How can truly hypothyroid patients be accurately diagnosed within the enlarged subclinical category?
My main concern with the new guidelines is for the health of patients who are truly hypothyroid despite TSH and T4 levels that place them within the now broader subclinical hypothyroidism category.
I believe “false-negatives” will genuinely suffer without appropriate therapy if they are over 30 and not pregnant. A person is a false negative when they are denied the diagnosis and therapy for overt hypothyroidism because they are miscategorized as subclinical.
The 21-item review by Feller et al, 2018 said quite explicitly in their “Limitations” section that because only 2 of the 21 studies focused on people with TSH higher than 10, the findings of their review “may not be generalizable to people with subclinical hypothyroidism and a [TSH] level higher than 10 mIU/L.” Therefore, why didn't the guidelines keep the TSH subclinical / clinical boundary at 10 mIU/L?
If the TSH-T4 paradigm contributed to overtreatment and ineffective therapy, and if this paradigm resulted in many false positives, then how is it helpful to expand the gray area created by this paradigm, use it to make the subclinical category even wider, and then forbid therapy within that category? This creates a larger gray area for false negatives.
I propose a better way forward: Acknowledge the flaws of the TSH-T4 diagnosis paradigm, and then take steps to improve thyroid diagnosis. Surely medicine wishes to prevent harm. Identify the genuinely hypothyroid patients in this category.
Research has shown that persons with low-normal Free T4 levels may be genuinely hypothyroid despite a TSH below 10 or 20. An individual’s homeostatic set-point for T3, T4 and TSH is ~50% the width of the population reference range (1-2). This means that a patient whose T4 or T3 set point is at the top of reference range will be genuinely hypothyroid near the bottom of range. A patient in this biochemical state can even suffer myxedema coma (3).
TSH suppression by non-thyroidal factors can misclassify a patient as subclinical despite being truly hypothyroid. A patient’s TSH secretion may be unable to rise appropriately because of TSH-lowering medications and substances (4); high cortisol (5); fasting, depression, or exhausting exercise (6); rexinoids (vitamin A) (7, 8); and/or nonthyroidal illness (9).
The Free T4 reference range may also misclassify SH patients who are truly hypothyroid. The range may be skewed too low by including blood samples of patients with T4-lowering medicines and health conditions. Both iodine deficiency and iodine excess can reduce T4, as well as any factor that reduces TSH stimulation of the thyroid.
But there are ways to improve diagnosis, starting with symptoms.
The symptoms of hypothyroidism are commonly dismissed by logical fallacies. The reasoning is that because the symptoms of hypothyroidism _can_ be caused by other health conditions, they _are_ caused by other health conditions, especially if the TSH and T4 levels persuade. But symptoms are the natural physiological effects of T3 hormone insufficiency, not the direct effects of TSH or T4. To say that all the classic hypothyroid symptoms are “nonspecific” to hypothyroidism leaves no symptoms that are specific to hypothyroidism.
The guidelines in Box 3 state that "there is no clear evidence on how to attribute symptoms to SCH reliably, even with severe symptoms" -- this is not true.
Clinical scoring guides may detect hypothyroidism when TSH and T4 alone would place people in an expanding gray area of uncertain diagnosis. In 2003, research confirmed the usefulness of a 1997 clinical score for hypothyroidism, (10) proving that patients’ clinical score, ankle reflex response, total cholesterol, and creatine kinase significantly correlated with T4 and T3 levels. (11) In 2011, a review of thyroid clinical scoring scales reaffirmed their continued relevance for diagnosis. (12) The research found that TSH did not strongly correlate with signs of “tissue hypothyroidism” throughout the body. Symptoms shouldn't have to agree with TSH. Research on the pituitary and hypothalamus has revealed TSH is a unique, local, organ-specific response that cannot speak for the rest of the body's T3 sufficiency. (13)
Here's another tool: A free, clinically tested computer application (SPINA-thyr) assesses thyroid gland function, pituitary dysfunction, and T4-T3 conversion efficiency based on advanced mathematical modelling of the HPT axis. (14-15) All it requires is a practitioner to input Free T3, Free T4 and TSH results, units and reference ranges. Including the Free T3 test result is a critical element. T3 is the most powerful, essential thyroid hormone. No mathematical model of the HPT axis can be complete without it. Triangulation between three test results yields more insight than two hormone levels that largely mirror each other.
Additional methods can rule out normal thyroid gland function among subclinical patients. In a person with a healthy thyroid gland, insulin resistance and obesity inflates Free T3 levels; this may distinguish them from hypothyroid patients with T3 lower in reference. (16) A simple ankle reflex test with a normal or fast response has a strong negative predictive value -- it can rule out hypothyroidism (7). Bring back the wrongly maligned “photomotogram.” (8)
Many relevant tests have been buried and forgotten by a medical paradigm that claimed TSH and T4 testing was enough – and this very paradigm led to the charge of "ineffective" overtreatment of healthy patients within the vague subclinical category.
As for the "ineffectiveness" of all "thyroid hormones" in therapy, in the 21 trials reviewed by Feller et al, false-positive patients may have vastly outnumbered those with true thyroid dysfunction. Would not the inclusion of false positives in trials bias the results against false negatives who were truly hypothyroid? Wouldn't the averages make it appear that levothyroxine monotherapy benefited few to none?
I hope subclinical hypothyroidism guidelines committees will take these points into consideration. You could prevent patients’ unnecessary suffering with “nonspecific” yet truly hypothyroid symptoms. You could prevent the misattribution of hypothyroidism to other diseases. You could prevent denial of effective T4 and/or T3 thyroid therapy to those who need it.
1. 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
2. Andersen, S., Bruun, N. H., Pedersen, K. M., & Laurberg, P. (2003). Biologic Variation is Important for Interpretation of Thyroid Function Tests. Thyroid, 13(11), 1069–1078. https://doi.org/10.1089/105072503770867237
3. Mallipedhi, A., Vali, H., & Okosieme, O. (2011). Myxedema coma in a patient with subclinical hypothyroidism. Thyroid: Official Journal of the American Thyroid Association, 21(1), 87–89. LINK: https://www.ncbi.nlm.nih.gov/pubmed/21058937
4. Haugen, B. R. (2009). Drugs that suppress TSH or cause central hypothyroidism. Best Practice & Research. Clinical Endocrinology & Metabolism, 23(6), 793–800. https://doi.org/10.1016/j.beem.2009.08.003
5. Samuels, M. H. (2000). Effects of variations in physiological cortisol levels on thyrotropin secretion in subjects with adrenal insufficiency: a clinical research center study. The Journal of Clinical Endocrinology and Metabolism, 85(4), 1388–1393. https://doi.org/10.1210/jcem.85.4.6540
6. 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
7. Sharma, V., Hays, W. R., Wood, W. M., Pugazhenthi, U., Germain, S., L, D., … Haugen, B. R. (2006). Effects of Rexinoids on Thyrotrope Function and the Hypothalamic-Pituitary-Thyroid Axis. Endocrinology, 147(3), 1438–1451. https://doi.org/10.1210/en.2005-0706
8. Farhangi, M. A., Keshavarz, S. A., Eshraghian, M., Ostadrahimi, A., & Saboor-Yaraghi, A. A. (2012). The effect of vitamin A supplementation on thyroid function in premenopausal women. Journal of the American College of Nutrition, 31(4), 268–274.
9. Roelfsema, F., & Veldhuis, J. D. (2013). Thyrotropin Secretion Patterns in Health and Disease. Endocrine Reviews, 34(5), 619–657. https://doi.org/10.1210/er.2012-1076
10. Zulewski, H., Müller, B., Exer, P., Miserez, A. R., & Staub, J. J. (1997). Estimation of tissue hypothyroidism by a new clinical score: evaluation of patients with various grades of hypothyroidism and controls. The Journal of Clinical Endocrinology and Metabolism, 82(3), 771–776. https://doi.org/10.1210/jcem.82.3.3810
11. Meier, C., Trittibach, P., Guglielmetti, M., Staub, J.-J., & Müller, B. (2003). Serum thyroid stimulating hormone in assessment of severity of tissue hypothyroidism in patients with overt primary thyroid failure: cross sectional survey. BMJ, 326(7384), 311–312. https://doi.org/10.1136/bmj.326.7384.311
12. Kalra, S., Khandelwal, S. K., & Goyal, A. (2011). Clinical scoring scales in thyroidology: A compendium. Indian Journal of Endocrinology and Metabolism, 15(Suppl2), S89–S94. https://doi.org/10.4103/2230-8210.83332
13. 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
14. Dietrich, J., Fischer, M., Jauch, J., Pantke, E., Gärtner, R., & Pickardt, C. (1999). SPINA-THYR: A novel systems theoretic approach to determine the secretion capacity of the thyroid gland. EFIM-2, 10(5 (Suppl 1)), S34.
15. 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
16. Ferrannini, E., Iervasi, G., Cobb, J., Ndreu, R., & Nannipieri, M. (2017). Insulin resistance and normal thyroid hormone levels: prospective study and metabolomic analysis. American Journal of Physiology-Endocrinology and Metabolism, 312(5), E429–E436. https://doi.org/10.1152/ajpendo.00464.2016
Competing interests: No competing interests