Is T3 from conversion within the cell shown in fT3 blood result?

[ondrej41]

Couldn't find the answer. As far as I understand there is a different pool of T3 from D2 conversion inside cells

[jimh111]

Yes and no, some is. Most of our serum T3 comes from D2. The amount of T3 from thyroidal secretion, D1 or D2 will vary as T3 and T4 levels vary. More D2 when hormone levels are low.

I like to refer to T3 and 'D2T3' to mean overall T3 and D2 derived T3. Not all D2T3 gets into the serum. The best example is D2T3 produced in brown adipose tisssue (BAT) during cold exposure. BAT D2 activity can increase by up to a factor of 50 on cold exposure but we don't see a large increase in serum T3 levels.

You raise an interesting question because it really is D2T3 that matters from a hypothyroid patient's point of view, since it will reflect brain T3 levels.

Just a correction, all conversion takes place within cells, whilst D1 produces T3 for circulation D2 is responsible for local regulation of T3 levels in tissus such as the pituitary, brain and BAT.

There is evidence that TSH promotes D2 in at least some tissues. My view is that if a person is secreting too little TSH for whatever reason it will cause local hypothyroidism which is not corrected by restoring normal T3 levels.

[ondrej41 in reply to jimh111]

Thanks, it is an explanation I was hoping about. How do you think, presumably if D2T3 conversion is lower than optimal, it can lead to a situation, when additional T3 from tablet can't cover the missing effect of lower D2 conversion locally?

[ondrej41 in reply to ondrej41]

I believe I saw some people on the forum who have good fT3 levels on thyroid hormone therapy, but still not feeling either well or well enough. Personally for me it looks like T3 gives energetic and mind-clearer, but not a full or ideal effect and taking more T3 just overstimulates me. But earlier when I took T4 and it was enough for my cells as it had continious effect, every thing clicked in place. I can see D2T3 like one explanation, but other can be an effect of T3 and T4 doses on cortisol and their both effects on the symptoms

[jimh111 in reply to ondrej41]

Some tissues have little or no deiodinase capability and rely on circulating T3. Other tissues such as the brain have a preference for T4 and use D2 / D3 to control local levels of T3. If there is reduced D2 activity you can increase circulating T3 levels to compensate but this will be too much for the other tissues that don't rely on D2. No option is risk free.

[ondrej41 in reply to jimh111]

"There is evidence that TSH promotes D2 in at least some tissues. My view is that if a person is secreting too little TSH for whatever reason it will cause local hypothyroidism which is not corrected by restoring normal T3 levels"

So on hormone replacement therapy someone with good levels of FT3, high-range FT4 and very low TSH can have lower production of T3 in cells (and be more symptomatic) than with the same levels of FT3, low-range FT4 and higher TSH? Because low TSH and high FT4 promotes lower D2 activity

[jimh111 in reply to ondrej41]

It's more complicated than that. Firstly, there will be differences between individuals in their genetic makeup, what polymorphisms they have etc. We are each designed to have different TSH, fT3, fT4 levels.

Some cells use D2 to locally regulate T3, these cells will be dependant upon T4 availability and D2 activity. Other cells rely on circulating T3. In practice cell types will vary between these two extreems.

In the examples you give I suspect T3 levels will be higher in the cells that expresss D2 activity when TSH is high.

A better and more common comparison is a patient with subclinical hypothroidism (high TSH, low normal fT4 and normal fT3). These patients often do well, which is why there is some logic in not prescribing until TSH goes above 10 - provided the patient has no symptoms.

We often see another form where the patients have normal TSH and low normal fT3, fT4. These patients often have substantial symptoms and respond poorly to levothyroxine.

[ondrej41 in reply to jimh111]

So for treating hypothyroidism and its symptoms it's more than just move FT3 to the ideal spot? I have seen results of patients with top of the range FT3, but they still were not feeling quite right.

"A better and more common comparison is a patient with subclinical hypothroidism (high TSH, low normal fT4 and normal fT3). These patients often do well, which is why there is some logic in not prescribing until TSH goes above 10 - provided the patient has no symptoms"

But if this kind of patient has symptoms, it can be due to thing that normal FT3 level is too low for the particular patient, or because there are other requirements to get enough active T3 on a cell level?

[jimh111 in reply to ondrej41]

I was giving an example of a group of patients who can have a high TSH and still be well because their D2 activity has stepped up. Doctors see these patients and then think anyone with a lower TSH cannot be hypo. The concept I'm trying to get across is that not all patients with an elevated TSH will be hypo and some patients with a normal TSH will be hypo. It's very complicated and you have to try and see where the T3 is coming from. (Patients who are doing well with an elevated TSH are probably at risk of cardiac and bone problems even though they are doing fine).

[ondrej41 in reply to jimh111]

I understand it and agree. I was just curious about reasons that inside the given groups of patients with similar tendencies there are some symptomatic and some not. With elevated TSH there will be more D2 activity, and someone doing well, as you say, but for others elevated TSH is a disaster. The explanation could be that they are lacking of that activity due to, for example, genetics?

To see where the T3 is coming from - you mean one could add a dose of Levo and look at changes to FT3 after some time on it?

[jimh111 in reply to ondrej41]

As fT4 falls TSH rises and increased deiodinase is able to compensate and maintain fT3 levels. As fT4 falls further there is insufficient T4 to convert to T3 and the patient becomes clinically hypothyroid. This is the progression of 'simple' primary hypothyroidism. Genetics will no doubt affect their ability to cope and how well they respond to levothyroxiine only therapy.

We can't really see where the T3 is coming from. However, we know that D2 activity increases as hormone levels fall so we can look at fT3 levels when fT4 is average or a little below average. As fT4 becomes low we can't deduce much from blood fT3 levels because they are affected by lack of T4. I believe this reduced D2 activity caused by a low TSH has much greater effect than D2 polymorphisms.

I see patients on these forums with a normal TSH and low normal fT3 / fT4. I deduce these patients have reduced D2 activity and it is probably due to the TSH being lower than it should be for someone with the same fT3, fT4 levels. If you give these patients some levothyroxine they improve but do not fully recover. Giving them more L-T4 does not help. I deduce it is because the L-T4 lowers TSH and so reduces D2 activity. These patients need some T3, more than the amount needed to restore normal blood T3 levels. There haven't been studies to prove this, it is my own theory.

[ondrej41 in reply to jimh111]

It seems like a great guide for the type of thyroid patients with normal TSH and symptoms. However, I'm afraid that doctors will never verify your theory in foreseeable future. For example, my friend, who runs an endocrinological clinic, believes that as soon as there are sufficient T4 levels and TSH, T3 will be optimal for the patient. But at least he is aware of that each patient has his own optimal ranges for thyroid hormones.

"We can't really see where the T3 is coming from. However, we know that D2 activity increases as hormone levels fall so we can look at fT3 levels when fT4 is average or a little below average."

What do you mean by average - an average for the reference range or an average for the particular patient? Because in SCH fT4 can be close to the middle of the range, but TSH is raised. I would assume it can be explained by invidividual's subnormal hormone levels - or, if I apply your theory in other way, maybe also by low D1 activity, and that why there is raised D2 by TSH to compensate for sufficient fT3 levels.

[jimh111 in reply to ondrej41]

It's really difficult to assess where the T3 is coming from but we have to try. The reference interval describes where 95% of the healthy population is so we can use this as a guidline. Individual patient variations are small. The confusion arises when doctors see TSH, fT3 and fT4 as independant variables. You have to regard them as a single system. Patients with a raised TSH, average fT4 are responding normally to an impaired thyroid. The T3 in these patients will be coming primarily from the thyroid and D2 activity, D1 activity takes over when fT4 is high. It's difficult to judge whether T3 is coming from the thyroid, from D1 or D2. We can get an inkling from looking at fT3 levels when D1 activity is low, i.e. when fT4 is not high. it's not precise but it's all we've got.

[Hashihouseman in reply to jimh111]

At last someone who has taken the trouble to understand thyroid systems in more detail.... in particular the compartalisation of thyroid hormone pools and activity and the significant interplay between TSH and D2 mediation do not get enough attention here or in clinical practice. I have often felt the significant downsides of suppressing TSH on energy levels and wellness in general....... understanding more detail and the subtlety of allostatic responses can help explain apparant confusing or unintuitive responses to medication when more is sometimes less! With the caveat of everybody is unique it seems foolish to ignore the apparant set points for the holy trinity of TSH T3 T4 in the healthy population as the optimal target for treatment of the sick thyroid population..... the median levels from the healthy population (never showing suppressed TSH) are surely a good place to start rather some poorly evidenced notion that supressed TSH and higher than normal T4 are the test results to aim for - i cant help thinking its using a sledgehammer to crack a safe.........

[jimh111 in reply to Hashihouseman]

Thank-you. I don't have much internet access at the moment so apologies for slow reply. We would ideally like to measure thyroid hormone activity in the brain. A thought that crossed my mind is that this might be done indirectly by monitoring sleep activity. Certainly I find that when my L-T3 dose is ideal I sleep more deeply and my dreams are vivid. The only concern is that the blood hormone levels that give optimal brain response may be too much for the rest of the body, unless we have good TSH levels.

[diogenes Remembering]

There is a great difference between the rather steady levels of FT3 in the blood, and the fluctuating demands of individuals cells in individual tissues. Organs have to respond minute by minute to different influences and therefore the demand on T3 to cover those needs must similarly change. So not only are FT3 levels within cells different from blood levels, but they themselves change as needed. The FT3 in the circulation is a steady backup to allow immediate supply gross, when fineturning by cells serves their unique time-dependent needs.

[ondrej41 in reply to diogenes]

But the only mechanism for cells to have target levels of T3 is deiosinases, isn't it? So when someone takes too high dose of T3, fT3 goes up and he can get hyperthyroid symptoms - and these symptoms should come from too much T3 in cells. Isn't it because deiodinases can't cope with it, because their work is dependent on levels of fT3, fT4 and TSH, and genes?

I'm trying to understand why some people even on this forum could have their fT3 high enough, but still feel hypothyroid or not as well as they can. So I thought may be it;s because fT3 is not the only thing and there is invisible (on blood tests) T3 inside cells from D2, which is lower than optimal on replacement therapy, if it is not ideal for a person.

[diogenes Remembering in reply to ondrej41]

The T3 in cells will be a combination of T3 already made and circulating through the blood, and any extra needed by deiodinases converting T4 to T3 in a particular cell. If cells are resistant to T3 then of course more T3 would be needed to get the right level inside the cell. High FT3 in the blood indicates hyperthyroidism, which will swamp the cells' requirements regardless of any more deiodinase activity which will only make things worse.

[ondrej41 in reply to diogenes]

So I had in mind situation (especially on manual hormone replacement) when there is D3 deiodinase which can inactivate excessive T3 to T2 and also block conversion from T4 to T3. Maybe this could prevent person going to hyperthyroid state and instead gives him hypothyroid symptoms, or a mix, when he excessed sweet spot.

Could I ask if TSH can respond not only to thyroid levels in blood, but also to levels within cell, generated from local conversion? Because (as I read in one paper) in subclinical hypothyroidism there is a modified HPT axis comparing to normal person's. So there is enough thyroid hormone in blood and TSH is high and conversion should be higher. But SCH is still associated with health problems and often symptoms (which are low action in cells, but TSH presumably goes by blood). I can't connect it

[diogenes Remembering in reply to ondrej41]

TSH response is probably to blood levels, because the hormone levels there enter the pituitary and do not reflect individual different levels in cells elsewhere. In SCHypo, for a given TSH, FT4 is on average lower by 1 pmol/L from health, and in SCHyper, 1 pmol/L higher. This means that in SCH the thyroid is stressed but not actually diseased. It may either become dseased later or simply go back to normality. There is no safe prediction but wait and see. There is one more complication, in that the way one draws graphs to distinguish hypo, eu and hyperthyroidism is as done at present incorrect. If it is done properly, a significant number of SCH's are no longer that, but in the normal range.

[ondrej41 in reply to diogenes]

I wonder how can we distinguish if SCH is just an equilibrium between TSH, FT4, FT3 to reach given FT3 or high TSH in SCH can really be interpreted as the body's need for more thyroid hormone and automatically lower T3 levels in cells. If we supplement thyroid hormone in SCH, do we actually increase T3 levels in cells (or overall T3 levels) longer term, or we just get a new set-point for all values and T3 will be on previous level?

"In SCHypo, for a given TSH, FT4 is on average lower by 1 pmol/L from health, and in SCHyper, 1 pmol/L higher"

So in SCHypo we can simply add thyroid hormone to reach lacking 1 pmol/L and this will lead to euthyroid state?

[diogenes Remembering in reply to ondrej41]

SCHypo is a multifactorial feature. For some its just a temporary episode that has been caught purely at random and will return to normal soon. For others its an initial indication that perhaps sometime in the future, overt hypothyroidism will occur. I believe that for all of us, healthy apparently, periods of SCH will occur owing to stress, injury etc. If we show no symptoms we shan't be measured and the episode passes unnoticed. So I don't think giving T4 willynilly is necessarily useful - the individuality of presentation should decide.

[ondrej41 in reply to diogenes]

Can't argue with that. It's complicating because SCH is just a term to explain blood results when in reality person can only be hypothyroid or not.

Could I ask if healthy thyroids are somehow limited to produce amount of hormones (limited by thyroid capacity)?

[diogenes Remembering in reply to ondrej41]

In health, there is a limit which is dictated by thyroid size and activity. But when the thyroid slowly disintegrates, the remnant tries its best to keep things going. Though T4 production is reduced, T3 production tries to keep as normal as possible until the very last moment. Our individuality is determined by thyroid size and activity on he one hand, and conversion of T4 by the body on the other.

[ondrej41 in reply to diogenes]

I thought why in long-term SCH there is an elevation in TSH and not the production of more T4 if the thyroid is capable for it. Because, as I saw, in Thyroid Hormone Resistance there is high TSH and also high T4, so healthy thyroid can potentially produce a bunch of T4. But it's usually not in SCH, so logically thyroid in long-term SCH can have limited capacity

[diogenes Remembering in reply to ondrej41]

SCHypo is a consequence of the thyroid being slightly underactive as regards T4 production and thus a slightly higher TSH in response. As I said it may resolve as a temporary effect or it may herald more serious problems in the future, near or later.