This is part 2 of a post which began with the question “How do we get enough T3 into our thyroid hormone receptors?”
In this post, I discuss the factors that can prevent T3 from getting into receptors.
There are two factors that usually operate together: 1) the “variable rate” of T4 conversion in cells, and 2) a lowered supply of Free T3 entering cells.
- TH = Thyroid hormone
- TR = Thyroid receptor
- D1, D2, D3 = Three types of deiodinases that convert thyroid hormones within our cells.
Here is a model of a D2-expressing cell, a “thyrotroph” cell in the pituitary gland. The receptors in the nucleus are in the smaller gray sphere:
See Part 1 for a description of the 10 steps by which T3 journeys from blood into the receptor, and back out again into bloodstream:
High or high-normal FT4 can reduce intracellular T3
That black box in Bianco & Kim’s 2006 diagram above says “variable rate.” It also shows a red-colored D2 with gray “Ub, ub, ub” circles above it.
What is this trying to teach?
Deiodinase type 2 is a vulnerable conversion enzyme, and it’s vulnerable to inactivation by excess T4 as levels rise within and beyond reference range.
“Ub” means “ubiquitination.” That’s the technical term for the type of inactivation that D2 enzyme experiences.
D2’s variable rate of conversion occurs because the D2 enzyme that converts FT4 is inactivated or “ubiquitinated” as FT4 rises through the reference range.
Bianco & Kim, 2006 explain:
“As a result of ubiquitination, D2-mediated T4-to-T3 conversion occurs at variable rates, decreasing as serum T4 concentration increases.
Ultimately, these processes determine nuclear TR saturation, which includes contributions from both T3(T3) [Free T3] and T3(T4) [converted T3] as indicated, with only a minor fraction of the TRs being unoccupied under normal conditions.”(Bianco & Kim, 2006)
This T4-inactivating function of D2 is explained in the article “Ubiquitination: The glass ceiling of T4 monotherapy,”
The “variable rate” of conversion means that you can’t count on D2 enzyme always converting T4 to T3 at a constant rate, because it depends on the amount of T4 entering cells.
- As FT4 drops lower and below range, T4-T3 conversion will rise higher, but only in cells that express D2 enzymes.
- As FT4 rises higher in reference and above, T4-T3 conversion rate will drop lower and lower in cells that depend on D2 enzymes for a lot of their T3 receptor occupancy.
Low circulating FT3 reduces T4-T3 conversion by Deiodinase type 1
Deiodinase type 1 (D1) is not pictured in the image above. That’s because Bianco has spent most of his scientific career focusing on D2 instead.
D1 is the thyroid hormone conversion enzyme that is largely found in cells in the thyroid, liver, and kidney.
D1 is a two-faced enzyme. Scientists say that at normal T3 and T4 concentrations, D1 converts 50% of T4 to T3 and the other 50% of T4 gets converted to Reverse T3.
However, “cleaning up the hormonal garbage,” converting RT3 into T2, is D1’s higher priority activity than “making garbage” by converting T4 to RT3.
Therefore, it will convert RT3 to T2 into a higher rate than it converts T4 to RT3! This enzyme is ecologically responsible. It cleans up its own RT3 garbage, in addition to some RT3 garbage created by another enzyme called D3.
The D1 enzyme’s net effect will be a T3 gain.
D1 enzyme’s virtuous behavior of cleaning up RT3 garbage plus donating T3 made me nickname this hormone the “philanthropist enzyme.”
- See more about D1 here “Meet deiodinase type 1 (D1): The philanthropist enzyme”
What upregulates D1? D1 gets strengthened in T4-T3 conversion when T3 levels are higher because it is an enzyme that has a T3 receptor “response element” on it.
As T3 rises above mid reference, D1 optimizes T4-T3 conversion: it converts less into Reverse T3, more into T3.
What downregulates D1? When T3 levels are low in reference or below reference, D1 will be handicapped and will not convert T4 to T3 as efficiently.
You can think of D1 as an “intensifier” of your body’s T3 status:
- If you’re T3-rich, you get T3-richer.
- If you’re T3-poor, you get T3-poorer.
When you have more than the usual amount of T3, you can get even more T3 out of your enhanced D1 activity. When you have less T3, you get less T3 from handicapped D1 activity.
Excess T3 and/or T4 prevents some T3 from getting into receptors.
You might be thinking, “Wait a minute, you just said that if I’m T3-rich, I’ll get T3-richer!”
But that’s only true of the function of D1 enzyme. If you continued to get more T3 by having more T3, your T3 supply would skyrocket. We have to talk about the enzyme that protects your body from excess T3 — Deiodinase type 3 (D3).
The role of Deiodinase Type 3 is first of all to inactivate T3 into an inactve form of T3 called 3,3-T2, and meanwhile, to convert T4 into RT3.
In adult life at normal FT4 levels, D3 is only expressed in a few tissues like the brain, and central nervous system, skin, certain bone cells, and placenta.
But Bianco and colleagues explain that in any tissue, D3 can be reawakened or re-expressed to the high levels that it once had in our bodies during fetal life, in the womb. What causes D3 to upregulate?
- High T3 and/or T4 levels entering cells that drives up T3 signaling from thyroid receptor type alpha1, expressed in bone and heart.
- Severe illness, and
- Long term severe fasting or calorie restriction.
Bianco et al, 2019 explains that while D2-expressing cells turn T4 into T3 and add T3 to the intracellular environment, D3-expressing cells delete both T4 and T3 from the intracellular environment.
D2 (regulated by DIO2 gene) and D3 (regulated by DIO3 gene) are opposites in their impact on Thyroid Receptor (TR) occupancy rates:
“There are instances in which TR occupancy does not reflect the levels of plasma T3.
For example, in cells that express DIO2, intracellular T3 levels are higher than expected from circulating T3.”
“Additionally, in cells that express DIO3, T3 can enter but could be inactivated before reaching TRs.”(Bianco & Kim, 2006)
You can think of D2 expressing cells as T3 hormone-producing spillways, because they give back a lot of FT3 to circulation.
Bianco and his coworkers call D3 expressing cells a “thyroid hormone sink.” Both T3 and T4 go down the metabolic drain.
Ideally, a balance is achieved between D2- and D3-expressing cells (and D1-expressing cells) in a given tissue so that the net impact is a good level of TR occupancy in all cells combined, across an organ or tissue. This determines its overall hypothyroid/euthyroid status.
Low circulating FT3 reduces T3 in receptors
The image above teaches another implied lesson:
We need a healthy baseline FT3 in blood because the rate of T4-T3 conversion does not account for 100% of T3 bound to receptors. We always need T3 entering cells to “top up” the T4-T3 conversion rate.
When you have a shortfall in circulating T3, your D2-expressing cells don’t suddenly decide to work harder at T4-T3 conversion.
D2 is not upregulated by low T3. D2 does not care if the cell in which it resides lacks T3. It won’t notice the crisis of T3 deficiency in the receptor.
Therefore, collectively across many cells, the organ can become hypothyroid if circulating FT3 is insufficient and FT4 is too high and inactivating D2.
Organ damage in tissues expressing much of our D1 and/or D2
The tissue most abundant in D1 and D2 per unit of volume is a small but mighty gland:
- The thyroid gland.
Many people forget, or never learned, that blood carries not only TSH, but circulating T4, into the thyroid gland. Thyroid cells convert some T4 to T3 at a rate regulated by TSH stimulation of the thyroid. The secretion rate contributes both new T3 and T4, plus some extra T3 that was converted by T4 within the thyroid. Healthy thyroids do not express D3.
Outside of the thyroid gland, D1 is richly expressed in
These three organs are responsible for exchanging thyroid hormone with bloodstream at a high rate.
Bloodstream FT3 levels can be significantly lowered in people who have severe thyroid disability, kidney failure, and liver disease because you will have fewer active cells that express D1 and D2 enzymes.
Reduced length of time T3 is bound to receptors
Another factor that reduces T3 receptor signaling is time — how long will T3 remain bound to receptors?
D2-converted T3 behaves very differently in the cell from D1-converted T3.
We get more “bang per buck” out of locally converting T4 into T3 in our D2-expressing cells, according to Bianco et al, 2019.
- The T3 we convert from T4 within a D2-x cell remains bound to the nuclear receptor for a longer time (“several hours”). Scientists think it’s because D2 enzyme is located in the endoplasmic reticulum, a structure located close to the nucleus.
- The T3 we convert from T4 within a D1-x cell (not shown in the image) remains bound to the receptor for less time (“~ 30 minutes”) before quickly exiting the cell to contribute to T3 circulation, likely because D1 enzyme is located just inside the cell membrane, close to where transporters enable hormones to exit the cell.
- The longer time spent in the nuclear receptor of D2-x cells adds up to a 6x greater potency / effect of T3 occupancy in the nuclei of D2 cells versus D1 cells.
Based on binding time differences, a little active D2 goes a long way in keeping T3 bound to receptors, and it takes more Free T3 to ensure that the D1-expressing cell’s receptors are sufficiently occupied.
Many factors can get in the way of intracellular T3 entering nuclear thyroid hormone receptors:
- Some cells do not express D1 or D2 enzymes, but other enzymes like D3, or none at all. Only the cells that express D1 or D2 can create T3 from T4 inside the cell
- D1 can be downregulated by low T3, and
- D2 can be inactivated by high-normal T4 via “ubiquitination.”
- D3 always inactivates T3 and reduces the amount of T3 bound to receptors in the nucleus. It can express itself in any tissue experiencing T3 or T4 excess, severe illness, and long-term severe calorie restriction.
- A significant amount of T3 is always derived from Free T3 entering cells and not being converted into non-T3 before it gets to the nucleus.
- Humans can’t live without sufficient T3 in blood.
Tissues can be in a hypothyroid state if they fall significantly below their required level of T3 receptor occupancy across all their cells.
Some tissues in the human body can be in a genuinely hypothyroid state even when FT3, FT4 and TSH levels are within reference, because low-normal FT3 and high-normal FT4 can downregulate D1 and D2.
The heart is especially vulnerable to lower circulating T3 levels because it does not accept or process T4 very efficiently. Heart tissue does not express much D1 or D2, and only in certain cell types:
“Cardiac tissue does not appreciably convert T4 to T3; therefore, the heart is dependent on available serum T3.”(Danzi & Klein, 2020)
In addition, transporters prefer to carry T3 into the heart cells, not T4:
“our data suggest that T4 is not transported into the heart.”(Danzi & Klein, 2020)
The sensitivity of cardiovascular tissues to circulating T3 levels, regardless of TSH levels, was demonstrated in a study of 2,078 healthy people:
“Heart rate was robustly positively associated with (quartiles of) free T3 (FT3) and T3, both in subjects with TSH levels within reference (0.27–4.2 μU/L) and in narrow TSH range (0.5–2.5 μU/L; p <0.0001).
FT3 and T3 were negatively associated with left ventricular (LV) end-diastolic volume but positively associated with relative wall thickness.
Total T3 (TT3) was associated with enhanced ventricular contraction (as assessed by tissue Doppler imaging).
Free thyroxine, FT3, and TT3 were positively associated with late ventricular filling, and TT3 was associated with early ventricular filling.
Conclusion: “variation in thyroid hormone levels, even within the reference range, exerts effects on the heart.”(Roef et al, 2013)
When Free T3 drops below mid-reference range (the average level found in healthy-thyroid populations), the incidence of medically-evaluated hypothyroid symptoms increases at an alarming rate (Larisch et al, 2018; Ito et al, 2019), even if a person is not significantly ill.
Hoermann et al, 2015 explain how thyroidless (athyreotic) people lose T3 during levothyroxine (LT4) monotherapy:
“athyreotic patients are particularly vulnerable, with approximately 15% living in a chronically low-T3 state below reference, even if they are able to normalize TSH.
Three remarkable phenomena have been observed in l-T4-treated patients,
(1) a dissociation between FT3 and FT4 [a significantly lower FT3:FT4 ratio],
(2) a disjoint between TSH and FT3 [the FT3 remains low during normal TSH], and
(3) an L-T4-related conversion inefficiency [excess T4 causes reduced T4-T3 conversion].
Hence, L-T4 dose escalation may not invariably remedy T3 deficiency but could actually hinder its attainment.”(Hoermann net al, 2015)
The implications for thyroid therapy are significant.
When Free T3 is kept below reference, or even below individual setpoints, on a chronic basis (as it is in uncounted millions of T4-monotherapy patients worldwide), we are often in a hypothyroid state in many of our organs, such as the heart, that depend more on circulating T3 than on locally converted T3.
No wonder so many of us are symptomatic while our FT3 levels are never measured, much less optimized to fit our individual metabolic needs.
The lesson of all the literature on Low T3 Syndrome, also known as nonthyroidal illness (NTIS), is that Free T3 has a “basement” level below which it cannot go.
Standard TSH-normalized LT4 therapy may prevent enough T3 from getting to receptors.
Endocrinologists know that T4 monotherapy artificially lowers FT3 on a chronic basis.
We know that illness can lower the FT3 level, but it is not yet known whether a therapy-induced lower FT3 can induce illness.
It is an ethical failure of endocrinology as a field that nobody has studied the long-term harms of chronically low(er) T3 levels unnaturally induced by thyroid therapy.
Nor are there any large, systematic studies of the vulnerability of thyroidless patients with chronic low T3 who then undergo lower T3 worsened by nonthyroidal illness syndrome (NTIS) who cannot recover health by raising their TSH to stimulate T3’s replenishment.
It would raise too much alarm if it was discovered (or more likely, confirmed) that these reduced FT3 levels were harming many patients. Why would they study something that could undermine their status, and the status of their preferred form of thyroid therapy?
The lack of research on chronic lower FT3 in thyroid therapy is a conscious or unconscious strategy that protects the status of the TSH-T4 paradigm of thyroid therapy and maintains the status quo of suffering and illness for many patients.
Abdalla and Bianco stated in 2014:
“Whereas it has become widely accepted that serum T3 is relatively lower in hypothyroid patients maintained on levothyroxine alone, it is unclear whether this is clinically relevant.
In addition, it is equally unclear whether those patients that remain symptomatic despite having normal serum TSH levels are the same patients that cannot maintain serum T3 levels within the normal range.
Clinical trials are needed to answer these questions, particularly trials with outcomes including objective biological responses to T3.“
Wait a minute. “It is unclear”? Why don’t they know? It is astonishing that this fundamental question has not been answered yet:
- Does lower FT3 induced by LT4 monotherapy prevent sufficient T3 from getting into receptors?
Some ethical scientists have taken up the call to do the missing research, not on NTIS in the context of thyroid therapy, but on symptomatic lower FT3 vs. non-symptomatic sufficient FT3 in thyroid therapy.
Clinical trials by Larisch et al in 2018 and by Ito et al, and Hoermann et al in 2019 are beginning to answer the question. They would say yes, lowered T3 is clinically relevant in levothyroxine therapy! Patients do begin to experience relief from hypothyroid symptoms more often as FT3 levels rise higher than mid-range, and in some patients with poor T4-T3 conversion, this FT3 may only be achieved when FT4 rises high enough to drive TSH below reference without thyrotoxicosis.
When will these new findings begin to change anti-FT3 testing policy and fear-based restrictions against T3-inclusive therapy in hypothyroid people?
See also Part 1
Click to view reference list
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