What can prevent T3 from getting into thyroid receptors?

What-can-prevent

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. 

Abbreviations:

  • TH = Thyroid hormone
  • TR = Thyroid receptor
  • D1, D2, D3 = Three types of deiodinases that convert thyroid hormones within our cells.

The diagram

Once again, here is a model of one type of D2-expressing cell. The receptors in the nucleus are in the smaller gray sphere:

Bianco-Fig-3-Thyrotroph-D2

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. 

Changes in D2 cause a variable rate

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.

Paradoxically, D2 is vulnerable to the overabundance of the very hormone, T4, that it focuses on converting. 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.”

This T4-inactivating function of D2 inspired me to title one of my past posts “Ubiquitination: The glass ceiling of T4 monotherapy,” because the local D2 top-up of T3 receptor occupancy has a limit, a glass ceiling that nobody can see or predict.

D2 can’t just work harder to fill empty receptors.

The image above teaches another implied lesson: We need the baseline FT3 because the rate of T4-T3 conversion is not entirely determined locally in tissues and cells.

The cell or tissue can’t decide to increase its local T4-T3 conversion rate just because its desired number of occupied receptors is falling short, or the FT3 level is falling short.

FT4 levels in blood is something that the individual cell can’t change.

Serum FT4 concentration level is like the weather. 

But that’s largely what establishes the D2-mediated conversion rate in cells in that tissue.

As FT4 rises higher in reference and above, T4-T3 conversion rate will drop lower and lower.

Therefore, collectively across many cells, the organ can become hypothyroid if circulating FT3 is insufficient and FT4 is too high to keep D2 functioning at a healthy conversion rate. 

Another wildcard: Deiodinase type 1

Deiodinase type 1 (D1) is not pictured in the image above. It’s the thyroid hormone conversion enzyme that is largely found in cells in the thyroid, liver, kidney and pituitary.

D1 is a two-faced enzyme. It’s sometimes a friend, sometimes a foe. At normal T3 and T4 concentrations, D1 converts 50% of T4 to T3 and the other 50% of T4 gets converted to Reverse T3.

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. 

However, 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 — 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.

In addition, if your thyroid is damaged, dead or missing, OR your liver, or kidney are damaged, you will also be hindered in your D1 thyroid hormone conversion ability because you will have fewer active cells that express D1 enzyme. Bloodstream FT3 levels can be significantly lowered in people who have severe thyroid disability, kidney failure, and liver disease because these three organs exchange thyroid hormone with bloodstream at a high rate using D1, and they also express D2 to varying levels.

D3-expressing cells have low TR occupancy

The degree to which a tissue or organ is hypothyroid can also depend on the degree to which it expresses Deiodinase Type 3 (D3) in cells.

Deiodinase Type 3 will inactivate FT4 into Reverse T3, while also inactivating circulating FT3 into T2. 

In adult life and at normal FT4 levels, D3 is only expressed in a few tissues like the brain and central nervous system and the skin.

But Bianco and colleagues explain that in any tissue, D3 is upregulated by higher-normal and excess T4 and/or T3 as well as by various states of illness and fasting.

Bianco et al, 2019 explains:

“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.”

In other words,

  • Cells that express D2 enzyme will use more circulating FT4 to top up the local T3 within the cell and fill more receptors.
  • But cells that express D3 will inactivate FT4 into Reverse T3, while also inactivating circulating FT3 into T2.

You can think of D2 expressing cells as T3 hormone-producing spillways, because they give back a lot of FT3 to circulation.

Bianco et al 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.

A healthy balance in thyroid hormone supply & deiodinase activity will yield a healthy FT3 level, but when D3 dominates in tissues, it reduces FT3.

Length of time T3 is bound to receptors

Another factor is that D2-converted T3 behaves very differently from D1-converted T3.

However, at the cell receptor level, D1 cells don’t bind with T3 hormones for a very long time.

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”), and scientists think it’s because D2 enzyme is located so 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 wall, 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.

This has implications for people on desiccated thyroid (NDT) and T3-dominant therapies who will have significantly lower FT4 and higher FT3 levels. Higher-normal FT3 results in higher D1 and D3 expression, and the higher D3 expression will always decrease D2 expression (Bianco et al, 2019).

Based on binding time differences, their FT3 may spend far less time bound to receptors than the T3 that is converted locally in less active D2-expressing cells.

Therefore, while a lower FT4 will enable some thyroid patients to have access to their baseline FT3, they will require a lot more FT3 in bloodstream than “normal” to compensate for a lower FT4.

Some patients will require a FT3 to fluctuate occasionally above reference range to compensate for lower FT4 during T3-dominant therapy.

If the doctor does not realize more FT3 is required in the lower FT4 state, they may reduce the dose and cause hypothyroidism.

Health implications of the model

Tissues can be in a hypothyroid state if they fall significantly below their required level of T3 receptor occupancy across all their cells, even if your Free T3 is still within normal reference range.

Some tissues in the human body can be in a genuinely hypothyroid state even when T3 levels are within reference.

The heart is especially vulnerable to lower circulating T3 levels because it does not accept or process T4:

  • “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, not T4: “our data suggest that T4 is not transported into the heart.” (Danzi & Klein, 2020)

The sensitivity of cardiovascular tissues to T3 levels, regardless of TSH, 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).

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.”

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 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” in health. 

In all states of critical illness; as well as in chronic kidney, liver, and heart failure; and also after heart surgery, the baseline FT3 level can and will drop lower than the person’s healthy baseline to reduce the metabolic rate, and this can be temporarily protective. However, we cannot remain below the FT3 baseline on a chronic basis, or we will put life and health at risk. 

The TSH-stimulated healthy thyroid gland is necessary for natural FT3 and FT4 recovery from NTIS, and TSH can even temporarily rise above reference to stimulate a hefty T3 and T4 refill from the pharmacy in the neck.

The ethical failure in thyroid therapy research

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. We know that illness can lower the FT3 level, but it is not yet known whether a therapy-induced lower FT3 can induce illness.

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.

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.

Endocrinologists know that T4 monotherapy artificially lowers FT3 on a chronic basis.

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?

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.

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 — yes, lowered T3 is clinically relevant in levothyroxine therapy! Patients do begin to experience relief from hypothyroid symptoms more often when FT3 levels higher than mid-range, associated with TSH levels slightly below reference.

When will these new findings begin to change anti-T3 thyroid testing policy and fear-based restrictions against T3 therapy in hypothyroid people?

See also Part 1

REFERENCES

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Ataoğlu, H. E., Ahbab, S., Serez, M. K., Yamak, M., Kayaş, D., Canbaz, E. T., … Yenigün, M. (2018). Prognostic significance of high free T4 and low free T3 levels in non-thyroidal illness syndrome. European Journal of Internal Medicine. https://doi.org/10.1016/j.ejim.2018.07.018

Bianco, A. C., & Kim, B. W. (2006). Deiodinases: Implications of the local control of thyroid hormone action. Journal of Clinical Investigation, 116(10), 2571–2579. https://doi.org/10.1172/JCI29812

Bianco, A. C., Dumitrescu, A., Gereben, B., Ribeiro, M. O., Fonseca, T. L., Fernandes, G. W., & Bocco, B. M. L. C. (2019). Paradigms of Dynamic Control of Thyroid Hormone Signaling. Endocrine Reviews, 40(4), 1000–1047. https://doi.org/10.1210/er.2018-00275

Idrees, T., Price, J. D., Piccariello, T., & Bianco, A. C. (2019). Sustained Release T3 Therapy: Animal Models and Translational Applications. Frontiers in Endocrinology, 10, 544. https://doi.org/10.3389/fendo.2019.00544

Hoermann, R., Midgley, J. E. M., Larisch, R., & Dietrich, J. W. (2015). Homeostatic Control of the Thyroid–Pituitary Axis: Perspectives for Diagnosis and Treatment. Frontiers in Endocrinology, 6. https://doi.org/10.3389/fendo.2015.00177

Hoermann, R., Midgley, J. E. M., Larisch, R., & Dietrich, J. W. (2019a). Functional and Symptomatic Individuality in the Response to Levothyroxine Treatment. Frontiers in Endocrinology, 10. https://doi.org/10.3389/fendo.2019.00664

Hoermann, R., Midgley, J. E. M., Larisch, R., & Dietrich, J. W. (2019b). Individualised requirements for optimum treatment of hypothyroidism: Complex needs, limited options. Drugs in Context, 8, 212597. https://doi.org/10.7573/dic.212597

Ito, M., Miyauchi, A., Hisakado, M., Yoshioka, W., Kudo, T., Nishihara, E., … Nakamura, H. (2019). Thyroid function related symptoms during levothyroxine monotherapy in athyreotic patients. Endocrine Journal. https://doi.org/10.1507/endocrj.EJ19-0094

Larisch, R., Midgley, J. E. M., Dietrich, J. W., & Hoermann, R. (2018). Symptomatic Relief is Related to Serum Free Triiodothyronine Concentrations during Follow-up in Levothyroxine-Treated Patients with Differentiated Thyroid Cancer. Experimental and Clinical Endocrinology & Diabetes: Official Journal, German Society of Endocrinology [and] German Diabetes Association, 126(9), 546–552. https://doi.org/10.1055/s-0043-125064

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Categories: T3 hormone, Tissue hypothyroidism

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