Thyroid therapy paradigm shift: T3 hormone testing is a battleground.

The T3 paradigm shift in thyroid therapy is occurring at a time when Canadian health policy, driven by an old paradigm, is shutting down testing of Free T3.

It’s hard to see through the confusion because thyroid science is in the midst of this shift. Outdated beliefs rigidly hang on while new beliefs move forward.

Here’s the gist.

Blood levels of T3 exchange with all our tissues. Although some T4 becomes T3 and then T2 within tissues, a lot of that T3 crosses back into the bloodstream where it can be reused. There are fast exchanging tissues like blood vessels and liver that interact directly with T3 in blood and then there are slow exchanging tissues like bone and muscle.

Research has discovered that bloodstream levels of T3 are tightly controlled in health. Abdalla and Bianco’s 2014 article “Defending plasma T3 is a biological priority” illustrated this and called for a paradigm shift in the way we view T3.

T3 in blood is the main anchor in thyroid hormone health throughout the body.

In health, blood T3 is the target of many failsafe systems, the most important of which is the partnership between TSH and the living thyroid gland.

In a healthy population, the average blood T3 rarely moves beyond a narrow band in the middle of the population reference range, but each person’s T3 range is located differently within the population range. Some of us require more T3 than others.

When we lose thyroid gland tissue, we can no longer defend our body’s healthy FT3 level in bloodstream, as argued by Abdalla and Bianco. Conversion of T4 to T3 cannot compensate in all organs. Subtle shifts in T4 and T3 ratio and supply in blood can bias conversion beyond bloodstream.

Bianco, former president of the American Thyroid Association and coauthor of thyroid guidelines, has advanced the T3 paradigm. But he has not yet moved past trust in TSH during therapy.

Hoermann, Midgley, Dietrich and Larisch are moving forward with the T3 paradigm for people on T4 therapy, with about a dozen articles since 2012 showing that T3 level in blood should be a major target in thyroid therapy, and in this context, TSH cannot be trusted.

In the context of thyroid therapy and thyroid tissue loss, TSH- T4- T3 hormone relationships can change significantly.

In the context of thyroid therapy, we are now subject to poor T4-T3 conversion capacity as well as underdose, overdose, and … a medication-driven dysfunctional T4- dominant ratio that nature never induces in response to low T3 in blood.

In the context of thyroid therapy, TSH is no longer an accurate judge or regulator of blood levels of T3 because the pituitary assumes the living thyroid is still providing a variable ratio of T3 to T4 in response to TSH.

In the context of thyroid therapy, the pituitary gland is unable to raise TSH in response to lowered T3 in blood whenever T4 is sufficient — that’s biologically impossible. BUT medicine currently misunderstands this, thinking that pituitary TSH secretion would rise if the patient lacks T3.

No, the pituitary is not omniscient. It can’t sense if blood vessels, brain or kidney lack T3.

TSH will not rise to flag a T3 deficit located anywhere outside the tissues of the hypothalamus and pituitary gland.

The pituitary is biased by its local supply of T3. It converts T4 to T3 locally at a very different rate from all other tissues and glands.

Pituitary T3 is protected while blood T3 can fall dangerously low, causing a large percentage of the rest of the body to suffer. Organs and tissues will be hypofunctional to the degree that they can’t make up for the loss in blood T3 by converting T4-T3 locally like the pituitary gland can.

In the context of thyroid therapy, blood T3 must now be directly monitored and protected medically if we want to ensure blood carries enough T3 to the organs and tissues that depend largely on blood T3.

Dismissal of FT3 evidence and trust in TSH during thyroid therapy are uninformed institutionalized choices. They are the products of an outdated paradigm.

Health care policymakers have the power to choose.

• Tania S. Smith

REFERENCES

In two sections.

1. KEY ARTICLES BY BIANCO AND COLLEAGUES

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

Arrojo e Drigo, R., & Bianco, A. C. (2011). Type 2 deiodinase at the crossroads of thyroid hormone action. The International Journal of Biochemistry & Cell Biology, 43(10), 1432–1441. https://doi.org/10.1016/j.biocel.2011.05.016

Bianco, A. C., & da Conceição, R. R. (2018). The Deiodinase Trio and Thyroid Hormone Signaling. Methods in Molecular Biology (Clifton, N.J.), 1801, 67–83. https://doi.org/10.1007/978-1-4939-7902-8_8

Bianco, A. C., & Kim, B. S. (2018). Pathophysiological relevance of deiodinase polymorphism. Current Opinion in Endocrinology, Diabetes, and Obesity, 25(5), 341–346. https://doi.org/10.1097/MED.0000000000000428

Bianco Lab. (2016, January 13). The history and future of treatment of hypothyroidism. PMID: 26747302 [Video and audio Interview]. Retrieved August 3, 2018, from http://deiodinase.org/2016/01/13/mcaninch-hypothyroidism/

Casula, S., & Bianco, A. C. (2012). Thyroid Hormone Deiodinases and Cancer. Frontiers in Endocrinology, 3. https://doi.org/10.3389/fendo.2012.00074

Christoffolete, M. A., Ribeiro, R., Singru, P., Fekete, C., da Silva, W. S., Gordon, D. F., … Bianco, A. C. (2006). Atypical expression of type 2 iodothyronine deiodinase in thyrotrophs explains the thyroxine-mediated pituitary thyrotropin feedback mechanism. Endocrinology, 147(4), 1735–1743. https://doi.org/10.1210/en.2005-1300

Gereben, Balázs, 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

Gustafson, C. (2014). Antonio C. Bianco, MD, PhD: Is T4 Enough for Patients With Hypothyroid Dysfunction? Integrative Medicine, 13(3), 20.

Jo, S., Fonseca, T. L., Bocco, B. M. L. C., Fernandes, G. W., McAninch, E. A., Bolin, A. P., … Bianco, A. C. (2018). Type 2 deiodinase polymorphism causes ER stress and hypothyroidism in the brain. The Journal of Clinical Investigation. https://doi.org/10.1172/JCI123176

Kim, B. W., & Bianco, A. C. (2009). For some, L-thyroxine replacement might not be enough: a genetic rationale. The Journal of Clinical Endocrinology and Metabolism, 94(5), 1521–1523. https://doi.org/10.1210/jc.2009-0410

McAninch, E. A., & Bianco, A. C. (2014). Thyroid hormone signaling in energy homeostasis and energy metabolism. Annals of the New York Academy of Sciences, 1311, 77–87. https://doi.org/10.1111/nyas.12374

McAninch, E. A., & Bianco, A. C. (2016b). The history and future of treatment of hypothyroidism. Annals of Internal Medicine, 164(1), 50–56. https://doi.org/10.7326/M15-1799

McAninch, E. A., Rajan, K. B., Miller, C. H., & Bianco, A. C. (2018). Systemic Thyroid Hormone Status During Levothyroxine Therapy In Hypothyroidism: A Systematic Review and Meta-Analysis. The Journal of Clinical Endocrinology & Metabolism. https://doi.org/10.1210/jc.2018-01361

Mohácsik, P., Zeöld, A., Bianco, A. C., & Gereben, B. (2011b). Thyroid hormone and the neuroglia: both source and target. Journal of Thyroid Research, 2011, 215718. https://doi.org/10.4061/2011/215718

Peterson, S. J., McAninch, E. A., & Bianco, A. C. (2016). Is a Normal TSH Synonymous With “Euthyroidism” in Levothyroxine Monotherapy? The Journal of Clinical Endocrinology & Metabolism, 101(12), 4964–4973. https://doi.org/10.1210/jc.2016-2660

Peterson, Sarah J., Cappola, A. R., Castro, M. R., Dayan, C. M., Farwell, A. P., Hennessey, J. V., … Bianco, A. C. (2018). An Online Survey of Hypothyroid Patients Demonstrates Prominent Dissatisfaction. Thyroid, 28(6), 707–721.

2. SELECTED ARTICLES BY HOERMANN, MIDGLEY AND COLLEAGUES

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

Chatzitomaris, A., Hoermann, R., Midgley, J. E., Hering, S., Urban, A., Dietrich, B., … Dietrich, J. W. (2017). Thyroid Allostasis–Adaptive Responses of Thyrotropic Feedback Control to Conditions of Strain, Stress, and Developmental Programming. Frontiers in Endocrinology, 8. https://doi.org/10.3389/fendo.2017.00163

Dietrich, J. W., Landgrafe-Mende, G., Wiora, E., Chatzitomaris, A., Klein, H. H., Midgley, J. E. M., & Hoermann, R. (2016). Calculated Parameters of Thyroid Homeostasis: Emerging Tools for Differential Diagnosis and Clinical Research. Frontiers in Endocrinology, 7. https://doi.org/10.3389/fendo.2016.00057

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

Hoermann, Rudolf, Eckl, W., Hoermann, C., & Larisch, R. (2010b). Complex relationship between free thyroxine and TSH in the regulation of thyroid function. European Journal of Endocrinology, 162(6), 1123–1129. https://doi.org/10.1530/EJE-10-0106

Hoermann, Rudolf, Midgley, J. E. M., Dietrich, J. W., & Larisch, R. (2017). Dual control of pituitary thyroid stimulating hormone secretion by thyroxine and triiodothyronine in athyreotic patients. Therapeutic Advances in Endocrinology and Metabolism, 8(6), 83–95. https://doi.org/10.1177/2042018817716401

Hoermann, Rudolf, Midgley, J. E. M., Giacobino, A., Eckl, W. A., Wahl, H. G., Dietrich, J. W., & Larisch, R. (2014). Homeostatic equilibria between free thyroid hormones and pituitary thyrotropin are modulated by various influences including age, body mass index and treatment. Clinical Endocrinology, 81(6), 907–915. https://doi.org/10.1111/cen.12527

Hoermann, Rudolf, 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

Hoermann, Rudolf, 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

Hoermann, Rudolf, Midgley, J. E. M., Larisch, R., & Dietrich, J. W. (2017a). 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

Hoermann, Rudolf, Midgley, J. E. M., Larisch, R., & Dietrich, J. W. (2018a). 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

Hoermann, Rudolf, Midgley, J. E. M., Larisch, R., & Dietrich, J. W. (2018b). The role of functional thyroid capacity in pituitary thyroid feedback regulation. European Journal of Clinical Investigation, 48(10), e13003. https://doi.org/10.1111/eci.13003

Hoermann, Rudolf, Midgley, J. E. M., Larisch, R., & Dietrich, J. W. C. (2017b). Advances in applied homeostatic modelling of the relationship between thyrotropin and free thyroxine. PLoS ONE, 12(11), e0187232. https://doi.org/10.1371/journal.pone.0187232

Hoermann, Rudolf, Schumm-Draeger, P.-M., & Mann, K. (1993). Inhibition of Functional and Immunological Responses to Thyroid-Stimulating Antibodies from Patients with Graves’ Disease by Blockade of the Thyrotropin Receptor. Thyroid, 3(4), 273–278. https://doi.org/10.1089/thy.1993.3.273

Hoermann, Rudolf, & Suomen kilpirauhaspotilaat ry. (2018). Professor Hoermann responded to statements from Finnish endocrinologist. Retrieved from http://kilpirauhaspotilaat.fi/artikkeli/professor-hoermann-responded-to-statements-from-finnish-endocrinologist

Larisch, R., Giacobino, A., Eckl, W., Wahl, H.-G., Midgley, J. E. M., & Hoermann, R. (2015). Reference range for thyrotropin. Post hoc assessment. Nuklearmedizin. Nuclear Medicine, 54(3), 112–117. https://doi.org/10.3413/Nukmed-0671-14-06

Larisch, R., Midgley, J. E. M., Dietrich, J. W., & Hoermann, R. (2018a). 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

Midgley, John E. M., Hoermann, R., Larisch, R., & Dietrich, J. W. (2013). Physiological states and functional relation between thyrotropin and free thyroxine in thyroid health and disease: in vivo and in silico data suggest a hierarchical model. Journal of Clinical Pathology, 66(4), 335–342. https://doi.org/10.1136/jclinpath-2012-201213

Midgley, John 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

Midgley, John E. M., Toft, A. D., Larisch, R., Dietrich, J. W., & Hoermann, R. (2019). Time for a reassessment of the treatment of hypothyroidism. BMC Endocrine Disorders, 19(1), 37. https://doi.org/10.1186/s12902-019-0365-4

Midgley, John Edward M. (2006). Thyroid hormone-uptake test: A concept based on false premises. Journal of Clinical Ligand Assay, 29(3), 146–151.

Rowe, M., Hoermann, R., & Warmingham, P. (2017, August 27). The Diagnosis and Treatment of Hypothyroidism: A Patient’s Perspective. Retrieved from http://www.thyroiduk.org.uk/tuk/research/TUK-advisors.html