Are there any tests that give an indication of tissue level we patients can get hold of? I see sometimes a package of things including cholesterol is used to give some indication?
Sex hormone binding globulin (SHBG) levels in serum seem to be indicative of eu- or hypothyroidism overall. But specific tissue tests are still in the blue skies for now.
Thanks for posting this, I will read it carefully when I have time. One initial point, humans have much more peripheral control of thyroid hormone than rodents. So, it may be that tissue levels will be more stable in humans but still subject to a similar variation with possibly a greater difference between circulating and tissue levels. For example, in healthy subjects the brain takes in mostly T4 using D2 to control T3 levels. Clearly this implies brain T3 levels are different to circulating levels.
As regards markers for thyroid hormone activity cholesterol, lipids and SHBG are crude markers. SHBG is specific to the action of TRB1 receptors. In a report on endocrine disruptinng chemicals the WHO and UNEHP called for urgent action to identify end point markers for thyroid hormone activity although I'm not aware of any progress. Dr Carla Moran at Addenbrookes is currently carrying out research into biochemical markers to identify TRA1 activity. Although very technical and specific this work may throw up some better markers. My view is that the best markers are ankle reflex time and dry skin. Both are very specific to hypothyroidism.
I've read this paper. It confirms earlier research that tissue T3, T4 levels vary considerably. Local regulation of T3 is thought to be controlled by the deiodinases and cellular transport proteins. Humans have more local regulation than rodents. i.e. there are greater discrepancies between blood and tissue levels in humans. T3 levels in the human brain are tightly controlled by type-2 (D2) and type-3 (D3) deiodinase.
A disadvantage with this study is the use of propylthiouracil (PTU) since as well as inhibiting the production of thyroid hormones it blocks type-1 deiodinase (D1) which is expressed principally in the liver and kidneys. This will disturb the serum T3 / T4 ratio and render the liver and kidney data invalid in PTU treated rats. It would have been better to use athyreotic rats.
In the brain supply of T3 by D2 appears to be local to specific cell types, thus measures of total brain hormone levels may underestimate the importance of this local regulation.
A concern I have is that as patients we want to take into account how we feel when on thyroid medication, not just go by serum hormone levels. A complication is that if we have impaired D2 activity (I believe some patients do) then it will affect the brain more that other organs such as the heart. The brain is highly dependant upon D2 and D3 regulation. If we then take T3 in the form of liothyronine or NDT to overcome impaired D2 activity we will need more hormone for the brain than the heart. How we feel is largely determined by our brain response to hormone. Consequently there is a risk of having cardiac thyrotoxicity if brain T3 levels are fully restored. This is why I'm cautious about T3 medication, we have to keep an eye on cardiac signs and perhaps adopt a compromise dosage. This can be seen in this study, Brain T3 levels show less variability than heart T3 levels. This is likely to be more pronounced in humans. Don't shoot the messenger! The same is likely to apply to patients with resistance to thyroid hormone (RTH) who may require supraphysiological doses of thyroid hormone. At higher hormone levels brain T3 will be more tightly controlled than other tissues.
I absolutely agree that, if at all possible,patients should have some T4 added to their T3 to form a conversion "buffer" to reduce such local overdoses. It seems however that some cannot. Therefore it becomes the old story " would you rather feel well or be biochemically appropriate".
It’s curious that some patients find that adding L-T4 makes them feel worse, even if their fT4 isn’t high. I feel quite sure that TSH promotes D2 activity (in addition to low T4 levels promoting D2) but finding it very difficult to obtain evidence. T3 levels are preserved in the initial stages of primary hypothyroidism when TSH is high and fT4 is falling. We tend not to see this in patients with a normal TSH and low fT4, their fT3 is often low. TSH stimulation of D2 might explain why these patients are worse when you give them extra hormone in the form of T4, it lowers their TSH, D2 activity and fT3 (particularly tissue T3 levels).
T3 medication has more inherent risk than T4 because it bypasses deiodinase safety mechanisms. However, in patients with impaired D2 or RTH T3 would seem to be the better option. By bypassing D2 (and D1) you can deliver T3 to D2 dependant tissues with a lower equivalent dose than L-T4 therapy. You also avoid the generation of excess rT3 by D1. Graham Leese published a study ncbi.nlm.nih.gov/pubmed/269... that showed no increased risk with L-T3 therapy. I think this is in part due to superior care by the doctors who are willing to prescribe L-T3. In expert hands a sharp knife is safer than a blunt one.
It still leaves the problem of achieving appropriate tissue T3 levels in patients with impaired D2 or RTH, how to correct brain hypothyroidism without cardiac thyrotoxicity. I think a degree of compromise is needed. The ultimate solution is to correct the D2 impairment or cure the RTH (for non-genetic forms). This would enable clinical euthyroidism with normal levels of thyroid hormone.
We've demonstrated a direct feedforward TSH-T3 shunt in the thyroid itself. This is responsible for the circadian rhythm peak of FT3 which occurs after the TSH circadian rhythm peak. Without this, there should be no circadian rhythm. Furthermore, the T3 directly produced by the thyroid although a minority product compared with body T4-T3 conversion, is a key controlling element in health that modulates body conversion. It therefore acts as a kind of conductor of the whole orchestra. As the thyroid declines, the T4-T3 system tries to keep as normal an FT3 as it can in the blood. Only at the last moment, when very little active thyroid is left, does the whole system collapse. Obviously the loss of the internal thyroid shunt is fatal to the overall control of T3 production. I agree that T3-only therapy is tricky to control, hough it would be improved by slow-release T3 tablets. A bit of T4 to provide a baseline modulatory power would always be helpful if tolerable.
I have a little Word document of forum posts of patients with an fT4 around 13.0 and fT3 less than 4.0 with a low normal TSH. These patients have quite severe symptoms. Usually in primary hypothroidism the TSH is very high as fT4 falls towards or below its lower limit and fT3 stays mid-interval or even in the upper half. The low TSH can be explained by a down-regulated axis but the only explanation I can find for the low fT3 is a role for TSH in peripheral D2. Certainly many tissues expressing D2 have TSH receptors, it's just a matter of getting the evidence. When I finally finish gathering all the information I will post on the forum.
Although I find minimal benefit in levothyroxine I take 50 mcg as a buffer and also on the basis that its non-genomic effects may be important. Certainly T4 has a minor direct role in bone formation, so it seems sensible to have a little circulating.
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