In thyroid disease and therapy, even when TSH is normalized, we can still be genuinely hypothyroid if we do not have enough T3 getting into our thyroid hormone receptors in cells throughout the body.
Most people know there’s two ways we get T3 into our cells’ nuclei:
- From circulating Free T3, and
- From circulating Free T4 hormone that is converted into T3 at a variable rate.
However, most doctors are not taught about our cells’ and tissues’ high priority for and dependence upon circulating T3, nor are they taught about the largest factor that can reduce T4’s local variable conversion rate to T3, nor are they taught about the direct correspondence between Free T3 levels and T3 nuclear occupancy rate, which determines hypothyroid or euthyroid status both locally and globally in the body.
The body’s dependence on a baseline of healthy circulating T3 is a principle that Antonio Bianco has emphasized in numerous publications.
Who is Antonio Bianco? Quite a prominent leader in the endocrinology community. He is one of the world’s leading researchers on thyroid hormone conversion, and he served as the American Thyroid Association’s president in 2015.
In this post I use an image by Bianco and Kim in 2006 to show how circulating T4 and T3 contribute to nuclear receptor occupancy rate.
I outline 10 steps that T3 takes to get from bloodstream into receptors and then back out to the bloodstream again.
Landmark scientific reviews by Bianco and his colleagues, supported by many others’ scientific studies, argue strongly that we must never dismiss or underestimate the body’s dependency on Free T3 in blood.
It is never an excuse for neglecting Free T3 testing to say “blood levels of FT3 do not correspond to local tissue levels of T3.” Bianco acknowledges this fact, and nevertheless, he asserts that Free T3 is profoundly significant. It is because bloodstream FT3 largely arises from, and therefore represents, net tissue-level T4-T3 conversion rates across the body.
The health implications of Free T3 reductions within the reference range are immense, especially for certain organs that depend almost 100% on Free T3, such as the heart, as you shall learn in Part2 of this series.
- 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 one type of D2-expressing cell. The receptors in the nucleus are in the smaller gray sphere:
The diagram above by Bianco & Kim, 2006 depicts pituitary “thyrotrophs.” These are the cells in the pituitary gland that secrete TSH.
In this particular organ and cell type, here is the journey of T3 into and out of the nucleus, in 10 steps:
- T3 and T4 cannot enter cells by passive diffusion. As they enter the cell, they must be carried on transmembrane thyroid hormone transporters, some of which have a relatively higher preference for T3 and others which have a relatively higher preference for T4.
- T3 hormone does not need to be converted. It is already in the active form, ready to bind with receptors. If it is not inactivated to T2 by D3 enzyme expressed in the cell (D3 is not shown in this diagram), a large percentage of T3 entering on transporters can be ushered directly into the nucleus.
- Circulating Free T3 fills the bottom layer of the gray sphere of nuclear receptors. Of course, nuclei don’t have “layers,” but TRs are distributed throughout the nucleus. This visually depicts the fact that each tissue depends on a baseline amount of circulating T3.
- Deiodinase type 2 (D2) enzyme activity (and in other cells, D1, not shown) converts T4 hormone locally into T3, but at a highly “variable rate” because D2 will be progressively deactivated as T4 rises within reference range. (Analogy: You can imagine that the D2 enzyme is like an office worker who gets overworked and discouraged when too much T4 paperwork gets put on his desk that requires processing.)
- T3 converted locally from T4 tops up T3 levels within the nuclear compartment. T4 is the second priority source for T3, a source that enables customization of T3 availability from tissue to tissue, as long as D2 and D1 enzymes can convert T4 locally at a healthy rate. The cell is simply not equipped to make extra T3 supply locally from converted T4 if or when FT3 supply falls short. T4 is nature’s version of “sustained-release T3” except that T3 production is highly variable.
- In this particular tissue, a certain percentage of “unoccupied receptors” is necessary for euthyroid status. If too many of the unoccupied receptors are occupied, it will create localized thyrotoxicosis. If too few are occupied, the tissue will be hypothyroid. Therefore, T3 hormone sufficiency is the ultimate determiner of euthyroid status throughout the body.
- The T3 bound to receptors will enable genomic signalling. In this cell located in the pituitary thyrotrophs, T3 will perform genetic transcription of TSH mRNA (see the arrow under the gray sphere), which, together with TRH hormone from the hypothalamus, co-regulates the level of TSH hormone secretion. In a different tissue or organ, T3 binding will signal to different genes that enable other essential biological processes to occur.
- After binding with TRs for 30 minutes to several hours, each T3 molecule exits the nucleus and returns to the cell’s cytosol (the green area in the model).
- The ratio of T3 and T4 hormones floating in the cytosol is then transported out of the cell by the same thyroid hormone transporters that brought T4 and T3 into the cell (exit transport is not shown in the diagram). The rate of hormone influx matches the rate of hormone efflux, much like breathing in and breathing out.
- This means that intracellular T3 and T4 ratios and levels directly affect FT3 and FT4 concentrations in blood. There is no “secret compartment” for T3 in the body, no “black hole” that sucks up T3 and never lets it go back into blood. There are only different rates at which each tissue exchanges hormones with blood, and one “global” rate of exchange that is comprised of the net rate of all tissues. The body converts and recycles T3 and T4 hormone among many cells and tissues until they are converted to other thyroid metabolites and/or excreted from the body.
To start nice and simple, this is a very narrow view of something far more complex and variable.
- This image only shows ONE type of thyroid hormone conversion process, just the D2 pathway. There are three deiodinases that convert thyroid hormones (D1, D2 and D3). One cell may express D1 or D2 while a neighboring cell may express D3.
- The image also simplifies it to ONE tissue’s cells. Each tissue or organ requires a different average T3 receptor occupancy rate for health. Some cells and tissues depend almost 100% on FT3 from blood and will suffer when FT3 is insufficient yet still within reference range.
How many receptors need to be occupied by T3?
Some cells are highly responsive to thyroid hormone because their nucleus is packed with so many receptors.
The number of TRs “vary from very few (minimally responsive cells) to as many as 8,000 TR molecules per cell, as seen in liver, pituitary, and BAT [Brown adipose tissue; brown fat].” (Bianco et al, 2009)
This teaches the principle that some tissues are designed to be extremely T3-regulated because up to 8,000 receptors per cell can toggle genomic activity on and off in that organ.
However, it’s not about the sheer number of receptors in the cell, but the ideal percentage of occupancy in a particular tissue or organ, that determines what euthyroid status is.
- Some tissues require 50% receptor occupancy (with the other 50% empty),
- Other tissues require 75% occupancy (25% empty),
- Still other tissues need close to 100% occupancy to be euthyroid.
The percentage of occupied nuclear receptors determines the level and type of T3 gene-transcription activity within that cell.
The T3 hormone acts on receptors like a “toggle switch,” essentially turning on genes that were previously repressed, or turning off genes that were previously active.
Unoccupied receptors are not inactive, but are in a state that is changed when T3 occupies them. (Vella & Hollenberg, 2017)
The high priority of circulating T3
Bianco et al, 2019 explains why Free T3 / Total T3 in blood is so vital:
“Circulating T3 levels are important determinants of TH signaling. Indeed, in most tissues the level of TR occupancy, expression of T3-responsive genes, and downstream biologic effects are greatly influenced by circulating T3 levels. In other words, as long as TH transmembrane transporters are available, T3 from plasma will enter cells at levels that occupy half [50%] of the TR pool. Conversely, a drop in plasma T3 will reduce TR occupancy in most tissues as well.” (Bianco et al, 2019)
Thyroid hormone sufficiency is about how much T3 hormone gets into nuclear receptors. That is to a significant degree determined by circulating T3.
There’s a strong direct relationship between Free T3 and T3 binding with nuclear receptors:
“as T3 levels increase, T3–TR binding increases following an asymptote curve that reflects higher TR occupancy.” (Bianco et al, 2019)
The term “asymptote curve” has significance when discovering drugs that have a direct effect on the human body, and when designing laboratory tests. The term refers to the shape of a line graph plotting the association between a drug (or hormone concentration) and the body’s response (See image below).
An angled line plotting a direct linear relationship begins to curve and then flattens out at the very high and low concentrations. It simply means that once the receptors reach saturation, adding more T3 to blood makes little difference, and if too many receptors are empty, removing more T3 from blood makes little difference to TR occupancy rate.
But everywhere in between the two extremes, adding or removing T3 from blood will directly affect TR occupancy rate.
The nature of this FT3 supply – T3 signaling relationship is so sensitive that even within the normal reference range, T3 receptor occupancy rate can be significantly affected.
Therefore, there is a strong physiological basis for an “optimal Free T3” level in blood.
What is the normal average FT3 vs. optimal FT3?
Many studies of large healthy populations with healthy thyroids have shown that Free T3 levels on average sit at 40-60% of the reference range, depending on the FT3 assay and the population’s iodine and selenium status, while Free T4 sits at 30-40% of its reference range.
However, population averages are extremely deceptive in thyroid science.
Reference ranges simply provide a general landscape into which hormone concentrations can be “mapped,” and they cannot be used to prescribe a location in the range where an individual will find health. This is especially true in thyroid disease and thyroid therapy, which both directly interfere with “natural” homeostasis.
In a natural state without thyroid disease or thyroid hormone ingestion, the TSH and FT4 in the individual can and will fluctuate widely, both daily and over weeks or months, with the goal of stabilizing the FT3 at an individually-optimized level.
The FT3 must also adjust to each individual, because our metabolic demands differ from person to person and throughout our lives.
In the 2000s, it was discovered that the population’s Free T3 reference range is too wide to fit any single individual — In a healthy individual, Free T3 will not vary more than 38% of its reference range (Ankrah-Tetteh et al, 2008). Free T3 has an individual variance that is far narrower than TSH, Total T4, Free T4 and Total T3.
This image from Ankrah-Tetteh shows 10 people whose Free T3 hormone was tested over time, and the degree to which they varied. As you can see, the window of variation is narrow and there are some people sitting in the upper half of reference range. The lower part of reference from 3.4 to 4.0 is not used by any of them.
Therefore, healthy normo-thyroid individuals vary widely in the location of their ideal TSH, FT4 and FT3 euthyroid “metabolic set point” (their personal FT3 healthy range) depending on their individual body’s needs.
It is therefore a fundamental flaw to presume that the lower boundary of a FT3 population reference range is where true tissue hypothyroidism begins in an individual.
There’s another reason why one should avoid getting anywhere close to the lower boundary of Free T3 during therapy. The FT3 reference range has not been as carefully screened (as the TSH range has been) to exclude blood samples that are not healthy.
How do we know for sure whether the reference range calculation (often done by the laboratory themselves) includes blood tested from hypothyroid patients on therapy whose TSH and FT4 may be normal, but whose FT3 is often low, or people who have chronic health conditions like heart disease that lower FT3?
Overreliance on the lower boundary of FT3 as a cutoff can cause harm to treated patients.
For example, one published case study discovered that a treated thyroid patient was forced to maintain her body’s functions at FT4 and FT3 levels near the very bottom of a laboratory’s reference range, which caused her to fall into the life-threatening state of “myxedema coma,” and the researchers reasoned that her individual healthy setpoint was probably located near the top of the reference ranges (Mallipedhi et al, 2011). She required emergency T3 therapy to recover health. Myxedema coma has a high fatality rate.
Luckily, if you have a healthy thyroid gland and aren’t taking thyroid hormones, TSH regulation takes care of your T4 and T3 levels and compensates for any inadequate T4-T3 conversion. In health, the FT4 and FT3 maintain a relatively stable ratio of 0.32 pmol/L — the two hormones tend to rise and fall with each other.
However, in thyroid disease and therapy, people are extremely vulnerable to inappropriate T3 depletion caused by improperly dosed or insufficiently converted thyroid hormone medication. The HPT axis no longer protects FT3. In levothyroxine thyroid therapy, the FT3:FT4 ratio varies widely and is significantly lower than in healthy people: a good converter may have a ratio of 0.28 while a poor converter will have a ratio at or below 0.23 pmol/L.
The stability of T3 levels in UNtreated patients
In people whose HPT axis is co-regulated naturally by TSH and thyroid tissue, without any interference from thyroid hormone medication and dose changes, the T3 level is extremely stable within each individual, not varying much at all within the reference range over a year of the person’s life.
Bianco & Abdallah in 2014 emphasized that “Plasma T3 levels are relatively stable over time.” “Serum T3 is remarkably stable over periods of days, weeks or months in healthy adult individuals, despite a relatively short half-life (approximately 12–18 h).”
For example, FT3 measured once a month for 13 months only varied within a small portion of the reference range, as shown in the figure below from Karmisholt et al, 2008, in UNtreated “subclinically hypothyroid” individuals (elevated TSH but FT4 and/or FT3 still within reference).
Karmisholt et al discovered that both FT3 and FT4 were equally stable over a year within each patient, even as the TSH increased above reference range. One standard deviation (SD) in FT3 levels was only 0.1 to 0.4 pmol/L per patient.
The body’s amazingly tight control over FT3 levels is especially surprising when you consider that the FT3 reference range is very narrow, approximately 3.0 to 3.5 pmol/L at most laboratories, and that T3 has a very short half-life in blood, as Abdalla & Bianco state above.
A change of 1.0 pmol/L in FT3 would be biologically significant to thyroid hormone receptor occupancy, as it represents up a small fraction of the population’s reference range but could represent 100% of an individual’s more limited set-point within reference range.
The tight control we see in FT3 data is also a reflection of the high quality of our current lab testing technologies. Today’s assay technologies for FT3 and FT4 often yield far more precise and reliable data than even the so-called “highly sensitive” TSH assay (it is more sensitive than previous TSH tests).
For example, Ankrah-Tetteh and colleagues found the coefficient of variation (CV) when testing the same blood sample over and over on the same technology was 2.4% for FT4 and 1.2% for FT3. This means that their lab’s FT3 test was 2x more precise than FT4. In contrast, their TSH test had a wider CV of 13.5%, giving much more varied results for exactly the same blood sample!
Consider the efficiency, economy and clinical precision of testing FT3 and FT4, not just TSH: Given the variability of changes over 1 year within an individual, Karmisholt and colleagues calculated that you would need only three (3) FT4 and/or FT3 samples, but 19 TSH samples, to discover an individual’s current thyroid hormone “set point” with 80% precision.
Stabilizing T3 levels is the goal of the healthy HPT axis
The principle that FT3 is the body’s target for maintaining optimal function (by maintaining T3 hormone receptor occupancy) is a profound paradigm shift for many doctors who are taught to judge thyroid status by TSH, with the occasional aid of FT4:
“That the level of serum T3 is a main target around which serum T4 and TSH are adjusted constitutes a shift in the paradigm traditionally accepted for the function of the hypothalamus–pituitary–thyroid axis.” Bianco & Abdallah, 2014)
Essentially, T3 is like the sun, around which the earth (T4) rotates.
TSH is depicted as the “moon” in the diagram’s corrected half because it has a closer relationship to T4 levels than to T3 levels. The TSH focuses on hormone production, while the deiodinases, a complex system of their own, focus on T4-T3 conversion.
To believe that the body’s health is regulated by TSH is a backwards way of viewing the system from the perspective of the laboratory test result that will give the most variable numbers.
The laboratory test result with the least variable number and smallest number in health is actually the core and target of the system, T3.
(NOTE: The major flaw in the “solar system” visual model is that in thyroid hormone metabolism, the T3 is not the mighty sun because it can’t sustain or fuel itself. It is fragile, like a young child protected by two parents. T3 requires T4 and TSH and a healthy thyroid gland (gland not shown!) to defend and adjust T3’s position in the universe.)
FT3 must be the target of the healthy HPT axis because circulating T3 sets the level of T3 signaling in receptors in all tissues.
The body’s need for FT3 depends on FT4 level and T4 conversion rate.
In addition, the ideal FT3 level in blood cannot be interpreted in isolation. It depends on concurrent availability of FT4 and the individual’s rate of conversion from T4 to T3 within cells.
The principle of T3 compensation for T4, but not the reverse, is illustrated in diverse circumstances in real life.
- As FT4 drops, your body will need more FT3 in blood to compensate for less T4 converting to T3 in cells.
- For example, in mild iodine deficiency and in mild hypothyroidism before treatment, the TSH-overstimulated thyroid will prioritize T3 production over T4 production. This can maintain metabolic health in spite of lower T4 levels.
- For example, in T3 monotherapy, if T4 is entirely absent from blood, an individual will need approximately “twofold” (2x) the normal amount of T3 in circulation to maintain euthyroid status in the pituitary (Busnardo et al, 1983)
- As FT4 rises, T4-T3 conversion rate reduces in cells, so a higher FT4 cannot metabolically compensate for lower FT3.
- For example, the highest risk for death in low T3 syndrome exists when the FT4 is slightly above reference while FT3 is below reference while TSH is normal. (Ataoglu et al, 2018) Such patients are not hyperthyroid due to T4, but rather hypothyroid due to lack of T3 receptor occupancy.
- For example, a patient can be metabolically hypothyroid and symptomatic even despite a TSH-suppressing FT4 is above reference if their FT3 is concurrently below reference range due to poor conversion. (Larisch et al, 2018)
- Giving a very sick, very hypothyroid patient T4 medication alone can be damaging and counterproductive, but giving them a robust T3/T4 combination can bring recovery (Scoscia & Baglioni, 2010).
Not the end of the story: Cofactors
Building on top of the baseline of “enough T3 in nuclear receptors” are yet other factors that can reduce or enhance T3 signalling.
Once T3 thyroid hormone binds to receptors, it still needs “cofactors” to enable thyroid hormone signalling to genes.
For example, scientists have discovered that rexinoid receptors — the receptors for Vitamin A — act synergistically with T3 in its receptors to enable signalling in the pituitary and liver, suppressing TSH levels in mouse models. (Sharma et al, 2006)
Nevertheless, the baseline of T3 receptor occupancy is absolutely necessary for health.
All the cofactors in the world can’t enable an unoccupied T3 receptor to send the signal it would if it was occupied.
What we’ve learned so far
Getting enough T3 into thyroid hormone receptors in nuclei of cells throughout every tissue and organ — That is the baseline of global euthyroid status, and nothing less.
T3 receptor occupancy and signalling depends mostly on your FT3 level, and secondarily on your FT4 supply and variable rate of T4-T3 conversion.
Whether a FT3 is sufficient or not for an individual depends on the context.
You need to know the concurrent FT4. Higher FT4 concentrations will convert less efficiently. Outside of thyroid conditions that add extra T3 supply, the FT4:FT3 ratio in blood can provide a very good estimate of global T4-T3 conversion efficiency.
Implications for thyroid therapy
FT3 changes within reference range can be very significant to thyroid patients’ health and symptoms, as proven by recent clinical research.
A thyroid hormone medication change resulting in a rise of 1.0 pmol/L can drastically shift thyroid hormone receptor occupancy rates.
If a FT3 rise is significant enough, it can free a patient from chronic hypothyroid symptoms, or it can cause symptoms of thyrotoxicosis.
In thyroid therapy, knowledge of a person’s natural, healthy individual FT3 and FT4 setpoint is usually unavailable. Even if it were available, such as pre-thyroidectomy for thyroid cancer, the influence of thyroid disease and the metabolic distortions of thyroid therapy will substantially change one’s “healthy” setpoint (Hoermann et al, 2019a, b).
The ratios and levels of FT3 and FT4 in blood will rarely be “natural” in therapy, but the level of T3 they deliver to cells can still be therapeutic and sufficient.
Measuring Free T3 (and FT4) in relation to symptoms, and adjusting medication accordingly, can help a patient achieve their individually-optimal thyroid hormone health and freedom from both hypothyroid and hyperthyroid symptoms (Larisch et al, 2018; Ito et al, 2019; Hoermann et al, 2019a, b).
Part 2 & References
Part 2 discusses how T4-T3 conversion occurs at a variable rate in cells and the problems this can cause during thyroid therapy.