Reverse T3: The Four Top Causes of High Reverse T3

Here’s the Full Story on T3…

Hey there Linda – thanks so much for reaching out, and thank you for the kind words. This is for you, your daughter, and for everyone else who is curious about reverse T3 (commonly referred to as rT3).

The most common questions I hear include:

• Is there a reverse T3 test?
• What is the best reverse T3 level range?
• Can a high dose of T3 lower my rT3?
• How do you lower your reverse T3 levels?

The 4 Main Causes of High Reverse T3

Here is a big-picture answer to your questions – high levels of rT3 come about from just a few key-causes:

1. Too much thyroid hormone. The most common cause of high reverse T3, by far, is an excessive dose of thyroid medication. Some who have Graves’ disease can also have high rT3 (but they are less commonly tested for it).
2. An undiagnosed stressor on the body, like an illness, a medication reaction, or an infection.
3. A lab error. This is especially true if you are on thyroid medication or have autoimmune thyroid disease.
4. No reason – it is possible for rT3 to be high in healthy people.

Seriously, that is it.

Do You Need A Reverse T3 Test?

Reverse T3 & The Great Divide

What Is Reverse T3?

T3 is one of the active hormones made by your thyroid. Quite simply, rT3 is its inactive form. It is the same molecule, but a mirror image – a reverse.

Imagine a pair of gloves – one right and one left. They both have the same number of fingers and thumbs, but one is a mirror image of the other.

Your right hand will fit in the right glove better than in the left. So, too, there are cases where one version of a molecule works in living systems differently than its mirror image.

For a better understanding, it would help to give an overview of thyroid hormones and how they are made. Below is an image that illustrates the production of thyroid hormones. I know it looks daunting and a bit science-y, but hang tight, I’m here with you.

Let’s start at the upper right where the word ‘blood’ is written inside the red column. Below the word ‘blood,’ is an arrow pointing to a letter ‘I’ – representing the iodine in the bloodstream.

How Reverse T3 Works

Iodine is pulled into the thyroid by a mechanism called the sodium iodine symporter (Na/I).

This is basically a pump that pulls iodine inside the thyroid against a strong gradient. It is so powerful that your thyroid may have 50 to 100 times as much iodine as your blood does.

Once iodine is inside your thyroid gland, it is brought into a nursery of cells known as a thyroid follicle. There it is mixed with a protein called thyroglobulin which is made from the amino acid tyrosine (that mixing occurs in the pink section on the far left of the image).

When four iodine atoms are mixed with thyroglobulin, the result is the hormone thyroxine (also called T4). Get it? ’T’ is for thyroglobulin, and 4 is for the four iodine atoms. I told you it would be easy!

About 90% of the hormone the thyroid makes is T4. Another 10% is T3, which, now that you get the lingo – you could guess is nothing more than a thyroglobulin protein with three iodine atoms attached.

How Thyroid Medications Relate

Levothyroxine (Synthroid, Tirosint, Levoxyl) contains T4, as does compound T4. Cytomel (liothyronine) contains T3 as does compound T3.

Natural Desiccated Thyroid (NDT – brands such as Armour, Westhroid, Naturethroid, WP Thyroid, and NP Thyroid) contain T4, T3, and T2. Compounded medications can also combine T4 and T3 but do not include T2.

Blood tests for T4 and T3 can measure the total amount of active and inactive hormone or just the active fraction. Tests for the active fraction are called free T3 and free T4. Tests for both are called Total T3 and Total T4 or just T3 and T4. The free tests are preferable and used in most cases at present.

When the body calls upon the thyroid to release hormone, the T4, and the T3 into the yellow orb on the lower portion of the image and then enters into the bloodstream.

Regulating Thyroid Hormones

Thyroid hormones are regulated in two different ways:

1. By the brain, controlling how much hormone is released by the thyroid.
2. What we call peripheral metabolism. This includes all the mechanisms outside of the thyroid that convert, activate, and break down the thyroid hormones.

So, what about rT3? We have to step outside the thyroid before it even enters the story. 95-98% of the rT3 in the body is made outside of the thyroid.¹ The image below shows what happens to thyroid hormones when they leave the nest and circulate through your body.

The Main Enzymes

The conversion of thyroid hormones is done by three main enzymes that selectively remove iodine atoms. They are called deiodinase 1, 2, and 3 or D1, D2, and D3 for short. As a nutritional point of interest, these enzymes depend on adequate selenium and zinc to work properly.

D1 is most active in the liver and the kidney and can act on the inner or outer ring of T4, therefore it can make T3 or rT3. It turns out that much of our knowledge about these enzymes comes from animal studies, mostly rats. Rats have greater D1 activity in their livers than do humans.³

In humans, D2 is probably a larger contributor to circulating rT3. It is most active in the heart, muscles, fat, and nervous system. It can only act on the outer ring and can only make T3. D3 is in the placenta and in the brain, it can only make rT3. It is also found in hemangiomas.

In fact, neonates with large hemangiomas may have so much D3 activity that they end up in a hypothyroid state.⁴ The human liver has more to do with getting rid of old rT3 and converting it into T2 than it does with forming rT3 out of T4.⁵

What Causes Higher Reverse T3?

If it is normal to make most thyroid hormones into rT3, how is it possible that we can get too much of it? First, imagine that you are heading home from a long day from work and are eager to unwind and relax.

In the last mile before you reach your driveway, you start your car and it starts to sputter and stall. Would you drive that last mile home, slowly and carefully, or as fast as you could?

Most of us would take it slow. We know that if we drive gently, the car has a better chance of making it a little bit longer. It would be far better to make it home and deal with the car tomorrow then it would be to break down on the side of the road late at night.

When we are sick, our bodies make the same decision. Think of thyroid hormones as the gas pedal. When there is something wrong, your body wants you to take it easy so it can put more of your energy into recovering. It does this by inactivating a larger amount of thyroid hormones than it does when you are healthy.

What the Research Says

In the mid-1970s, researchers identified a condition they named Non-Thyroidal Illness Syndrome (NTIS). The name implies abnormal thyroid levels in the context of illness that are not caused by the thyroid.

If someone’s thyroid quit making hormones, it was normal that T4 and T3 would get low. But in these cases, there was enough T4 and the TSH levels did not suggest hypothyroidism, but T3 was too low. If the researchers happened to test for rT3, it was often elevated in these cases (but sometimes it was normal or even low).

Along with NTIS, this phenomenon is called Euthyroid Sick Syndrome (ESS), or low T3 syndrome. There has been some tendency to refer to the condition as ESS when identified in hospitalized patients and NITS when non-hospitalized patients are also included.

NTIS is turned on by many mechanisms which can work alone or in various combinations. One that the hypothalamus may quit telling the pituitary to tell the thyroid to work.

Other mechanisms behind NTIS include:

• Increased formation of rT3
• Lower production of T3 by the liver
• Tissue resistance to thyroid hormones⁶

rT3 to T2 Conversion

A final factor is the blockage of rT3 to T2 conversion. This effect is likely the largest contributor to high rT3 levels because it prevents rT3 from being eliminated.

Normally rT3 is broken down into T2. Since T2 is also an active thyroid hormone, its formation is blocked during NTIS. This lack of T2 formation removes the normal route by which rT3 is eliminated, causing it to build up. In fact, T2 blockage is responsible for more of the buildup of rT3 than is T4 conversion.⁷

NTIS is well known to happen to people who were critically ill, as in the Intensive Care Unit. Conditions in which this is seen include:

• Fasting⁸
• Starvation
• Protein malnutrition
• Severe trauma
• Heart attack
• Chronic kidney disease
• Diabetic ketoacidosis
• Anorexia nervosa
• Cirrhosis
• Severe burns
• Sepsis

Many experts posit that less T3 is an adaptive response to spare the energy levels and raise the odds of healing.

At least, I assumed so until writing this article but I have seen arguments on both sides.

Whether or not the body’s efforts to lower T3 are helpful or not, there is no current evidence that giving T3 makes things better.

Additional Studies

Researchers have conducted many studies in which critically ill people with severe NTIS were given thyroid medication and they compared the results against those who were not.

Some studies suggested it could help with the final stages of congestive heart failure. Larger follow up studies showed that it did not. That was about as close as there were to any signs of benefit.

Many studies were done with many other conditions. Some gave T4, others gave T3 but the results were the same. If you are sick and your body is turning lots of your T4 into rT3, it won’t help matters to give more hormone.⁹

This does not mean that no one with NTIS should ever be on any thyroid medication. There are times where someone was already on treatment for hypothyroidism and something else went wrong.

In those cases, they would likely need to stay on treatment and it might need to be modified. Other times, whatever else went wrong ended up causing hypothyroidism and along with a low T3, they got a high TSH and a low T4.

What Is The Optimal Reverse T3 Level Range?

When rT3 Measurements Are Not Accurate

Is Reverse T3 A Cause In Itself

rT3 is often elevated in NTIS as a symptom of the condition, not a cause of the condition. Imagine aliens looking at London from above and mistakenly thinking that umbrellas cause rain rather than vice versa. It is not a trivial distinction.

If rT3 caused NTIS, you could prevent NTIS by starving the body of the T4 which it makes into T3. This is a strategy many alternative doctors attempt and it is an error of backward causality. Making the body unable to form rT3 does not heal the symptoms that go with NTIS.

T3 is an active thyroid hormone and rT3 is inactive. However, it is not a blocker of thyroid hormone activity. It is erroneous to attribute symptoms to the presence of rT3.

In those same situations, the symptoms would be from whatever abnormality gave rise to the production of rT3. The one thing rT3 does do is activate reparative mechanisms within the brain.¹³

T2 is a thyroid hormone that is rarely discussed, yet it has biological activity distinct from T3 and T4. rT3 may also be the body’s preferred source of T2.¹⁴ It also seems that rT3 levels do not fluctuate throughout the day as TSH, T3, and T4 do.¹⁵

Follow-up studies were done to expand our understanding of rT3. One study looked at fasting patients and the role that NTIS played in muscle loss. They found that fasting patients given T3 medication had higher rates of muscle loss than those who did not.

Interestingly they also gave them medications that contained rT3, but they had no effects either way. It seemed that the body benefited because it had less T3, not because it had more rT3.¹⁶

Does This Only Happen In The Hospital?

No. Since the early 1990s, it has been recognized that a similar phenomenon can occur in less critical situations that can affect people who are not sick enough to be hospitalized.

In such milder cases, NTIS is likely caused by inflammatory cytokines as in the case of infections; abnormal amounts of thyroid binding proteins as in the case of oral contraceptives; or disturbances in the cortisol rhythm as in the case of chronic stress.

Some specific examples of these include:

• Prolonged caloric deprivation (fasting)¹⁷
• Low carbohydrate and ketogenic diets¹⁸
• Malnutrition
• HIV infection
• Heart disease
• Liver disease including fatty liver syndrome
• Diabetes
• PTSD
• Depression
• Chronic obstructive pulmonary disease

Why would low-carb diets raise rT3? When we do not consume foods that we can use as sources of glucose, our liver first breaks down its stored glycogen into glucose. When it runs out of glycogen, it converts muscle tissue into glucose.

Understanding Glucagon

Both of these conversions are driven by the hormone glucagon. It has been shown that high levels of glucagon not only correlate with NTIS but giving glucagon can elicit NTIS.¹⁹

In one study of women fasting for 14 days, T3 levels dropped to 1/2 of their pre-fasting levels.

One subgroup of these women was given continuous intravenous T3.

Their T3 rose temporarily yet within a few days their levels had dropped again. Basically, their bodies neutralized it as fast as they were given it.

Some medications can also cause this reaction. They include:

• Amiodarone
• Propranolol
• Oral contraceptives
• Dopamine
• Dobutamine
• Glucocorticoids (prednisone, Kenalog, others)
• Furosemide
• Nonsteroidal anti-inflammatory drugs (NSAIDs)
• Heparin
• Anticonvulsants
• Metformin

Thyroid medications still don’t help NTIS in non-hospitalized patients. Not only do they not help, but many current studies have shown a higher rate of death in those treated with thyroid hormones.²⁰

Before we move on to the alternative ideas about reverse T3, here is a quick recap:

• rT3 is the normal default by-product of the main hormone produced by the thyroid, T4.
• The body intentionally makes higher amounts of it during some type of crisis metabolic stress.
• Efforts to work against the body’s attempt to lower T3 and raise free T4 seem to be not helpful or dangerous.

Reverse T3: Alternative Thyroid Views

My Experience

It Was Too Late

The Results

The Wilson Model

Dr. Broda Barnes

What I Discovered

Dr. Broda Barnes and Basal Body Temperature

• Thyroid blood tests were inaccurate
• Symptoms and basal body temperature (BBT) were more reliable tools both for diagnosing thyroid disease and determining the best dose of thyroid replacement
• Natural Desiccated Thyroid (NDT) was superior to synthetic T3 or T4 medication
• Thyroid patients often needed to take hydrocortisone to manage symptoms

• Thyroid uptake
• Protein-bound iodine
• Basal metabolic rate

• Axillary temperatures = oral temperatures.
• The thyroid is the prime regulator of BBT.
• BBT should not deviate from 97.8ºF to 98.2ºF.
• The BBT goes up as thyroid doses go up.
• Thyroid doses are safe unless the body temperature elevates.

Do Axillary Temperatures Equal Oral Temperatures?

Is The Thyroid The Prime Regulator of BBT?

Is BBT In Healthy Populations Always Within the Range of 97.8 to 98.2?

Does BBT Elevate As Thyroid Doses Increase?

Are thyroid doses safe unless the body temperature elevates?

Wilson’s Syndrome

Barnes really was the first prominent doctor to offer a model of thyroid care that differed from the mainstream model. The alternative views on rT3 are largely from E. Denis Wilson – who was influenced by Barnes.

Like Barnes, Dr. Wilson relies on BBT to diagnose who stood to benefit from thyroid treatment and to determine when the treatment levels are ideal. Unlike Barnes, Dr. Wilson concedes that blood markers are adequate to diagnose hypothyroidism.

However, Wilson argues that certain symptoms, in the absence of overt hypothyroidism, are caused by a problem with rT3 metabolism.

His list of symptoms includes:³²

Wilson’s Syndrome

He first called this rT3 problem Wilson’s Syndrome, naming it after himself.

Doctors who discover new diseases are sometimes honored by having their name ascribed to the condition. By routine, this is done by the doctor’s peers, and usually after his or her death.

Another complication with the self-appointed moniker is that there was an unrelated condition called Wilson’s Disease. In more recent years, Wilson has renamed the “condition” Wilson’s Temperature Syndrome (WTS).

Since Wilson believes that rT3 is the cause of the symptoms, his proposed solution is to make the body unable to produce as much rT3 by withholding thyroid medicines that contain T4, such as Synthroid or NDT and preventing the body from releasing its own T4. Dr. Wilson recommends T3 in the form of compounded sustained release T3 for treatment.

By in large, Dr. Wilson acknowledges that Non-Thyroidal illness (NTIS) is the mechanism by which rT3 elevates. He departs from agreed-on facts with the claim that high levels of rT3 somehow block D1, D2, or D3 enzymes and become self-perpetuating.

What Did Others Think?

Others wondered this same thing in the 1970s, but research showed it not to be the case. In NTIS, illness does trigger a higher rate of rT3 formation, but the condition is known to reverse if the underlying illness resolves.

The solution Dr. Wilson proposes is to take T3 medications in sufficient quantities to overcome this blockage. By ingesting high enough doses of T3, one could resume a better proportion of T3 to rT3 and reactivate the body’s ability to form T3. By his logic, he also withholds T4 containing medications so that there is no more substrate to make into rT3.

He further claimed that much of these thyroid hormone reactions occur only within the cell membranes and therefore do not show up on blood tests. He states that NTIS can happen without any measurable changes to blood levels of T3 or rT3.

A frequent criticism of Wilson’s logic is that if there is no way we can measure this intracellular excess of rT3, how does he know it is occurring? His two responses are that the basal body temperature (BBT) shows that T3 is inhibited.

Therefore, patients with WTS symptoms and a BBT below his range can respond to T3 treatment. As mentioned in Barnes, the selected target of BBT is far narrower than the range found in healthy people.

The Core Claim Of WTS

Wilson’s argument lives or dies based on this core claim: Can high rT3 block T4 even after the cause of high rT3 has resolved? All of the known pathophysiologies regarding rT3 and NTIS says that it is not.

To be fair, I found every reference that I could that Dr. Wilson used to support this claim. The following was the quote from his work that I feel most fairly made this point.

Analysis of the evidence for WTS

When writing this paper, I wanted to be fair and look at any references or citations Dr. Wilson had for this claim.

In one passage from a presentation he made, he states it as such:

“rT3 can competitively inhibit T4 to T3 conversion, which could lead to more rT3 accumulating, and the start of a vicious cycle.”³³

He goes on to say:

“A study has demonstrated that in vitro, rT3 can inhibit the conversion of T4 to T3 presumably by competitive inhibition.”

The crux of his work rests on the accuracy or the falsehood of this statement. If rT3 can inhibit T3 formation, the body can get stuck and his premises have merit. If it does not, they do not.

The reference he cites is a 1977 paper by Dr. Schimmel.³⁴ I found no other references to Dr. Wilson’s claim that rT3 could block T3 formation. I read the paper in its entirety and the sole passage that could have offered support was the following:

“A similar but more complicated scheme would require separate 5′-deiodinases, one specific for T4 and another for rT3. Reverse triiodothyronine accumulated as a result of decreased rT3 deiodination could then secondarily inhibit T4 deiodination to T3 if the in-vitro observations cited above apply to in-vivo conditions”

Digging Deeper Into Research

This was not a conclusion but speculation about what might happen in a test tube. The passage went on to explain how the speculation had already been disproven in a human study:

“Against this possibility, however, is recent data that short-term administration of rT3 to normal subjects did not alter serum T4 or T3 concentrations (60).”³⁵

In this 1976 study, researchers gave volunteers doses 80 mcg of rT3 every 6 hours for two days, as they monitored their blood levels of T3, rT3, T4, TSH, and prolactin. They also did a thyrotropin-releasing hormone test on day two to look for any change in the hypothalamic function.

The results were as follows: The present studies have demonstrated that physiologic increases in serum rT3 concentration do not alter the basal serum concentrations of T4, T3, TSH and prolactin or the serum TSH, prolactin and T3 responses to iv TRH.

The rise in serum rT3 concentration which followed the daily administration of 320 pg rT3 to these normal subjects was similar to the rT3 concentration often found in patients with a wide variety of nonthyroidal illnesses”

The findings from this study are congruent with that we have learned since. rT3 does not block T3 formation. It forms when the body is preferentially making T4 into T3 but there is no point at which rT3 creates a vicious cycle as Wilson claims.

The Modern Model of NTIS

This proves that the modern model of NTIS is not about the thyroid. rT3 did not block T3 formation. The reason the body formed rT3 was the cause of the decreased T3 formation. If the underlying reason were not resolved, adding more T3 would not fix things.

I also found the claim about rT3 blocking T3 in Dr. Wilson’s book.

“. . .rt3 is a competitive inhibitor of T3 blocking T3 from binding to its receptor which blocks T3 effect, 209-214 reduces metabolism, ^209,212,213 suppress D1 and D2 and T4 to T3 conversion,^{210, 212, 215-218} and blocks T4 and T3 uptake into the cell.^{208, 219} All of these effects reduce intracellular T3 levels and thyroid activity.”³⁶

I will address each of these citations individually. If any supported his premise, I would have been happy to have changed my mind. It would be wonderful if we had a simple answer for the long list of symptoms he mentioned.

It would even be fun if the solution were unexpected and went against commonly-held beliefs. Please look at the evidence Dr. Wilson cited and decide if they support the claims being made:

Reference #208³⁷

This study monitored blood markers including rT3, T3, TSH, T4, urea, and triglycerides in obese patients on 6 weeks of a 300 calorie per day diet.

I read the full study, nowhere in it did they say or even suggest to the idea that rT3 could block T3. In fact, they concluded the exact opposite:

“Since in the first stage of treatment T, and rT, change in opposite directions, while in the subsequent period (2-4 wk of dietary restriction) serum rT, declines, and T3 remains almost constant, the results seem to indicate that conversion of T4 into T, or into rT, is mediated by separate processes.”

Reference #209³⁸

This study was a test tube study. In it, it was shown that cells soaked in T3 had higher ATP/ADP ratios than did cells soaked in rT3. When the rT3 was removed and the T3 was put back, the ratios changed back.

Nowhere in this study was any evidence that rT3 blocked T3 in cells or much less in humans.

Reference #210³⁹

This was a study of mice that had their livers partially removed and were made to lack a CAR receptor. The closest statement that had any connection with Wilson’s premise was:

“Injection of rT3 into normal mice revealed that rT3 is capable of repressing the known thyroid hormone-regulated genes Tat, Bteb, and Cpt-1 in the liver.”

In other words, injecting rT3 in mice repressed some liver genes. It did not say that rT3 blocked T3 or its effects.

Reference #211⁴⁰

I read the full study. It was a test tube study about binding properties of apoB/E receptors. I’d highly recommend reading the study as a cure for insomnia.

Here are it’s conclusions as an example:

“ApoE is synthesized by several tissues, most of which are targets for thyroid hormones (27-31). Among the endocrine organs, apoE has been found in the cytoplasm of the thyroid follicular epithelial cells (25).

ApoE is also synthesized by astrocytes in the central nervous system (30,31) and by glial cells of damaged nerves in the course of axon regeneration (32, 33). ApoA-I is synthesized in the brain (34) and accumulates locally during nerve repair. ApoE and apoA-I are the major apos circulating in the cerebrospinal fluid, and lo20% (sp) of these are not associated with lipids (35).

Because the developing nervous system is sensitive to thyroid hormone action and possesses apoB/E receptors (34, 36), a possible advantage might exist in the local synthesis of apoE and the local accumulation of apoE-T4 complexes.”

The word “Thyroid” was used on occasion, but nowhere in it was any discussion about rT3 blocking the effect of T3.

Reference #212⁴¹

Just the title of this should give one pause:

“The relationship between basal metabolic rate (BMR) and concentrations of plasma thyroid hormones in fasting cockerels.”

I think this is the line that got Wilson’s attention:
“The data show that the reduction in plasma T3 level and increase in the rT3 one during starvation may be due to inhibition of deiodination of T4 to T3, since rT3 is a competitive inhibitor of this reaction”

We will ignore the fact that what happens to fasting cockerels may not apply to what happens to people.

Competitive Inhibitors can be reversible or irreversible. When they are reversible their effect stop when the concentrations change. When they are irreversible they do not.⁴² It is true that rT3 is a competitive inhibitor for T3 but it is a reversible inhibitor, not an irreversible inhibitor.

This distinction is defined by the dissociative constants, as shown in this rat study:⁴³ Once the formation of rT3 slows, through negative feedback, the levels of it drop, and it no longer cannot inhibit T3 in humans or in starving cockerels.

Reference #213⁴⁴

This study (Pittman and Barker) was from 1959-1960 and was not available from any source I could find, nor was its abstract. I did find it mentioned in a later study which stated:

“An anti-thyroxine and antimetabolic effect of rT3 has also been demonstrated (Pittman and Barker 1959; Pittman et al I960). However, in all these studies pharmacological doses of rT3 were used, and the physiological significance of these actions is, therefore, questionable”⁴⁵

In other words, this study was not considered valid by later scientists because in it, the researchers gave the subjects high amounts of rT3 from synthetic sources.

Reference #214⁴⁶

“A Study of the Characteristics of the Rat Placental Iodothyronine 5-Monodeiodinase: Evidence That It Is Distinct from the Rat Hepatic Iodothyronine 5’-Monodeiodinase”

Nope – another block time lost that I’ll never get back and still no evidence that rT3 permanently blocks T3 formation. Nothing was even close in this study.

Reference #215⁴⁷

I read this one too, another rat study. Also, it did not say that rT3 irreversibly blocks T4 synthesis. In fact, it showed that T3 production was robust and can work by more mechanisms than were previously expected.

“We conclude that virtually all the T3 produced from low doses of exogenous T4 given to hypothyroid rats is generated via a PTU-insensitive pathway, presumably catalyzed by the 51-II.

This is a consequence of the enhanced activity of this low Km enzyme together with the concomitant decrease in the hepatic and renal 51-I characteristic of the hypothyroid state.

The results indicate that in some circumstances, 51-II activity may contribute to the extracellular, as well as intracellular, T3 pool.”

Reference #216⁴⁸

Rat study again. The closest thing to his point is this:

“It is conceivable that rT3 produced locally from T4 also plays a role in the regulation of the enzyme.”

It is conceivable it may have a regulatory role. Never suggests an ongoing reaction that gets stuck.

Reference #217⁴⁹

Exact same idea and conclusion as the last study except that it was done within the brains of rats. It is worth noting that in the cerebral cortex, rT3 is made preferentially as it may have a protective role.

Reference #218⁵⁰

Here is another case where the title alone makes it a non-starter.

A study of extrathyroidal conversion of thyroxine (T4) to 3,3′,5-triiodothyronine (T3) in vitro.

It was a 1970 study of what happens to thyroid hormones in a test tube. Not even a rat.

What they found was that fT3 did inhibit T3 formation in the test tube, but only when T4 levels were too low. Wilson claims the exact opposite, that low levels of T4 are essential to stop rT3 from inhibiting T3 formation.

From the study:

“Reverse T3 had little or no inhibitory effect when the T4 to rT3 concentration ratio (T4/rT3) in the incubation medium was 200 (and corresponding T4/rT3 molar ratio,167) or more.”

They noted that the typical ratio in humans was 215.

Reference #219⁵¹

This was another test tube study. Its purpose was to see how thyroid hormones were absorbed by choriocarcinoma cells. The rationale was that these cells’ response might give some clue to the absorption of thyroid hormones by the human placenta in early pregnancy.

As tangential to the question at hand as this was, it still not show any inhibition by rT3. Here were the conclusions

“In summary, we demonstrated the presence of a saturable uptake mechanism for rT3 in the human choriocarcinoma cell line JAr.

This uptake process was similar to the uptake of T3 and T4 previously described by us in these cells.

The kinetic parameters of inhibition of rT3 uptake by T3 and T4 and of T3 and T4 uptake by rT3 suggested that rT3, T3 and T4 may share the same transporter in JAr cells.

Reverse T3 did not inhibit T4 efflux and therefore did not provide a mechanism for control of maternofetal T4 transport”

Finding Plausible Evidence

I expected to find at least some plausible evidence given the number of citations, but I did not.

I tried hard to find any other evidence better than those sources cited but I could not. The closest study was one in which they gave mice high dose rT3 to see if it would change the levels of T3, T4 or TSH. It did not.⁵²

The only effect that thyroid hormones have been shown to have on the deiodinase enzymes are the exact opposite that is claimed in the WTS model.

If someone were in a hypothyroid state, the net effect of thyroid hormones would be to encourage the formation of T3, not to block it.⁵³

If Wilson’s ideas were not correct, how come they are still going around?

There are examples where initial ideas become disproved but nonetheless linger on.

Have you heard that bees’ defy the principles of aeronautics because their wings are too small to give them lift? It is not true, but it still makes the rounds.

Did you also know that the Flat Earth Society has more members now than at any time in the past? This is just another unfortunate example of that.

Are High Doses Of Reverse T3 Dangerous?

1. TSH suppression
2. Supraphysiologic dosing
3. Circadian rhythm disruption
4. Compounded thyroid medications

WTS and Adrenal Fatigue

While writing this piece, I realized that the misunderstandings behind WTS are a perfect parallel for those behind adrenal fatigue.

The central error of adrenal fatigue is the idea that those who have it have fatigued adrenal glands. The thought is that when someone with adrenal fatigue has low cortisol, it is because their adrenal glands are unable to produce cortisol.

In fact, the axis in which the adrenals operate (the hypothalamic/pituitary/adrenal axis) is intentionally lowering the body’s exposure to cortisol.

This is unlike diseases, like Addison’s, in which the immune system damages the adrenals and leaves them unable to meet the body’s need for cortisol.

The mistaken idea that adrenal fatigue stems from broken adrenals gives rise to the strategy of helping it by giving cortisol or other substances toward the goal of causing the glands to make more cortisol.

These efforts may help by placebo, by treating symptoms that were about to get better on their own, or because cortisol can be a stimulant.

NTIS is identical. The T3 and rT3 levels are not abnormal from any defect from the thyroid. Rather, they shift due to orchestrated changes in response to a medical or psychological stressor.

Just as giving cortisol is not the answer for adrenal fatigue, giving more T3 is not the answer for low high rT3.

TSH Suppression

T3-prescribing doctors commonly deny the dangers of a TSH below the normal range of 0.4. Many doctors state that it is harmless unless the T3 levels are elevated. They claim that when enough thyroid hormone is present, TSH is no longer needed as it serves no other purpose.

TSH is released from the anterior stalk of the pituitary gland and circulates through the bloodstream. It is taken up by tissues that have receptors for it. There are two types of TSH receptors: alpha and beta.

“The thyroid hormone receptor alpha (TRa) is predominantly expressed in the brain, heart, and bone. The thyroid hormone receptor beta (TRb1) is expressed in the liver, kidney, and thyroid.

The TRb2 is primarily in the retina, cochlea, and pituitary. Mutations in TRa or TRb can result in disease which is beyond the scope of this review.”⁵⁴

TSH is important for normal function of the:

• Brain
• Heart
• Bones
• Liver
• Kidneys
• Retina
• Cochlea
• Pituitary Gland

All of these suggest that it is not simply important for the thyroid. This is why these organs are known sites of side effects from hyperthyroidism.

TSH is used for many purposes apart from thyroid function such as bone metabolism. To quote a recent study:

“The role of TSH on bone has been hampered by the dogma that TSH exerts functions exclusively within the thyroid. However, within the past few decades, TSH has been shown to exert physiologic effects on both osteoblasts and osteoclasts”

Circadian Rhythm Disruption

Many patients on T3 therapy are given thyroid hormones 2-5 times daily throughout the daytime.

There is a diurnal variation in thyroid hormone secretion with highest values between midnight and 4:00 am and the lowest values in the late afternoon. Thyroid hormones are a regulatory part of the body’s normal circadian rhythm.⁵⁸

When thyroid hormones peak at other times of day, they can disrupt the circadian rhythm which can lead to issues of insomnia, weight gain, poorer blood sugar regulation, and poorer stress response.

Supraphysiologic Dosing

In nearly all cases of T3-only prescribing, the amounts of hormone given exceed the normal amount produced by the thyroid gland. How much thyroid hormone the body makes is largely a function of gender and menstrual status.

Menstruating women make more hormone because estrogen causes an increase in thyroid hormone binding globulin (TBG) which neutralizes thyroid hormones.

A menopausal woman will produce roughly 2.34 mcg of T4 per kilogram of body weight per day. for menstruating women, the number is roughly 2.44, and for men, it is roughly 1.73.

An average sized menstruating woman of 140 pounds (63.3 kg) would, therefore, produce (63.3 x 2.44 = 155 mcg of T4 daily. Considering that T3 is roughly 5 times the potency of T4, this would mean that her day’s production of thyroid hormone would be roughly 31 mcg of T3.

If a prescribed T3 dose is higher than the full daily production, it is considered supraphysiologic and carries additional risks. When I encounter patients on T3 only therapy, most are on 75 – 200 mcg of T3 daily – well above their needs.

Compounded Thyroid Medications

T3 advocates often prescribe sustained released T3 made by compounding pharmacies. The majority of compounding pharmacies purchase T3 as a purified powder. In preparation, most prescriptions are hand-mixed blends of T3 powder and a diluting powder, the combination of which is encapsulated.

Serendipitous Case Study

I wish this article was not necessary, but I had an encounter that showed me it is probably even more necessary than I realized.

Between the days in which I worked on this article, I happened to be doing a book signing. While talking to those in line, it came up that one woman was on T3 to help with her high rT3 levels.

She explained how she was a physician and felt that this therapy was the only way she could regain her energy levels.

She was happy to share a few details when I asked: she was taking compounded T3 in a dose of 30 mcg four times daily. Her TSH was not low per her best memory. I estimated her to weight 110 pounds (50 kg) at the most and to be well before a normal menopausal age.

As we spoke, I estimated her body’s total thyroid needs to be about 110-120 mcg of T4. I explained to her that her dose was about 5 times more than her thyroid would ever make by itself (30 mcg T3 x 4 times daily = 120 mcg T3 x 5 to equal T4 = 600 mcg.)

My Analysis

If her TSH is suppressed, she is in danger. Should her TSH not be suppressed, the compounding pharmacy is not consistently manufacturing her pills.

If the next batch had the full potency, it could trigger a heart attack by the sudden increase. They could even make it more powerful than prescribed by mistake since their quality control is so poor.

I told her that she should not have to live life with fatigue but the task at hand was to find out why she was tired and address the cause, not to find the most effective stimulant available regardless of its safety.

When I asked why she thought she was tired, she said that she “crashed her adrenals” between work and raising young children.

I asked her if she would consider using cocaine instead of T3 if it worked as well. She said no, of course not. When I asked her why not – she said because it would be dangerous. I never wanted her to take cocaine, but I did want to make a point.

I then asked her why she assumed her T3 protocol was safe. He had prescribed T3 to many patients and seen no apparent problems.

I told her that risks are probabilistic, not absolute. Few would debate that smoking is a risk factor for lung cancer.

The Results

Did you know that if you tracked a group of 992 smokers for a year, it is likely you would not see a single case of lung cancer?

In a given year there is a 0.08% chance that a given smoker will develop lung cancer.

They are at risk and at much higher risk than a nonsmoker, but it would be easy to miss that if we relied solely on personal experience.

A harsher version of this point is the illustrated words heard by the man falling off the Empire State Building as he descended past the 30th floor – “so far, so good!”

My heart went out for her. It seemed that she was receptive to my warning. I’d hate to think of her being at unnecessary risk for early death.

One of the paradoxes I don’t hear mentioned is that fact that taking too much thyroid hormones can cause someone to feel as if they have too little.

Imagine that some with thyroid disease had symptoms of fatigue that were caused by anemia. Say that they took steps to treat their anemia but did not see results soon enough. Their doctor, meaning well, decided to raise their thyroid dose to help them have more energy.

Likely, it would have worked for several weeks or maybe even a month or two. Even if someone has a reason to be tired, stimulants can give more energy temporarily. Excess T3 can act as a stimulant.

What Could Have Happened

Back to this example, after the boost from the extra thyroid wore off, her body could have developed a secondary cause of fatigue – hyperthyroidism.

Even if her anemia got better, she might still be tired. Had her doctor asked her to wait for the anemia treatment to work, she would be set.

In this situation, her fatigue becomes even more of a puzzle. Last time she took more thyroid it helped, so perhaps she and her doctor try it again.

Along with fatigue, hyperthyroidism has many other symptoms that can be mistakenly blamed on high rT3, ‘thyroid resistance’ or other factors. Examples include:

• Frequent bowel movements
• Feeling tired
• Feeling nervous
• Increased sweating
• Increased appetite
• Racing heart
• Hair loss
• Shaking hands
• Irregular menstrual cycles
• Insomnia
• Weakness
• Hypoglycemia
• Adrenal insufficiency
• Susceptibility to infections⁵⁹

Neo Wilson rT3 Model

It is the nature of ideas to shift as they mature over time and spread from group to group. Wilson did not advocate testing for rT3. He felt that the only diagnostic tools needed were the presence of his 63 symptoms and the BBT.

He is still training doctors in his model, which is essentially unchanged since the early 1990s. However, many ideas he championed within his model have taken on a life of their own in alternative medicine.

Just as testing is more relevant to alternative medicine today than in the 1990s, it is more central to the ‘neo-Wilson’ model then it was to the original.

The Neo-Wilson rT3 model could be summarized as:

• High rT3 levels can cause unexplained hypothyroid symptoms. rT3 is seen as the actual source for symptoms, not just a bystander.
• Those with high rT3 should not use T4-only thyroid medication like Synthroid. Some doctors use natural desiccated thyroid like Naturethroid, some use compounded T3 and T4 combinations. There are many neo-Wilson docs who suggest just T3, although many of them use non-compounded T3 (Cytomel brand or generic liothyronine.)
• It is important to discover and treat the cause of high rT3. Most docs consider stress, dysbiosis, heavy metal toxicity, or chronic infections as the main causes. At least there is one step in the right direction.

Understanding Ratios Involved

Some argue that the ratios of T4 to rT3 or the ratios of T3 to rT3 are important.

While many of these ideas and ratios were speculated about in the 1970s, none were determined to be clinically relevant.

Their only existence is in alternative medicine circles which tout their importance without citing evidence.

rT3 to T3 ratios do predict complications in late-stage NTIS but are of no known relevance to non-hospitalized patients.⁶⁰

Some also are under the misapprehension that rT3 can be randomly generated despite the overall amount of thyroid hormone present. Others who use facets of Wilson’s ideas use high rT3 levels as justification to raise the T3 in their patients’ medication or exclusively use T3.

What Some Doctors Claim

Some doctors claim that when on T3 or NDT it is normal for the TSH to go low or to zero.

They argue that the body has enough thyroid hormone so it quits asking the thyroid to work. This is not how the pituitary-thyroid axis works.

Thyroid pills work because they elevate the amount of thyroid hormones in your bloodstream.

When these levels are high, the TSH is lowered. Even T3 or NDT lowers TSH. In a healthy state, the TSH is not too low. It only lowers below roughly 0.4 IU/mL when there is too much thyroid hormone.

Others claim that T4 is not essential and that only T3 is needed since T4 is made into T3. We now know that T4 by itself is essential for normal brain function and the repair of brain cells. It is also needed for repair of the lining of the blood vessels.

In fact, the D3 enzyme in the brain favors T4 over T3 by default. When people take high dose T3, they not only lack T4 but when they lower their TSH they block their own thyroid from producing T4. Like T3, T4 also boosts metabolism, but in some different ways that are outside of this discussion.

Breaking Down One Study

In one representative study on NTIS, 98 patients with chronic fatigue syndrome (CFS) were screened for it and compared against 99 patients who did not have CFS. Of those with CFS, 16 had Low T3 Syndrome, compared with 7 in the non-CFS group.

After comparing other variables, researchers found that inflammation was the common thread. Those with CFS who had high inflammation as measured by high-sensitive CRP levels had Low T3 syndrome. Those with normal CRP levels did not. The same applied to the control group. Only those with high CRP had Low T3 syndrome.⁶¹

The chart and the discussion below explain the typical progression of thyroid lab findings at varying levels of hypo and hyperthyroidism. The same pattern emerges whether someone is taking thyroid hormone or not.

*Please note that these patterns are typical and reflect normal hypothalamic, pituitary thyroid regulation and normal peripheral metabolism of thyroid hormones.

Overt Hypothyroidism

At this stage, there is a complete lack of thyroid hormones. The TSH is grossly elevated as a maximal effort to stimulate the thyroid into producing the hormone.

T4 and T3 are low because the mechanisms of peripheral regulation are no longer able to offset the deficit of hormone. Reverse T3 is also low because the body is converting as much of the T4 as it can into T3.

Subclinical Hypothyroidism

In this stage, the thyroid is being told to work harder and the body’s peripheral regulation is able to activate more T4 into T3 and maintain adequate amounts for the body’s needs.

If either the T4 falls below range, the person has hypothyroid symptoms or both – then this is called hypothyroidism and not subclinical hypothyroidism.

Euthyroidism

‘Eu’ is a prefix that means good. This is the normal range for thyroid hormones. Please note that this range may not reflect optimal thyroid function.

Subclinical Hyperthyroidism

As thyroid hormone levels start to elevate, the first step to change is that the TSH lowers and the reverse T3 starts to elevate. These mechanisms are able to prevent T3 and T4 from elevating.

It is common to see T3 levels low because the body is working hard 2 offset the extra burden of thyroid hormones. It is important to note that even this first stage of hyperthyroidism does carry hyperthyroid risks to the brain, the heart, and the bones.

This level is especially relevant to low T3 syndrome as many people who are incorrectly given this diagnosis are simply on excessive doses of thyroid hormone. Because of the body’s efforts to block the effect of too much hormone, they cannot have low T3 levels.

They can also have a mixture of symptoms some of which appear to be more hyperthyroid in nature and others are more hypothyroid in nature. For example, they may have a combination of anxiety, insomnia along with fatigue, and weight loss resistance.

Early Hyperthyroidism

At this stage, the TSH will be slightly lower and it is less common to see the T3 low. Reverse T3 will still be elevated.

Moderate Hyperthyroidism

Typically by this point, the body can no longer regulate T4 but maintains its efforts in preventing T3 from being too high. TSH will be lower and reverse T3 we will therefore still be elevated.

Overt Hyperthyroidism

This is the level at which the body can no longer control the excess amount of thyroid hormones. Both T3 and T4 are now elevated and TSH is maximally suppressed.

A Patient’s Journey Through WTS or the Neo-Wilson Model

I must open this section by owning the biases of my perspective. Since there are no peer-reviewed clinical outcome studies on Wilson’s model or its newer variants.

My experience comes from patients who have experienced the therapies or from doctors’ recounting their patients’ experiences.

If there were large numbers of patients who had lasting remission from their symptoms due to this approach, they would not seek out other guidance on their thyroid health and I would therefore not hear from them.

I could also argue that if the vast majority of patients had such outcomes, there should be few that attempt this approach and feel the need to try anything else. If these approaches were as safe as their advocates make them out to be, the stories of side effects and mortality should be non-existent. Neither of these premises is true.

What Wilson Claims

Wilson claims that after a cycle of raising T3 doses followed by lowering doses, the ‘optimal’ BBT is ‘captured’ and the patient’s symptoms now stay in remission without ongoing T3 therapy. The Neo Wilson claim is that by resolving various metabolic problems, rT3 will lower.

This is true, but in the Neo Wilson case, rT3 does not lower because most of the patients are still on some version of high dose thyroid replacement (usually including T4).

The typical case report is the same post-WTS or post-Neo Wilson. The patient is left on a stable dose of compounded sustained-release T3 that is well above their physiological maximum.

They are stuck in a state where they are aware of some mixture of side effects like insomnia, palpitations, tremors, and anxiety, but know that if they attempt to lower their dose they feel devastating fatigue.

They also generally suffer from some level of lower grade fatigue as well as generalized muscle weakness. It seems that if only they could tolerate a higher dose, these symptoms would resolve.

Would it Last?

They likely would, but it would not last. What they do not understand is that having too much thyroid hormone can make them feel like they have too little and that each time the dose is bumped up it takes a few weeks before the body is able to partially resist it.

The only way out is to reduce the thyroid dose to one that fits the body’s needs. For many of these patients, thyroid replacement was never needed in the first place. Based on how long they were taking high dose thyroid, they often have a chance of being able to come off of it completely.

Do You Need A Reverse T3 Test?

What Is A High Reverse T3 Level Range?

Why Is rT3 High?

Action Steps: How To Lower Reverse T3 Levels

Often it does help for a few weeks, but the results do not last. After a few rounds of the same cycle, they stumble across the concern of rT3. They get a blood test done, and sure enough, they have high levels of rT3. Remember, this is a person who is on thyroid medications and is already taking too high of a dose.

If a doctor understands the true nature of rT3, they should not be surprised at this finding in this context. Unfortunately, many are not, instead they are receiving the wrong impressions about what is ultimately the best course of action.

I do not order rT3. If a patient asks about it, I give them an explanation that summarizes this paper. If they have a lab that shows their rT3 is high, they ordered it themselves or another doctor ran it for them.

What If It’s Flagged As High?

When it is flagged as high, they have some other findings showing that they have too much thyroid hormone in their body. The main one is a low TSH, it is the first to emerge.

If they have a more dramatic excess or if they took their blood tests soon after taking their thyroid medication, they may also have a high T3 or T3.

Something that often confuses patients and doctors is the fact that those on too much thyroid medication can have the same symptoms that they would have if they had too little. If they raise the dose, the symptoms often go away for a few weeks and it seems like another dose increase is the best idea.

Many doctors talk about how it is more important to track symptoms or BBT than blood levels. The goal is to improve symptoms, but if a doctor ignores hyperthyroid blood levels, they are jeopardizing their patient’s health.

Can You Ignore A Low TSH?

Some say that you can ignore a low TSH as long as the T3 does not elevate. However, there are still risks from a low TSH and a normal T3. This is subclinical hyperthyroidism and those who have it have higher risks for premature death and other complications.⁶²

I’ve spoken to patients who feel that they only have more energy when they are hyperthyroid. This is a real problem, but taking an unsafe amount of thyroid hormones is not the answer. The goal is to find the other causes that are contributing to the symptoms and take care of them.

To further the point, imagine that we were talking about high dose amphetamines instead of thyroid hormones. You could likely imagine that if someone had an untreated cause of fatigue, they might temporarily feel more energetic after taking amphetamines.

However, it would be clear that taking amphetamines could be even more harmful to someone with an undiagnosed problem. The same is true for thyroid hormones.

Unexplained Hyperthyroidism

If you are not taking thyroid medication, but your rT3 is high and your TSH is low, you have endogenous (made from inside the body) hyperthyroidism. Over 90% of the time the culprit is Graves’ disease. Other causes include toxic nodular goiter, Hashitoxicosis, and pituitary adenomas.

I have seen too many cases in which hyperthyroid patients were not promptly diagnosed and treated. It can also happen that a doctor thinks it is not too bad and that it might go away on its own.

The last situation is the one I see the least. That is because I do not order rT3 tests nor do most other doctors. If a patient had any results from an rT3 test, the test was almost always ordered by a doctor who holds certain views about thyroid care.

These views often include a willingness to prescribe hormones at levels that can induce hyperthyroidism.

Undiagnosed Stressor

If you do have high rT3 but are not hyperthyroid, the answer is to find the cause. First, think about any medications you are on. Of those from the list earlier in the article, the most common ones used include oral contraceptives, estrogen replacement (even natural), metformin, and beta blockers like propranolol.

Next, think about your diet. If you have reduced your total food intake, your carbohydrate intake, or your protein intake, any of these can be the culprit.

Specifically, too little carbohydrate blocks D1 and D2 enzymes leading to lower T3 and in many cases higher levels of rT3.63 If you are low carb or keto, the most expedient way to improve your thyroid function is to add back some high-quality carbohydrate to your diet.

Next, do a thorough medical screening. A good panel of blood work, a cardiovascular workup, and spirometry (breathing test) can identify signs of chronic infection, diabetes or prediabetes, liver disease, heart disease, or chronic obstructive pulmonary disease.

Also, consider your mental health. Major stress, depression, or PTSD can all cause Low T3 Syndrome and high rT3. If you do have NTIS, you are best served to work with a good diagnostician. The best approach is not to try therapies to see if they make you feel better, the most important step is to find out what is wrong.

High rT3 From Lab Error

If you are on thyroid treatment or have thyroid antibodies, your rT3 levels may be artificially elevated. The immunoassay method used to measure rT3 is also inconsistent.

High rT3 is Not Always Significant

Many healthy people have high rT3 levels for no reason. Individuals can also have their rT3 levels fluctuate greatly for no apparent reason and with no relationship to their current health.

Reverse T3: What You Need To Know

The answer is to find the cause and treat it. For those who need thyroid medications, getting them right is part of the answer as well. Many do not need thyroid medication, but no one will feel well when they are on a type or dose of thyroid medication that is not right for them.