T4 but just could not take it.

Some years ago Dr Peatfield said it was likely that the enzyme that converts had stopped working and couldn't be restarted.

[TSH110 in reply to UrsaP]

I am not sure if you can have both hypo and hyperthyroidism. I have read some believe that it all starts as hyperthyroidism and the course of the disorder as the antibodies attack the thyroid and destroy it eventually leads to a state of hypothyroidism. That the two are just different sides of a coin so to speak. I was always full of energy when I was younger and have some gene markers for graves but not Hashimotos. I also got very mixed symptoms with some minor eye involvement more akin to Graves. I understood the hyper episodes occur as bits of the thyroid die as the antibodies attack it and dump their stores of thyroxine causing an excess of hormones then a reversion to a hypothyroid state ensues.

You must have had antibodies test positive from what you say. Have you tried requesting copies of your test results to see if that reveals anything helpful? I think you can have both types of antibodies so perhaps you can have both disorders at once. May be an expert in this area could elucidate...

Mostly it is hypothyroidism in my maternal line, some with lymphoma, mine was just autoimmune with no goitre and one errant sibling has hyperthyroidism. Nearly all of us have succumbed to some sort of thyroid problem. Another branch of grandmothers siblings all went blind with glaucoma which I understand can be related to thyroid problems.

There is still much for the medicos to discover I hope it becomes a very exciting area of research pulling in the best enquiring minds, rather than being viewed as the poor relative to diabetes, needing nothing more than a dose of daily Levothyroxine, after removing any pesky glands/ hitting a TSH of 10 or more. Talk about a blunt approach....small wonder so many never feel properly well again.

[UrsaP in reply to TSH110]

I think I may have read something somewhere that indicated it is possible to have both...possibly as you say - both sets of antibodies, but I never have antibodies showing when I had 'flare ups'. I also have had eye problems too, since around the same time, '82 - been seeing specialist about that intermittently. Always told not TED as HypO not HypEr. Again read recently 10% of TED caused by HypO. Was referred back to eye specialist last year, was having real problems with glasses prescription changed several times over just a few weeks. Specialist declined the referral and I could not get a reason?? Suspect because it says might say'Hypo' on the file - (whether hypothyroid or hypochondriac?? LOL - not!)

I asked to see my GP files earlier this year, was asked to go in to see them - I was largely print outs of summaries that I had already had, with the very old the of beige folder that the GP's use to right on and put docs inside. How things have changed. The paper work told me very little and I'm pretty sure I have not seen all my file, not by any stretch - no outer folder, wonder what is written on that!

I queried some very low FSH and LH levels taken in 2004 - that I did not recall, had to chase Dr - he even ignored the tel appointment I had made in the end to try to talk to him about it. He only rang me back when I spoke to a receptionist I know and said that I was wanting to cause trouble...he rang back about an hour later, and 'admitted' he had seen, but lost my letter???? Right!

It was around that same time that my tsh dropped very low, (was not on T3 at the time) He said that the previous Dr had noted low FSH and LH due to being on the pill. Would that be right ?? And when I queried that only a few months later I stopped the pill, yet the TSH stayed low since, he had no real explanation. He did agree, with persuasion, to redo the FSH but would not do the LH. FSH came back low Post Meno stage.

2004 was probably when I was heading into my worst ever health, Massive stress going on.

Anyway, apologies diogenes didn't mean to hijack the thread.

So many unanswered questions out there.

[TSH110 in reply to UrsaP]

Have you tried Moorfields eye hospital in London? I understand they have a drop in clinic it might be worth a punt they are supposed to be excellent. Mine was not diagnosed as TED but I am sure it was a minor case I was investigated fue myasthenia gravis but results were inconclusive it can just affect the eyes and often goes into remission. Perhaps I was a lucky one there. About 30% with it have no antibodies for MG.

[UrsaP in reply to TSH110]

No, must bear that in mind. Thank you. I have reoccurring ulcers in one eye...odd that it is always that same eye. Sensitivity to light, wear sunglasses in the rain! Always used Maui Jim sunglasses, expensive but brilliant anti glare, reckon they are the best lenses in the world. But as last year's problems left me needing distance as well as reading, I can't now just use sunglasses and their prescription sunglasses are out of my price range, especially if last years problem reoccurs, where the prescription changed several times in a very short time. Really miss them! Have polaroid, but just not a patch on Maui's.

I thought my flare ups might be Sjogrens, as when flare get really dry mouth too, or even lupus, but nothing showing in tests.

[TSH110 in reply to UrsaP]

MG causes difficulty in swallowing and doing repetitive tasks as the muscles fatigue very rapidly. It is not a very nice condition and very rare but with some association with thyroid problems - trust you don’t have it. You should try and go to Moorfields when an ulcer appears and see what they say.

[UrsaP in reply to TSH110]

Mg sounds awful. I don't have that, I think I would know if I did. Ulcers are bad enough thanks. They have left scarring all over my left eye, so live with permanent 'blurring' especially with light. But eye seem to compensate. Just more annoyed that can't get use my 'good' sunglasses!

[TSH110 in reply to UrsaP]

I checked Moorfields and the only option is A&E if they had a walk in clinic it has gone ☹️ you could go if it became acute esp if no one is looking after it for you. It sounds awful. I had a dog who got endless eye ulcers and had op after op. I later realised she must have been hypothyroid - it is a related condition and both her pups were diagnosed with it I feel sad because it must have killed her but no vet ever suggested it might be that, thinking back she has many other suspicious symptoms. Once I got it myself I put two and two together and realised her offspring were suffering from it, and tests were positive, but she had died by then. She was a total sweetheart of a doggie, I feel bad that she suffered unnecessarily and I was not knowledgable enough to help her - not for want of trying the times I took her to the vets - several at that...all useless.

Is there anything you can do to try and lessen the ulcers? Oddly occuloheel a homeopathic eyedrop for dogs ( they do human version too) really helped and I only tried it in desperation with no faith in it being efficacious whatsoever - worth a go perhaps? I think it is by Nelsons

[UrsaP in reply to TSH110]

It is very sad about your dog. I know cats can be susceptible to it too. My neighbour's cat was on thyroxine. That is the problem with animals they can't tell us what is happening. At least you realised that the pups had it and got them help.

I wonder if we would get better treatment if we went to vets?

I will look at Occuloheel. [I always found Nelsons teetha great for the kids.] I don't have the ulcer at the moment but when I do get it, it can come on very quickly. I have yet to find drops that really help.

[linda96 in reply to diogenes]

That's what I was thinking. Thank you for confirming.

[shaws Administrator]

Thank you and your team for working so hard and getting good information.

[UrsaP]

Great thread, lots of information to digest. Thank you diogenes , and all.

[Polly91]

Thank you v much Diogenes- wish my GP knew half what you & others on this forum know about the thyroid.

Xx

[lady_eve]

Fascinating. I look forward to reading it in full.

Thank you.