Why the Free T3 test matters so much

It is surprising that Free T3 is considered an unnecessary test since it is the most active, most essential thyroid hormone in the human body.

The research I outline in this post shows that Lower Free T3 levels in blood correlate with

• very poor health status both within and beyond “low T3 syndrome” — low T3 is not always caused by critical illness, but may coexist with chronic illness
• objectively-scored hypothyroid symptom complaints during thyroid therapy
• poorer outcomes in chronic diseases such as heart disease

Unfortunately, a patient’s Free T3 level cannot be inferred by their TSH. It could fall anywhere within or below reference while TSH and T4 are within reference.

Therefore, medicine’s current bias against Free T3 testing contradicts its importance in biology and is potentially very harmful, especially to patients on the standard thyroid therapy who are at risk of chronic lower T3.

Why is Free T3’s importance so controversial today?

If Free T3 levels are so significant to achieving true euthyroid status (thyroid hormone balance) in thyroid therapy, it would mean that at least 40 years of medical education and clinical practice based on the TSH and T4 paradigm have been blind to crucial evidence.

If this is true, a false medical ideology could have harmed millions of patients on T4-monotherapy, unnecessarily and unknowingly. The professionals who maintain guidelines will have a vested interest in maintaining a strong bias against T3’s role in hypothyroid therapy.

It would also mean that a huge empire built around TSH monotesting and the safety of T4 monotherapy could be starting to crumble, and many vested interests will want to protect this empire as long as they can.

The face of the controversy

A large body of research since 2011 confirms the importance of Free T3 testing and its corollary that TSH testing is not enough — too much research to cite here. (1-2)

Newer research takes a position that directly contradicts the standard guidelines’ dismissals of Free T3 testing in therapy. (3-4)

The American Thyroid Association, especially, continually attempts to minimize the “rare” patient that may truly require T3-inclusive therapies, and it overtly ridicules doctors who color outside the lines and doubt a normalized TSH to say it all. (For example, refs. 5-6)

The vehemence of controversy and the resistance to change should alert anyone that a fundamental paradigm shift is occurring. Some people are responding childishly by just putting their hands on their ears while yelling louder. Others have tried to attack the T3 paradigm with T3-T4 combination therapy studies that are designed to fail to show any benefit — on average, falling into the trap of Simpson’s paradox.

But merely stating dogma over and over and with increasing vehemence does not make it correct. It cannot disprove the research that shows something is going very wrong with treated hypothyroid patients’ lower Free T3 levels.

Ignoring the suffering of patients on L-T4 monotherapy when you have been given knowledge to resolve it is downright unethical. So let’s take a look at the current state of evidence.

What we’ve learned about Free T3 recently

Science has known for a long time that T3 is the most active and essential thyroid hormone. Only the “Free” portion of T3 can be transported into cells.

We no longer believe that thyroid hormone is passively diffused into cells. In fact, Free T3 is selectively preferred over Free T4 by some intracellular thyroid hormone transporters, and they differ in expression from tissue to tissue, organ to organ. Genetic defects in transporters can result in different levels of peripheral hypothyroidism in various organs and tissues. (7-9) This makes Free T3 levels in blood important for organs that require transport of Free T3 and cannot depend as much on serum Free T4.

Many studies show that maintaining upper-mid-range blood levels of Free T3 is essential for a symptom-free state of health both within and beyond thyroid therapy, (10-16).

Higher-normal Free T4 levels, which are common in T4-monotherapy, can result in significantly lower Free T3-T4 conversion beyond the bloodstream. (10, 17-19)

Such studies invalidate the blind faith in the truism that 80% of T4 converts to T3 beyond bloodstream. That estimate is based on healthy patients with normal thyroid hormone levels and normal T3:T4 ratios in serum. Many patients may suffer far lower rates of T4-T3 conversion than that ideal healthy norm.

Our thyroid patient community knows what research has confirmed: that symptomatic treated thyroid patients are often chronically low in Free T3 — we suffer in the lower half of reference range or lower — and that our symptoms often disappear when Free T3 is optimized in the upper half of reference. (11, 20)

As Hoermann et al showed in 2018 (11), within and below the TSH reference range, freedom from hypothyroid symptom complaints occurs at higher concentrations of Free T3.  Relief from symptoms occurs at different dosages of L-T4 in patients who have no thyroid gland. This pair of graphs shows the significant variation of biochemical response within the L-T4 treated population and the imprecision of TSH alone as a judge of effective therapy.

Figure 1 (from Hoermann et al, ref. 27): “Individual responses with shifted response curves between patients displaying varying [T4-T3] conversion rates (GD), and Free T3 concentrations.”

The data the graphs are based on is also published in Larisch et al’s 2018 study (11), which concluded that Free T3 levels associate strongly with symptom relief.

They also found that 1/3 of their patients (depicted with the red line in graphs above) were unable to achieve the symptom-relieving concentrations of Free T3 achieved by the other 2/3 of their colleagues, due to their poor T4-T3 conversion efficiency.

“an LT4 dose sufficient to maintain TSH within its reference range could not raise FT3 adequately in the majority of treated patients ….

Nor did it suffice to provide symptom relief to some patients, which could only be achieved after raising FT3 levels.

Even when escalating LT4 dose as a treatment strategy to suppress TSH levels below its reference range during early followup of the carcinoma patients, FT3 concentrations remained below the lower part of its reference range in one third of the presentations.” (11)

Why does this happen? Why isn’t giving T4 hormone producing enough T3 for these patients?

Under the altered HPT axis of thyroid therapy, a significant and abnormal TSH-T3 disjoint exists (22, 23) — in particular, the TSH that is locked in place by T4 dosing will no longer rise to signal the isolated chronic low T3 that “poor converters” of T4 hormone experience. (24)  In treated hypothyroidism, Free T3 levels simply do not behave normally in relation to TSH or Free T4.

It is a false analogy to compare TSH in healthy untreated patients with thyroid glands with TSH in treated patients without thyroid glands. The difference is more fundamental than loss of T4, it is a loss of the capacity to both secrete and convert T3 in some patients.

Sadly, there is no “perfect Free T3” number for a single patient, just a general target in the upper half of reference. Research has proven that even healthy human beings with normal thyroid glands have a T3 set point that is approximately 50% narrower than the population-wide 95% reference interval. (21) This means that while a mid-reference Free T3 may be acceptable for one patient, another may require Free T3 nearer the top of the same laboratory reference range. Anderson et al (21) explain that for T3, T4 and TSH,

“a test result within the laboratory reference range does not necessarily indicate a normal thyroid function in the individual. No mathematical trick may overcome this problem because an impractically large number of tests are required to determine the individual set-point.” (21)

Therefore, discerning the current location of Free T3 results within the reference range, (targeting higher Free T3) and assessing the FT3 result in relation to patient symptoms, is the best clinical approach to adjusting thyroid therapy to the individual patient.

There is no way any patient’s Free T3 can be predicted based on either TSH or T4, given the variation in T4-T3 conversion. This makes Free T3, together with clinical signs and symptoms, a crucial test for monitoring dosage and therapy.

End the suffering and stop costly illness

Chronic Low Free T3, despite higher-normal Free T4, is a cruel and unnecessary form of medical torture that can last the rest of our lives on therapy, a suffering that can worsen other serious and costly diseases.

As for costly diseases, consider heart failure. Recent studies show:

• A high Free T4 alone is strongly associated with atrial fibrillation, while an isolated lower T3 is associated with a significantly higher risk for adverse cardiac events. (25) Meanwhile, against dogma, high T3 and low TSH were not associated with risk. The study gains value because it included some Levothyroxine-treated patients whose data contributed to these risk associations.
• Levothyroxine monotherapy alone is associated with a much higher risk of early death and morbidity in heart failure (26)

References

1. Hoermann, R., Midgley, J. E. M., Larisch, R., & Dietrich, J. W. (2013). Is pituitary TSH an adequate measure of thyroid hormone-controlled homoeostasis during thyroxine treatment? European Journal of Endocrinology, 168(2), 271–280. https://doi.org/10.1530/EJE-12-0819

2. Dietrich, J. W., Landgrafe, G., & Fotiadou, E. H. (2012). TSH and Thyrotropic Agonists: Key Actors in Thyroid Homeostasis. Journal of Thyroid Research, 2012. https://doi.org/10.1155/2012/351864

3. 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

4. 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

5. Leung, A. M. (2018). Symptoms Strongly Drive the Consideration of Alternative Thyroid Hormone–Replacement Options in Patients with Hypothyroidism. Clinical Thyroidology, 30(11), 523–525. https://doi.org/10.1089/ct.2018;30.523-525

6. Jonklaas, J., Tefera, E., & Shara, N. (2018). Physician Choice of Hypothyroidism Therapy: Influence of Patient Characteristics. Thyroid, 28(11), 1416–1424. https://doi.org/10.1089/thy.2018.0325

7. Mayerl, S., Schmidt, M., Doycheva, D., Darras, V. M., Hüttner, S. S., Boelen, A., … von Maltzahn, J. (2018). Thyroid Hormone Transporters MCT8 and OATP1C1 Control Skeletal Muscle Regeneration. Stem Cell Reports, 10(6), 1959–1974. https://doi.org/10.1016/j.stemcr.2018.03.021

8. Carlé, A., Faber, J., Steffensen, R., Laurberg, P., & Nygaard, B. (2017). Hypothyroid Patients Encoding Combined MCT10 and DIO2 Gene Polymorphisms May Prefer L-T3 + L-T4 Combination Treatment – Data Using a Blind, Randomized, Clinical Study. European Thyroid Journal, 6(3), 143–151. https://doi.org/10.1159/000469709

9. Strømme, P., Groeneweg, S., Lima de Souza, E. C., Zevenbergen, C., Torgersbråten, A., Holmgren, A., … Visser, T. J. (2018). Mutated Thyroid Hormone Transporter OATP1C1 Associates with Severe Brain Hypometabolism and Juvenile Neurodegeneration. Thyroid, 28(11), 1406–1415. https://doi.org/10.1089/thy.2018.0595

10. 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

11. Larisch, R., Midgley, J. E. M., Dietrich, J. W., & Hoermann, R. (2018). Symptomatic Relief is Related to Serum Free Triiodothyronine Concentrations during Follow-up in Levothyroxine-Treated Patients with Differentiated Thyroid Cancer. Experimental and Clinical Endocrinology & Diabetes, 126(09), 546–552. https://doi.org/10.1055/s-0043-125064

12. Wang, C.-Y., Yu, T.-Y., Shih, S.-R., Huang, K.-C., & Chang, T.-C. (2018). Low total and free triiodothyronine levels are associated with insulin resistance in non-diabetic individuals. Scientific Reports, 8. https://doi.org/10.1038/s41598-018-29087-1

13. Maldonado-Araque, C., Valdés, S., Lago-Sampedro, A., Lillo-Muñoz, J. A., Garcia-Fuentes, E., Perez-Valero, V., … Rojo-Martínez, G. (2018). Iron deficiency is associated with Hypothyroxinemia and Hypotriiodothyroninemia in the Spanish general adult population: Di@bet.es study. Scientific Reports, 8(1). https://doi.org/10.1038/s41598-018-24352-9

14. Bertoli, A., Valentini, A., Cianfarani, M. A., Gasbarra, E., Tarantino, U., & Federici, M. (2017). Low FT3: a possible marker of frailty in the elderly. Clinical Interventions in Aging, 12, 335–341. https://doi.org/10.2147/CIA.S125934

15. Ceresini, G., Marina, M., Lauretani, F., Maggio, M., Bandinelli, S., Ceda, G. P., & Ferrucci, L. (2016). Relationship Between Circulating Thyroid-Stimulating Hormone, Free Thyroxine, and Free Triiodothyronine Concentrations and 9-Year Mortality in Euthyroid Elderly Adults. Journal of the American Geriatrics Society, 64(3), 553–560. https://doi.org/10.1111/jgs.14029

16. Kishi, T. (2015). Free triiodothyronine, not thyroid stimulating hormone, should be focused on for risk stratification in acute decompensated heart failure. Journal of Cardiology, 66(3), 201–202. https://doi.org/10.1016/j.jjcc.2015.05.001

17. 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

18. Gereben, B., McAninch, E. A., Ribeiro, M. O., & Bianco, A. C. (2015). Scope and limitations of iodothyronine deiodinases in hypothyroidism. Nature Reviews. Endocrinology, 11(11), 642–652. https://doi.org/10.1038/nrendo.2015.155

19. Sjoberg, S., Eriksson, M., Werner, S., & Bjellerup, P. (2011). L-thyroxine treatment in primary hypothyroidism does not increase the content of free triiodothyronine in cerebrospinal fluid: A pilot study. Scandinavian Journal of Clinical and Laboratory Investigation, 71(1), 63.

20. Hirata, Y., Fukuoka, H., Iguchi, G., & Iwahashi, Y. (2015). Median-lower normal levels of serum thyroxine are associated with low triiodothyronine levels and body temperature in patients with central hypothyroidism. European Journal of Endocrinology, 173(2), 247–256. https://doi.org/10.1530/EJE-15-0130

21. 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

22. 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

23. 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

24. Midgley, J. E. M., Larisch, R., Dietrich, J. W., & Hoermann, R. (2015). Variation in the biochemical response to l-thyroxine therapy and relationship with peripheral thyroid hormone conversion efficiency. Endocrine Connections, 4(4), 196–205. https://doi.org/10.1530/EC-15-0056

25. Kannan, L., Shaw, P. A., Morley, M. P., Brandimarto, J., Fang, J. C., Sweitzer, N. K., … Cappola, A. R. (2018). Thyroid Dysfunction in Heart Failure and Cardiovascular Outcomes. Circulation. Heart Failure, 11(12), e005266. https://doi.org/10.1161/CIRCHEARTFAILURE.118.005266

26. Einfeldt, M. N., Olsen, A.-M. S., Kristensen, S. L., Khalid, U., Faber, J., Torp-Pedersen, C., … Selmer, C. (2018). Long-term Outcome in Heart Failure Patients Treated with Levothyroxine: An Observational Nationwide Cohort Study. The Journal of Clinical Endocrinology and Metabolism, 103(12). https://doi.org/10.1210/jc.2018-01604

27. Hoermann, R., Midgley, J. E. M., Larisch, R., & Dietrich, J. W. (2018). Lessons from Randomised Clinical Trials for Triiodothyronine Treatment of Hypothyroidism: Have They Achieved Their Objectives? Journal of Thyroid Research, Article ID 3239197. https://doi.org/10.1155/2018/3239197