Another article by thyroidpatientsca published on June 25, 2020.
These days, we see quite a lot of appreciation of the DIO2 gene - and why variants can affect thyroid hormones in our bodies. Albeit it mostly in the form of patients asking about it and testing. But we see next to nothing beyond that. This article attempts, in a very clear way, to go far beyond a single SNP (single nucleotide polymorphism) and delves into the other deiodinase enzymes.
Very well worth a read - and a re-read.
Tissue RNA expression of DIO1, DIO2, and DIO3
By thyroidpatientsca on June 25, 2020 • ( 0 )
No, this is not just an article for thyroid science buffs.
Anyone who claims to understand thyroid hormone metabolism should become comfortable using the word “deiodinase.” It’s just as important a word for thyroid disease as “insulin” is for diabetes.
Three enzymes convert thyroid hormones throughout our bodies:
Deiodinase type 1,
Deiodinase type 2, and
Deiodinase type 3.
These enzymes are commonly abbreviated D1, D2 and D3.
The genes that regulate their synthesis are called DIO1, DIO2 and DIO3.
In the past decade, too much emphasis has been placed on genetic polymorphisms — hard-wired mutations — in DIO1 and DIO2 genes, such as the infamous DIO2 rs225014 Thr92Ala polymorphism.
We’ve understood a lot, but we’ve also understood the limitations of this perspective on genetic handicaps in thyroid hormone metabolism. For one thing, these genetics become more of a handicap after the thyroid gland is disabled or removed and can no longer compensate for poor T4-T3 conversion during hormone therapy.
Studies have just begun to look at the way epigenetic factors can more powerfully alter these enzymes’ function during our lifetime, during illness, and in response to T3-T4 ratio imbalances induced by thyroid hormone therapy.
Here’s a good illustration of the contrast between deiodinase genetics (polymorphisms) and epigenetics (RNA expression):
Recently, in 2016, a team of scientists discovered that the genetic programming for the deiodinases was NOT responsible for depression. They were disappointed to admit their hypothesis was not proven, but they then decided to use different methods to understand the phenomenon better through the lens of epigenetics. In 2017, the same research team published a study that announced that
Therefore, understanding how these enzymes’ RNA expression shifts during life, not just how genetic programming is determined at birth, is key.
This helps us to understand why some very puzzling thyroid symptoms (such as depression) respond in puzzling ways to T3 dosing even in people with healthy thyroids.
It also helps us understand many of the normal, expected symptoms of overtreatment, undertreatment and poor conversion in thyroid therapy for hypothyroid individuals.
In this post, you’ll find an explanation of epigenetic influences on DIO1, DIO1, DIO3, graphs of tissue RNA expression of these three genes, and discussions of their implications for human health, especially in women.
Thanks for posting. This group is better than average but not good enough!
The article raises some interesting points but doesn't seem to have a head or tail, to arrive at any conclusion or give a sense of balance.
The pretty deiodinase diagram which puts T3 and 3,5-T2 in yellow circles states 'Binds to receptors in nucleus of cells'. This is not so. T2 does not bind to thyroid hormone receptors, not to any significant extent. The reference they cite describes 'nongenomic actions of thyroid hormone'. T2 action is nongenomic, it does not involve binding to receptors.
(Thyroid hormone is active primarily via nuclear receptors, T3 binds to receptors which attach to response elements on the DNA to trigger expression. This process takes several hours. Thyroid hormones also have 'non-genomic' actions, they act a bit like an ordinary molecule, these effects tend to be rapid.)
I don't understand RNA but the diagrams of tissue RNA expression of deiodinase seem to give a misleading impression. The DIO1, DIO2 diagrams give the impression that the majority of deiodinase takes place in the thyroid. This is not so. In fact, the thyroid has very little D2 activity and moderate levels of D1 activity in normal circumstances. The thyroid is capable of remarkable feats when stimulated by high levels of TSH as in Hashimoto's. Perhaps the high expression of DIO1 and DIO2 genes gives a high headroom in case of life-threatening thyroid damage.
The general thrust of the article implies pateints' conversion problems may be due to missing the deiodinase that takes place in the thyroid. Certainly, this has an effect, bringing fT4 into the upper quartile lowers TSH and hence reduces deiodinase, especially D2 which regulates local T3 levels. However, if the loss of thyroidal deiodinase was the problem, a little T3, enough to normalise fT3 would cure the patient. This doesn't work, as evidenced by the L-T3 studies and by patient experience.
The same applies to the high DIO3 capability in the girly bits. It's often claimed (by endocrinologists that should know better) that T3 does not cross the placenta. We know this is false because many women on L-T3 or NDT with very low fT4 do not give birth to cretins. Perhaps this high expression of DIO3 in the female genitalia is there to prevent excess T3 crossing the placenta. This is speculation on my part but it would explain why women on high doses of T3 still have healthy babies.
If this high expression of DIO3 RNA was reflected in D3 activity, then a hysterectomy would cure any conversion problems! Sadly, this option has been used as endocrinologists misdiagnose menstrual problems due to hypothyroidism.
They quote a Panicker study that found a couple of DIO1 polymorphisms can lower T3 a touch so that the fT3:fT4 ratio changes and conclude that D1 is the main source of circulating T3. This is silly, these subjects just have slightly lower fT3 levels, that doesn't mean most T3 comes from D1. My guess is that some people rely a little more on circulating T3 and some a little more on using D2 to locally generate T3 from T4. Which is best probably depends on environmental challenges over millennia.
They also mention that D1 is down-regulated by rT3. This seems strange since D1 prefers to convert rT3 to T2 and D1 increases when T4 levels are high. We know that D1 takes over when thyroid hormone levels are high, i.e. when rT3 is high. They give no reference for their assertion. The only reference I could find was a study of some heart cells in a test tube with rT3 and other blogs mention D1 being down-regulated by rT3. Have they just grabbed some internet wisdom and copied it? Just guessing, maybe the heart wants to preserve rT3 levels during severe illness to reduce D2 and keep it beating gently. Who knows? Clearly D1 activity is high in most patients with high fT4 and high rT3.
I find these articles frustrating. They can easily misinform patients. It would be easy to stick to what is known, give a little more explanation or point out what is pure speculation. It seems that the authors just want to generate interesting copy rather than take some care to verify the information.
Thanks for posting, I'm not shooting the messenger, it's good to know this is out there.
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