Deiodinase Type 3 plays the T3-blocking role

D3-enzymes-soldiers

This is part 2 of a 2-part post (It was long, so I’ve decided to break it into two parts).

Images & principles were shared in yesterday’s post:

The myth and the correction

Well-meaning people have attributed to the hormone RT3 a “T3-blocking” function.

This is a myth. Reverse T3 does not block T3 from entering cells, nor does it plug receptors and prevent T3 molecules from binding with them.

But science shows that the T3-blocking function is largely performed by Deiodinase Type 3 (D3), the enzyme that makes T4 into RT3 and also makes T3 into an inactive form of T2 called 3,3-T2.

Basically, the myth blames the child (RT3 hormone) for the father’s (D3 enzyme’s) activity.

Many thyroid patients have called the problem “RT3 dominance.”

But the truth is, It’s “D3 enzyme dominance.”

The RT3 vs. D3 distinction matters.

Understanding this can empower us and help us adjust thyroid therapy, because we need to know when D3 is dominating — and how to tame it or overcome it.

D3 can still dominate in the body when RT3 hormone is low in blood. RT3 levels are limited by how much T4 you have in circulation, and you might not have enough T4 to turn into RT3.

Therefore, RT3 test results can’t always tell you the degree to which D3 is inactivating your even more precious T3 thyroid hormone.

After I explain what’s really going on in your cells, I give tips on how to read your dosing, symptoms, FT3 and FT4 to interpret D3’s relative level of activity in blocking T3.

How does D3 plays its T3-blocking role?

I imagine that D3 enzymes act like soldiers.

D3 is normally patrolling the boundary of the cell, inactivating hormones just after they enter the cell.

At times when the body is focusing on depleting T3 hormone (illness, thyroid hormone overdose, or hyperthyroidism), D3 changes its location, defending the inner fortress and working harder to prevent T3 entry into the nucleus.

Here’s the corrected & clarified image that I developed based on Bianco et al, 2019’s model:

Figure 1 from Bianco-corrected

Notice that RT3 is not blocking T3.

In these visuals, you will see that the net effect of Deiodinase Type 3 is not to “block” the receptors with RT3.  No, RT3 does not plug receptors like a plug in a bathtub drain.

You don’t need an RT3 plug to block the receptor in this scenario.

All you need is a bunch of D3 soldiers defending the nucleus fortress in more and more cells that express D3.

In the D3-expressing (D3x) cell, the aim is to simply prevent T3 from entering the nucleus by converting it to an inactive hormone before it gets there. That way, more nuclear receptors remain unoccupied by T3, because it’s more rarely a T3 hormone gets past D3 without transformation.

The more D3-x cells you have in a given tissue or throughout your body, the less T3 is activating receptors. These particular receptors are unoccupied for a longer time, or not at all.

Why don’t RT3 hormone molecules get into the nucleus?

Answer: Neither Reverse T2 nor RT3 have enough affinity to the thyroid hormone receptors in the nucleus to bind with it.

You’ll notice that Bianco’s image, and my image above, does not put any hormone other than T3 into the nucleus of either the D3-expressing cell or the D2-expressing cell.

Long ago, research proved that RT3 lacks an iodine atom at a key position on the molecule. It is handicapped and can’t bind to the nuclear receptors.

RT3 does not have the correct iodine “key” to put into the receptor’s “lock.”

See the red arrows in this image to notice where “inactive” RT3 is missing the key iodine atom from its inner (blue) ring:

T4-T3-RT3

Bolger & Jorgensen (1980) measured 57 thyroid hormones’ affinity to the nucleus receptors in rat tissues in the lab. (Some of these were lab-invented thyroid hormone variants). They found that RT3 and all other hormones lacking this iodine atom at this exact position on the inner ring had less than 1% the affinity of T3 for the nuclear receptors.

The RT3 “key” does not fit into the nuclear receptor’s “lock.”

This is why “inner ring” de-iodin-ation (iodine removal) is always discussed in science as a way of ensuring “inactivation” of the thyroid hormone molecule.

However, it doesn’t inactivate RT3 from binding to an entirely different receptor for thyroid hormones. We now know that T4 and RT3 bind to receptors on the cell wall, called “integrin” receptors, where they don’t compete with T3 and sometimes don’t do friendly things. But that’s the subject of an entirely different post, the one on Cancer, T4, and RT3.

The main lesson here is that RT3 and 3,3-T2, the product of conversion by D3, cannot bind to nuclear receptors.

RT3 is not a T3 receptor “plug” that blocks T3 from binding.

What makes D3 dominate?

Deiodinase Type 3 will dominate and RT3 levels will rise when you have too much thyroid hormone above your current set-point in a given tissue or in your bloodstream.

Your body decides how much is “too much.”

  • “Too much” could actually change if you become very sick and your body decides to lower its metabolic rate.
  • You could have too much T3, T4, or too much of both.

In thyroid therapy, D3 overactivity can be cloaked (and invisibly stoked) by T3 or desiccated thyroid hormone dosing.

  • T3 depletion within the cell and tissue will not result in FT3 depletion in blood if there is enough daily resupply of T3 hormone and an enhanced D1 enzyme.
  • Yes, this is what often happens in what patients have dubbed “pooling.”

D3 dominance can be perpetuated by T4-dominant thyroid therapy especially in the context of chronic illness and/or poor DIO2 / DIO1 expression (induced or genetic).

  • The body’s setpoint for thyroid hormone will become lowered in the early phase of severe illness, triggering D3 to dump thyroid hormone to lower the metabolic rate and energy expenditure. But an undiminished rate of T4 dosing in this context can daily trigger a state of local T4 excess above this lowered setpoint and can keep DIO3 upregulated and D1 & D2 downregulated.
  • One does not require illness to be a trigger for D3 dominance. To the degree that FT4 and/or FT3 rises above your metabolic setpoint in health and is maintained by daily dosing or excess thyroidal secretion, DIO2 can become downregulated and the body will protect itself from excess by upregulating DIO3.

D3, D2 and D1 can have independent activity

This model of thyroid deiodinase enzyme activity means that D1 or D2 enzyme can be active converting T4 to T3 in some cells while D3 is active in other cells converting T4 and T3 to their inactive metabolites — at the same time.

The D2/D1 pathway can still operate to some degree independently of the D3 conversion pathway.

The existence of RT3 within D3-expressing (D3-x) cells cannot prevent FT3 hormone from entering neighboring D2-x cells and activating receptors in their nuclei.

The separate pathways of D2 and D3 ensure that their operation cannot cancel out each other’s activity within a given cell, but at the level of a specific tissue or organ with an illness (i.e. liver cirrhosis, cardiac ischemia), the local T3 depletion can be more severe than FT3 levels shown in blood. (See our review of research, “The impact of thyroid hormone dysfunction on ischemic heart disease”)

Nevertheless, the deiodinases in all cells of your body contribute to the “global” environment of circulating hormones which in turn influence how D1, D2, and D3 behave.

In a similar way, industries can cause air pollution that affects their own workers, or they can also produce healthy food that benefits their own workers.

How can thyrotoxicosis occur in spite of D3 dominance?

The highest RT3 levels found naturally in human beings are in hyperthyroid people. (See “Reverse T3 in the context of health status, dosages, and thyroid levels.”)

If it were not possible to overcome D3 dominance, thyrotoxicosis would be impossible in Graves’ disease and in cases of thyroid hormone overdose.

Thyrotoxicosis will occur when thyroid hormone oversupply (from dosing and/or from the thyroid gland) not only overcomes D3 dominance and D2 ubiquitination, but far exceeds the deiodinases’ collective capacity to protect the body.

All it takes for thyrotoxicosis to occur is

  • a continual rate of T3 resupply that exceeds the rate of T3 depletion far beyond the degree it needs to in order to maintain health, and/or
  • a continual rate of T4 supply that is nevertheless converted to excess T3, even if D2 is working at a slower rate.

In the military analogy, thyroid hormones have to be a larger army that overcomes the opposing D3 army in spite of weak D2 reinforcements and stormy weather.

If you combine both FT4 and FT3 excess with Graves’ disease antibodies that powerfully upregulate the DIO1 enzyme and thereby escalate T3 secretion and T4-T3 conversion in functional thyroid tissue, you have a recipe for disaster even if the person has very high RT3 levels in circulation.

Excess RT3 can’t stop thyrotoxicosis. You need powerful anti-thyroid medications fighting on your side.

RT3 is not the obstacle to T4-T3 conversion.

Conversion to RT3 is not the major obstacle to levothyroxine potency. When RT3 is high-normal or high due to similar-range FT4 levels, total and Free T3 levels can still be euthyroid or elevated due to cells expressing D2 and/or D1 enzymes.

Instead, two factors are the major obstacles: the variable loss of thyroid tissue, and handicaps in extrathyroidal thyroid hormone metabolism.

The global T4-T3 conversion rate falls in a body that is no longer equipped with a thyroid gland. The thyroid gland, among all human tissues, is the one most richly endowed with T4-converting D1 and D2 enzymes (See “Tissue RNA expression of DIO1, DIO2, and DIO3“). The thyroid is a metabolic engine, not just a hormone-secreting gland.

In addition, some humans simply have less efficient D1 and D2 enzymes. A high degree of variation was found among 14 healthy human beings’ T4-T3 conversion rate in Pilo’s famous kinetic study in 1990. The T4 conversion rate was between The research reveals that the thyroid-healthy person’s T3:T4 secretion ratio and T3 secretion rate compensates for shortfalls in their T4-T3 conversion rate.

Therefore, the degree to which an individual patient will convert LT4 medication to the truly active ingredient is a roll of the dice.

In the body without a functional thyroid gland, there is no thyroidal T3 secretion to compensate for poor T4-T3 conversion beyond the thyroid. A low conversion rate results in an unpredictable FT3:FT4 ratio among patients, given each thyroid-disabled person’s genetics, health status, concurrent medications, diet, age and other factors.

Unfortunately, the TSH can be very deceptive in the poor converter of T4 hormone who is treated with thyroid medication. TSH normalization is not an indication of a normal peripheral T4-T3 conversion rate. Due to local pituitary expression of deiodinase activity, FT4 levels during LT4 monotherapy will continue to deceptively normalize TSH while being blind to a severe shortfall in FT3, as shown in research since 2010. This shortfall in FT3 per unit of TSH in thyroid therapy is what researchers have called the “TSH-T3 disjoint.” (See “The TSH-T3 disjoint in thyroid therapy“)

In the context of T4 monotherapy, unless a person is severely ill, a normal RT3:FT4 ratio in the context of the FT3:FT4 ratio is indicative of whether a person is a “poor converter” of T4 hormone or not (See a review of the research that established reference ranges for the FT3:FT4 ratio, as measured in pmol/L: “Gullo: LT4 monotherapy and thyroid loss invert FT3 and FT4 per unit of TSH)

While on LT4 monotherapy, the free SPINA-Thyr app can be used to detect very poor T4-T3 conversion rates. See Midgley et al, 2015 for a discussion of the “poor converter.”

  • When the Free T3:T4 ratio is extremely high (FT3 is much higher than the FT4 than in the average person), a higher FT3 can compensate for a low-normal or low FT4 because T3 is the active hormone. This can prevent hypothyroidism from resulting from low levels of FT4. At the same time, a low or low-normal FT4 can prevent a simultaneously high-normal FT3 from causing thyrotoxicosis. When FT4 is low enough in a person dosed with T3 hormone, there is less T4-T3 conversion adding to T3 in cells.
  • However, when the opposite happens and the FT3:FT4 ratio is low during T4 monotherapy, a higher FT4 level cannot compensate for a significantly low(er) FT3, and some or all organs will be hypothyroid regardless of whether the TSH is normal, low or suppressed.

Our thyroid hormone receptors always need T3 to enable healthy bodily functions, even in a person who cannot secrete TSH due to hypothalamus or pituitary dysfunction (central hypothyroidism). The lack of TSH alone can never render a person thyrotoxic. Only an excess of T3 receptor binding in tissues do that.

Our cells require a baseline of circulating FT3 to compensate for shortfalls in T4-T3 conversion in D2-expressing cells, especially in organs that do not express D2 as strongly as the pituitary does.

One must read RT3, FT4 and FT3 levels together.

The research must drive home the point that we ought never to judge RT3 in isolation from FT4 and FT3. Reference ranges in lab results artificially separate these hormones. But RT3 can only be derived from T4.

One does not always need to test Reverse T3! It can be costly to the patient if it is a patient-pay test!

The most important ratio in monitoring thyroid hormone metabolic health is the FT3:FT4 ratio, not the RT3 level or the RT3:FT3 ratio.

A person with good understanding of thyroid hormone action can “read” D2, D3 and D1 activity from FT3 and FT4 in context.

RT3 just adds a little extra clarity about the degree to which some cells are D3-dominant in the person due to illness, hyperthyroidism, or overdose.

Conclusion: In therapy, test FT3 regularly, and occasionally RT3.

Systemic medical ignorance of chronic “Low T3 syndrome” and chronic poor T4-T3 conversion in treated LT4 monotherapy is caused by endocrinologists’ refusal to engage in self-incriminating FT3 and RT3 testing and research.

The biochemistry of nonthyroidal illness induced by LT4 monotherapy prior to illness is more common and more tragic than doctors realize. It is happening because of systemic overreliance on TSH without FT3 testing, and ignorance of how the RT3 level can distinguish between poor conversion, illness, hyperthyroidism, and thyroid hormone overdose.

Professional self-protection may be a motive to avoid recommending FT3 and RT3 testing in the context of the field’s favorite form of thyroid therapy. Using these tests properly would demonstrate which patients with low T3 are ill, and which ones are poor converters of T4 and deserve to raise their FT3 levels using T3 synthetic hormone or desiccated thyroid.

An honest set of endocrinologists could condemn decades of misguided thyroid clinical guidelines … if they ever performed a rigorous scientific inquiry into the LT4-treated Low-T3 population’s health outcomes in chronic and critical illness, while RT3 is elevated.

  • Tania S. Smith

Other posts on Reverse T3 and deiodinases

REFERENCES

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 https://www.ncbi.nlm.nih.gov/pubmed/31033998

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

Bolger, M. B., & Jorgensen, E. C. (1980). Molecular interactions between thyroid hormone analogs and the rat liver nuclear receptor. Partitioning of equilibrium binding free energy changes into substituent group interactions. The Journal of Biological Chemistry, 255(21), 10271–10278.

Gereben, B., McAninch, E. A., Ribeiro, M. O., & Bianco, A. C. (2015). Scope and limitations of iodothyronine deiodinases in hypothyroidism. Nature Reviews. Endocrinology, 11(11), 642–652. https://doi.org/10.1038/nrendo.2015.155

Groeneweg, S., Visser, W. E., & Visser, T. J. (2017). Disorder of thyroid hormone transport into the tissues. Best Practice & Research. Clinical Endocrinology & Metabolism, 31(2), 241–253. https://doi.org/10.1016/j.beem.2017.05.001

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

Midgley, J. E. M., Larisch, R., Dietrich, J. W., & Hoermann, R. (2015). Variation in the biochemical response to l-thyroxine therapy and relationship with peripheral thyroid hormone conversion efficiency. Endocrine Connections, 4(4), 196–205. https://doi.org/10.1530/EC-15-0056

Visser, W. E., Friesema, E. C. H., & Visser, T. J. (2011). Minireview: Thyroid Hormone Transporters: The Knowns and the Unknowns. Molecular Endocrinology, 25(1), 1–14. https://doi.org/10.1210/me.2010-0095



Categories: Deiodinase Type 3, RT3 - Reverse T3, T3 hormone, T3 sufficiency, TH Receptors

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