In 1981, Canadians argued T3 was the best test in thyroid therapy

Canadians can take pride in their historical defense of T3 testing in thyroid therapy. Our job defending the T3 test today is to remind people of what has changed since then in thyroid testing, and what is still the same.

In 1981, Min Min Wong and Robert Volpé, MD published an article in the Canadian Medical Association Journal arguing in support of T3 testing to monitor levothyroxine (LT4) therapy.

In fact, their argument was a direct answer to the direct question in their article’s title:

  • “What is the best test for monitoring levothyroxine therapy?”

Their answer was “T3.”

These were two Canadian doctors who hailed from the clinical investigation unit in the Department of Medicine, the Wellesley Hospital, Toronto; and the University of Toronto.

T3 testing confusion and misunderstanding has been with us for a very long time. Many clinicians still have not learned the facts, and our current 2012 American thyroid therapy guidelines remain TSH-T4-biased and T3-blinded.

Lately, some Canadian endocrinologists have been tempted to take the cue from American guidelines rather than think critically and scientifically about the various circumstances for thyroid testing.

The core misunderstandings are centered on the circumstances in which T3 testing is clinically meaningful in therapy versus the circumstances in which it is diagnostically irrelevant outside of it.

In this article, I engage in a fictional interview with Wong and Volpé across the decades. I unearth various insights from their review of research and clinical evidence. Their answers to my questions consist of quotations and paraphrases from their article.

I also provide response and commentary to explain some of their statements, and I bring the T3 testing debate up to date as of 2019.

In our dialogue, you will learn:

  • The high priority that clinicians in 1981 placed on T4 testing in the context of thyroid therapy.
  • The historical confusion between the Total T3 and the T3 Uptake test, and why a T3 uptake test was not very useful even then.
  • Why we cannot depend on T3 when screening for thyroid gland failure.
  • Enduring myths regarding the precision and reliability of T3 testing, despite research that has continued to dismiss the myths.
  • The unusual vulnerability and variability of T3 levels in thyroid patients, and why our T3 requires monitoring, not just TSH and T4.

TP.CA: How was thyroid therapy monitored in 1981?

Wong & Volpé: “Serum thyroxine (T4) levels, but not total serum triiodothyronine (T3) levels, are commonly determined to monitor therapy when levothyroxine is used for replacement (in hypothyroidism) or for goitre suppression.”

TP.CA: Dear doctors, I see that you were living in the days before the rise of the TSH test.  Measuring T4 levels is quite prominent, but the TSH is only brought up twice in your entire article in the context of its inverse relationship to T4.

You are also talking about Total T4 and Total T3 tests because your generation didn’t yet have access to Free T4 and Free T3 tests.

Another interesting fact is that you mention “goitre suppression” as an indication for levothyroxine (LT4) therapy. A goiter, or a swollen thyroid gland, is commonly found in people whose thyroid is under high TSH stimulation, either due to thyroid disease or iodine deficiency, or Graves’ disease antibody stimulation. As of 2016, a research review stated that “The use of levothyroxine (LT4) to reduce the volume of the goiter is still a controversial treatment for large goiters.” (Knobel, 2016)

TP.CA: Why did people in 1981 prefer the T4 test? 

Wong & Volpé: “There are two reasons for this apparent preference of T4 tests:

  1. They were developed first, and
  2. Many clinicians are unaware of the biologic importance of the total serum T3 level and of the availability and vagaries of methods of measuring it.”

TP.CA: I see. The testing technologies were available for T4 before they were available for T3. Your second reason is actually three things that clinicians are unaware of , which you’ll explain in due course.

TP.CA: Why were people in 1981 confused about the T3 test?

Wong & Volpé: “Indeed, there is still some confusion about the use of the term “T3”. In this paper we will be discussing the total serum T3 concentration.

Physicians who are used to ordering a “T3 test” have been led to expect, and have received the results of, a completely different procedure — the T3 resin uptake test.

This procedure does not measure the serum T3 concentration but, rather, is an indirect measure of the binding of thyroid hormones to plasma proteins. The T3 resin uptake test is not useful by itself; it is only useful in helping to calculate the free thyroxine index (by multiplying the serum T4 level by the T3 resin uptake).” 

TP.CA: I understand now that even the terminology of T3 testing was confusing back in the 1980s. This contributed to generate confusion about the T3 test’s value.

Perhaps some people generalized too far to dismiss Total T3 testing at a time when the limitations of the “T3 Resin Uptake” test were being critiqued in the literature.

Even in 2019 it is possible to get this older test done, a “T3 uptake test.” Some people today mistakenly think this test is about T3 being taken up into cells, when it’s not.

The T3U test is more about the uptake of hormones by carrier proteins like Thyroxine Binding Globulin (TBG) in bloodstream versus the amount of T4 or T3 that is “free” to enter cells.

You explain the use of the old-fashioned T3U test very well, as a way of estimating the Free T4 fraction (the FT4-index) from the Total T4. This was often necessary in the days while the Free T4 test was being developed; the FT4 test was not yet available at most laboratories.  The calculation yielded only an estimate or “FT4 index.”

The Free T4 test has now largely replaced the need for a T3U + TT4 test calculation.

We can also measure TBG levels directly, now, too — though that’s rarely done anymore unless doctors suspect a problem with binding levels during pregnancy or estrogen therapy, or to diagnose a genetic problem with hormone binding.

When dosing blood thinners like Heparin commonly used in hospitals, it changes T4 and T3 hormone binding — that’s a major reason why the Total T4 and Total T3 are often preferred as tests in hospitals (Medscape, n.d.).

Today, Free T4 and Free T3 are preferred in outpatient use, even according to the American Thyroid Association’s 2012 guidelines (Garber et al, 2012, p. 998-999).

TP.CA Why does T3 testing have drawbacks in certain situations?

Wong & Volpé: “Use of the total serum T3 level for diagnostic purposes has many disadvantages, including

  1. the fact that many ill patients with nonthyroidal disturbances have reduced levels and, conversely,
  2. patients with mild hypothyroidism have normal levels.”

TP.CA: I’d like to emphasize and elaborate. These are two situations that do NOT relate to monitoring “healthy” people on LT4 therapy whose T3 may be chronically below their body’s needs!

It is so obvious that you mean T3 has disadvantages when used in diagnostic testing for primary thyroid gland failure. In other words, screening for thyroid disease.

  1. 1. When a person is severely ill or has chronic diseases of the heart, liver or kidney, T3 levels can be lowered by the illness itself, as has been discovered in many decades of research on Low T3 syndrome / Nonthyroidal Illness Syndrome (NTIS). (Moura Neto & Zantut-Wittmann, 2016; Rhee et al, 2015; Van den Berghe, 2014, Song et al, 2018). However, low T3 can be chronic outside of the context of NTIS when it is induced and maintained by ineffective thyroid therapy.
  2. 2. When a person is mildly hypothyroid but is not yet on thyroid therapy, they often have normal T3 levels because the extra TSH stimulation will promote a higher rate of T3 synthesis by the thyroid gland as it becomes less capable of secreting T4 (Citterio et al, 2017). Outside of thyroid disease and therapy, the TSH also upregulates T4-T3 conversion as blood flows through functional thyroid gland tissue (Hoermann et al, 2018; Garber et al, 2012). This is the body’s way of maintaining T3 levels, which are far more crucial than T4 levels for health (Bianco et al, 2019). However, this flexible T3:T4 ratio and rate is a role that can never be replaced by a thyroid hormone pill.

Therefore, T3 testing will not diagnose thyroid gland failure because 1) the thyroid gland itself can be completely healthy in nonthyroidal illness, and 2) the thyroid has not yet failed enough to cause T3 loss and symptoms in mild hypothyroidism.

Both of these circumstances are very different from testing for the purpose of monitoring thyroid therapy.

In addition, Wong and Volpé, despite what you say about the poor diagnostic value of TT3 testing in illness, we now know that low T3 is still a strong prognostic indicator of risk of death in critical illness.

As of 2019, it is finally being acknowledged that chronic low T3 can be pathological in nature (Moura Neto & Zantut-Wittmann, 2016; Rhee et al, 2015; Van den Berghe, 2014, Song et al, 2018). Even though many people still believe low T3 to be protective in the early phases of critical illness, it can quickly become a metabolic handicap. Contemporary scholars argue that the body must be capable of eventually recovering from Low T3 by stimulating extra T3 and T4 secretion from the thyroid gland to support recovery of health. The failure of TSH to rise and stimulate a healthy thyroid can be deadly, but the fate of the thyroidless in NTIS has been insufficiently studied.

Wong and Volpe, I notice that despite these two shortcomings, you still maintain the “biological importance” of T3.

You ethically presume there’s a valid reason to be concerned with the health of people on thyroid therapy in regard to their lower T3 levels. 

TP.CA What was your biggest drawback in testing Total T3?

You mentioned “many disadvantages” of testing T3, but you only listed two so far.  What other disadvantages are there?

Wong & Volpé: “Moreover, measurement of the serum T3 level may not be as readily available as measurement of the serum T4 level.”

TP.CA: So you’re saying that not many laboratories had made available the Total T3 test yet, so doctors didn’t have access to it.

Yeah, I’d say that not having local access to a test is a disadvantage to using it! 

TP.CA: Why wasn’t T3 testing readily available yet?

Were there some incorrect beliefs and biases circulating against the T3 test?

Apparently there were, since you had to speak against them.

Wong & Volpé:  “Nevertheless, the currently available radioimmunoassays for serum T3 are just as precise, reproducible and dependable as those for serum T4, and the normal limits for the T3 concentration vary only slightly from technique to technique and from laboratory to laboratory. 

However, it may be the disadvantages cited that have made clinicians reluctant to use a T3 assay when it would be of real value–namely, in determining the appropriateness of given dosages of levothyroxine.” 

TP.CA: For so many decades, people knowledgeable about T3 testing have had to deal with unfounded attacks on the test’s precision and reliability.

You’d think that as of 2019, people would be listening to the international experts who test the standard T3 and T4 laboratory assays and have shown them BOTH to be EQUALLY precise and reliable for use in clinical and research settings!

The experts have stated as much in no less than four publications between 2010 and 2017 by the IFCC Working Group for Standardization of Thyroid Function Tests (Thienpont et al 2010; 2013; 2015; 2017).

These publications have pointed out that there is no question regarding the high level of precision and reliability of today’s Free T3 and Free T4 tests.

Enduring skepticism about the validity and reliability of T3 assays is evidence of an anti-T3 bias in medicine among those who do not specialize in thyroid therapy. It is unwarranted that only T3 has been singled out for these myths when the validity and reliability of the T3 test is equal to that of T4 in clinical practice and in research.

The only issue remaining in T3 and T4 testing is what you identified: “the normal limits for the T3 concentration vary only slightly from technique to technique and from laboratory to laboratory.”

In other words,

  • One laboratory may give a result of 1.7 nmol/L (1.2-2.8 nmol/L range via Roche Cobas assay system) and
  • Another laboratory may give a result of 1.6 nmol/L (0.92 to 2.76 range, perhaps using a different assay manufacturer, at Mount Sinai hospital)

This is an issue for both T4 and T3 test standardization among manufacturers, NOT an issue about the technological and clinical validity and usefulness of the T3 test within thyroid therapy. 

As for clinical utility, when a patient and doctor stick with the same laboratory from test to test, they can still get very precise and reliable results from T4 and T3 tests that help a doctor “in determining the appropriateness of given dosages of levothyroxine.” 

In 2019, international efforts on refining T3 and T4 tests now focus on reducing this “between-method variability” to establish more standardized, universal reference ranges across laboratories and assays (Spencer, 2017).

TP.CA What research convinced you that T3 was so biologically important?

Wong & Volpé: “T3 is a more potent hormone than T4 with possibly three to five times more metabolic activity.

Moreover, it has been estimated that at least 85% of the biologic effect of thyroid hormones is due to T3 (5-9).

Thyroxine may have some intrinsic metabolic activity of its own (10-11), but most of its activity occurs only after it has been converted to T3 (12-14). 

TP.CA: You are working with the studies of T3 and T4 hormone which had already revealed that thyroid hormone receptors in the cell nucleus had a 10-15% affinity to T4, compared to a 100% affinity to bind with T3.

As of 2019, we still have not found any genomic activity for T4 in these receptors located in the nucleus.

However, you had not yet learned to distinguish T3’s effect on the nuclear receptor from T4’s non-genomic effects on the cell wall receptors, which in no way is a substitute for T3 activity in receptors.

Also, you had yet to understand the synergy between T4 and T3 within the cell. For instance, there is an increased binding time for T3 in cell nuclear receptors when it is converted from T4 in Deiodinase type 2 expressing cells (Bianco et al, 2019). This effect can give the appearance of T4 activity.

TP.CA: What convinced you of thyroid patients’ vulnerability to T3 loss?

Wong & Volpé: In untreated euthyroid persons, approximately 70% of the T3 is derived from T4 that is converted peripherally to T3, while approximately 30% is secreted by the thyroid (15-19).  

In thyroxine-treated patients, in whom the thyroidal secretion of T3 is either low because of thyroid damage or suppressed because of the thyroxine therapy, we would expect the T3 to be derived almost exclusively from the extrathyroidal conversion of exogenous T4 to T3. Evidence for this process was first reported by Braverman and colleagues in 1970 and was later obtained in other studies.

Thus, when a patient is receiving thyroxine therapy the serum T3 level should be approximately 30% lower than expected for a given serum T4 level.

We conducted a study to determine whether these considerations would be borne out in practice. If we found that an inappropriate test was being used we would be able to avoid future misinterpretations of test results.”

TP.CA: Wow! You were actually interested in the extent of our T3 loss on LT4 monotherapy? How kind and caring of you!

How CANADIAN of you to care for the thyroid disabled, who are mostly women past childbearing age.

You cite a ratio of 70/30 for periperal T4-T3 conversion versus T3 from thyroidal secretion. As of 1981, many studies of thyroid hormone kinetics had already been performed. “Kinetics” studies estimated thyroid secretion rates for T4 and T3 and T4-T3 conversion rates by having people ingest radioactive-iodine-tagged thyroid hormone molecules and seeing how the body metabolized them. There were another 9 years of such studies before the most recent one by Pilo et al in 1990 gave a higher average of 80/20 ratio of peripheral vs. thyroidal T3.

Such studies were theoretical in nature, so you as scholars wanted to see the real effect on people’s T3 levels in blood.

TP.CA: I’ll summarize your investigation of 51 patients.

TP. CA: You studied 44 women and 7 men who had been on levothyroxine for at least 3 months, who had various causes of hypothyroidism. “From clinical assessments all were thought to be euthyroid.” — This meant they were euthyroid on the basis of expert medical assessment of symptoms and signs, not on the basis of TSH.

You classified them based on their daily dose of 0.1 mg (100 mcg), 0.15, 0.2 and 0.3 mg per day, and you found patients in each category with low T3 and high T3.

You found they were unlike people who were not on thyroid therapy.

Wong & Volpé: “the T4 levels did not appear to correlate with the total serum T3 levels.”

You were expecting to see that the T3 level lagged behind T4 by 30% in each patient, given the theory.

Instead, you found not only a lower T3 level but a high degree of variability among patients.

People with elevated T4 levels were nevertheless not in a thyrotoxic state because their T3 levels were significantly lower, and in some cases, T3 was below the reference range, arguing the need for a dose raise (or a change in thyroid therapy to a mode that includes T3 hormone).

In a few patients, you discovered the T3 level was higher than expected because some had partially functioning thyroid glands, and some had Graves’ disease antibodies overstimulating a thyroid remnant that was only partly neutralized by radioiodine therapy. A few had T3-secreting thyroid nodules. Therefore, T3 was diagnostic in revealing these anomalies that could have gone unnoticed without showing the unusual T3:T4 ratio.

TP.CA: What did you conclude?

Wong & Volpé: “If only the serum T4 level, the free T4 level or the free T4 index is used to monitor levothyroxine therapy, the clinician may be misled into thinking that the patient is being overtreated and may reduce the daily dose of levothyroxine to suboptimal levels. However, the finding of a normal total serum T3 level should make it evident that the dose of levothyroxine is indeed appropriate.

Measurement of the serum TSH level is helpful in determining when
enough thyroxine is being provided, since the TSH level will be correspondingly reduced. However, this procedure is not helpful in determining whether too much thyroxine is being prescribed.

Thus, the best test for the appropriateness of a given daily dose of levothyroxine is the total serum T3 level, not the T4 level.

When the T3 level is above normal, one should seriously consider the possibility of autonomous thyroid function and a resulting additive effect of the endogenous and exogenous thyroid hormone.

It is therefore our view that if routine assessment of thyroid function
in patients receiving levothyroxine replacement or suppressive therapy is to be carried out by physicians, determination of the total serum T3 level should be an essential part of it.”

TP.CA: In 2019, does our sensitive TSH assay improve monitoring?

No. It does not matter how sensitive our TSH assays are, they are still an assay of the TSH hormone, which has limited utility beyond screening.

This early finding and reasoning by Wong & Volpé has been confirmed by more sophisticated clinical studies as of 2019.

Hoermann et al aptly wrote this in 2016:

“TSH has gained a dominant but misguided role in interpreting thyroid function testing.”

“TSH has assumed a dominant and statistically independent role as the result of its exceptional sensitivity, compared to thyroid hormones, thus divorcing it from its physiological roots as an indirect controlling element. This, in turn, has fostered a widely held belief that its exceptional sensitivity in response translates into superior diagnostic performance, thereby making the additional consideration of thyroid hormones largely redundant.” 

Such a belief in TSH is misguided, according to Hoermann et al:

“While TSH alone can play a role as a sensitive screening test in asymptomatic subjects, it cannot also simultaneously assume the second role of a reliable diagnostic tool (gold standard) for defining true euthyroidism.”

“The clinical interpretation of TSH should therefore be appropriately scaled back. TSH reference intervals for euthyroidism are uncertainly defined. From a homeostatic perspective, all three parameters TSH, FT4, and FT3 must be viewed together.”  (Hoermann et al, 2016)

In other words, TSH’s role in monitoring thyroid therapy is weak while its role in screening thyroid failure prior to therapy remains strong.

The converse is true of T3 testing: its role in monitoring therapy is essential, and its role in screening for thyroid failure prior to therapy is unnecessary whenever the TSH is elevated and T4 is below reference.

These two uses of TSH, screening to discover thyroid gland failure vs. monitoring to determine euthyroidism, must be separated from each other to avoid misinterpretation of test results.

Lessons and applications for thyroid testing today

In the context of thyroid therapy, patients are especially vulnerable to chronic T3 hormone loss, and we must monitor T3 to remain vigilant.

Our recent thyroid scientific research has proven that there is a “TSH-T3 disconnect” in thyroid therapy. Scientists point to a less than individually optimal T3 level as a cause of unresolved hypothyroid symptoms, since the TSH and T4 are unable to defend adequate serum T3 concentrations as they do when a healthy thyroid gland is present. In the context of therapy, when T3 is optimal and the symptoms have been eliminated, the TSH will often be below reference range without any clinical signs or symptoms of thyrotoxicosis. (Larisch et al, 2018; Hoermann et al, 2019a, b; Ito et al, 2019)

As mentioned in this 1981 article, TSH largely reflects the inverse of the T4 level during levothyroxine monotherapy. This is a biological principle that remains constant in and out of therapy except in cases of central hypothyroidism (hypothalamus and pituitary compromise).

But in thyroid disease and therapy, the HPT axis and the thyroid hormone economy are fundamentally altered, and the therapist must prioritize the active thyroid hormone T3 over the prohormone T4, which converts at an unpredictable and individualized rate.

To the degree thyroid tissue is rendered inert or removed, the thyroid-stimulating hormone (TSH) has little to no regulatory or predictive role anymore.

TSH in LT4 therapy is utterly blind to a greatly reduced T3 level when T4 is above mid-reference. Therefore, TSH does not sensitively reflect the concurrent T3 level, which will be unique in each thyroid patient based on their particular degree and type of thyroid disease and their ability to convert T4 into T3.

In thyroid disease and therapy, the T3:T4 ratio in bloodstream bears no reliable relationship to the LT4 dose, the T4 level, or the TSH level.

Because these normal hormone relationships are broken, when T3 is normal or low and clinical assessment yields euthyroid or hypothyroid status, the patient is not thyrotoxic, regardless of what an elevated T4 and low TSH would say.

Clinicians cannot use any estimate, theory, or statistical “average” peripheral conversion rate versus thyroidal secretion rate to predict the T3 level in an individual from the T4 or the TSH in the context of thyroid disease and therapy.

Both in 1981 and in 2019, the T3 test provides valuable metabolic information for therapy adjustment that is not gathered by any other test.

The healthy HPT axis defends T3 levels and restores them when they are temporarily lost. Thyroid patients do not necessarily have access to this natural T3-defense mechanism.

Therefore, we must do everything possible to defend routine access to Free T3 testing in thyroid therapy.

REFERENCES

Citterio, C. E., Veluswamy, B., Morgan, S. J., Galton, V. A., Banga, J. P., Atkins, S., … Arvan, P. (2017). De novo triiodothyronine formation from thyrocytes activated by thyroid-stimulating hormone. The Journal of Biological Chemistry, 292(37), 15434–15444. https://doi.org/10.1074/jbc.M117.784447

Garber, J. R., Cobin, R. H., Gharib, H., Hennessey, J. V., Klein, I. L., Mechanick, J. I., … Woeber, K. A. (2012). Clinical practice guidelines for hypothyroidism in adults: Cosponsored by the American Association of Clinical Endocrinologists and the American Thyroid Association. Endocrine Practice, 18(6), 988–1028. https://doi.org/10.4158/EP12280.GL

Hoermann, R., Midgley, J. E. M., Larisch, R., & Dietrich, J. W. (2016). Relational Stability in the Expression of Normality, Variation, and Control of Thyroid Function. Frontiers in Endocrinology, 7. https://doi.org/10.3389/fendo.2016.00142

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Song, Y., Li, J., Bian, S., Qin, Z., Song, Y., Jin, J., … Huang, L. (2018). Association between Low Free Triiodothyronine Levels and Poor Prognosis in Patients with Acute ST-Elevation Myocardial Infarction [Research article]. https://doi.org/10.1155/2018/9803851

Spencer, C. A. (2017). Assay of Thyroid Hormones and Related Substances. In L. J. De Groot, G. Chrousos, K. Dungan, K. R. Feingold, A. Grossman, J. M. Hershman, … A. Vinik (Eds.), Endotext (Originally published 2000; Updated February 20, 2017). Retrieved from http://www.ncbi.nlm.nih.gov/books/NBK279113/

Thienpont, L. M., Faix, J. D., & Beastall, G. (2015). Standardization of Free T4 and Harmonization of TSH Measurements: A Request for Input from Endocrinologists and Other Physicians. European Thyroid Journal, 4(4), 271–272. https://doi.org/10.1159/000440614

Thienpont, L. M., Van Uytfanghe, K., Beastall, G., Faix, J. D., Ieiri, T., Miller, W. G., … IFCC Working Group on Standardization of Thyroid Function Tests. (2010). Report of the IFCC Working Group for Standardization of Thyroid Function Tests; part 2: Free thyroxine and free triiodothyronine. Clinical Chemistry, 56(6), 912–920. https://doi.org/10.1373/clinchem.2009.140194

Thienpont, L. M., Van Uytfanghe, K., De Grande, L. A. C., Reynders, D., Das, B., Faix, J. D., … IFCC Committee for Standardization of Thyroid Function Tests (C-STFT). (2017). Harmonization of Serum Thyroid-Stimulating Hormone Measurements Paves the Way for the Adoption of a More Uniform Reference Interval. Clinical Chemistry, 63(7), 1248–1260. https://doi.org/10.1373/clinchem.2016.269456

Thienpont, L. M., Van Uytfanghe, K., Poppe, K., & Velkeniers, B. (2013). Determination of free thyroid hormones. Best Practice & Research. Clinical Endocrinology & Metabolism, 27(5), 689–700. https://doi.org/10.1016/j.beem.2013.05.012

Van den Berghe, G. (2014). Non-thyroidal illness in the ICU: A syndrome with different faces. Thyroid: Official Journal of the American Thyroid Association, 24(10), 1456–1465. https://doi.org/10.1089/thy.2014.0201

Wong, M. M., & Volpé, R. (1981). What is the best test for monitoring levothyroxine therapy? Canadian Medical Association Journal, 124(9), 1181–1183. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1705308/

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Categories: Test quality control, Testing policy, Thyroid science history

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