For those of you who have strong stomachs, here is a magisterial piece from Tania Smith on thyroidpatientsca website. It is very comprehensive so I shall download it to refresh my memory of a rather complex control system.
The 7 lessons of the thyroid hormone deiodinases
BY THYROIDPATIENTSCA on FEBRUARY 3, 2021 • ( 0 )
link thyroidpatients.ca/2021/02/...
i'm off to have a read..... i may be some time.
🤣🤣🤣 you need to put some effort into it but slowly the scales fall from my eyes...
i can only 'get it' properly if i put this thyroidpatients.ca/2021/01/... up next to it , cos i can never remember which deiodinase does what... and even then it's not always easy cos D1 seems to do one of 2 actions depending on what mood it's in 
Edit .oh that didn't work, try again.
thyroidpatients.ca/2021/01/...
A bout halfway down theres a diagram
"The function of each deiodinase
In the following diagram, you can see D1, D2 and D3 located at the arrows between hormone types."
Yes...it’s all a bit confused in my mind thanks for the tip, I’ll check out the graphic and hope some more of the jigsaw puzzle pieces of the function of deiodinases fall into place to make a clearer picture that both illuminates and delights!
Is this the picture you meant?
Brilliant , thankyou x
This is a better picture thyroidmanager.org/wp-conte... but you will need to register for free to see it.
Thanks for that jimh111 it looks very helpful, the link goes right to the JPEG ☺️ No need to register 👍🏽😁👍🏽
Here is the linked image:
Thanks, I don't know how to stick in the image, cut + paste doesn't work.
Save the image as a file on your computer. Then click on the Image icon along the bottom of the Reply box (currently the rightmost of six icons) - and guide it to the image.
Oh, a bit like Wordpress! Never looked beyond the first two icons as I occasionally use bold or italics. Thanks.
Thanks for drawing our attention to this diogenes . It is a really interesting and informative read.
🎶🦻❤️ - Thank you so much, diogenes - as always, much appreciated. 🍀
Summed up as ‘the importance of T3’ - for anyone wondering whether to read , or not.
Yes. #7 - "T3-inclusive thyroid therapy can compensate for deiodinase dysfunction and imbalance, but it must be flexibly adapted to the individual’s disability to be effective. Deiodinase disabilities may make a higher T3, lower T4 and/or lower TSH necessary to achieve euthyroid thyroid hormone signaling levels."
Yes, what we have been trying to tell our doctors who are in a panic over our low TSH.
More specifically:
"Biochemical overcompensation: Abnormal blood levels of T3, T4, and/or TSH
Sometimes blood levels need to overcompensate for the unseen deiodinase imbalances within tissues and cells.
Ensuring the bloodstream has a FT3 above the mid-range population mean (Larisch et al, 2018) can supply the T3 that is missing from cells due to a severely handicapped thyroid gland.
Adding deiodinase dysfunction to thyroid failure may require a compensation involving much higher-than-mean FT3 with a lower FT4 to counterbalance it.
Therapeutic compensation will affect the hypothalamus and pituitary by moving the TSH lower, due to the “TSH-T3 disjoint” seen in thyroid therapy."
Definitely worth a read.
This is really interesting. How do we ensure good deiodinase function? Good vitamin levels (particularly b12 & b’s, folate etc)?How do we get those who treat us to take note?
This article gives a good overview of the deiodinases as does the more detailed article “Thyroid hormone journey: Metabolism” published a month earlier. There are some minor errors and some points I disagree with.
Topic 1. “T3 signals at the cell membrane integrin receptor, although its affinity is lower than that of T4 at this receptor (Davis et al, 2018)”. This is correct but underestimates the extent T4 binds to the receptor on plasma membrane integrin αvβ3. This is important as it spreads cancer and explains why hypothyroidism reduces cancer as pointed out in your recent post healthunlocked.com/thyroidu... . T4 has massively more affinity for this receptor than T3 does (~100x if I remember) so hypothyroidism, (or T3 therapy which lowers T4) reduces cancer risk. Studies have shown T3 therapy reduces cancer progress by reducing T4 levels. As far as hypothyroidism goes this receptor mechanism isn’t important, we don’t need to worry about it.
Topic 2. The details given are correct, but it gives the impression that D1 is desirable. D1 activity increases in hyperthyroidism converting T4 to T3 & T4 to rT3, also T3 to T2 & rT3 to T2. D1 is less efficient that D2 which converts T4 to T3 and rT3 to T2. D1 is thought to be a means of providing some circulating T3 whilst recycling iodine. If you are hypothyroid you need more D2 activity and less D1. D2 provides twice as much T3 as D1 and does so close to the cell nucleus. D2 good, D1 bad!
Topic 5. “TSH is not a significant regulator of D1 or D2 outside the thyroid gland, except in extrathyroidal tissues that express both TSH receptors and D2”. I strongly disagree with this claim, although the second part of the sentence is correct. Most, if not all tissues that express D2 have TSH receptors. The brain (tiredness, brain fog), skeletal muscles (myalgias), skin (dry skin), brown fat (feeling cold), bone etc. all have TSH receptors. When TSH is added to sample tissues of brown fat, bone, or brain cells D2 activity is increased. The statement “D2 is not upregulated directly by TSH, but by cAMP signaling (sic) in cells.” Is correct - but TSH generates cAMP! Deiodinase is regulated by local T3, T4 levels but also subject to central regulation as in low-T3 syndrome, TSH is the obvious candidate for this function. Similar to TSH being subject to feedback by fT3, fT4 and feedforward by TRH. I have seen over 50 cases on this forum of patients with a subnormal TSH and low normal fT3, fT4 with severe symptoms. A study giving patients TSH could be useful but human TSH taken from cadavers is too dangerous and unfortunately human recombinant TSH is a synthetic analogue designed to stimulate secretion rather than deiodinase.
“FT3 tests should be taken 12+ hours after a T3 dose” True if dosing once daily but two or three doses per day are preferable.
This gives a good overview of deiodinase. Patients with a subnormal TSH have severe symptoms even if their TSH, fT3, fT4 are hovering around ‘normal’. We need to bite the bullet and explain why this happens, why these patients need disproportionate amounts of liothyronine (around 50 mcg daily) to recover. Why they need T3 and why T4 sometimes makes them worse. Look at what is happening in the cells, specifically D2 activity, and how this might be reflected in TFTs. If we could restore normal TSH levels in some of these patients and their symptoms resolved there would be definitive proof of the role of TSH.
I don't think this is the whole story. Deiodinases are considerably affected by association with a protein called ubiquitin and in my view changes in ubiquitinisation (horrible word indicating formation of complex between ubiquitin and deiodinase) occur which are more important, transient and localised than TSH action. Also when we say TSH is suppressed, what we mean really is that the TSH measured by the assay is absent. This does not mean that isomers, fragments or indeed other entities we don't measure aren't present to do the job that TSH (measured) once did. Redundancy is rife in the working of the human body. I don't buy the view that TSH (thyroidally specific) is anything principally but an indicator of pituitary-thyroid interaction and when there is no thyroid this entity is inhibited easily by either a) the unnatural pure T4 therapy orb) the equally unnatural T3 therapy. We have I believe developed a complete HPT axis theory of working which explains the whole axis by an astonishingly simple paradigm, and not only that applies to endocrine working generally. This I think should clarify the matter as far as it can be.
I very much agree. I picture a model whereby deiodinase is controlled by local and general influences, feedback and feedforward mechanisms.
Ubiquitin regulates deiodinase in peripheral tissues but only to a small extent in the pituitary, hypothalamus. This makes sense the body wants to regulate T3 levels but the pituitary needs to 'see it as it is', if ubiquitin reduced deiodinase in the pituitary, hypothalamus they would not be able to assess serum fT4 levels. I did have a quick look last week to see if I could find a ubiquitin antagonist, this would be a way of enhancing peripheral deiodinase activity.
I always try to write 'TSH is low' as this is a statement of fact. I only refer to a 'suppressed TSH' where I can be confident TSH is low because of excess hormone or Graves' stimulating antibodies. I use the term 'subnormal TSH' where I feel TSH is lower than it would be in a healthy person, i.e. a form of central hypothyroidism which may not be due to damaged pituitary or hypothalamic tissue.
TSH is perhaps the worst marker for thyroid status, the pituitary is more unique that any other tissue, i.e. more different in how it handles thyroid hormone with different receptors, deiodinase mechanisms etc. An added complication is that TSH is not a single molecule but a group of them 'isoforms' with different bioactivity. As you are aware the assay measures presence not activity as expressed by Dr Gordon Skinner ‘it is surely errant to equate biological activity with immunological presence; a graveyard has a high density of people with little activity‘.
I take the view that TSH has functions beyond the thyroid and we should strive to maintain normal TSH, fT3 and fT4 levels. This is not possible with levothyroxine monotherapy which requires higher fT4 , lower TSH and so will reduce the peripheral affects of TSH (including deiodinase). A subnormal TSH will have profound effects on deiodinase and hence local T3 levels, this is one situation where thyroidpatientsca's comment 'Adding deiodinase dysfunction to thyroid failure may require a compensation involving much higher-than-mean FT3 with a lower FT4 to counterbalance it.' applies.
Pure speculation but I sometimes see posts on the forum from Graves' patients who say they were happy on levothyroxine for a year or two and then it suddenly stopped working. I wonder if this coincided with a fall in stimulating antibodies (TSI) which tend to fall a year or so after thyroidectomy.
