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:
Here’s the corrected & clarified image that I developed based on Bianco et al, 2019’s model:
Well-meaning people have attributed to the hormone RT3 a “T3-blocking” function.
But science shows that the T3-blocking function is largely performed by Deiodinase Type 3 (D3), the enzyme that makes T4 into RT3 and makes T3 into T2.
It’s more than a semantic distinction between “RT3 dominance” and “D3 dominance.”
D3 can still dominate in the body when RT3 hormone is low in blood.
It’s Deiodinase Type 3 that plays a 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, D3 changes its location, defending the inner fortress and working harder to prevent T3 entry into the nucleus.
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 T2 nor RT3 have enough affinity to the thyroid hormone receptors in the nucleus.
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, so it is handicapped and can’t bind to the nuclear receptors.
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 had less than 1% the affinity of T3 for the nuclear receptors.
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. RT3 does not bind to nuclear receptors.
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 and D2 parallel activity
This model of thyroid hormone activity means that if you have a good supply of circulating T4 and/or T3 hormones, they can be inactivated in some cells and activated in others “in parallel.”
The two separate pathways of D2 and D3 ensure that their operation cannot cancel out each other’s activity within a given cell.
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 D2/D1 pathway can still operate to some degree independently of the D3 conversion pathway.
Nevertheless, they all 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, and they can also produce healthy food that benefits their own workers.
How can thyrotoxicosis occur in spite of D3 dominance?
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.
If it were not possible to overcome D3 dominance, thyrotoxicosis would be impossible in Graves’ disease and in cases of thyroid hormone overdose.
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. You need powerful anti-thyroid medications fighting on your side.
One must read FT4 and FT3 levels together
These images must drive home the point that we ought never to judge FT4 or FT3 in isolation from each other.
Reference ranges in lab results artificially separate these hormones.
But T3 is not a separate hormone from T4.
When the Free T3:T4 ratio is extremely high or extremely low (one is much higher than the other), FT3 will compensate for FT4 because T3 is the active hormone.
However, when the opposite happens, a higher FT4 level can never compensate for a significantly low(er) FT3. This is because our cells require a baseline of FT3 before they top up with a variable rate of T4-T3 conversion in D2-expressing cells.
Individuals vary so much in thyroid hormone metabolism, especially in thyroid disease and thyroid therapy, that you cannot assume adequate FT3 from looking only at FT4 or TSH levels.
One ought always to consider baseline FT3 levels in context of concurrent FT4 availability, and see how the body responds as dosing and levels change over time.
One does not always need to test Reverse T3! It can be costly to the patient!
A person with good understanding of thyroid hormone action can “read” D2, D3 and D1 activity from FT3 and FT4 in context.
For that matter, RT3 is not separate from FT4 either, because RT3 can only derive from FT4 molecules.
FT4+RT3 can add together to ubiquitinate D2 to a higher degree, since T4, followed by RT3, are the two main “substrates” of D2, and the substrates inactivate this enzyme.
Deiodinases in people who are fine on T4 monotherapy
Many of the people who fare well on T4 monotherapy still have some functional thyroid tissue that helps to convert T4 into T3 as TSH-containing blood flows through it.
Even in some thyroidless people on TSH-suppressive LT4 monotherapy, some are relatively “good converters” whose FT3 levels can actually increase beyond reference when FT4 rises above reference range. (Larisch et all, 2018)
Some people may have a higher thyroid hormone metabolic setpoint or “thyroid hormone resistance” that does not trigger D3 dominance at higher doses and also prevents TSH from being too easily suppressed at higher doses.
Some people may have a more robust DIO2 and/or DIO1 gene.
If D2 permits FT3 to rise sufficiently, DIO1 will also be upregulated as FT3 rises, and this will boost conversion further.
Problems with insufficient FT3 in LT4 motherapy
Three major categories of problems can occur:
a) Underdose — not enough thyroid hormone supply is given to maintain euthyroid T3 receptor occupancy levels in tissues across the human body.
In most cases this is because doctors do not understand that even in perfect thyroid health the TSH rarely rises above 2.5 mU/L except in old age and in recovery from illness. The TSH population reference range is a statistical artifact that is too wide to fit even a perfectly healthy individual.
The phenomenon is logical.
There is no mathematical magic that will render a treated patient “euthyroid” at a TSH in the upper half of reference if their setpoint is only achievable alongside a far lower TSH.
Why in the name of biology should anyone force a patient with little to no productive thyroid tissue to live with a TSH higher than 2.5 if doing so cannot result in raising FT3 to their individually optimal range (often within the upper half of reference range) that removes their hypothyroid symptoms? (Larisch et al, 2018)
b) A poor converter on T4-dominant therapy — the T4-T3 ratio will be extremely imbalanced in favor of higher FT4 and much lower FT3 in a person whose D2 enzyme is incapable of handling the metabolic imbalance.
Such a person may have difficulty raising FT3 into reference range in spite of high-normal FT4. Even mid-range FT3 may be insufficient for such a person to achieve euthyroid T3 receptor occupancy because of their D3 dominance in many cells will inactivate Free T3 before it can reach nuclei.
Usually the FT3:FT4 ratio is enough to diagnose a poor converter, but Reverse T3 testing can be a useful confirmation of the degree to FT4 is too high above their setpoint and is worsening the Low FT3 status of a poor converter.
c) Mild to moderate undiagnosed central hypothyroidism (pituitary TSH hyposecretion). A doctor unaware of this may reduce LT4 dose when TSH falls below reference and thereby cause underdose. A reduced TSH or non-bioactive TSH can be caused by medication, diet, or genetics or undiagnosed central organ damage or disease.
TSH-based dosing can cloak this, especially if central hypo occurs gradually over years of thyroid therapy. After proper diagnosis, a doctor should permit LT4 dose to rise and TSH to fall low enough below range to permit FT3 to rise.
Could you be in category B or C?
While on LT4 monotherapy, the free SPINA-Thyr app can be used to detect both mild pituitary hyposecretion (a TSH that is deceptively low given FT4 levels) and very poor T4-T3 conversion rates. See Midgley et al, 2015 for a discussion of the “poor converter.”
LT4 pharmaceutical conversion is uncertain
The degree to which an individual patient will convert LT4 medication to the truly active ingredient is a roll of the dice.
This is a pharmaceutical with an absolutely unknown amount of “truly active” ingredient (T3) that must be unlocked by D2 or D1 more than it is inactivated by D3.
LT4 hormone pharmaceuticals are
- variably converted to T3 by D2, at a slower rate as both FT4 & RT3 rise in reference
- variably converted to T3 by D1, at a slower rate when FT3 is low-normal or low
- variably inactivated to RT3 by D3, at a faster rate as FT4 and/or FT3 rise in reference
Variation is even more unpredictable given each person’s unique thyroid gland status, genetics, health status, concurrent medications, diet, age and other factors.
Today, thyroid therapy focuses on controlling LT4 dosing down to the microgram and trying to enhance its absorption.
But no pharmacist or doctor can use Dosage + TSH/FT4 to predict the nanograms per liter per day of T3 or RT3 produced within the individual patient’s tissues and bloodstream.
Predictions based on statistical averages are foolish in the context of wide flexibility and variation built into thyroid hormone deiodinase economy.
Unique D2 behavior in the hypothalamus biases TSH low
When a patient’s T3:T4 ratio is incredibly low due to poor adaptation to LT4 monotherapy, the distorted FT4 and FT3 ratio that results will be metabolized very differently in the hypothalamus and pituitary than in all peripheral tissues.
LT4 monotherapy can induce the biochemistry of nonthyroidal illness, even without the illness as trigger. It can be maintained on a chronic basis. Even if this biochemistry does not directly cause an illness, it can certainly hinder recovery after illness or injury.
Part of the biochemistry of nonthyroidal illness is a falsely normalized TSH.
We now know that in the hypothalamus, D2 enzyme is uniquely robust and not as subject to ubiquitination as FT4 rises, and therefore TSH will not rise appropriately in response to FT3 loss. TSH will only rise after FT4 also lowers enough to permit it to do so.
The inappropriately normalized (rather than elevated) TSH is the inevitable result of maintained D2 dominance in hypothalamus.
A deceptively normal TSH in spite of low(er) FT3 can maintain medically-authorized torture under a doctor and health care system unenlightened by thyroid science.
TSH-Deiodinase self-protection and deception
A deceptively normal TSH signal is a natural result of deiodinase imbalances in the body from which the hypothalamus or pituitary are uniquely protected during Low T3 syndrome.
If TSH-regulating organs were not protected from severe low T3 by a more robust D2, damage could occur to pituitary and hypothalamus tissues responsible for regulating many other hormones and endocrine functions in the body. Damage could prevent recovery of health via the return of TSH stimulation of a thyroid that resupplies FT3.
Another kind of self-protectionism and damage control is occurring in the medical system.
Systemic medical ignorance of chronic “Low T3 syndrome” in treated T4 patients is caused by endocrinologists’ refusal to engage in self-incriminating 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.
There is no better reason than professional self-protection than to avoid recommending FT3 testing in the context of the field’s favorite form of thyroid therapy.
Smart endocrinologists are cautious about the implications of their research for their field of medicine, and legal implications.
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.
- Tania S. Smith
Earlier posts on Reverse T3 and deiodinases
- GRAPHIC and discussion: T3 Depletion
- Recovery from T3 depletion
- How the three deiodinases regulate T3
- Deiodinase type 3 and Reverse T3
- Interpreting Free T3 and Free T4 in therapy
- Do you have a Reverse T3 problem?
- Thyroid hormone conversion
- The Low T3 Syndrome in memes
- Ubiquitination: The glass ceiling of T4 monotherapy
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