Principles and Practical tips for Reverse T3, FT3, FT4

This post follows up on several recent posts on the topic of Reverse T3 (RT3) and our thyroid hormone conversion enzymes, the three deiodinases.

Here I’m providing some practical tips about Reverse T3 testing, test interpretation, and where we should be focusing our attention.

In these posts, I aim to improve thyroid therapy by debunking myths about Reverse T3 hormone and replacing them with more complete understandings that can help us make wise therapy decisions together with our good scientific-minded thyroid doctors.

In previous posts, I have proven that:

• Reverse T3 doesn’t actually have a role in “blocking” T3 from entering cell nucleus receptors or entering cells. Deiodinase Type 3 plays the blocking role, not RT3.
• Different cells express different thyroid-hormone-converting deiodinases (D1, D2, D3), as shown in visuals and recent publications. This discovery has significant implications for thyroid therapy.
• Reverse T3 does not hinder T3-T4 conversion in the body to the degree some have claimed. It certainly hinders a lot less than taking doses of anti-thyroid medication. Free T4 and Free T3 levels are a lot more influential in hindering conversion than Reverse T3.

I outline my moderate position on Reverse T3 testing:

• Yes, higher levels of Reverse T3 often go hand in hand with illness and poor T4 conversion. But you can have low or no RT3 in blood and still be ill. RT3 is a signal that can mean many things in different contexts, and lower is not always better.
• Yes, Reverse T3 testing can be a useful for resolving puzzles and confirming problems in thyroid therapy. But it does not have to be tested routinely if you have the wisdom to interpret Free T3 and Free T4.

Test Reverse T3 as a troubleshooting investigation.

Reverse T3 plays a valuable role in understanding what went wrong with the “endocrine math” of T4 conversion because a significant amount of T4 gets converted to RT3 in normal life, yielding a normal reference range for Total RT3 of 8-25 ng/dL — In comparison, the normal range for Total T3 is 76-181 ng/dL, which is 7 to 10 times higher.

However, an even a huger percent of T4 converts to RT3 in poor converters of T4 medication and in illness. Sometimes low Total T3 concentrations can rival higher RT3 concentrations.

Here are some scenarios (many others may exist).

Perhaps you are dosing a lot of T4 but you aren’t getting much FT4 in blood. You want to know if your FT4 is just not being well absorbed through GI tract due to gut health or diet or other meds, or if it is getting converted to Reverse T3.

You know what your baseline Reverse T3 is when you’re not sick. Then you get sick and you notice you’re losing Free T3. Again, you want to check whether you’re losing FT3 because of illness-triggered excess conversion to RT3, or some other problem with medication absorption. This will help you decide what degree you need to focus on managing your illness and adjusting your dosing at the same time.

You are not faring well on your dose of T4 monotherapy and your Free T3 divided by your Free T4 (in pmol/L) is lower than 0.24, which means you are a poorer converter of T4 hormone than the average thyroidless patient in Table 2 of Gullo et al, 2011’s study of 1,811 patients. Your doctor doesn’t believe you are suffering because your Free T3 is in the “normal” range. It has not yet fallen below reference where it qualifies as a biochemical indicator of “Low T3 syndrome” or underdose. You order a Reverse T3 test to find out the degree to which RT3 is high due to D3 dominance and D1 suppression. You hope it might enlighten and persuade your doctor about the degree to which you’re not capable of metabolizing your LT4 medication like others are.

In these ways, RT3 can be a confirmation of a hypothesis or an answer to a thyroid therapy puzzle.

Basic principles for interpreting RT3

Keep in mind whenever you test that Lower T4 will usually yield lower RT3 and vice versa.

FT4 is the biggest single influence on RT3 production in a state of health because we can only make RT3 from T4.

FT4 level is also what determines the conversion rate of T4 to T3 in tissues.  Deiodinase Type 2 activity is adjusted by the T4 level (and likely also by the RT3 level that comes along with it).

• If you lower FT4, you won’t make as much RT3 from it. Untreated hypothyroid people are low in Reverse T3 because FT4 is too low, and their conversion rate can’t compensate, so they are also also below their healthy FT3 level.
• If you raise FT4, you will make more RT3 and yield less T3 from it. Your FT3 will fall unless you are dosing T3 hormone, or you have a thyroid gland oversecreting T3, or an overactive deiodinase type 1.

If your RT3 level far exceeds your FT4 level as percent of reference range, you could be ill, fasting, or overdosing T3 or T4 and triggering your body to get rid of T4 by converting it to RT3. In any case, your body may not be able to handle the current level of FT4, but you may keep refilling FT4 with a daily dose.

Reasons not to test RT3 routinely

Save your money and save healthcare resources by educating yourself about the power of the deiodinases in health and disease and therapy.

• A well-educated patient and doctor should be able to deduce most of what they need to know from FT3 and FT4 levels and ratios.*
• We know that some FT4 will always go down the alternative conversion pathway to RT3, but a lot of other stuff will happen too.
• We don’t have a T2 test available in most clinical laboratories and we are not panicking from loss of this crucial information.
• We don’t have a Tetrac test or a T3 Sulfate test and we are not panicking.
• Your body will build up RT3 in blood when your T3 is low, so RT3 tests can reflect slower clearance rate in that condition, not just excess RT3 production.

We are never going to be able to do the complete endocrine math, but you can make intelligent hypotheses* about what might be going on.

Ultimately the proof is in the bottom line, the Free T3 and Free T4 levels and ratios that are the combined effect of our dosing and our deiodinases.

* To make good hypotheses, you need good theory and good data. The best resources for both are all the thyroid scientific articles by Antonio Bianco and colleagues; Rudolph Hoermann, John E. Midgley, Johannes Dietrich, and Larisch; see also Ito and colleagues; and Gullo and colleagues — these are the sources I rely on the most frequently in all my writings on this website, and I list a few good ones in references.

What most powerfully hinders T4-T3 conversion?

Actually, it’s not Reverse T3.

Follow the journey of thyroid hormones.

First you take a daily dose of T4 and/or T3 in your medication, and/or you may or may not produce hormone from functional thyroid gland tissue in response to TSH.

Every minute of every day, your levels and ratios of Free T3 and Free T4 (and RT3) are continually being fine tuned. Hormones are entering cells where they are being converted by three deiodinases (D1, D2, D3) in different cells, and then they are transported back out into bloodstream as T4, T3, RT3 and T2 and other metabolites. (Antonio Bianco and colleagues in 2019 have published a vast article with a revolutionizing image of the D2-expressing cell and the D3-expressing cell, which I discuss in this post).

Your metabolic “setpoint” is the key to the role of RT3.

Making T4 into RT3 is a powerful way your body tries to defend FT3 levels and local tissue T3 levels around that point of optimal equilibrium.

Imagine an airplane that must adjust in 360 degrees to compensate for wind velocity and weather and many other factors. Many adjustments the happy passengers can’t see are necessary in order for pilots to get the airplane where it needs to go without shaking the cargo too much or crashing. Thyroid doctors & patients are like airplane co-pilots.

In thyroid disease and therapy, this complex system can become very dysfunctional.

(Note that in thyroid science, even the word “setpoint” / “set point,” a common term, has become controversial. It is deceptive because the thyroid system guards a shifting setpoint that must adjust and compensate for the sake of health. This is what Hoermann et al (2016) are talking about when they discuss “relational stability” in thyroid function.)

What’s the FT3 and FT4 (and RT3) average “setpoint” for healthy people?

Thyroid normalcy as well as health status determines the average TSH, FT4, RT3 and FT3 in relation to statistical laboratory reference ranges for 95% of the healthy population. This is a protected population without thyroid disability or thyroid therapy throwing a wrench in the works.

1. Large population studies of healthy normo-thyroid people place the average FT3 at around 40-50% of reference (Gullo et al, 2011, 2017; as discussed here), and the healthy individual’s FT3 does not vary up and down more than 38% of the reference range (Ankrah-Tetteh et al, 2008, as discussed here).
2. The same research shows the average FT4 falls at around 30-40% of reference, and an individual’s healthy FT4 does not vary up and down more than 41% of reference.
3. It’s difficult to find average RT3 levels for a healthy population except by looking at control groups in the few nonthyroidal illness studies that use them and give RT3 measures. In a recent study, the healthy control group of 25 people with a mean FT4 at 16.59 (38% of range) and mean FT3 at 4.60 (52% of range) had a mean Reverse T3 (RT3) of 378.59 (possibly in pmol/L). Their RT3 range was huge, from 73.73 to 689.23 units. They don’t supply their laboratory’s ranges or units, and they don’t give a 95% reference interval, but the standard deviation is 157.28 pmol/L and the average RT3 falls at 49% of the full range. (Dubczak et al, 2019, Table II)

For most thyroid patients, this statistically “average” equilibrium and set of ratios between all indicators, including TSH, is now unachievable. We must consider that a healthy individual likely does not fit into this “average shoe size,” either.

The level of FT3 and FT4 are dependent on each other.  If you have an “abnormally” lower FT4, you must raise FT3 to compensate.  There is no compensation for lower FT3.

For thyroid patients in whom the population average FT3 – FT4 (and RT3) biochemistry is still achievable, TSH is likely to be lowered by it, and it may now come at a health cost, not a health benefit.

Why must we target statistically average normalcy when we are now fundamentally abnormal in a way a static pill can’t fix?

It is unwise to imitate average statistical thyroid normalcy as an unchanging “stasis” or ideal.  It may not be any individual’s healthy stasis, and we don’t have the thyroidal equipment to maintain flexible “homeostasis” by fine-tuning it.

How do people maintain FT3 and FT4 around their setpoint, or fail to protect it?

Free T3 is the target of thyroid hormone homeostasis.

In today’s models of thyroid homeostasis (Bianco et al, 2019), FT3 levels are the target of the HPT axis. The partnership between TSH and healthy thyroid tissue is the most important means to this end.

Varying levels of TSH and FT4 and conversion to RT3 aim to defend and stabilize FT3 levels needed for health, but FT3 levels are at risk in critical illness and in thyroid disease & therapy.

This is why it’s so illogical to make TSH the target of thyroid therapy, when it’s not the body’s target. FT3 is.  Free T3 provides the baseline supply to nuclear receptors in all cells within tissues and organs.

When Free T3 falls low, T4-T3 conversion rates cannot always rise sufficiently to compensate, and a larger percent of nuclear receptors will be unoccupied.

The body adjusts FT3 via cooperation between

• 1. the healthy-thyroid HPT axis (hypothalamus – pituitary – thyroid axis) and
• 2. the three deiodinases that convert thyroid hormones.

Thyroid tissue is the core of nature’s negotiation (achievement of homeostatic equilibrium) between two systems (HPT axis & the deiodinases).

Both of these systems can fail to different degrees during illness and thyroid disease & its therapy.

Complex multi-directional feedback mechanisms at many levels establish backup systems to defend FT3. The rate of conversion to Reverse T3 is one of these backup systems.

In therapy, we don’t self-regulate homeostasis via TSH to the degree that we lack thyroid tissue to respond to TSH.

Our thyroid disease, dosing and therapy choices now regulate our T3 and T4 supply/intake, instead of just the TSH.

In thyroid disability & therapy, we are rendered more vulnerable to deiodinase imbalance (and therefore to TSH, FT4, FT3 and RT3 imbalances) because we have lost thyroid tissue.  (Hoermann et al; Midgley et al; Ito et al, 2017)

TSH used to fine-tune secretion and conversion in thyroid tissue and enhance T3 supply whenever Free T3 fell short.

The TSH-T3 disjoint in therapy

In thyroid disease and therapy, we can’t compensate for our DIO1 / DIO2 genetic handicaps or imbalanced deiodinases without individually-adjusted therapeutic intervention.

In therapy, TSH is no longer as strongly associated with T3 status in bloodstream or tissues, creating a TSH-T3 disjoint. (It’s explained and proven by research by Larisch et al, 2018; Ito et al 2012, 2015, 2019)

The TSH-T3 disjoint in therapy means our TSH is statistically lower than it would be in “normo-thyroid” people when we have sufficient FT3 in blood.

When our TSH is in range, our Free T3 can be insufficient for our tissues and cells.

In most people without thyroids, it requires TSH below the normo-thyroid range to achieve the average normo-thyroid level of Free T3.

Our FT3 and/or FT4 needs to be higher than in the normo-thyroid population to ensure enough supply to tissues.

Because either our FT3 or FT4 will be higher than our body expects, it will inevitably trigger a higher rate of 1) reverse conversion and 2) a greater level of TSH suppression, but these effects can counterbalance each other. A suppressed TSH no longer necessarily signals thyrotoxicosis because we have a higher rate of T4 and T3 inactivation in tissues.

Let’s see where treated thyroid patients lose T3 and where RT3 plays a role.

• If your FT4 is in the upper 1/3 of reference, you are losing more T3 than normal because D2’s T4-T3 conversion rate will be lower because of ubiquitination.
• If your FT3 is in the lower 1/3 of reference, you are losing more T3 than normal because D1’s T4-T3 conversion rate will be lower because D1 is powered by T3.
• If your FT4 and/or FT3 are in the upper 1/3 of reference, D3 will dominate over D2.
  • D3 will convert more FT4 to RT3 than normal and you’ll get less T3 out of it.
  • D3 will convert more of your FT3 to T2 than normal and you’ll lose T3.
• If you are severely ill or fasting, your D3 may dominate over both D2 and D1 even more powerfully because your body will dump T3 to lower metabolic rate. D1 is less active when T3 is low, so your RT3 level in blood will also inflate from a low clearance rate.
• Take away continual conversion to other metabolites like tetrac, T3 sulfate, and excretion.

This is what leads to your Free T3 and Free T4 availability in blood.

Notice that I’ve mentioned RT3 twice. Notice there are many statements starting with “If.”

What determines cellular euthyroidism?

The answer is “baseline circulating Free T3” plus a variable rate of T4-T3 conversion, in which RT3 plays one role among many.

Ultimately, thyroid hormone sufficiency is about how much T3 hormone gets into nuclear receptors, and that is to a significant degree determined by circulating T3, NOT by circulating Reverse T3.

Bianco et al, in 2019 say this about the importance of circulating / plasma T3 levels:

“Circulating T3 levels are important determinants of TH [Thyroid Hormone] signaling. Indeed, in most tissues the level of TR [Thyroid Receptor] 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.

For example, studies in rats estimate that a mere 10% drop in plasma T3 levels reduces liver and kidney TR occupancy by ~15%

As I’ve shown from Bianco’s article in previous posts, RT3 cannot block circulating Free T3 from getting into D2 or D1-expressing cells.

Only D3-expressing cells will turn your FT4 into RT3 and your T3 into T2.

D2 and D1 expressing cells will always still welcome your circulating FT3 into their cytoplasm and nucleus, even if D2 and D1 are not converting T4 efficiently.

Therefore, circulating RT3 can’t singlehandedly cause “cellular hypothyroidism.” Instead, Low circulating T3 plus lower D1 and D2 expression and higher D3 expression causes hypothyroidism in tissues and organs.

RT3 is like paying T4 tax.

Yes, T4 conversion to Reverse T3 can get in the way of sufficient Free T3 levels. But:

• Reverse T3 is the tax we pay for T4 infrastructure. Whenever you have any FT4, conversion to RT3 always happens. It’s inevitable. Doctors like to say that “T4 converts to T3 in peripheral tissues.” But “T4 converts to RT3 in peripheral tissues.”
• Income tax never exceeds your income. Your body will never make more RT3 than you have FT4 supply to make it from. You will never, ever stop converting some T4 into T3 at the same time.
• Some people deserve tax breaks and T3 income support. We have three types of thyroid hormone medications on the market and two of them contain T3 hormone. Dosing T3 is a direct investment in the health of citizens who are handicapped in secretion and conversion.

What should we fear? Fear low baseline Free T3 resulting in reduced T3 receptor occupancy. New thyroid research proves hypothyroidism is actually hypo-T3-ism.

Therapy failures steal some of our precious FT3 and give us RT3 instead, keeping our TSH deceptively normal. It’s a cruel cheat that can seriously compromise our health.

We must do everything we can to defend our body’s baseline Free T3. This is the core issue in thyroid therapy and its failure, which I’ll continue to explore on this website.

• Tania S. Smith

REFERENCES

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Ankrah-Tetteh, T., Wijeratne, S., & Swaminathan, R. (2008). Intraindividual variation in serum thyroid hormones, parathyroid hormone and insulin-like growth factor-1. Annals of Clinical Biochemistry, 45(Pt 2), 167–169. https://doi.org/10.1258/acb.2007.007103

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

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