The basics of thyroid hormone action, transport and conversion

Thyroid hormone action, transport and conversion

This comprehensive educational post collects the basics of thyroid hormone, transport and conversion.

T3 action on nuclear receptors

Every organ and tissue in your body must maintain a healthy level of T3 hormone activity to function properly.

Bloodstream T3 supply and local T3 action powerfully influences how every organ operates, from our liver to our pancreas, kidney, and heart; and it influences every tissue, from our tendons to our muscles, bones, blood cells, and skin.

This is what makes symptoms of hypothyroidism and hyperthyroidism so systemic and so difficult to interpret. Beyond the basic and common effects of thyroid hormone on metabolic rate, symptoms are variable from person to person. Thyroid hormone imbalance can manifest in areas of the body that are currently the most vulnerable in a given individual, and T3 imbalance can worsen other existing health conditions.

Thyroid hormone receptors are in two locations:

1) In the nucelus of cells, in “nuclear receptors,” where T3 hormone has its powerful and essential biological activity.

2) On the cell wall, where they can bind to integrin αvβ3. This is where T4 and RT3 have their most significant activity, but not all of it is beneficial, as cancer researchers are learning.

The receptors on the cell wall generally perform “non-genomic” actions, while the ones in the nucleus have “genomic” action. The hormone T3 in the nucleus essential instructions to genes to get work done in our bodies.

Here, I focus on receptor type #1 above — the most important thyroid hormone receptors located deep in the center of the cell, in the nucleus.

T3 is just one simple hormone molecule, but its effects on this receptor are diverse and widespread.

  • The genes activated by T3 hormone vary from organ to organ, tissue to tissue.
  • There are thousands of genes directly influenced by T3. We haven’t yet explored all of these metabolic pathways of influence.

Thyroid hormone action on receptors

In the nucleus receptors, T3 turns on and off genes.

  • When T3 hormone binds to a nuclear receptor, it flicks a toggle switch that turns on or off various genes that are connected to that particular receptor.
  • When the receptors are empty of T3, they are not inactive or unstimulated, they’re just in a different state than the “bound” receptor.
  • When T3 enters that receptor, a gene that was previously “on” can be toggled “off,” and a gene that was “off” can be toggled “on.” It’s an essential, functional molecule.

Therefore, it is incorrect to imagine T3 only as a stimulant, like caffeine, even though increasing T3 plays an important role in driving up metabolic rate and energy expenditure.

Managing T3 receptor occupancy

Our bodies need to make sure nuclear receptors are sometimes empty, sometimes occupied by T3. As explained by Bianco’s publications and Visser & Hollenberg,

  • If too many T3 receptors in the nucleus are empty, that tissue or organ can become hypothyroid and can become dysfunctional.
  • If too many receptors are bound to T3 for too long, the tissue is thyrotoxic and can also become dysfunctional.
  • Each receptor can be occupied by T3 for minutes or hours, depending on the type of cell and how much T3 is available within it.
  • Each tissue or organ needs a different percentage of T3 hormone to bind to thyroid hormone receptors located in the nucleus of its cells. In some tissues, a higher percent must be occupied at all times.

This is the reason why we need to have enough T3, but not too much T3, available in our circulation, getting into our cells, and finally gaining access to our cellular receptors.

Therefore, T3 transport into and out of the cells and receptors is carefully regulated at a local level, tissue by tissue, and its conversion from T4 and into T3 or Reverse T3 is carefully regulated locally, tissue by tissue.

The importance of baseline circulating Free T3

The body’s local T4-T3 activation in receptors does not mean measuring Free T3 is unimportant. It’s quite the contrary. Maintaining a minimum baseline FT3 level is essential for human health. As explained by Bianco’s publications,

  • The T3 that enters cells from circulating FT3 in blood supplies on average about 50% of bound nuclear receptors.
  • Cells convert T4 to T3 at a rate that flexibly “tops up” the nuclear receptor occupancy rate beyond the necessary level that bloodstream FT3 supplies.
  • Large population studies of healthy people place the average FT3 around 40-50% of reference range when FT4 is concurrently 30-40% of its reference.
  • When circulating FT3 falls lower than the body’s needs, the baseline supply for receptors in the nucleus drops, and local T4-T3 conversion cannot always compensate (due to principles explained below under “Thyroid hormone conversion”).

Maintaining circulating FT3 in thyroid therapy

The principle of baseline FT3 requirements for T3 receptor occupancy (discussed above)  has important implications for thyroid hormone dosing in thyroid disease.

Because of this local T4-T3 conversion “top up” principle,

  • As FT3 rises within reference range, less FT4 is needed to convert and “top up” local receptor occupancy.
  • The body’s need for net circulating FT3 will rise as the FT4 level reduces, because lower FT4 means less raw material for local T4-T3 conversion.
  • Unfortunately, attempting to increase FT4 too far within reference will not always result in a rise in FT3 (due to lack of thyroidal T4-T3 conversion capacity and principles explained below under “Thyroid hormone conversion”).

Thyroid hormone transport

Thyroid hormone transport

There are two types of transport, bloodstream transport and intercellular transport.

Bloodstream transport

Thyroid hormones attach to binding sites on carrier proteins like Thyroxine Binding Globulin (TBG). The binding of hormones enables your hormone molecules to distribute more evenly throughout bloodstream and slows down the clearance rate. It prevents too many hormone molecules from being available to enter cells (these make the distinction between “bound” and “free” hormone).

  • Only unbound, “free” T4 and T3 can be transported into the cell to be converted, and that’s why we measure Free hormones (FT3 and FT4), not Total T3 or Total T4.
  • Far more hormone is bound than free. Only <0.5 % fraction of free hormone is immediately available to tissues.
  • approximately 0.03 per cent of the total serum T4 is free.
  • approximately 0.3 per cent of the total serum T3 is free.
  • A different set of binding proteins influence T4 binding and T3 binding.
  • Various drugs and hormones can influence the ratio that is bound to free. For example, a significant rise in Estrogen can increase thyroxine binding globulin (TBG) so that less is free than bound. Your thyroid has to make more T4 to maintain adequate free levels, or you have to raise your thyroid hormone dose to compensate.

Intercellular transport

More important are the “intercellular” transporters that carry thyroid hormones across cell walls, into and out of our cells.

  • Free hormone transport into the cell is performed by thyroid hormone transporters (THTs) with puzzling acronyms such as MCT8, MCT10, OATP1C1, LAT1 and LAT2. (see a huge list in Table 1 in Visser et al, 2011, a free article).
  • It can be helpful to imagine these transporters like “buses” that have “priority seating” for high priority thyroid hormones.
  • Most transporters have dedicated seating for T3 and T4 hormone. Some of them prefer to transport T3 more than T4, and others prefer to transport T4 more than T3.
  • The strong preference most transporters have to T3 and T4 means that you don’t have to worry about RT3 hormone taking up their reserved seats whenever FT4 and FT3 are present in blood to be transported into cells.
  • Different tissues and organs have different sets of transporters available.

2-way transport

  • Transporters carry hormones into cells AND out of cells, like breathing in and out.
  • The 2-way function of transporters means the thyroid hormone concentration in blood partly represents what you secrete (or ingest from thyroid medication) and partly represents what your cells have already converted and returned back to blood.

Thyroid hormone conversion

T4-T3-RT3

Where and when we convert thyroid hormones

  • Conversion happens inside cell walls, not within blood.
  • Conversion happens in cells all over the body in every organ and tissue, including the thyroid gland and pituitary gland.
  • Conversion happens every minute of every day.
  • We convert thyroid hormones at different rates in different tissues.

Vocabulary, usage and spelling

  • The act of removing iodine is “de-iodination.” It’s another word for “conversion.”
  • The enzyme that removes iodine is a “deiodinase.” There are 3 types, and they are abbreviated D1, D2, and D3.
  • The genes responsible for the enzymes are DIO1, DIO2, and DIO3 (spelled d-i-o + 1, 2, or 3)

How conversion happens in cells

  • T4 becomes either T3 or Reverse T3 (RT3) when a deiodinase removes an 1 iodine atom from either of two different locations on the molecule.
  • T3 and RT3 also become two forms of T2 after a deiodinase removes 1 iodine atom.
  • T2 and T1 also get deiodinated.
  • The body recycles iodine molecules and takes them up again within the thyroid gland, which concentrates iodine as it synthesizes T4 and T3

In scientific article you will sometimes see people discuss two basic types of conversion. They correspond to the two hexagons (“rings”) in the molecules shown above in pink and blue.

  • Outer ring deiodination (ORD or 5′ deiodination) takes iodine away from the outer ring of the molecule. This is the step that ACTIVATES T4 molecule into T3. This is a removal from the pink ring in the image above.
  • Inner ring deiodination (IRD or 3′ deidination) takes iodine away from the inner molecule and INACTIVATES the resulting molecule from binding with the nuclear receptor. RT3 is inactivated and cannot bind with the receptor. This is a removal from the blue ring in the image above.

The three deiodinases

Three-deiodinases

Deiodinase Type 1 converts various thyroid hormones, mostly in liver, kidney, and thyroid gland.

(Sources for this section: Gereben et al, 2008; Groeneweg et al, 2017; Bianco et al, 2019)

D1’s main job is to convert Reverse T3 into T2 and to clear T3-Sulfate.

  • Our bodies make a lot of Reverse T3 every minute of every day, so Deiodinase Type 1 is mainly a “scavenging” hormone that helps our bodies to process RT3.
  • Science still doesn’t quite understand T3 sulfate and its function, but apparently T3 can become T3S and then our bodies can recombine T3S into T3 hormone.

D1 has relatively less affinity for T4 than for RT3 and T3S, but it plays an important role in converting T4 into both T3 and RT3.

  • Therefore, D1 is a two-faced enzyme when it comes to deiodinating T4.
  • Science still doesn’t quite understand what makes D1 sometimes convert T4 to T3 and sometimes convert T4 to Reverse T3, but they believe that it converts to T3 about half the time in the average healthy person with a thyroid.
  • It is also very strange that this enzyme both creates and destroys Reverse T3.
  • Some theorists believe that D1 was the first enzyme to evolve because it is so multi-functional.

The location of D1 within cells is near the cell wall, so the hormones it converts can quickly exit via the transporters and re-enter our bloodstream circulation.

  • When D1 converts T4 to T3, the T3 it converts spends only about 30 minutes bound to the nucleus (a short time), and then T3 gets transported out into blood to be recirculated to other cells.
  • It was once believed that D1 contributed most or all of our bloodstream T3, but that has been disproven.
  • In health, at average levels, about 15% of our circulating T3 is made by D1.

D1 is most strongly expressed in liver, kidney, thyroid, and pituitary. These are are organs that exchange thyroid hormone and blood very quickly.

  • Therefore, D1’s net contribution to bloodstream T3 can be significantly impaired when a major D1-expressing organ is impaired or diseased.

Another aspect that makes D1’s activity so influential is that it is powerfully upregulated by T3 hormone, unlike the other two deiodinases.

  • I imagine T3 hormone “turbo-boosting” D1’s function so that the body can quickly increase T3 levels when it needs to.
  • The more T3 we make, the more this deiodinase makes T3; it’s like a domino effect.
  • Therefore, T4-T3 conversion can be escalated by this deiodinase when Free T3 levels are in upper-normal reference range, and it is powerfully upregulated in Graves’ disease.
  • As your FT3 rises higher than mid-range, a higher % of your circulating FT3 is produced by D1.

You know the saying “When you have money, you can make money?” Well, when you have a lot of T3 you can make even more T3, using this D1 enzyme.  It’s like depositing money in a high-yield investment and getting dividend cheques. Be careful not to add too much T3 if you’re already abundant, or you can overconvert your existing FT4 and you might escalate your FT3 levels too high.

D1 is upregulated by

  • Higher T3 hormone levels
  • TSH,
  • TSH-receptor antibodies in Graves’ disease
  • retinoic acid (a metabolite of Vitamin A).
  • and others…

D1’s activity is powerfully inhibited by

  • Low T3 supply
  • PTU (a medication for Graves’ disease),
  • glucocorticoids,
  • beta-blockers,
  • calorie restrictive dieting,
  • and others…

A major reason why excess RT3 concentration in blood occurs when T3 is low is that the lack of T3 suppresses D1 activity. This makes D1 less efficient in clearing RT3 from bloodstream.

Deiodinase Type 2 is the most essential T4-T3 converter.

D2 is responsible for most (50-70%) of our T4-T3 conversion in tissues and throughout our body.

However, this deiodinase is extremely vulnerable to its “preferred substrate” T4, and secondarily RT3.

  • As T4 (and RT3) rise within normal range and above, these hormones progressively inactivate D2 enzyme and reduce its T4-T3 conversion rate. This D2 inactivation process is called “ubiquitination.”
  • Conversely, D2 becomes reactivated and more highly expressed when T4 levels are lower.

However, there are exceptions to D2’s vulnerability, as Bianco and team (2019) explain.

  1. D2 inactivation does not occur within the thyroid in Graves’ disease.
  2. D2 inactivation does not occur within the hypothalamus and pituitary, which continue to convert T4 to local T3 at a high rate. Unhindered rates of T4-T3 conversion in the hypothalamus and pituitary can produce a TSH that is normalized or low despite lower FT3 levels.

Deiodinase Type 3 is a powerful inactivator of thyroid hormone.

Figure 1 from Bianco-corrected

Its main role is to inactivate T3 into 3,3′-T2 hormone before it reaches the cell’s thyroid receptor in the nucleus. It does this to protect the body from excess T3-receptor activation and maintain local tissue thyroid hormone balance. It also quickly lowers metabolic rate during the early phase of critical illness by reducing T3 binding to nuclear receptors and lowering circulating T3 levels.

D3 is also responsible for almost all of our daily normal Reverse T3 production from T4 hormone.

D3 raises the rate of RT3 and T2 production during illness and states of excess thyroid hormone.

This deiodinase is powerfully upregulated in fetal life and quickly becomes dormant after birth. In healthy adult life it is mostly dormant, residing in the placenta, central nervous system, and skin. However, it can quickly return to dominance over DIO2 in any tissue during critical illness and hypoxia. It is also the dominant deiodinase in states of excess thyroid hormone T3, and secondarily of excess T4. During adult reexpression in illness, it becomes most abundant in liver, lungs, heart, and brain.

D3 expression is decreased in hypothyroid low T4 & T3 states and in tissues where DIO2 is upregulated.

Deiodinases in illness and recovery

The process of T3 loss and T3 recovery is the main subject of research on nonthyroidal illness syndrome (NTIS), also called “Low T3 Syndrome.”

Bianco et al’s 2019 review discusses this process as it occurs in diseases affecting various organs and tissues. I have also studied this research tradition extensively over many years to ensure certainty about the following key principles:

  • In illness, a specific damaged tissue and often the entire body goes through an initial phase of thyroid hormone inactivation, when D3 is overactive in “dumping” T3 (inactivation, degradation, catabolism). T3 loss is believed to be protective in this phase, and the main result is to lower metabolic rate and energy expenditure. Global T3 loss in blood is more severe when the cardiovascular system, liver, or kidneys are damaged.
  • In some organs and tissues, T3 loss initiates a process of cellular proliferation. This may seem paradoxical, but remember that certain genes become more active when T3 receptors are unoccupied. In addition, we now understand that Reverse T3, a major product of T4 inactivation, binds to receptors on the cell wall where its activity there, alongside T4, can enhance cell proliferation in cancers.
  • In the later phase of recovery, the body and damaged organ must replace T3. This occurs globally by synthesizing more hormone in the thyroid gland to replace T3 loss in bloodstream, and by boosting conversion from T4 into T3 in tissues. If this phase does not occur at the right time and at a proper rate, the body can undergo a crisis of T3 hormone supply that can worsen or sustain illness.
  • The depth of low T3 and duration of low T3 is a significant predictor of death rate in critical illness and in elderly or frail individuals.  Higher concurrent FT4 levels during low FT3 can actually worsen the risk of death. (See our review of Ataoglu et al, 2018)

Recovery from T3 depletion in thyroid therapy

During the recovery phase, to compensate for a lower-than-baseline FT3 in the context of thyroid disease and therapy, one must depend on either

a) TSH-stimulated increase in a living thyroid fragment’s T3:T4 secretion ratio and T4-T3 conversion rate, and/or

b) A shift in T4-T3 medication dosing toward less T4 and compensatory T3, which would imitate what a healthy thyroid would do.

Insufficient research on NTIS in the thyroid-disabled population (who have been routinely excluded from most NTIS studies), together with what thyroid science teaches about NTIS recovery, has left us only with reasonable speculation about the likelihood of higher rates of death and poor recovery in thyroidless patients maintained on T4 therapy alone. This reveals a critical need for research in thyroid therapy, as life may be at risk.

Next steps

Now that you’ve reviewed the basics, I recommend this post so you can “see” how your deiodinases work in parallel in different cells:

If you are thirsting for more practical advice on dosing your thyroid hormones, I recommend this:

Tania S. Smith

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

Bianco, A. C., & da Conceição, R. R. (2018). The Deiodinase Trio and Thyroid Hormone Signaling. Methods in Molecular Biology (Clifton, N.J.), 1801, 67–83. https://doi.org/10.1007/978-1-4939-7902-8_8

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

Gereben, B., Zeöld, A., Dentice, M., Salvatore, D., & Bianco, A. C. (2008). Activation and inactivation of thyroid hormone by deiodinases: Local action with general consequences. Cellular and Molecular Life Sciences: CMLS, 65(4), 570–590. https://doi.org/10.1007/s00018-007-7396-0

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

Larsen, P. R., & Zavacki, A. M. (2012). Role of the Iodothyronine Deiodinases in the Physiology and Pathophysiology of Thyroid Hormone Action. European Thyroid Journal, 1(4), 232–242. https://doi.org/10.1159/000343922

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

Refetoff, S. (2000). Thyroid Hormone Serum Transport Proteins. In K. R. Feingold, B. Anawalt, A. Boyce, G. Chrousos, K. Dungan, A. Grossman, … D. P. Wilson (Eds.), Endotext. Retrieved from http://www.ncbi.nlm.nih.gov/books/NBK285566/

Schweizer, U., Johannes, J., Bayer, D., & Braun, D. (2014). Structure and Function of Thyroid Hormone Plasma Membrane Transporters. European Thyroid Journal, 3(3), 143–153. https://doi.org/10.1159/000367858

St. Germain, D. L., Galton, V. A., & Hernandez, A. (2009). Defining the Roles of the Iodothyronine Deiodinases: Current Concepts and Challenges. Endocrinology, 150(3), 1097–1107. https://doi.org/10.1210/en.2008-1588

Vella, K. R., & Hollenberg, A. N. (2017). The actions of thyroid hormone signaling in the nucleus. Molecular and Cellular Endocrinology, 458, 127–135. https://doi.org/10.1016/j.mce.2017.03.001

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

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Categories: Deiodinase Type 2, Deiodinase Type 3, Deiodinases, Healthy thyroid axis, RT3 - Reverse T3, T2 hormone, T3 hormone, T3 sufficiency, T4 hormone, TH Receptors, Tissue hypothyroidism, Transporters

2 replies

  1. Amazing job! Thanks

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