Why Is It Important to test for Free T3 (FT3)?

In this article the thyroid specialist Dr Conway will explain why is it so important to test for free T3 (FT3).



Why is it so important to test for Free T3 (FT3)?

It always surprises me when patients email my clinic for an appointment and ask the question, “Do you test for Free T3?”.  The answer is “Yes I do. How else will I know how your thyroid is functioning?” Yet most people do not test, and consider it completely unnecessary. 

FT3 is the most essential thyroid hormone in the body.  It is the only active thyroid hormone (T4 is the precursor to this hormone), and indicates how well your thyroid, and therefore your body, is functioning. 

Research shows that low FT3 levels (even with high FT4 and an in-range TSH) correlate with more hypothyroid symptoms, poor health and poor outcomes in chronic disease.  And many patients suffer far lower rates of T4-T3 conversion than the ideal healthy norm. 

Higher-normal FT4 levels, common in T4-monotherapy, can result in significantly lower FT3 levels as the body  converts the FT4 into reverse T3 (RT3) which is the inactive form of T3. 

Blooods

In practice this means that where a patient is undergoing T4 monotherapy but experiencing hypothyroid symptoms, my initial treatment is often to reduce their levothyroxine and add in thyroid friendly supplements, as this pushes the conversion back from T4 -> RT3 into T4 -> T3.

There is no “perfect FT3” number for a single patient. The general target is in the upper half of reference and in practice I often see patients who feel great with a T3 of around 4, whereas others need 5+. 

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.

Fundamentally, if we don’t test for FT3, we will never know how well someone is converting and if additional T3 is needed.  This in fact may be exactly why the NHS doesn’t test for it, as we are unable to prescribe T3 or NDT within the NHS.

Below are some extracts from studies done around T3 and the thyroid:

  • Studies have found that 1/3 of their patients  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)

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

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

Written by Dr Georgina Conway, 7th May 2021

www.thethyroidclinic.co.uk

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