Question Pilo’s study: Iodine dosing biases T4:T3 secretion

This post continues my series that examines two ratios T4:T3 thyroid hormone secreted by “the” thyroid gland. The single origin of both these ratios is an article by Pilo et al published in 1990.   

A simple summary: In Pilo’s’ study, the huge doses of iodine these 14 people were given every day during the 8-day study could have compromised the amount and ratio of T3 and T4 they secreted from their thyroid glands. The ratio and level could have also shifted over the first few days of the study. These are not natural conditions for thyroid secretion. The findings of this study are suspect.

Another lesson — if you have a thyroid gland, you should be very careful about how much iodine you ingest. Even Jonklaas, 2014 strongly caution about supplementing with iodine in their guidelines for therapy in hypothyroidism.

IODINE MEGADOSES

The 14 people that Pilo et al recruited were dosed with “5 drops of Lugol’s solution twice daily for the entire duration of the experiment.”

According to Lugol’s website, each drop contains an equivalent 6.25mg of iodine, and 5 drops 2x per day is a dose of 62.5 mg, plus whatever iodine these people were getting from food or iodized salt.

The National Institute of Health’s (NIH) Iodine Fact Sheet says that the “tolerable upper intake levels for iodine” in adults are 1,100 mcg per day. That’s given in micrograms (written either as mcg or µg). Divide by 1000 to get 1.1 milligrams (mg).

How much does the math say the patients in Pilo’s study were ingesting? Divide 62.5 mg by 1.1 mg.

That’s > 56 times the upper limit of iodine every day during the study.  

CAN THIS MUCH IODINE AFFECT T3 & T4?

Yes, these are doses of iodine that can affect TSH, T3 and T4 levels and ratios.

Pilo’s study claimed that “None of the subjects was taking any drugs that could affect the metabolism of thyroid hormones, or their binding to carrier proteins, for at least 2 mo before the study,” but iodine affects mainly the production/secretion rate and potentially the ratio of thyroid hormones, and this statement only covered metabolism and the months before the study began.

The NIH says this: “High intakes of iodine can cause some of the same symptoms as iodine deficiency—including goiter, elevated TSH levels, and hypothyroidism—because excess iodine in susceptible individuals inhibits thyroid hormone synthesis and thereby increases TSH stimulation, which can produce goiter. Iodine-induced hyperthyroidism can also result from high iodine intakes, usually when iodine is administered to treat iodine deficiency.”

The thyroid’s response to iodine loading is known as the “Wolff-Chaikoff effect.” The body’s response differs depending on whether the dose is low, moderate, or high.

Dayan and Panicker (2009) further explain how iodine dosing influences TSH, T4 and T3 test results. They classified 15 days of 80 mg of oral iodine as “acute administration,” but any doses greater than 500 mcg/day can have an effect on test results, as shown in their Figure 5.4 on the right-hand side of the image I’ve provided.

Dayan and Panicker consider the T4 and T3 only “slightly decreased” because it is within reference range, but the percentage of decrease is relative to the baseline of iodine consumption in a given population. There was no control population with which to compare in this study.

(NOTE: I’ve reproduced figures for the purposes of review and criticism, within Canadian “fair dealing” copyright law)

IODINE LOADING OVER TIME

According to Nagataki (1972, 1990), during moderate dosing, T3 and T4 decrease abruptly and the ratio of thyroid hormone precursors MIT and DIT increase. A process of “adaptation” to large doses occurs over several days, reducing the rate of transport of iodine into the gland over time.

Nagataki says the first 30 hours show significant alterations in iodine uptake in gland vs plasma concentrations.

In Pilo’s study, blood samples were collected at many intervals over 192 hours (divided by 24 hours = 8 days).

Since iodine excess in Pilo’s study could have begun on hour 1 of day 1 and proceeded for 8 days, how did the iodine dosing change the thyroid’s secretion of T4 and T3 during the measurements taken 9 times during the first 24 hours and then every 12-24 hours thereafter for 8 days?

Changing secretion means changing thyroid hormone binding and clearance. Increasing or decreasing the T4 levels will increase or decrease its conversion to T3. It is well known that less T4 converts to T3 when T4 is high in reference (Bianco et al, 2002).

It should make any reasonable endocrinologist wonder what iodine dosing did to them after the baseline measurements revealed in Pilo’s study.

If Pilo et al’s 14 people had NOT been dosed with so much iodine, we might have arrived at a “magic ratio” that was quite different.

WHY DID PILO DOSE IODINE?

Prior studies by members of Pilo’s group and others also practiced iodine loading in similar studies using chromatography.

Chopra, 1976 explained why: It was because they used radioactive iodine to mark T3 and T4 molecules and measure them in blood draws.

The thyroid gland could easily re-use these radioactive iodine atoms within thyroid hormone synthesis as part of the normal process of iodine recycling in the human body.

Giving a patient more non-radioactive iodine was an attempt to minimize the thyroid gland from taking up once again the radioactive atoms of iodine: There would be relatively more non-radioactive iodine molecules in circulation than radioactive ones.

ARE WE THE ONLY ONES WHO NOTICED?

In all my reading of thyroid research literature, I have only seen ONE discussion of the practice of iodine dosing in Pilo’s paper.

Hoermann et al (2015) remarked this iodine dosing could have shifted the results for T3 and T4. They say this about the estimate that 20% of our daily T3 comes from the thyroid gland:

“The assumption of this proportion relies on a few reports only, prominently a study by Pilo et al. [3, 4]. Although this study was well designed, participants were given high doses of iodine (Lugol solution), which is known to act as a blocker of thyroid hormone secretion and deiodination. This might have led to an underestimation of the thyroid-derived hormone, casting doubt on the study’s physiological relevance.

Hoermann go on to add their contrasting data:

“Indeed, our data indicate a significantly greater direct contribution of T3 from the thyroidal pool and, more importantly, suggest that its loss in athyreotic patients may not be readily compensated owing to an impaired T3-homeostatic regulation.”

In other words, they found that patients without thyroid glands lacked more than 20% of their T3 supply, and they could not compensate for the loss of a thyroid’s T3 secretion by simply converting T4 medication into T3 hormone. They had a significant T3 handicap.

IN CONCLUSION

It is completely baffling given how many people have relied on the integrity of this single experiment to establish an average ratio of thyroidal secretion in “normal” people who are not dosed with 10 drops of Lugol’s iodine per day.

This article has been cited by 121 other research works since its publication. Those 121 articles have been cited, collectively, in over 5700 additional scientific publications.

On behalf of the millions of thyroid patients worldwide whose thyroid therapy’s T4:T3 ratio is justified by the results of this experiment by Pilo, we say this:

Stop continuing to cite this old article with such confidence in its findings. Use caution.

It’s time to perform a better experiment with less biased methods.

– Tania S. Smith and Linda Sanday

ACKNOWLEDGMENT: UK thyroid patient leader Linda Sanday collaborated with me on the ideas and research in this article and a few others coming in this series. She agreed to be acknowledged by name.

REFERENCES

Bianco, A. C., Salvatore, D., Gereben, B., Berry, M. J., & Larsen, P. R. (2002). Biochemistry, cellular and molecular biology, and physiological roles of the iodothyronine selenodeiodinases. Endocrine Reviews, 23(1), 38–89. https://doi.org/10.1210/edrv.23.1.0455

Dayan, C. M., & Panicker, V. (2009). Interpretation of Thyroid Function Tests and Their Relationship to Iodine Nutrition-Chapter 5:Changes in TSH, Free T4, and Free T3 Resulting from Iodine Deficiency and Iodine Excess. In Comprehensive Handbook of Iodine (pp. 47–54). Elsevier Inc.

Hoermann, R., Midgley, J. E. M., Larisch, R., & Dietrich, J. W. (2015). Integration of Peripheral and Glandular Regulation of Triiodothyronine Production by Thyrotropin in Untreated and Thyroxine-Treated Subjects. Hormone and Metabolic Research = Hormon- Und Stoffwechselforschung = Hormones Et Metabolisme, 47(9), 674–680. https://doi.org/10.1055/s-0034-1398616

Jonklaas, J., Bianco, A. C., Bauer, A. J., Burman, K. D., Cappola, A. R., Celi, F. S., … Sawka, A. M. (2014). Guidelines for the Treatment of Hypothyroidism: Prepared by the American Thyroid Association Task Force on Thyroid Hormone Replacement. Thyroid, 24(12), 1670–1751. https://doi.org/10.1089/thy.2014.0028

Lugol’s. (n.d.). Calculating Number of MG’s of Iodine per Drop of Lugol’s Solution. Retrieved April 7, 2019, from http://www.lugols.com/calculating.html

Nagataki, S., Uchimura, H., Masuyama, Y., Nakao, K., & Ito, K. (1972). Triiodothyronine and thyroxine in thyroid glands of euthyroid Japanese subjects. The Journal of Clinical Endocrinology and Metabolism, 35(1), 18–23. https://doi.org/10.1210/jcem-35-1-18

Nagataki, S. (1990). Iodine metabolism. Thyroid, 1(1), 55–57. Retrieved from https://www-liebertpub-com.ezproxy.lib.ucalgary.ca/doi/pdf/10.1089/thy.1990.1.25

National Institutes of Health. (n.d.). Iodine: Fact Sheet for Health Professionals. Retrieved April 7, 2019, from https://ods.od.nih.gov/factsheets/Iodine-HealthProfessional/

Pilo A, Iervasi G, Vitek F, Ferdeghini M, Cazzuola F, Bianchi R: Thyroidal and peripheral production of 3,5,3′-triiodothyronine in humans by multicompartmental analysis. Am J Physiol 1990; 258:E715–E726.