Deiodinase Type 3, not RT3, plays the T3-blocking role

A lot of internet myths and misinformation surrounds Reverse T3 (RT3). Well-meaning people have attributed to the hormone a “T3-blocking” function.

However, the enzyme deiodinase type 3 (D3) (NOT Vitamin D3, which is very different) is the main blocker of T3 hormone.

Deiodinase type 3 (D3), regulated by the DIO3 gene, is the enzyme that rises to dominate in states of severe illness and states of excess T4 and/or excess T3.

The role of D3 enzyme is two-fold:

1. It converts T4 to RT3.
2. It converts T3 to an inactive form of T2 called 3,3′-T2.

When D3 is working properly, it defends us from hyperthyroidism. It’s an intracellular defense mechanism.

When D3 is temporarily upregulated in acute illnesses, it temporarily gives us extra intracellular and circulating iodine by removing iodine atoms from T4 and T3 molecules.

But when D3 enzyme becomes chronically upregulated and the D1 and D2 enzymes become downregulated, it can cause a chronic problem of metabolic imbalance that steals intracellular T3.

While this happens, the imbalanced enzyme activity in cells causes RT3 to build up in blood, as RT3 is created at a faster rate than it is converted to inactive T2.

Essentially, hypothyroid symptoms and higher mortality rates are not caused by RT3 gain, but by chronic intracellular T3 losses.

Circulating T3 is still entering cells, but a lot of T3 is being taken apart inside cells before it can reach the receptors in the nucleus of the cell and in mitochondria.

When Free T3 levels are high-normal in blood but FT4 is low-normal or low, the speed of T3 losses can contribute to intracellular hypothyroidism.

When FT3:FT4 ratios fall low while intracellular T3 is being lost, mortality rates increase.

The behavior of RT3 in relationship to FT3 and FT4 in blood are clues to what is happening inside cells, but only if one understands the enzymes that metabolize these hormones.

Understanding more about D1, D2, and D3 enzymes is essential to understanding how intracellular T3 is prevented from entering receptors.

Understanding D3 enzyme in particular is essential to understanding what can block T3 from getting into receptors to cause hypothyroidism and worsen or prolong a state of illness, or derail thyroid therapy.

After I explain how RT3-blocking beliefs tend to arise from incomplete evidence and reasoning, I explain what’s really going on in your cells.

Finally, I give tips on how to read your dosing, symptoms, FT3 and FT4 to interpret D3 enzyme’s relative level of activity in blocking T3.

How the RT3-blocking myth arose

If RT3 can’t block T3, why do so many websites and celebrity physicians teach this?

There is evidence that points to high RT3 as a bad sign.

However, it’s a common logical fallacy to mistake correlation for causation.

Many intelligent people, including scientists and physicians, jump from correlation to causation without realizing it. It is easy to believe that when two things, A and B, often happen at the same time, A could be the cause of B.

It is not always easy to see that a third factor, C, could cause both A and B to occur simultaneously as effects. The third factor C may be hidden from one’s view, not measured, or not fully understood.

Here’s how so many intelligent physicians have come to an incorrect conclusion about RT3 as a T3-blocker.

First of all, high circulating RT3 is often seen hand in hand with low circulating T3 during illness. The high RT3:T3 ratio is a hallmark of “low T3 syndrome,” or what is now more commonly called “nonthyroidal illness syndrome” (NTIS), because it often occurs even in people with perfectly healthy thyroid glands.

Therefore, because high RT3 and low T3 occur in illness, many people find it easy to believe that high RT3 causes T3 to fall low.

Some have even come to believe that high RT3 can cause illness, even though the high RT3 or low T3 is rarely present before a heart attack or major surgery.

Secondly, high-normal RT3 is often seen hand in hand with high-normal Free T4 (T4) during levothyroxine monotherapy. Some people on levothyroxine are very inefficient at converting T4 hormone into T3 hormone. In these people, high-normal RT3 levels and high-normal FT4 levels will coincide with low-normal or low Free T3 (FT3) levels.

Many people with poor thyroid function and low FT3:FT4 ratios, whose FT4 and RT3 are high normal, suffer hypothyroid symptoms. This is easily explained:

• as FT4 rises above the population median, it converts to T3 less efficiently in cells due to “ubiquitination” of the D2 enzyme.
• as FT3 falls below the population median, D1 enzyme becomes sluggish, since D1 is regulated by T3 signaling in receptors. The D1 enzyme converts T4 to T3 in thyroid, liver, and kidney.
• as D1 is downregulated by low-normal FT3 levels, RT3 builds up in blood per unit of T4, because D1 enzyme is the main pathway of RT3 clearance to T2.

Therefore, many people without an understanding of D2 and D1 believe that thyroid hormone dosing mistakes, namely dosing too much T4, causes people to have high or high-normal RT3, which then causes T3 to fall low. That cause-effect pathway is false.

Without “seeing” D2 and D1 behavior, they cannot “see” that both severe thyroid dysfunction and some individual’s metabolic response to an imbalanced hormone treatment can lead to intracellular T3 loss and hypothyroid symptoms.

Notice that this imbalance does not require D3 upregulation. Intracellular T3 losses can occur even when RT3 production is not elevated by illness-dysregulated metabolism and even when T3 is not being lost by illness-dysregulated metabolism.

Thirdly, a paradox occurs in cases where RT3 and FT3 are both high-normal. In some people on desiccated thyroid (NDT / DTE) therapy, RT3 can climb to high-normal or high levels. In many of these people with high-normal RT3, illness and/or hypothyroid symptoms occur, even though their FT3 is high-normal at the same time.

Therefore, many people have correctly concluded that the problem can’t be caused by low circulating T3 alone. They reasonably consider that there has to be a problem at the cellular level.

Overall, three RT3-blocking theories have arisen at the cellular level:

1. High-normal RT3 can cause T3 to “pool” in blood and not enter cells (FALSE), and/or
2. High-normal RT3 can cause T4-T3 conversion to be inhibited in cells (FALSE), and/or
3. High-normal RT3 levels can plug T3 receptors and block T3 from binding to them (FALSE).

These beliefs were proven false long ago in an experiment by Shulkin & Utiger in 1984, titled “Reverse triiodothyronine does not alter pituitary-thyroid function in normal subjects.”

They overdosed people with Reverse T3 until they had not just “high-normal” RT3, but 10-fold the amount of normal RT3 in blood.

What were the results? The healthy people did not become hypothyroid or unhealthy. Even their pituitary gland continued to perform T4-T3 conversion and T3 transport and signaling, because TSH did not rise.

The key was that these were healthy people with healthy thyroids dosed with RT3 whose FT3:FT4 ratios were not abnormal when the experiment started. They were not producing their own endogenous excess RT3 per unit of FT4 due to “nonthyroidal illness syndrome” (NTIS) that dysregulated their metabolism. Their metabolism was not taking apart their T3 at a high rate. Their bodies were capable of continuing to convert T4 to T3 despite excess RT3.

Finally, several “scapegoat” theories have arisen to explain why symptoms and illnesses don’t always coincide with high-normal RT3 and don’t always disappear when RT3 falls low:

1. Iron problems
2. Cortisol problems
3. Any other health problems, including other nutritional deficiencies and excesses, thyroid autoimmunity, or even not pursuing a gluten-free diet
4. Patient or physician error, such as not performing an RT3-reducing protocol properly with the steps in the right order, or not dosing T3, cortisol, or iron properly.

Certainly, iron and cortisol and many other substances can interact with thyroid hormones in powerful and complex ways. However, a reasonable person should be suspicious that there’s a problem with a theory that shifts the blame to explain their theory’s failures.

When RT3 can no longer be blamed, theorists blame everything else but RT3, including blaming the patient for not following a protocol properly.

Something is missing from these theories that blame higher circulating levels of RT3 hormone.

The main misunderstanding is about D3 enzyme’s intracellular T3-blocking role.

Misunderstandings about T4-T3 conversion, T3 transport and receptors get in the way of understanding D3 enzyme as a T3 blocker.

Is RT3 or D3 guilty of crimes against T3? No.

Let’s imagine a criminal court case.

Reduced T3 signaling is the only way a hypothyroid state can be created.

At a fundamental level, the crime has to be the disappearance of T3 from receptor cites in the nucleus, or a reduction in T3 receptor sensitivity.

Which hormone, transporter, receptor, or enzyme is to blame? Let’s look at the evidence accessible to people who are trying to solve this crime.

• Reverse T3 is like a corpse, a less active hormone that appears when T4 is inactivated by D3.
• 3,3′-T2 is also like a corpse, a less active hormone that appears when T3 is inactivated by D3.

In some countries (especially the U.S.) people have access to RT3 tests in addition to FT4 and FT3 tests.

However,

• Nobody but researchers has access to T2 tests. So we can’t see T2 accumulating in cells or in blood. (And besides, 3,3′-T2 may also disappear from blood if an overactive D3 enzyme is responsible for converting it to T1 hormone.)
• Only researchers, not clinicians or patients, have the scientific tools to measure Dio3 mRNA and D3 activity levels in tissue samples.
• Few people read thyroid science to discover how D3 behaves under various conditions.

Therefore, all most people can see is increased RT3 in blood and decreased T3 in blood.

So we end up blaming too many “T4 corpses” (RT3 molecules) for appearing in blood. That must be the crime. What appears to be the solution? Clean up the corpses. “Detox RT3!”

Basically, the anti-RT3 myths blame the hormone RT3 for the D3 enzyme’s activity.

People also praise an increase in T3 dosing and decrease in T4 dosing for solving the problem. But T3 dosing can “cover up” the intracellular crime by making RT3 “corpses” disappear.

Sometimes T3’s disappearance is resupplied by dosing T3 (or a T3-secreting nodule, or Graves’ disease antibodies), and this prevents T3’s intracellular disappearance from showing up in blood levels. Higher T3 also upregulates D1 enzyme, which is responsible for clearing RT3.

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

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

T3-driven shifts in dosing and D1 activity do not necessarily reduce D3 activity. D3 can be driven by illness and/or T3 excess, not just T4 excess.

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 alone (whether its concentration is rising or falling) can’t always tell you the degree to which D3 is inactivating your even more precious T3 thyroid hormone.

Understanding more can empower us and help us adjust thyroid therapy, because we may need to know when D3 is dominating even when RT3 is low — and how to tame it or overcome it.

But doesn’t science show that RT3 can inhibit T4-T3 conversion? No.

The concept of RT3 as an inhibitor of T4-T3 conversion arose because there is one condition in which it is true.

Early thyroid scientists experimented with unnaturally high doses of RT3 to see what they would do. These old experiments showed that enzymes become less inefficient at T4-T3 conversion if cells are flooded with RT3 in higher quantities than the body itself can produce from T4 hormone.

The old science has been misinterpreted. If you don’t read the science carefully, it is possible to overlook the one condition necessary for RT3 to block T3 in a living human being: The level of RT3 has to be higher than any disease could ever produce from T4-RT3 conversion rates.

(See the science explained in “RT3 inhibits T4-T3 conversion. How worried should we be?“)

Essentially, you would need to dose RT3 pharmaceuticals to obtain doses high enough to block T4-T3 conversion. And yet, Shuklin & Utiger’s 1984 study overdosed RT3 and found no problems occur.

This leads to a logical follow-up question: Why didn’t RT3 become a pharmaceutical, if it could potentially help people combat excess T3 during hyperthyroidism? Is there a profit-based motive, such as the defense of competing anti-thyroid drugs that do not work as effectively?

No, there’s a very good biological reason why RT3 pharmaceuticals are unnecessary. RT3 levels are already extremely high in overt autoimmune hyperthyroidism (Graves’ Disease)

• See the graphs comparing their RT3 levels with other health conditions in “Reverse T3 in the context of health status, dosages, and thyroid levels.”

In overt Graves’ disease, when T4 supply rises to levels two or three times higher than normal, RT3 levels also rise higher than those found in any health condition known to science.

If an extremely high level of T4-RT3 conversion could block T3 from entering cells and binding to receptors, Graves’ hyperthyroidism should be incapable of causing thyrotoxicosis.

But as we all know, thyrotoxicosis happens due to excess circulating T4 and T3 — in spite of excess circulating RT3.

Anti-thyroid drugs methimazole, carbimazole, and PTU are truly more effective than RT3 at treating Graves’ disease because they can block T3 production and secretion within the thyroid gland, where TSH-receptor antibodies have their most profound effect.

How does D3 enzyme break apart T3 in cells?

Imagine that D3 enzymes act like soldiers.

D3 is normally patrolling the boundary of the cell, inactivating hormones just after they enter the cell. (NOTE: earlier scientists used to think D3’s catalytic center was located on the outside of the cell membrane, but this theory was later corrected.)

At times when the body is focusing on depleting T3 hormone (illness, thyroid hormone overdose, or hyperthyroidism), D3 is capable of changing 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, which didn’t show the correct hormone types exiting the cell:

Notice that RT3 (empty pink circles) is not blocking T3 (the solid pink circles).

In these visuals, you will see that the net effect of Deiodinase Type 3 is to deplete T3 within the intracellular space, not to “block” the receptors with RT3. 

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

In the D3-expressing (D3x) cell, the aim is to simply prevent T3 from entering the nucleus by converting it to another 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.

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

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 receptors?

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.

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

As a result, only T3 has the iodine “key” to enter the receptor’s “lock.”

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

This principle was proven many decades ago in a comprehensive in vitro experiment. Bolger & Jorgensen (1980) measured 57 synthetic thyroid hormones’ affinity to the nucleus receptors in rat tissues in the lab. (Most of these were lab-invented thyroid hormone variants that do not exist in nature).

They found that RT3 and all other thyroid 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 simply lacks the “key” to fit into the nuclear receptor’s “lock.”

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

However, RT3 is not entirely inactive as a hormone. This missing key 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 membrane, 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 to any degree that inhibits intracellular T3 from binding to them.

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 T3 and/or T4 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 excessive 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 also be perpetuated by T4-dominant thyroid therapy especially in the context of poor DIO2 / DIO1 expression (induced by illness, 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 always require illness to be a trigger for D3 dominance. To the degree that FT4 and/or FT3 rises above your metabolic setpoint in health, the body will protect itself from excess by upregulating DIO3. The enzyme can express itself in any organ or tissue, even if it is not normally expressing D3 enzyme in health (Bianco et al, 2019). This is what happens in extreme Graves’ hyperthyroidism.

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 Free T3 hormone from entering neighboring D2-x cells and activating receptors in their nuclei.

Technically, D2 can convert T3 to T2, but D2’s main role is T4-T3 conversion, and it is a very low priority of D2 enzyme to convert T3 hormone, so Free T3 entering D2-x cells is more likely to bypass D2 conversion and head straight for the nucleus.

The separate pathways of D1, D2 and D3 ensure that their operation cannot cancel out each other’s activity within a given cell.

A single, individual cell with a T3 deficiency or excess is not enough to cause a hypothyroid or hyperthyroid state. It requires many cells to work together at a tissue level, for example heart muscle tissue.

At the level of a specific tissue or organ with an illness (i.e. 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. A person with severe heart disease will be likely to have a lower than normal FT3 level and higher than normal RT3 level.

How can thyrotoxicosis occur in spite of D3 dominance?

As mentioned above, 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.”)

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 enhance thyroid function and powerfully upregulate the DIO1 enzyme and thereby escalate T3 secretion and T4-T3 conversion, you have a recipe for disaster even if the person has very high RT3 levels in circulation.

RT3 is not the obstacle to T4-T3 conversion, but loss of D1 and D2 efficiency is.

In therapy for hypothyroidism, excess 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 T3 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 loss of healthy, D1- and D2-expressing thyroid tissue, and
• Handicaps in extrathyroidal thyroid hormone metabolism via D1 and/or D2.

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, as shown above.

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 most active T3 hormone is a roll of the dice.

In the body without a functional thyroid gland, there is no thyroidal T3 secretion to compensate in case you are a person with 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.

Lab tests can indirectly reveal D3 dominance and D1, D2 efficiency

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

Lab tests can give insight into T4-T3 conversion rates if one understands that D1, D2, and D3 are working together to adjust our FT3 and FT4 levels.

The most important ratio in monitoring thyroid hormone metabolic health is the FT3:FT4 ratio, not the TSH in isolation, not the FT3 or FT4 in isolation, and not the RT3 level or the RT3:T3 ratio.

To get a glimpse into cells, one must read RT3, FT4 and FT3 levels together.

Prior to thyroid therapy, and in the context of T4 monotherapy 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)

• 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.

The free SPINA-Thyr app can also be used to measure the degree to which the FT3:FT4 ratio is abnormal. See Midgley et al, 2015 for a discussion of the “poor converter.”

The TSH test is still helpful in understanding the degree to which stimulation of any thyroid tissue can boost or maintain FT3 levels in a state of health. As TSH rises through normal range in people with healthy thyroids, if they are not severely ill, the FT3:FT4 ratio generally stays the same or rises slightly. If FT3 falls as TSH rises in normal range, the individual does not have enough thyroid function to maintain a normal HPT axis. (A complete scientific theory of the HPT axis must account for the normal TSH-FT3 relationship, not just the normal TSH-FT4 relationship.)

Mere 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“)

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 intracellular T3 signaling in tissues can 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.

Internet myths and disinformation about RT3 are everywhere.

Why isn’t the truth about D3’s T3-blocking role being trumpeted from the rooftops?

It’s because so many people are convinced by and are quite satisfied with widely-circulating RT3-blaming theories and the concept of RT3 dominance.

One place these myths are collected is a website that grew out of a Yahoo discussion group sometime before 2010. It was moved to a website called “Reverse T3 and Thyroid Resistance” currently at http://www.thyroidrt3.com/, [archived here].

People who believe RT3 blocks T3 often cite Kent Holtorf, an alternative physician who misunderstood the science on RT3 in his article on thyroid hormone transport in 2014 in an alternative medicine journal. See our post “RT3 inhibits T4-T3 conversion. How worried should we be?,” which has debunked one of Holtorf’s false generalizations from a scientific experiment. In short, early in vitro experiments in the lab proved that when RT3 is artificially added in high amounts to cell cultures, it could inhibit T4-T3 conversion. But this is not what one sees in vivo when naturally-produced RT3 is in circulation.

As a result of false generalizations from narrow experiments, it has now become a strong belief among many that high-normal RT3 levels and high RT3:T3 ratios in blood can block T3 transport into cells, hinder the enzymes that perform T4-T3 conversion, and plug receptors in the nucleus and prevent T3 from binding to them.

It has even been claimed that RT3 functions as a “metabolic brake.” The analogy of the brake pedal versus the gas pedal seems perfectly reasonable, but it’s just not scientifically correct.

RT3-blocking claims are persuasively explained by vivid metaphors and graphics in many celebrity physicians’ blogs, videos, and books. They are then echoed by thyroid patient communities and spread widely in online thyroid patient support groups.

But saying something a million times online does not make it truer.

Many of these well-meaning people are intelligent and clinically observant. They see the association between high or high-normal RT3 levels, high RT3:T3 ratios, illnesses and/or hypothyroid symptoms. On the other hand, they also see the association between low-normal RT3 levels during T3-inclusive thyroid therapy and the alleviation of illness and hypothyroid symptoms. RT3 must be implicated in a crime against T3 hormone, right?

However, these theories fail to explain major contradictions in a logical or scientific manner. When high levels of circulating RT3 cannot be blamed, they often blame iron, cortisol, or non-compliance to a therapeutic protocol. There’s a logic problem with these blame-shifting excuses. Any excuse that shifts blame when RT3 is low can also be used to minimize the blame when RT3 is high.

Most people who support anti-RT3 theories do not understand the three deiodinase enzymes (D1, D2 and D3). In fact, many of the blogs and websites that blame RT3 do not even use the word “deiodinase.”

I understand why people don’t talk about deiodinases. I can easily forgive people for being reluctant to talk about them.

Not only is the word “deiodinase” technical and unfamiliar, but deiodinases are complex. People want to use other words. It’s like a mother or father being reluctant to use the words “vagina” or “cervix” or “uterus” when explaining human sexual reproduction to a child.

Sadly, partly because of reluctance to use scientific and technical vocabulary, and partly because of the complexity of this metabolic system, the average physician and patient do not understand how thyroid hormone conversion works.

• What causes these deiodinases to become imbalanced?
• How do the deiodinases interact with transporters and receptors?

All sorts of answers to these questions can be wrong if your basic understanding of the mechanisms is incorrect.

So many physicians and patients think that the only type of thyroid hormone conversion going on in cells is T4-T3 conversion and T4-RT3 conversion, the end. Some people understand enough to know that D2 enzyme and Dio2 genetic polymorphisms are important, and that some people are poor converters of T4 to T3, but understanding often becomes dim beyond that point

Conclusion

The research on the synergy between these enzymes drives home the point that we ought never to judge RT3 in isolation from FT4 and FT3.

Scientists and laboratories artificially separate these hormones, but they are interrelated.

• RT3 increases in parallel with FT4 because it is a natural, inevitable byproduct of FT4, primarily via D3 enzyme.
• RT3 falls as FT3 hormone levels increase in D1-dominant organs (thyroid, liver, kidney) because D1 is regulated by T3.

As for T4-T3 conversion,

• T4-T3 conversion rates via D1 are enhanced by higher FT3, and are not hindered by RT3.
• T4-T3 conversion rates via D2 are inhibited by higher FT4, and are not as powerfully hindered by RT3.

Regardless of RT3 levels, the key signal of poor T4-T3 conversion is a low FT3:FT4 ratio in blood.

RT3 excess in relationship to FT4 diagnoses the cause of the low FT3:FT4 ratio. It tells you whether the low FT3:FT4 ratio is caused by:

1. nonthyroidal illness syndrome upregulating D3 and downregulating D1 and D2,
2. or poor T4-T3 conversion due to thyroid function loss and a poor metabolic response to T4-dominant hormone dosing,
3. or both 1 and 2 combined.

One does not always need to test Reverse T3! If the FT3:FT4 ratio is not low or reducing, it can be costly to the patient if it is a patient-pay test!

RT3 just adds extra clarity about the degree to which some cells are D3-dominant or D1-inefficient.

For more guidance, see the list of RT3 posts below.

• Tania S. Smith

Other 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
• Reverse T3 in the context of health status, dosages, and thyroid levels

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. https://www.jbc.org/content/255/21/10271.full.pdf

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

Holtorf, K. (2014). Thyroid Hormone Transport into Cellular Tissue. Journal of Restorative Medicine, 3(1), 53–68. https://doi.org/10.14200/jrm.2014.3.0104 (Caution. this is a poorly argued article that spreads misinformation.)

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

Shulkin, B. L., & Utiger, R. D. (1984). Reverse triiodothyronine does not alter pituitary-thyroid function in normal subjects. The Journal of Clinical Endocrinology and Metabolism, 58(6), 1184–1187. https://doi.org/10.1210/jcem-58-6-1184

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