The two T4-T3 ratios that confine thyroid therapy

Here are the two most pervasive, limiting, and potentially harmful presumptions about T3:T4 hormone ratios in thyroid science today.  

Ratio #1: There is a perfect physiological T4:T3 ratio secreted from the healthy human thyroid gland, and it is approximately 15:1. (Various ratios are cited, most often from 13:1 to 16:1)

Ratio #2: In the human body, 20% of our T3 supply comes from the thyroid gland and 80% of T3 is converted from T4 outside the thyroid gland in peripheral tissues.

Ratio 1 about “the” thyroid gland’s T4/T3 secretion ratio feeds into Ratio 2 about “the” human body’s rate and ratio of T4-T3 conversion, because how much we convert partly depends on how much we secrete.

(I’m putting “the” in quotation marks because this is the way people often say it when citing these ratios as dogma.)

These ratios have been circulating for decades now as if they are absolute truths, like “the” law of gravity. But they actually are not.

They are cherry-picked factoids.

A “factoid,” according to Oxford Dictionaries, is  “an item of unreliable information that is reported and repeated so often that it becomes accepted as fact.”

“Cherry-picking” is a colloquial term that a Wikipedia page currently explains this way:

“Cherry picking, suppressing evidence, or the fallacy of incomplete evidence is the act of pointing to individual cases or data that seem to confirm a particular position while ignoring a significant portion of related cases or data that may contradict that position. It is a kind of fallacy of selective attention, the most common example of which is the confirmation bias. Cherry picking may be committed intentionally or unintentionally. This fallacy is a major problem in public debate.”

These cherry-picked ratios have risen to the status of unquestioned and decontextualized dogmas (factoids), and they are being used to support medical-ideological positions rather than to promote human health.

“The” secretion ratio of “the” healthy thyroid gland is the main justification attackers use for denigrating desiccated thyroid pharmaceuticals because they provide an “unphysiological” ratio closer to 4.2 to 1 rather than 14:1. It is also the justification for limiting combination therapy regimes to very small doses of synthetic T3 alongside very large doses of synthetic T4.

The 20% 80% ratio, on the other hand, is used to promote and justify levothyroxine monotherapy. (The secretion ratio would not be the right factoid to justify it, because standard T4 medication contains an “unphysiological” ratio of 100:0.) The 80-20 ratio emphasizes that “the” human body gets most of its T3 from converting T4. That’s supposed to reassure us that “the” human bodies without any thyroid tissue will be just fine operating at 80% of their total T3 production + conversion capacity.

SERIES GOALS

In this series of blog posts, I will ask these key questions only a small percentage of thyroid doctors seem to be asking:

1. To what degree is thyroid therapy today limited or hindered by these ratios? (I’ll examine some of the ways these ratios are used. What appear to be the motivations for invoking them? What are the effects of invoking them?)
2. How trustworthy are these ratios? What kind of evidence are they based on? (I’ll look into the main source of these ratios, a single research article from 1990 by Pilo and colleagues that studied 14 people with a wide range of ratios.)
3. What does other thyroid research say about these ratios? Is there really a single, static ratio of secretion and conversion in a state of thyroid gland health, or in thyroid therapy, which we should all aspire to? (I’ll bring some of this research into the series)
4. Which are the thyroid hormone ratios, levels and ranges that are most likely to matter the most to our health outcomes, according to research? (Again, I’ll cite research that discusses these.)

COUNTER-FACTS

I offer to you a fuller range of T4:T3 secretion and conversion ratios found in humans, from Wiersinga’s 1979 doctoral thesis, “The peripheral conversion of thyroxine (T4) into triiodothyronine (T3) and reverse triiodothyronine (rT3).” (1)

Anyone can read the thesis online. Go to page 5 in this thesis and you will see the diagram, which I also ethically reproduce on my blog within fair use copyright law for the purposes of critique and review.

As far as I’m aware, nobody since 1979 has updated this information and compiled it in a single article that includes T4, T3, RT3 and gives “ranges” as numbers, so I’m giving you the latest research results!

(HISTORICAL NOTE:  Don’t be too bothered by the date of 1979. It’s still just as true today. Have human bodies evolved a lot since then? It’s at least as as true as the methods were that discovered it. The methods used in the 1970s that Wiersinga relied on were virtually the same “gel chromatography” methods used by Pilo and his team 11 years later, in 1990, to yield his ratios that have been cemented into dogma. So we’re comparing apples to apples here, and Wiersinga and Pilo could be equally flawed or equally true, yet they each provide research results we can consider valid scientific “data.” The ratios people continue to quote over and over again still come from Pilo’s 1990 article, and going back 11 years is not that much farther.)

In Wiersinga’s diagram, he outlined that T3 secretion from a human thyroid gland ranges from 5.9 to 11.1 nmol/day, and T4 secretion approximately 116 nmol per day.

Interestingly, he doesn’t give a range for T4 secretion, but he does for everything else.

The T3 T4 ratio (expressed with T3 first) on his diagram ranges from 5.1 to 9.6% of total gland hormone production.

If you invert the T3:T4 and express it as a T4:T3 ratio (not counting, for now, the smaller amounts of RT3 secreted by the thyroid), you get a range from “19.6 to 1” to “10.41 to 1.”

Now let’s calculate his version of the 20% – 80% ratio. Keep in mind the math is not perfectly realistic because a min/max of a range can’t simply be added to another range’s min/max in biology. Secretion and conversion are two systems that are not merely additive but affect each other dynamically in the context of a large range of health and environmental factors.

Anyway, let’s see what the math says.

This diagram shows that peripheral conversion of T4 yields between 22 to 66 nmol of T3 per day.

It also states that the range of total T3 supply every day, from both secretion + conversion, is anywhere between 34 and 72 nmol/day.

Let’s say one person makes the minimum of 34 nmol/day, and that represents their 100% supply that day. They might not be secreting much in that state, so let’s guess they have the lowest end of the secretion range, which is 5.9 nmol/day. Then we divide 5.9 nmol by 34 nmol and we get 17.3% of T3 from gland secretion.

Let’s say they’re secreting a lot of hormone, but not converting their T4 very efficiently to T3. In that case, 11.1 nmol/day divided by 34 is 32.6% of their T3 coming from secretion, 67.4% from T4-T3 conversion.

If you do the same math on the upper end of the two ratios you get 5.9 / 72, which is a miniscule 8.2% T3 secretion rate, or 11.1 / 72, which is a 15.4% secretion rate.

Based on this diagram, we now have two secretion rates describing a range:

Between 10.41 to 1 and 19.6 to 1 (T4:T3)

We now have four T3 secretion / T3 conversion relationships across a wide range:

8.2% / 91.8% — 15.4% / 84.6% — 17.3% / 82.7% — 32.6% / 67.4%

The problem is, you can’t just average two ratios or four ratios and get a single ratio that’s perfectly “healthy.”

THERE IS NO PERFECT RATIO

Why not? Because the human body requires the thyroid hormone system to have a lot of flexibility to adapt to all sorts of stressors.

That’s why the laboratory reference range for Free T4 ranges widely, approximately between 10 pmol/L and 25 pmol/L (the range will depend on the testing technology and the lab’s population statistics based on random people who could be sick or healthy).

What factors are involved in your T3:T4 secretion ratio?

Whether you have a 100% functional gland or only a 20% functional gland, your secretion ratio will largely vary based on TSH stimulation.

Generally, the more TSH-receptor stimulation you have to your thyroid gland tissue, the more it ramps up T3 production compared to T4 production. This principle has been known since at least the 1970s. (2,3) New research calls it the “TSH-T3 shunt.” (4,5)

TSH stimulation creates a variable T3:T4 ratio even within the range of health. Variations in thyroidal T3 & T4 secretion ratios will occur as TSH varies from low to high within the reference range, to the degree that you have gland tissue that can respond.

Based on the same principle, thyroid secretion ratios shift based on TSH-receptor antibody stimulation if you have Graves’ disease antibodies in circulation. (6-8) Plus, some kinds of thyroid nodules can hypersecrete T3. (9)

As for conversion, flexibility is also the rule in health. Variations in T4-T3 conversion will occur as T4 rises (when less converts to T3) and T4 lowers (when more converts to T3) because of the interrelationships between the deiodinases, three enzymes that convert thyroid hormones throughout the body. (10,11)

As Abdalla and Bianco explain in their 2014 scientific article titled “Defending plasma T3 is a biological priority,” the thyroid hormone system is designed to protect T3. (12)

In some ways it’s similar to the way the human body needs to regulate blood sugar levels in the “goldilocks zone” — not too much and not too little.

Therefore, T3 level matters more than T3 ratio.

These two flexible systems (secretion and conversion), even in a state of perfect health, normally work together ensure that the body’s T3 levels are maintained exactly where they need to be within the individual’s “set point” for T3.

Here’s an important biological fact to keep in mind regarding ratios vs. levels: An individual’s homeostatic set point for thyroid hormone is about 50% the width of the healthy population-wide reference range. (13,14)

You can’t know whether the center of your optimal T3 range is 6 pmol/L or 5.1 pmol/L unless you test it during adulthood in perfect health without the influence of medication, to obtain a baseline. But your T3 levels will still vary within your individual healthy range.

Here’s basically how it works:

When the body needs more T3, it increases TSH, which then stimulates more T4 production and ramps up T3 production slightly more to give the body a swift T3 injection. Then, TSH will fall again if or when T4 rises too high. In the mean time, the body will put the breaks on T4-T3 conversion rates in blood and tissues to prevent excess T3. Later, if T4 falls a little too low for health because of a drop in TSH stimulation, the body will convert more of its T4 to T3 to maintain the T3 supply in the interim, but eventually the TSH will wake up when it’s needed once again to stimulate more T4 and the ratio of T3 production.

Notice that as TSH and T4 move up and down in response to each other, they do so in order to fine-tune the T3 level. Every healthy human being with a healthy thyroid and no interfering thyroid medication has a built-in system that optimizes their bloodstream T3.

This is why, if you average together a large population of healthy people’s Free T3, you get a result that hovers just above the mid-point of the T3 reference range, and it stays there no matter how low or high their TSH goes. You see this in the healthy control populations in studies of the HPT axis. (15-17)

Bottom line: The T3 level matters more to human health than the T3:T4 secretion ratio or the T4-T3 conversion rate.

In a state of health, without any artificial interference from thyroid hormone therapy, T3:T4 ratios will be and must be flexible, because T3 levels must be protected and carefully regulated and finely adjusted to fit the situation.

It’s like a family, in which the T3 is the child staying at home, while mom (T4) and dad (TSH) travel around gathering supplies to defend and protect their baby.

That’s what it means for the body to “defend” plasma T3, in other words, bloodstream levels of T3.

The Free T3 reference range is only about 3 pmol/L wide. That’s pretty small.

If the homeostatic set point of an individual is 50% as wide as the population’s range, that means that without the interference of thyroid disease or thyroid therapy, an individual’s healthy Free T3 levels will fluctuate over a range of 1.5 pmol/L. That’s pretty small.

Thyroid therapy has for too long focused on the variable that inversely amplifies T4 (the TSH) and the thyroid hormone that is the most abundant (T4).

As a result, thyroid therapy has underestimated the tiny yet essential battery that powers all our cells in every tissue and organ (T3). Why? because it comes in small quantities that are challenging to measure, especially when low.

It’s bio-logically logical to make optimal Free T3 the target of health because a healthy human body can and will naturally do everything it can to protect its T3 levels.

The human body never “targets” a static T4:T3 secretion ratio.

The human body never assumes a static T4-T3 conversion rate.

So why should thyroid therapy?

– Tania S. Smith

REFERENCES

1. Wiersinga, W. M. (1979). The peripheral conversion of thyroxine into triiodothyronine (T3) and reverse triiodothyronine (rT3) (PhD, University of Amsterdam). Retrieved from https://inis.iaea.org/collection/NCLCollectionStore/_Public/11/544/11544357.pdf

2. Kabadi, U. M., & Cech, R. (1997). Normal thyroxine and elevated thyrotropin concentrations: evolving hypothyroidism or persistent euthyroidism with reset thyrostat. Journal of Endocrinological Investigation, 20(6), 319–326. https://doi.org/10.1007/BF03350310

3. Laurberg, P. (1984). Mechanisms governing the relative proportions of thyroxine and 3,5,3’-triiodothyronine in thyroid secretion. Metabolism: Clinical and Experimental, 33(4), 379–392.

4. Dietrich, J. W., Midgley, J. E. M., Larisch, R., & Hoermann, R. (2015). Of rats and men: thyroid homeostasis in rodents and human beings. The Lancet Diabetes & Endocrinology, 3(12), 932–933. https://doi.org/10.1016/S2213-8587(15)00421-0

5. Berberich, J., Dietrich, J. W., Hoermann, R., & Müller, M. A. (2018). Mathematical Modeling of the Pituitary–Thyroid Feedback Loop: Role of a TSH-T3-Shunt and Sensitivity Analysis. Frontiers in Endocrinology, 9. https://doi.org/10.3389/fendo.2018.00091

6-9: These references supported text that was moved into a future post.

10. Too, H. C., Shibata, M., Yayota, M., & Iwasawa, A. (2017). Iodothyronine deiodinases: key enzymes behind the action of thyroid hormone. Reviews in Agricultural Science, 5(0), 45-55–55. https://doi.org/10.7831/ras.5.44-55

11. Werneck de Castro, J. P., Fonseca, T. L., Ueta, C. B., & McAninch, E. A. (2015). Differences in hypothalamic type 2 deiodinase ubiquitination explain localized sensitivity to thyroxine. Journal of Clinical Investigation, 125(2), 769–781. https://doi.org/10.1172/JCI77588

12. Abdalla, S. M., & Bianco, A. C. (2014). Defending plasma T3 is a biological priority. Clinical Endocrinology, 81(5), 633–641. https://doi.org/10.1111/cen.12538

13. Andersen, S., Bruun, N. H., Pedersen, K. M., & Laurberg, P. (2003). Biologic Variation is Important for Interpretation of Thyroid Function Tests. Thyroid, 13(11), 1069–1078. https://doi.org/10.1089/105072503770867237

14. Andersen, S., Pedersen, K. M., Bruun, N. H., & Laurberg, P. (2002). Narrow Individual Variations in Serum T4 and T3 in Normal Subjects: A Clue to the Understanding of Subclinical Thyroid Disease. The Journal of Clinical Endocrinology & Metabolism, 87(3), 1068–1072. https://doi.org/10.1210/jcem.87.3.8165

15. Gullo, D., Latina, A., Frasca, F., Squatrito, S., Belfiore, A., & Vigneri, R. (2017). Seasonal variations in TSH serum levels in athyreotic patients under L-thyroxine replacement monotherapy. Clinical Endocrinology, 87(2), 207–215. https://doi.org/10.1111/cen.13351

16. Gullo, D., Latina, A., Frasca, F., Le Moli, R., Pellegriti, G., & Vigneri, R. (2011). Levothyroxine Monotherapy Cannot Guarantee Euthyroidism in All Athyreotic Patients. PLoS ONE, 6(8). https://doi.org/10.1371/journal.pone.0022552

17. Hoermann, R., Midgley, J. E. M., Larisch, R., & Dietrich, J. W. (2017). Recent advances in thyroid hormone regulation: Toward a new paradigm for optimal diagnosis and treatment. Frontiers in Endocrinology, 8. https://doi.org/10.3389/fendo.2017.00364