A common misunderstanding promoted by conventional physicians is that RT3 is a useless, obsolete test.
Another misunderstanding currently in circulation among thyroid therapy practitioners and patients is that one ought to target a low-normal or low level of Reverse T3 (RT3) during thyroid therapy.
Neither is a tenable, evidence-based conclusion.
In this post, I provide a collection of research graphs and quotations showing diverse Reverse T3 levels coexisting with health, in various illnesses, and alongside various T3 and T4 levels.
These graphs and quotations complement the ones I’ve already provided in previous posts reviewing the science on Reverse T3 (listed at the end of the article).
I’ve collected key visual evidence into a single post along with some interpretive aids to decode them. It is necessary and timely. Human health is at stake. RT3 misunderstanding can lead to therapy mistakes and harm. Timely RT3 measurements can provide a differential diagnostic in cases of chronically poor T4-T3 conversion or illness.
After reviewing the evidence, it ought to become clearer when and how RT3 testing is useful.
You’ll see that RT3 is most highly elevated in extreme cases of autoimmune hyperthyroidism. In true hyper, the presence of excess RT3 cannot prevent both thyroid hormones from rising. It can’t stop T4-T3 conversion in cells. It can’t prevent severe symptoms of thyrotoxicosis. Therefore, claims that endogenous levels of RT3 hormone can block T3 transport, metabolism or signaling are highly unscientific. As you will see, it is not a toxin or blocker unless you are dosing 100x the amount a human body can produce.
Another insight is that the RT3 test ought not to be the subject of scientific ridicule or dismissal. It is false reasoning to say that RT3 is an obsolete thyroid test just because it is so often misinterpreted in isolation. RT3 is not a routine test whose result always has a simple and obvious meaning, such as “that number is not optimal” or “that number is out of range.”
RT3 levels are best interpreted in relationship to total (or free) T4 and T3 levels by using hormone ratios. A person needs to notice whether one ratio is inverse to the other, or whether one or both ratios is extreme. Judgment is aided by an informed understanding of D1, D2 and D3 enzyme synergy in tissues across the human body.
RT3 is an indicator with many faces. In the right hands, it can provide insight into protective and pathological metabolic mechanisms, illnesses, thyroid hormone overdose/underdose, and various types of hyperthyroidism and hypothyroidism.
Below are graphs, quotes, and data from three early studies that show enough detail to give understanding:
- Nicod et al, 1976 — Hypo, hyper, sick patients, and healthy controls, RT3 compared to T3
- Burman et al, 1977 — Hypo, hyper, sick patients, controls, and underdosed / overdosed patients on LT4
- Desai et al, 1984 — children adequately treated or overdosed with T4, and controls
In the late 1970s, scientists were trying to develop Reverse T3 tests with radioimmunoassay methods. One of the first assay attempts was reported by Chopra in 1974 (not shown here).
The assays, despite their pioneer status, showed general patterns in Reverse T3 levels between groups of patients, and between RT3, T4, and T3 hormones.
Even though this data is decades old and performed on instruments now refined for better precision, there are no more recent data sets that compare RT3 levels among so many groups of patients.
Older articles often communicated in greater detail than contemporary scientific publications. Scatterplots were much more common in those days. Each dot in a scatterplot represents a single patient’s data point. The visual emphasizes the importance of each individual person. Scatterplots also reveal the skew, shape and range of the full data sets. Other visuals more popular today, such as bar graphs, often conceal the individuals — along with the biases in data sets (Weissgerber et al, 2015).
Copyright fair dealing note
Nicod et al, 1976
1. Total RT3 is normally lower than T4 and T3
The quantity of Total T3 in blood, on average, dominates over that of Total RT3 by 3.66x in healthy people.
As one can see in Nicod’s graph above, the RT3 reference range for this assay (the dark bar on the right) is lower than the Total T3 reference range, and far lower than the T4 reference range (not shown in the graph). This is how they expressed their reference ranges:
- RT3 450 ± 200 pg/mL (Range 245 – 641 pg/mL) at age 20 to 60
- T3 1650 ± 460 pg/mL at age 20 to 60
- T4 82 ± 39 ng/mL (equal to 82,000 ± 39,000 pg/mL)
The quantity of Total T4 is 182.2x the value of Total RT3 in health.
The graph above makes the phrase “RT3 dominance” of questionable logic, except in acutely or chronically ill individuals whose RT3 concentrations numerically dominated over Total T3 expressed in the same unit. (Unfortunately, the graph does not connect an individual’s FT3 level with their corresponding RT3 level.)
The highest RT3 levels are found in untreated hyperthyroidism.
“Serum rT3 concentrations in hyperthyroid subjects ranged from 762 to 2581 pg/ml (mean = 1560), …
The corresponding T3 concentrations were 1750 to 8550 pg/ml (mean = 4210)”(Nicod et al, 1976)
The presence of extremely high RT3 in blood did not seem to reduce T3 levels.
Therefore, high natural RT3 levels do not hinder T4-T3 conversion rate.
What’s going on?
As the T4 levels (not shown) and T3 levels rise higher and higher, the body tries to get rid of excess hormone.
The high levels of RT3 in hyperthyroidism imply that Deiodinase Type 3 (D3), which converts T4 to RT3 and T3 to T2, is upregulated in hyperthyroidism.
“the primary role of Dio3 is to protect tissues against the increased metabolism that comes with increased thyroid hormone levels.” (Huang et al, 2011)
D3 enzyme continues to be very active even at very high levels of T4 and T3. D3 is not inactivated by excess T4 or T3 because its natural role is to break down excess hormone. There is no known limit to D3 upregulation besides pharmaceutical doses of iopanoic acid, a substance that hinders all three deiodinases from functioning. (Huang et al, 2011)
The lowest RT3 levels were found in untreated hypothyroidism. This is because Free T4 (not shown) is low and there is less T4 becoming RT3.
RT3 “in hypothyroid subjects [ranged] from undetectable to 395 pg/ml.”
“The corresponding T3 concentrations were … 230 to 1050 pg/ml (mean = 590)”(Nicod et al, 1976)
Usually the T4-T3 conversion rate via D2 enzyme is boosted in thyroid failure as T4 falls below reference and TSH stimulation increases on the thyroid gland fragment.
However, these patients’ Total T3 was below reference, revealing that their thyroid gland was severely damaged or missing, unable to defend their T3 levels (See “The thyroid gland is a T3 shield“).
The decrease in both RT3 and T3 shows that a lower RT3 could not shield or defend their T3 levels, either. Lowering RT3 does not boost T4-T3 conversion.
Nicod and team considered both hypothyroidism and hyperthyroidism cases in which there are
“changes of serum rT3 and T3 in the same direction.”
- In hyper, as T3 rises, RT3 also rises.
- In hypo, as T3 falls, RT3 also falls.
The behavior of RT3 in cases of illness is different from hypothyroidism and hyperthyroidism. In illness, they are
“Changes of serum rT3 and T3 in [the] opposite direction.”
The three vertical scatterplots on the left of the graph above show 1) Acute & chronic diseases; 2) renal insufficiency (kidney disease) and 3) anorexia nervosa.
The group of 24 patients with acute and chronic disease included both infectious and non-infectious diseases:
“The group of infectious diseases consisted of 3 acute septicemias, one subacute osteomyelitis, 5 acute bronchopneumonias, one generalized mononucleosis, and one florid pulmonary tuberculosis.
The group of noninfectious diseases included 5 cases of decompensated cirrhosis, 3 chronic leukemias, and 1 multiple myeloma at the end stage, two colonic, one mammary, and one ovarian carcinoma with multiple metastatic dissemination.”
As for the 7 patients with anorexia nervosa, all were female, 12-23 years old:
“The patients weighed 36 to 46 kg, they were 63 to 85% of their ideal weight. Two of these patients were hospitalized, the remaining were clinically stable and ambulant.”
“In 7 patients with anorexia nervosa, serum rT3 concentrations ranged from 536 to 1058 pg/ml (mean = 807) and serum T3 concentrations from 790 to 1980 pg/ml (mean = 1350).
In the group of sick patients, rT3 ranged from 151 to 2400 pg/ml (mean = 980; n = 24) and T3 concentration from 130 to 1720 pg/ml (mean = 890).”(Nicod et al, 1976)
Nicod et al, 1976 Summary
Keep in mind the contrast between Hypothyroidism and hyperthyroidism as cases in which there are “changes of serum rT3 and T3 in the same direction” (both can rise or fall together) versus illnesses, in which we see “Changes of serum rT3 and T3 in [the] opposite direction.”
This becomes a major clue to the wise use of RT3 testing proposed in the conclusion, especially when the RT3:T4 ratio is kept in view as well.
Burman et al, 1977
Following Nicod et al, 1976 by one year, another group set out to develop a RT3 hormone assay and compared levels among diverse population types.
This time, the populations included T4-hormone dosed individuals. Missing from Burman’s examination is any study of RT3 in illness.
1. Normal ranges
- RT3 60 ± 12 ng/100 mL Normal range 36 – 84 ng/dL
- T3 137 ± 11 SE ng/100 mL
- T4 7.2 ± 0.3 SE mcg/100 mL(equal to 82,000 ± 39,000 pg/mL)
2. Hypo- and hyper, under- and overdosed
Hypothyroid and hyperthyroid individuals were at the two extremes, confirming the data from Nicod et al, 1976.
Again, TSH was not the primary or sole diagnostic indicator to confirm hypothyroid or hyperthyroid status. The 11 hypo and 19 hyper patients “had typical clinical syndromes confirmed by T4, T3, and/or TSH concentrations.”
- Joining the untreated hypothyroid population with RT3 levels below range were underdosed athyreotic people (no thyroid gland, total thyroidectomy) on only 50 mcg per day (0.05 mg) of LT4 monotherapy. Being underdosed is similar to being hypothyroid.
- Joining the hyperthyroid individuals with some values over reference range were overdosed athyreotic patients on 400 mcg per day (0.4 mg). But the autoimmune hyper RT3 levels were still astronomically high compared to this overdose.
3. Normal (healthy) populations
This time, “normal” healthy populations’ RT3 levels were revealed as being, on average, mid-range, with the majority concentrated just below mid-range.
This is unsurprising since the average healthy population’s Free T4 (FT4) level is just below mid-range (Gullo et al, 2011). (Free hormones were difficult to measure at that time, so total levels were more commonly used).
The RT3 concentration likely echoed the T4’s position in range.
In health, “The rT3 level tends to follow the T4 level: low in hypothyroidism and high in hyperthyroidism.” (Mayo Clinic Laboratories).
Unfortunately, pairs of RT3-T4 combinations in each individual are disconnected on the graph.
Again, even health was assessed by more than just a normal TSH. The 21 healthy people (15 male, 6 female; mean age 33) were described as follows:
“These subjects were laboratory personnel not receiving any medication who were euthyroid as confirmed by serum T4 and/or T3 levels, clinical examination, and a normal thyrotropin response to thyrotropin-releasing hormone (TRH) administration.”(Burman et al, 1977)
4. The RT3:T4 ratio
Read that heading again — notice it does not say “RT3:T3” ratio, which a ratio that makes more sense in cases where nonthyroidal illness, which Nicod et al, 1976 was studying.
When Burman and team discuss the ratio, notice that they invert the position of RT3:T4 and make it a T4:RT3 ratio.
Ideally the RT3 should be the nominator because it is metabolically derived from T4. However, the mindset of the authors was to prioritize T4 hormone and to yield a whole number rather than a decimalized value like 0.0083
“The mean T4:reverse T3 serum concentration ratios in athyreotic patients receiving varying doses of L-T4, and in euthyroid subjects with intact thyroid glands were approximately 150:1 and 120:1, respectively.”(Burman et al, 1977)
The T4 unit is up to 150x the amount of RT3. This is the very opposite of the misguided concept of “RT3 dominance.” RT3 is obviously in the minority here.
Notice the researcher’s interpretation of the contrast between 150:1 (treated T4:RT3) and 120:1 (untreated healthy T4:RT3):
“These ratios suggest that for a given serum level of T4, slightly less reverse T3 was formed in the athyreotic patients than in the euthyroid subjects with intact thyroid
This finding, based on a mean (average), and “less Reverse T3 per unit of T4” was not aligned with the findings of later studies of RT3 in T4 monotherapy (as shown below in Desai et al, 1984).
Summary of Burman et al, 1977 data
In this table, I’ve provided the calculation of the ratio with RT3 as the nominator to emphasize the small amount of RT3 per unit of T4.
The T4:RT3 ratio [RT3:T4 ratio] is slightly lower in LT4- treated vs untreated healthy people, as discussed above.
Hyperthyroid individuals had a grossly inflated RT3:T4 ratio. Their ratio was significantly higher than the overdosed LT4 patients, even though their FT4 levels were not that much higher than the overdosed LT4 patients (16.6 versus 15.4). The key reason for the ratio’s inflation was their significantly higher T3 levels, as discussed below.
The treated patients’ RT3:T4 ratio did not differ significantly on average between underdose or overdose. (The same group of 9 patients was subjected to 50 mcg and 400 mcg). This illustrated a principle of a steady T4 and RT3 metabolic relationship outside of illness in people without thyroid glands whose only T3 and RT3 supply comes from dosed T4.
In none of these cases did the RT3:T4 ratio increase above normal while there was a T3:T4 ratio decrease below normal. Apparently this was because none of the patients had a “nonthyroidal illness.”
The T3/T4 ratios were inflated above normal both in untreated hypo- and hyperthyroidism, due to TSH-receptor stimulation of thyroid tissue, not because of the RT3 level.
- In the most common cause of hypothyroidism, Hashimoto’s thyroiditis, the failing thyroid’s T3 secretion rises higher than T4 secretion when a poorly-functioning thyroid fragment is overstimulated by high TSH levels. (Abdalla & Bianco, 2014). This demonstrates the flexibility of the thyroidal T3:T4 secretion ratio in response to TSH-receptor stimulation. There is little to no T4-RT3 conversion occurring because no excess T4 needs to be diverted from tissues.
- In the most common cause of hyperthyroidism, Graves’ Disease, T3 secretion rises higher as TSH-receptor antibodies overstimulate the thyroid gland, but the T3/T4 ratio is lower than in untreated hypothyroidism. This is partly because the T4-RT3 pathway is enhanced. The body is equipped with several metabolic defenses against T3 and T4 hormone excess, not just T4-RT3 conversion, as discussed in more detail below. Excess T4-RT3 conversion cannot prevent thyrotoxicosis in extreme cases.
Interestingly, the average treated patients’ T3:T4 ratio did not differ significantly between underdose and overdose. This mirrored their unchanged RT3:T4 ratio average. Their lack of thyroidal T3 secretion and lack of T3 dosing made this metabolic principle apparent:
- In the absence of a nonthyroidal illness, the natural rise in RT3 levels kept pace with their T4 levels and did not “cause” a poorer T4-T3 conversion rate.
Desai et al, 1984: Children on levothyroxine
In this study based in Bombay (Mumbai), India, they enrolled 40 children (1 to 14 years old) with congenital hypothyroidism who had been dosed with between 50 and 350 mcg of levothyroxine, and they compared them with 14 normal controls.
In 1984, a low TSH and high total T4 were considered insufficient information to determine thyroid status. Clinical assessment of signs and symptoms was essential to the art of thyroid medicine.
The TSH assay technology at the time was only sensitive to 1 mcU/L, and 10 was the normal upper limit, according to Desai. This imperfection in the assay is also why the TRH test was used to amplify TSH response.
In the graph below:
They found that 15 of the children (Group A) were “adequately” treated.
This assessment was not only based on their TSH value, but their TRH test (the body’s TSH and T4 response to a TRH hormone injection), Total T4, and TSH. The RT3 value added further insight. T3 was not considered in the diagnosis, unfortunately. This oversight becomes important later in the analysis.
The other 25 children (Group B) had some signs of overdose.
This assessment was not only based on a low TSH and a T4 that was higher than normal for their age, but also an unchanged TSH response to intravenous TRH. Yet their T3 levels, clinical signs and symptoms were inconclusive, so further study was warranted.
1. Reference ranges (means + SD/SE)
The ranges of the healthy controls are not shown above, but they were given in a table as the mean plus standard deviation (SD) and standard error (SE):
- Total T3 1.27 ng/mL (0.58 SD, 0.16 SE)
- Total T4 122.9 ng/mL (18.51 SD, 4.95 SE)
- Reverse T3 0.214 ng/mL (0.104 SD, 0.028 SE)
It is not easy to translate these into values in today’s reference ranges because the SD does not map onto the 95% reference interval, but the means are valuable. Unfortunately, no scatterplot graphs were given for healthy controls.
2. T3 was not inverse to RT3
Group B had higher levels than Group A, confirming what Nicod had found earlier, that RT3 rises in parallel with T3 on average.
Even in the case of healthy Group A, there is no clear inverse relationship between RT3 and T3. Therefore, neither group was showing the pattern seen in nonthyroidal illness syndrome (NTIS) that can, in extreme cases, lower T3 below normal range and raise RT3 above normal range, or in kidney failure, lower the T3 alone.
This is what distinguishes NTIS from overdose. In true overdose on T4 monotherapy, T3 does not fall as RT3 rises, but T3 remains high-normal or high together with high T4 and RT3 levels.
3. The RT3:T4 ratios compared
Like Burman and team, Desai and team also considered it valuable to calculate the RT3 and T4 hormone relationship, not just RT3 in relationship to T3. They compared the RT3:T4 ratio, RT3, Total T4 and Total T3 among the three groups of children:
In adequately treated patients who are not dosed with any T3 hormone, a significantly higher Total T4 than healthy controls is necessary to achieve anywhere close to the average Total T3 found in healthy controls (Ingbar et al, 1982).
The principle of “Less T3 per unit of T4” in LT4 monotherapy is seen in Free T3:T4 ratios, as shown in the review “Gullo: LT4 monotherapy and thyroid loss invert FT3 and FT4 per unit of TSH.”
Therefore, it is dubious whether all the children in Group A were “adequately treated.” Both their mean TT4 and mean TT3 were lower than healthy controls, and the majority of the TT3 levels were below the mean, due to some high outliers shown in the scatterplot.
Perhaps a few of the “adequately treated” patients had “inverted ratios” inconsistent with euthyroid status — a lower than average T3:T4 ratio alongside a higher than average RT3:T4 ratio (Ingbar et al, 1982). Unfortunately, Desai did not provide the T3:T4 ratio, which could have helped their team diagnose their patients.
The overtreated patients’ RT3:T4 ratio was 2x as high as the controls.
The elevated RT3 levels and RT3:T4 ratio in 23 of the 25 patients provided further evidence that in 92% (23) of the 25 children with low TSH, the dosage was in excess of their metabolic needs.
However, something was protecting them from excess T4.
4. Conversion to RT3 helped prevent elevated T3
In the right-hand panel of the graph Serum T3 was not significantly different in the majority of the overtreated children (Group B).
Only three children had T3 levels far above the majority.
The researchers puzzled over their lack of symptoms.
5. Why so few symptoms of hormone overdose?
The authors also reported that
“The lack of overt clinical hyperthyroidism among these 25 overtreated hypothyroid children with raised T4 concentrations was of interest.
Fifty percent had no symptoms or signs.”
Notice that they did not puzzle over their low TSH, but instead the paradox of their raised Total T4, concurrent with the lack of symptoms and signs.
I include their table below. It reveals that symptoms and signs were not clearly indicative of thyrotoxicosis (excess T3 and/or T4 signaling in tissues) in most of the overtreated children.
The authors explained further regarding the small subgroup with one or more signs of thyrotoxicosis:
“Four of the 25 overtreated children who had raised T3 and T4 concentrations were on high dose replacement treatment for more than two years.”
Among only those 4 children,
Their rT3 values varied from 0.6 – 2 ng/ml (0.92 – 3.07 nmol/l).
Two of them had irritability, and one had a short attention span.
Accelerated growth velocity was noted in one.
Two had a bone age deficit of 12-24 months and in the other two, bone age corresponded with the chronological age.”
Clearly, the team was confused by the mild to absent signs of thyrotoxicosis in these 4 patients.
This phenomenon was not well understood at the time, but Desai and team thought they had an explanation. Blind to the existence of D3 enzyme in 1982, they thought Reverse T3 (and T2) were to thank for the children’s protection.
6. Historical mistakes in understanding RT3
The title of Desai et al’s study is worth pondering:
“The importance of reverse triiodothyronine [RT3] in hypothyroid children on replacement treatment”
The authors correctly understood that RT3 testing was of value, and that something about the T4-RT3 conversion pathway was important.
However, they should have re-titled their article to include both RT3 and T3 measurement, because a major purpose of this pathway is to alter T3 concentrations in blood.
Something prevented thyrotoxicosis and normalized Total T3 in many of the T4-overdosed children:
“The physiological pathway for T4 degradation and metabolism, besides being important in thyroid hormone homeostasis, probably plays a protective role and prevents a raised concentration of T3“
They were right.
And then they said:
“It has recently been postulated that T4, although not devoid of calorigenic and biological effects, may behave more like a reservoir or prohormone for T3.
This may partly explain the absence of clinical hyperthyroidism in patients with very high T4 values.”
They understood that T4, as a hormone, only had limited effects before conversion to T3.
But Desai and team were also not quite right about the mechanisms surrounding RT3:
“The metabolic derivatives of rT3 — diiodothyronines, and in particular 3, 5-diiodothyronine — are potent inhibitors of T4 to T3 conversion.  rT3 itself can inhibit the calorigenic action of T4 and T3 in man.  It has been used to treat hyperthyroidism. It inhibits monodeiodination of T4 to T3, though it is not antagonistic to T4 in all its effects.”(Mistaken reasoning by Desai et al, 1984, citing 14. Ködding & Hesch, 1978; 15. Pittman et al, 1960; 16. Benua et al, 1959; 17. Chopra, 1977)
In 1984, the scientists that Desai and team were citing didn’t quite understand the mechanisms of thyroid hormone metabolism yet.
Desai’s team were dealing with patients whose RT3 was generated naturally from T4 hormone, but they grasped at studies of RT3 and 3’5′-T2 (diiodothyronine) dosing to explain what was going on.
Dosing synthetic RT3 is not the same as making one’s own RT3.
Many of the early studies injected supra-physiological doses of RT3 into rats or humans and then focused on the lowering of basal metabolic rate (BMR, calorigenic effects like body temperature and heart rate).
These were unnatural experiments involving combinations of T4, T3, and RT3 levels that do not occur in thyroid therapy or in autoimmune hyperthyroidism.
- Remember that Nicod and team found, above, in healthy humans, the reference range for Total T3 exceeds the reference range for RT3?
- And remember that Burman found mean T4:RT3 ratios of 150:1 and 120:1?
Therefore, an inversion of this ratio, dosing hundreds of times the value of RT3 than T4, is extremely unnatural.
For example, Pittman’s study in 1960 (Desai’s reference item 15) dosed 6 male patients with large doses of RT3 not found naturally in humans.
- One hypothyroid patient was on maintenance doses of T3 monotherapy at 100 mcg/day, and then 110 mg/day of RT3 (110,000 mcg of RT3) was added to his therapy. After 8 days, the addition of RT3 had reduced his metabolic rate from -12.0 to -24.3, putting him in a hypothyroid state.
- Another patient in Pittman’s 1960 study was on desiccated thyroid at 120 mg / day, and was dosed with 160 mg/day of RT3 (160,000 mcg/day), which made his MBR drop from -10.8 to -31.5 in only 6 days.
Therefore, RT3 was effective in causing hypothyroidism, but only at extreme, supraphysiological doses. (See: “RT3 inhibits T4-T3 conversion. How worried should we be?“)
No, we should not be worried about naturally-occurring levels of RT3.
And here’s why.
Later in the 1980s, some thyroid scientists understood a little more clearly. They realized three things:
- D2 enzyme was readily suppressed in overdose, but not because of RT3. It was because its far more abundant substrate, T4, largely inactivated it (St Germain et al, 1988),
- D1 enzyme is very resilient, and it requires “~100 fold” doses of RT3 or iopanoic acid to inhibit its function, compared to D2, (St Germain et al, 1988), and
- D1-suppressive RT3 mega-dosing is very different from the non-suppressive RT3 levels found in hyperthyroid patients:
“Whereas [an enzyme’s] inactivation by [its] substrate is the principal mechanism controlling 5DII [D2] activity,
it seems unlikely that this process influences 5DI [D1] activity under physiologic or even pathologic conditions;
the predominant effect of T4 on 5DI is one of activation,
and rT3 concentrations are probably insufficient to exert a significant inactivating effect.(St Germain, 1988)
Despite the mistaken theories in the 1960s through 1980s about how RT3 “inhibited” T4-T3 conversion, the scientists still observed and responsibly measured RT3, T4, T3, and thyroid symptoms and signs with the greatest accuracy they could.
We just can’t make the mistake of imagining that these older articles are always authorities on theorizing deiodinase functions.
They focused on D1, and to some degree, D2 enzyme, but most were still blind to the existence of D3 and its role in generating RT3 in hyperthyroidism and overtreatment. (Bianco et al, 2019)
Today in 2020, we’re looking back on this old literature. We’ve now benefited from genetic studies on rats bred without DIO3 genes, so we now know what D3 enzyme does (Hernandez et al, 2007). It’s now clear that “Deiodinase Type 3 plays the T3-blocking role,” but naturally occurring RT3 concentrations do not block T3.
7. D3 rendered many overdosed children metabolically euthyroid
It is now clear to any knowledgeable thyroid scientist what was happening to the overdosed children:
- Deiodinase type 2 (D2) enzyme was relatively inactivated by high T4 levels entering cells (Abdalla & Bianco, 2014),
- Their T3-upregulated D1 enzyme continued to convert T4 to T3 and RT3 to active T2 at a rate regulated by the level of T3 signaling in nuclear receptors (Maia et al, 2011)
- Any excess T3 signaling was upregulating Deiodinase type 3 (D3) enzyme (Barca-Mayo et al, 2011), and in thyrotoxic children, more of their T4 than normal was being converted to RT3.
Moreover, — and here’s the even more important part —
- Much of their excess T3 was simultaneously being converted to inactive 3,3-T2 (via D3) and active 3,5-T2 (via D1). (Chen et al, 2018; Bianco et al, 2019)
In this graph, you’ll see there are three types of T2. The 3′ and 5′ prefixes mean they have iodine located at positions 3 and 5 on one of the two rings of the molecule.
Two of the T2s are inactive (the ones with red arrows pointing to them). The active T2, 3,5-T2, is mildly functional in nuclear receptors, reduces TSH if dosed over 50 mcg, and feeds and co-regulates our mitochondria (Moreno et al, 2017).
Therefore, when D3 is upregulated in more and more cells in illness and overdose, the RT3:T4 ratio rises, half-life of T3 in blood shortens and the balance of T2 metabolites shifts. When the supply of T3 does not exceed the rate of its conversion to T2, the T3 concentration will fall. Circulating T3 and T4 continues to enter cells, but as more T4 is diverted down the RT3 pathway and T3 is broken apart by D3 before it reaches nuclear receptors, less T3 signaling occurs in cells.
8. T4 remained elevated in the overdosed children.
In Desai’s 25 LT4-overdosed children, why didn’t their T4 come down close to reference range as much as their T3 did? Here are three reasons:
- Total T4 supplies are immense compared to Total T3 even in health. In Desai’s study, healthy control children had T4 122.9 ng/mL and T3 1.27 ng/mL, a 96x larger supply of T4. (Even Free T4 overpowers Free T3 by a factor of about 3:1 in undosed people with healthy thyroid function)
- The children were (over)dosing T4 every day and replenishing its losses, but they were not dosing any T3 to replenish its losses. T3 was more vulnerable, unshielded by a T4-T3 converting thyroid gland, T3 therapy, or desiccated thyroid therapy.
- Their metabolic clearance rate of T3 was considerably sped up by D3 and D1 overactivity, and there’s less TT3 to get rid of compared to TT4. Our levels of T3 are the most vulnerable to D3 activity.
9. Desai’s patients were not “hyperthyroid.”
It’s more than just a verbal mistake to use the word “hyperthyroid” to T4-overdosed (or T3-overdosed) thyroidless patients.
The RT3, T4 and T3 concentrations in these three studies show why T4-treated patients without TSH receptor antibodies are unlike patients with endogenous Graves’ hyperthyroidism.
These two patient groups have very different T3, T4 and RT3 concentrations, even if their TSH is equally suppressed.
Even official endocrinology textbook definitions distinguish “hyperthyroidism” from “thyrotoxicosis” and distinguish them both from the TSH level (See “Thyrotoxicosis vs. Low TSH” )
In Graves’ disease, both T4 and T3 are continually being secreted by an overstimulated thyroid gland. Excess T3 upregulates the “T3-sensitive” genes of the enzymes D1 (Maia et al, 2011) and D3 (Barca-Mayo et al, 2011). RT3 at very high levels seen in hyperthyroidism might depress D1 function a little, but D3 function remains strong.
But without Graves’ disease, without a functional thyroid gland or TSH receptor antibodies, T3 levels can only come from D1 and D2 enzyme function outside their thyroid gland. The tissue that contains the most DIO1 and DIO2 mRNA expression is the thyroid gland. Therefore, the removal of their thyroid is not just a T4 and T3 synthesis handicap, but also a metabolic handicap. If they have genetic polymorphisms in DIO1 and/or DIO2, they will be further handicapped in their T3 supply even if overdosed on T4, as shown in the graph.
Conclusions from Desai’s study
In these children, excess RT3 was not high enough to play a role in reducing T4-T3 conversion, which Desai and team imagined.
- In Pittman’s 1960 study, even a huge dose of 1 mg (1,000 mcg) of RT3 only lowered an euthyroid person’s BMR from -12 to -13 after 7 days.
- A man taking 300 mcg of synthetic T4 had to be dosed on 80,000 mcg/day of RT3 for 6 days to lower his metabolic rate from -8.4 to -12.5.
Instead, the RT3 was a metabolic signal that D3-enzyme dominance was at work protecting many of them from excess T4-T3 conversion and from T3 signaling in cells.
RT3 was coincidental to the lack of thyrotoxicosis in many. The signs of thyrotoxicosis occurred in the few children whose D3 was not powerful enough to protect them from their T4 overdose. Indeed, “Deiodinase Type 3 plays the T3-blocking role.” The high-normal or mildly high Total T3 levels in many of the overtreated children likely rendered them metabolically euthyroid.
Therefore, it’s still very important to pay attention to signs and symptoms and T3 levels.
In fact, some children with low-normal T3 without any thyrotoxic symptoms could have been metabolically and clinically hypothyroid.
- Larisch et al. (2018) found in T4-dosed patients with Free T3 levels below mid-range, regardless of a concurrently low or suppressed TSH. (See also Hoermann et al, 2019)
But Desai and team did not think about investigating signs of tissue hypothyroidism.
One must also consider the circulating T3 levels are entering cells where Free T3 is converting to T2 at a faster rate due to D3 overactivity. Desai’s team studied Total T4 and Total T3 levels, unable to account for binding proteins.
Today, we have Free T4 and Free T3 tests, and doctors can cooperate with patients in assessing their symptoms of thyrotoxicosis and hypothyroidism.
Of course, overdose is always unwise. In any patient with grossly inflated Free T4 and over-range Free T3, it is unwise to constantly harass the deiodinases with the continual burden of both T4-RT3 and T3-T2 conversion. Illnesses can disrupt the delicate balance that may be maintaining euthyroid status.
Stop the Reverse T3 Madness.
A high-normal or even high RT3 is not always bad, since it may also be co-present with prevention of thyrotoxicosis, as it was in the case of many of Desai’s T4-overtreated children who were “asymptomatic.”
- RT3 can be a sign of metabolic mercy when FT3 is in the upper half of reference range and maintaining symptom-free status during T4 monotherapy, despite a low or suppressed TSH.
A low-normal RT3 makes no sense as a decontextualized treatment target, since a lack of this hormone does nothing to help a thyroidless hypothyroid or underdosed patient raise their T4-T3 conversion rate.
- Low RT3 is an empty gift box containing no bonus T3 inside it. Downregulating D3 does not necessarily upregulate D2 or D1 to an equal degree. These enzymes are independent.
Trying to “correct” a high-normal RT3 by lowering T4 and raising T3 may simply replace RT3 with an inactive T2 (“Reverse T2”). It may do nothing to treat a nonthyroidal illness that is powerfully upregulating D3 and downregulating D2 and D1 at the same time.
- The upregulation of D3 in illness is a more profound blocker of T4-T3 conversion and a stronger promoter of T3-T2 conversion than any amount of naturally-created RT3 will ever be.
The way out of the madness is to interpret RT3 in the context of FT3 and FT4, and signs and symptoms.
First, remember that Nicod and team found inverse RT3:T3 relationships only in illness:
- Untreated hypothyroidism and hyperthyroidism are cases in which there are “changes of serum rT3 and T3 in the same direction,”
- However, illness is a case in which one sees “changes of serum rT3 and T3 in [the] opposite direction.”
Yet there’s a challenge with this hormone relationship. The RT3:T3 ratio (T3:RT3 ratio) does not account for the amount of T4 in blood that is available to be converted to either of these hormones. It’s ungrounded. Un-anchored.
Both the T3 and the RT3 need to be anchored in the T4 level, the hormone of their origin, because T4 levels will change during illness and will vary from person to person in thyroid disease and therapy. As Nicod and team found, the severity of thyroid hormone catabolism in kidney disease is not revealed by RT3 because this hormone cannot rise high in renal failure. The chronic loss of T3, not the rise in RT3, is the deadly factor in kidney failure (Rhee et al, 2015).
Burman and team found the T4:RT3 ratio (basically the RT3:T4 ratio) to be relatively stable in health, just slightly different in those with a higher or lower T4 level.
Desai and team used the RT3:T4 ratio, not just the RT3 alone, as an indicator of T4 overdose.
As briefly explained by Ingbar et al in 1982, the RT3:T4 ratio, contrasted with the T3:T4 ratio, is a good differential diagnostic. Ingbar, Braverman and team saw the pattern you can see above:
- in illness, the RT3:T4 ratio rises while the T3:T4 ratio falls. (It’s also mildly inverse in LT4 overdose).
- in controls, untreated hypothyoridism and hyperthyroidism, as well as healthy treated LT4 patients, the RT3:T4 ratio rises or falls together with the T3:T4 ratio.
Finally, remember that overrelying on simple math may result in errors.
- RT3 concentrations, usually measured as a total hormone, not free.
- RT3 is dwarfed by Total T3 and especially by Total T4.
- Comparing RT3 with Free hormones, and when measuring RT3 in different units by a different assay technology (LCMS versus immunoassay), makes the hormone relationships shift and numeric ratio calculations will skew.
TIP: Converting their values to “percent of reference range” (or percent above/below range) helps minimize these mathematical biases. Comparing percentages enables one to see how elevated the RT3 is above the Free T4, and where the FT3 sits in relation to the FT4.
With these principles, one can maneuver RT3 testing into its most useful role: a diagnostic aid in adjusting thyroid medication to the individual patient’s metabolic handicaps and metabolic demands.
During therapy for thyroid disease, RT3 is not a target or an independent judge, but it does give useful metabolic information in context when solving an overall health puzzle or a thyroid therapy puzzle.
When wisely compared with the Free or Total T3:T4 ratio, the ratio of (Total) RT3 to its hormone of origin, Total T4, can effectively distinguish the presence of a nonthyroidal illness or a T4 overdose from the baseline metabolic function of the individual in health.
RT3 is not a simple indicator, but an insightful tool. It requires research, medical art and discernment, together with respectful patient-doctor collaboration, to understand what the RT3 level means and what, if anything, should be done, given a person’s thyroid gland status, treatment, and overall health.
- Tania S. Smith, Ph.D., Thyroid science analyst and President, Thyroid Patients Canada
Read more about Reverse T3
- “Deiodinase Type 3 plays the T3-blocking role.”
- “RT3 inhibits T4-T3 conversion. How worried should we be?”
- “What can prevent T3 from getting into thyroid receptors?“
- “The basics of thyroid hormone action, transport and conversion”
- “Think twice about cancelling patient-pay Reverse T3 tests“
- “Principles and Practical tips for Reverse T3, FT3, FT4“
- “Do you have a Reverse T3 problem?“
- “Deiodinase type 3 and Reverse T3“
- “Tissue RNA expression of DIO1, DIO2, and DIO3“