I’m kicking today off with a mea culpa. Last year, I published The Ultimate Guide to Thyroid Function Testing – Hypothyroidism Edition. In that post, I gave short shrift to a useless blood test called reverse T3 (rT3):
Forget you ever read about reverse T3, T0, T1, and T2. End of story.
If you’re reading this site, it’s probably because you like to understand things – believe me, I get that. I don’t ask for many favors, but I’m asking you to trust me this once…the above tests will add absolutely nothing to your medical care. It is totally unnecessary to invest your ATP in figuring out how to use or interpret these tests.
In retrospect, that may not have been the best way to encourage you to ignore the copious internet nonsense regarding testing for rT3. Over the last couple of years, my readers’ comments and emails have demonstrated that y’all are an intelligent and skeptical bunch. When I ask you to believe something simply because I say it is so, the little hairs on the back of your neck stand in indignant piloerection. In an attempt to make it right with you, I will address the myths out there about rT3, hopefully putting this issue to rest – for now.
Getting on the Same Page
As I’ve said before, this is not a medical-o-pedia site, so I assume you’ve already done the background, boring reading and have a certain level of familiarity with the subject. But, to quickly make sure we’re starting from the same point: the thyroid gland makes predominantly T4, plus some T3. Circulating T4 is converted to “active” T3 in our tissues by deiodinase enzymes. We have three types of deiodinase enzymes in different tissues, and their level of activity depends on the needs of that particular tissue at that moment.
When T4 is metabolized by Type 1 Deiodinase (D1) in our tissues to form active T3, some biologically inactive rT3 is also formed. When T4 is metabolized by Type 3 Deiodinase (D3) in our tissues, it is inactivated to rT3.
The classic pathways of thyroid hormone metabolism – Scientific Figure on ResearchGate.
rT3 and T2 have no known biologic function in humans, but rT3 has been investigated as a marker for distinguishing abnormal thyroid function tests seen in non-thyroidal illness from abnormal thyroid tests in the setting of an actual thyroid problem. Most of this investigation has been in critically ill patients, who tend to have higher levels of rT3. Because it is now well-established that this subset of patients has elevated rT3, it is extraordinarily rare for a physician to order the test, as it usually does not add any actionable information to the situation.
To the best of my knowledge, there are no data to guide the use of rT3 in the routine diagnostic workup of hypothyroidism in free-living (non-ICU dwelling) humans. Further, I am unaware of any data regarding how to use rT3 to guide thyroid hormone replacement therapy in people with known hypothyroidism. At best, it would appear difficult – at worst, impossible – to interpret a rT3 level in someone who takes levothyroxine (T4), as the drug itself may cross-react with the immunoassay, causing the rT3 level to be falsely high. In addition, there are data suggesting that the mere presence of additional T4 substrate (levothyroxine) in the blood can lead to increased inactivation of T4 to rT3 (see above diagram, again). In other words, if you load up the left side of the chemical equation, chemistry rules dictate that the reaction will be driven to the right.
Regular readers know that I often harp on the importance of knowing your assay. In the case of rT3, there is a liquid chromatography/tandem mass spectrometry (LC-MS/MS) assay that is less prone to interference. But who cares how good the assay is if we don’t know what to do with the results? Besides having no known biologic function, it should also be noted that the half-life of rT3 in the blood is 4 hours. Compare that to T3’s half-life of 1 day and T4 at 5-9 days, and you will appreciate another reason why doctors avoid placing much emphasis on the rT3 level.
So why is the alternative medicine world obsessed with esoteric testing that has no clinical value? The most cynical explanation is that they appropriate and bastardize impenetrable concepts to lend an air of credibility to the nonsense they peddle. Look, the regulation of deiodinase activity is extraordinarily complex. Consider this sentence from Visser et al‘s treatise Metabolism of Thyroid Hormone, posted on my favorite, consistently updated online thyroid textbook, Thyroid Manager:
Whereas initial studies focused on the role of the deiodinases in maintaining normal serum T3 concentrations, the paradigm has evolved that these enzymes can locally modify TH [HD: thyroid hormone] bioactivity independent of serum TH concentrations.
Translation: there are a few things we can measure and a lot we can’t measure when it comes to the metabolism and action of thyroid hormone at the blood, tissue and cellular levels. There are many moving parts here – so many that I wager there is much we still don’t understand about thyroid hormone metabolism. But let’s be clear about one thing: admitting that we don’t understand everything about thyroid hormone metabolism ≠ rT3 testing has value.
Alternative Medicine makes it possible to diagnose just about anyone on the planet with hypothyroidism. Don’t worry if your TSH, T4, and T3 are all normal. If you test your reverse T3 level enough times, you’re bound to eventually get a high reading, thus securing your diagnosis. With that, I will now debunk Alt Med’s claims about rT3 in Everything You Never Needed to Know About Reverse T3.
Claim: Elevated rT3 is the best marker for tissue hypothyroidism.
HD: False. For the average person reporting fatigue and weight gain, a normal TSH alone will usually rule out hypothyroidism. rT3 can be elevated in non-thyroidal illness (NTI). NTI is any systemic disease process in which thyroid function tests change (usually lowish T4 and T3 with a normal TSH) as a physiologic reaction to the NTI. In most diseases, treatment of the NTI itself will restore thyroid function tests to normal, and treatment with thyroid hormone is neither required nor advised. In fact, it is quite possible that thyroid hormone levels are down-regulated in these scenarios, as a normal protective response.
Claim: Elevated rT3 indicates that T4 replacement alone will be ineffective.
HD: False. Alternative Medicine appears to justify this by saying that high rT3 is a consequence of reduced uptake of T4 by the cell and reduced T4 to T3 conversion. While there is some truth to their statement, there are no data suggesting this proves therapy with levothyroxine alone will be inadequate. Once you give levothyroxine to such a person, there will be significantly more T4 substrate available. This alone has the potential to drive more T4 to T3 conversion, as well as greater cellular uptake of T4 (remember the laws of chemistry). The point here is, once you change the metabolic milieu by giving a therapeutic dose of T4, that initial elevation of rT3 doesn’t mean much. And, as described earlier, once you give T4, it makes no sense at all to check rT3 again to guide replacement. If you want a more nuanced discussion of whether to use T3 therapy in hypothyroidism, read T3 Or Not T3 – Exploring The Controversy.
Claim: The T3/rT3 ratio is the best marker of intracellular thyroid hormone levels.
HD: Mostly False. The T3/rT3 ratio has been studied as a prognostic tool in critically ill patients and the elderly. When it is very low, that’s bad. This tends to happen in illnesses that cause D1 activity to go down (less T4 to T3 conversion) and D3 activity to go up (more T4 to rT3 inactivation). The T3/rT3 ratio has not been found to be useful in assessing the average person with “hypothyroid” symptoms.
Claim: Elevated rT3 blocks T3 from binding to its receptors, causing tissue/cellular hypothyroidism.
HD: False. There is no credible evidence that this occurs, while there is plenty of evidence that this does not occur. rT3 does not bind to nor have transcriptional activity at the thyroid receptor. It certainly doesn’t enter the nucleus of the cell. Therefore, it has no effect on the ability of T3 to drive cellular metabolism, maintain body temperature, etc. So why does Alternative Medicine make this claim? The best I can figure is that there are data showing that rT3 binds to a specific thyroid hormone receptor in the cytoplasm of brain astrocytes, initiating actin polymerization. This is important for the structural integrity and motility of the cell. I think the next claim will demonstrate how Alt Med leaps from this to “blocking T3.”
Claim: Elevated rT3 decreases metabolic rate by decreasing T4 to T3 conversion.
HD: Mostly False. I had fun researching this one, as Alt Med does have some science on its side. However, as usual, they take an idea with a kernel of truth and extrapolate the heck out of it. I had to dig deep into the literature to attempt this explanation, and it’s a little dense, so bear with me. There are a bunch of papers from the 1970s through ’90s looking at the role of rT3, mostly in vitro studies using mouse cell lines or in vivo studies in animals (birds, mice, rats, dogs, lambs, oh my!). For example, Okamoto R et al published “Adverse effects of reverse triiodothyronine on cellular metabolism as assessed by 1H and 31P NMR spectroscopy” in Research in Experimental Medicine in 1997. The authors demonstrated that, in a culture of mouse cells, administering rT3 lowered the ATP/ADP ratio from 6.9 to 6.1.
What does that mean? Well, I’m not quite sure, as I don’t know how to translate that ATP/ADP ratio into something that is clinically meaningful. But Alt Med appears to know, as they cite this study to back up their claim. The experiment was done at a pH of 7.4, which is around where humans live, so maybe there’s a kernel of something interesting here. But, the more impressive ATP/ADP lowering effects were seen in part deux of that experiment, when the investigators subjected the cells to significant stress by lowering the pH to 6.7 – not something that human cells are likely to experience for very long.
In 1988, Sechman et al published “The Relationship Between Basal Metabolic Rate (BMR) and Concentrations of Plasma Thyroid Hormones in Fasting Cockerels.” Before you jump down my throat for veering off into the realm of birds’ thyroids, I only mention this study because it’s another classic example of a study cited by Alt Med as supporting the notion that elevated rT3 is the best marker for diagnosing hypothyroidism in humans who have normal TSH, T4, and T3 levels (AKA normal people).
In case you’re wondering, I pulled the paper and read it, so you won’t have to – you’re welcome. The investigators showed that withholding food from birds lowers both T3 and BMR and increases rT3 – a normal physiologic response to starvation. Upon refeeding, they show that T3 and BMR go back up (duh). They postulate that rT3 antagonizes the effect of T3, though I’m not sure why they felt the need to explain the lower BMR by invoking any mechanism other than that T3 production/conversion is reduced when the body is starving and needs to conserve energy. Their data certainly do not prove any antagonistic effect of rT3 on T3.
I don’t want to give the false impression that all of Alt Med’s “data” is from 2-3 decades ago, performed in animals that bear little resemblance to humans. They also cite a 1959 preliminary report by Pittman et al called “Antimetabolic Activity of 3, 3′, 5′-Triiodo-DL-Thyronine in Man.” I love this one, as I suspect there is no way you could get their study protocol past an IRB (Internal Review Board) nowadays.
In an effort to not completely burn out the attention span of the few readers who have stuck with me to this point, I will stick to the highlight reel. The investigators gave whopping doses of rT3 pills to a small group of hypothyroid, euthyroid, and hyperthyroid subjects. BMR remained unchanged in euthyroid and hyperthyroid people, while it went down in three out of four hypothyroid people. None of the hypothyroid people had any “hypothyroid” symptoms during the period of rT3 administration.
Putting the Nail in the Coffin
In my opinion, none of the above studies (or numerous similar ones) should be used to support Alt Med’s authoritative claim that elevated rT3 decreases metabolic rate in people. Given how deep Alt Med had to dig for this data and the weakness of said data for supporting their argument, I can only assume that they ignored other data I found that contradicts their argument. Or, they just have a very poor grasp of how to interpret these studies – could be that.
Before I get to the papers I discovered, let’s take a step back. The studies Alt Med cites found a possible metabolism-reducing effect of rT3…by administering high doses of it to cell cultures, animals, and humans. Giving a big dose of rT3 to a person and seeing what happens is completely different from observing what happens when rT3 is produced by the body in the course of normal thyroid hormone metabolism.
Think about it using this example: the adrenal glands secrete cortisol into the bloodstream. In the course of normal human physiology, the adrenals make more or less cortisol depending on the needs of the body. Now think about hydrocortisone, a medication used to replace cortisol in people who can’t make the hormone. If you give someone very high doses (supraphysiologic) of hydrocortisone for long enough, you can suppress their immune system, thrash their bone density, and make them gain a bunch of weight. Would you then say that the hormone cortisol is an immunosuppressant, decreases bone density, and causes weight gain? Of course not! I cannot emphasize this point enough: if you administer a pharmacologic dose of a naturally occurring substance, the reaction to that substance will probably be very different from what actually happens when the body produces it on its own.
When it comes to rT3, even many of the papers cited by Alt Med show that, when the molar ratio of T4:rT3 or T3:rT3 is high enough, any “negative” effect of rT3 disappears. In the case of normal human physiology, there appears to be no evidence that naturally occurring molar ratios ever result in rT3 blocking T4 to T3 conversion by acting as a competitive inhibitor.
Studies that Refute Alt Med’s Claims
I’m only going to torture you with two examples, as I know your brain is starting to hurt…
Galton et al published “Life without Thyroxine to 3,5,3’-Triiodothyronine Conversion: Studies in Mice Devoid of the 5’-Deiodinases” in Endocrinology in 2009. Although this is not a human study, at least it was done on live mice – not mouse cells. This was a “knockout study” in which the investigators bred mice that couldn’t make the Type 1 Deiodinase enzyme (D1KO), the Type 2 Deiodinase enzyme (D2KO), or either enzyme (D1/D2KO). You would think that D1KO and D2KO mice would have low T3 levels and stumble around their cages, unable to run through any of the tasks set up by the investigators, right? Well, you’d be wrong. They maintained normal T3 levels and had remarkably little impairment in locomotion, learning, and memory – all things that are impaired in hypothyroid mice.
Reverse T3 levels in D1KO mice were elevated two-fold over wild-type (WT) mice. D2KO mice had no change in rT3, while D1/D2KO mice had a six-fold elevation in rT3. If rT3 can decrease metabolic rate by impairing T4 to T3 conversion in a clinically meaningful way, you would expect the double-knockout mice to be fatter and have lower T3 levels. Interestingly, the D1/D2KO mice weighed 5% less than WT mice by 8 weeks (statistically significant) and were able to maintain a normal serum T3 level.
In 2015, Lado-Abeal published “Thyroid hormones are needed to sustain ‘inappropriately’ normal TSH during non-thyroidal illness syndrome: a clinical observation in severely ill patients with primary hypothyroidism.” The author studied seven critically ill patients who also had primary hypothyroidism that was un- or poorly-treated on admission to the ICU. I cite this paper for a couple of reasons. First, the pituitary-thyroid axis was found to be intact in these hypothyroid patients; in other words, the TSH was quite high and came down with appropriate levothyroxine treatment. Even severe NTI (non-thyroidal illness) did not make the TSH unreliable in patients with true hypothyroidism. So please stop telling me that we’re missing cases of primary hypothyroidism when people have mild forms of NTI. Second, the author found that rT3 was normal or elevated at baseline and continued to increase with stepwise increases in the levothyroxine dose. As stated earlier, this is totally expected. When you load up the left side of the chemical equation with T4, you will drive the production of whatever is on the right side – in this case, T3 and rT3. So, Alt Med, please stop checking rT3 in patients on thyroid hormone replacement therapy.
If you’ve hung in all the way to the end, congratulations! You are officially an Endocrinology nerd. If you’re a doctor, please feel free to print this out or link to it every time you get a request to add a reverse T3 to the next set of labs. If you are a layperson who is just really, really interested in your thyroid health, hopefully this will steer you away from engaging in fruitless testing that will not make you feel any better. Have any additional thoughts? Comment below!
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