The American Thyroid Association prolongs the suffering of patients with autoimmune thyroid damage whose TSH has not yet risen to >10 mIU/L or their Free T4 has not yet fallen below reference. (1, 2)
As I will outline in this post, medicine’s inability to distinguish “subclinical hypothyroidism” from true hypothyroidism stems from the misguided policy of dismissing Free T3 testing in hypothyroidism and overreliance on the TSH test.
Part of the problem is that medicine is handicapped by the incorrect assumption that any level of Free T3 that falls within the statistical reference range is acceptable to the individual human body.
The inclusion of Free T3 in diagnosis can solve this problem.
Even when Free T3 levels fall within statistical reference, the Free T3 level in relation to Free T4 and TSH is able to signal the point at which “functional thyroid capacity” has fallen below the threshold past which it can no longer maintain healthy Free T3 concentrations.
This is the conclusion of a 2018 study of untreated autoimmune thyroid patients compared with healthy controls in the subclinical TSH range. (3)
Hoermann, R., Midgley, J. E. M., Larisch, R., & Dietrich, J. W. (2018). 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
THE SCOPE OF THE PROBLEM
In Hashimoto’s thyroiditis, the TSH rise is not sudden or extreme. The TSH may not rise over 10 until after the thyroid gland has mostly fibrosed. This can sometimes take years or even decades.
In the early stages of Hashimoto’s a patient may have no symptoms because T3 levels are being kept afloat by the remnant of their thyroid that still functions under TSH overstimulation.
But when Hashimoto’s patients’ Free T3 levels drop too far below their body’s unique requirements, whether that means top of reference range or mid-reference range, they can experience deep and intense suffering for a very long time before treatment.
Thyroid Peroxidase (TPO) antibody status is sometimes used in addition to TSH and Free T4 to determine whether a person is at risk of autoimmune thyroid destruction from Hashimoto’s thyroiditis.
However, in Hashimoto’s, the TSH does not fluctuate with its characteristic antibodies. The presence or level of TPO antibodies cannot tell you just how dead the thyroid gland is at any point in its destruction.
WHAT FREE T3 CAN REVEAL
We have known since 2003 that it is not high TSH, nor Free T4, but low Free T3 that causes the clinical signs symptoms of hypothyroidism. (6)
In people with healthy thyroid glands, the TSH can temporarily rise above reference range when a patient is recovering from low T3 syndrome during illness; this is the body’s natural way of restoring T3 supply. (4)
In advanced age, an aging yet functioning thyroid gland may maintain thyroid hormone supply under continually higher levels of TSH stimulation. (5)
In both of the above circumstances, Free T3 levels rise higher than they do in persons with autoimmune thyroid gland failure prior to therapy.
Free T3 is the common denominator of hypothyroidism regardless of the cause: whether from thyroidectomy after cancer, or post-thyroid ablation in Graves’ disease, or from Atrophic Thyroiditis or Hashimoto’s.
This is true not only before therapy is initiated, but during treatment (7) — Free T3 is correlated with both objective and subjective signs of true hypothyroidism, while FT4 and TSH are not.
The use of TSH testing has led to the dismissal of thyroid patients’ symptoms because it is not capable of correlation with patients’ symptoms.
In contrast, Free T3 levels strongly correlate with patients’ level of suffering from hypothyroid symptoms and can validate a symptomatic presentation in the doctor’s office.
Therefore, definitions of hypothyroidism that rely on TSH and FT4 alone are false. They are secondary markers and cannot determine the degree to which someone is hypothyroid.
It is unreasonable to include Free T3 testing in the diagnosis of HYPERthyroidism and to exclude it from the opposite syndrome, HYPOthyroidism.
Just as Graves’ HYPERthyroidism may present with elevated Free T3 without elevation of T4, so too autoimmune HYPOthyroidism can present with a distorted Free T3:T4 ratio and levels that provide enough information to diagnose loss of “functional thyroid gland capacity.” (3)
HOW TO DIAGNOSE REDUCED THYROID CAPACITY
When only the TSH is outside of reference range, it requires careful medical training and discernment to notice when Free T3 and Free T4 results reveal a loss of thyroid gland capacity.
However, it is simple to diagnose true hypothyroidism in the subclinical TSH range by inputting Free T3, Free T4 and TSH into free open-source software, the SPINA-GT. (8)
“SPINA-GT,” also titled “SPINA-Thyr,” has been in development since the late 1990s. It takes common laboratory test values and performs calculations that account for potential interfering factors such as thyroid hormone binding and clearance. It has been validated to correlate with a wide variety of clinical diagnoses of thyroid disease. (9)
Anyone, even thyroid patients, can download and use SPINA-Thyr software.
SPINA software is useful not only to interpret the degree to which an untreated patient is suffering hypoT3ism despite a Free T3 level within reference, both before therapy and within T4 monotherapy. (It cannot account for the effects of T3 dosing in T3-based therapies.)
SPINA also reveals whether the TSH response to thyroid hormone levels is dysfunctional within T4 monotherapy. Twhich can occur revealing a problem with T4-T3 conversion, latent hypothalamus-pituitary dysfunction yielding a lower TSH than appropriate, or resistance to thyroid hormone (RTH) within the pituitary gland.
As shown in the image above, this patient’s Free T3 is within range at 7 pmol/L (3.5 – 6.6) and so is their Free T4 at 12 pmol/L (10 – 25). Only their TSH is mildly elevated to 7 mIU/L (0.3 – 4.5).
This patient would be declared “subclinically hypothyroid” and many endocrinologists would deny this patient any medical therapy for their thyroid hormone levels, but their SPINA-Thyr tells another story of significantly reduced thyroid gland function.
When you input the three parameters and deselect the condition of T4 therapy, SPINA gives four additional results useful for diagnosis, explained briefly in their article. (3)
1. GT: Functional thyroid capacity
First, the GT is the estimated functional thyroid capacity. This patient has a GT at 1.27 pmol/s. In autoimmune thyroid patients, the GT is more sensitive to thyroid dysfunction than the ultrasound calculation of thyroid volume. In Hashimoto’s thyroiditis, the thyroid may or may not shrink or expand, while fibrosis and scarring will reduce the thyroid gland’s ability to respond to TSH stimulation and therefore GT will be significantly lower.
The star after 1.27* in the SPINA-Thyr software reveals that GT is below reference. This person has autoimmune thyroid destruction causing reduced secretion.
In technical terms, the GT is the “calculated standardised estimate of the maximum possible T4 production per unit TSH. It is defined as the amount of T4 released per unit of time (pmol/s) at maximum glandular TSH stimulation.” (3)
2. TSH index
Secondly, the SPINA-Thyr program reveals that the TSHI, or TSH Index, is at 3.6 pmol/s (reference 1.3-4.1). This number tells you that the pituitary gland is behaving normally within functional parameters. The TSH is not being reduced by pituitary disorder.
3. TSHI thyrotroph thyroid hormone resistance index
In technical terms, the TSHI “estimates maximum pituitary TSH reserve by extrapolating the amount of TSH feedback inhibition for a measured FT4 concentration.” (3)
The third result from SPINA-Thyr is the TTSI, the “thyrotroph thyroid hormone resistance index” — this can help diagnose resistance to thyroid hormone (RTH) caused by reduced sensitivity of thyroid hormone receptors within the thyroid gland. When TTSH is significantly elevated (reference 100-150), a patient may have RTH (or, alternatively, they may have TSH levels falsely inflated by TSH-Receptor blocking antibodies).
This patient, with a TTSI of 336*, has an elevated TTSI, but it is mild resistance to thyroid hormone in the pituitary gland, compared to the elevated number found in more extreme and definitive cases.
Therefore, this person likely has a biological requirement for higher Free T3 levels than the mean level found in healthy controls, at least when judged by the thyroid hormone receptors in the pituitary gland alone.
The GT, TSHI, and TTSI do not rely on Free T3, but the researchers found that they correlate with the patients’ autoimmune thyroid disease diagnosis.
4. GD global deiodinase efficiency
A fourth variable provides even more insight, the “global deiodinase” (GD) factor. The software takes the Free T3 and Free T4 ratio and employs sensitive mathematical calculations.
It is well known that in subclinical hypothyroidism, increased secretion of T3 as well as increased conversion of T4 to T3 often maintains Free T3 levels to prevent the appearance of hypothyroid symptoms. However, when thyroid capacity drops too low, the thyroid can no longer maintain healthy Free T3 levels.
The Free T3:T4 ratio is the basis of this refined calculation by SPINA-GD. In technical terms, “SPINA‐GD (GD) estimates the maximum global activity of peripheral step‐up deiodinases per unit of time (nmol/s) from equilibrium levels of FT3, FT4 and constants for plasma protein binding, distribution and elimination.” (3)
This patient has a GD of 27.74 nmol/s (ref 20.0 – 40.0). The sGD shows you how far away from the mean level this result is, -0.45 standard deviation.
This means that their T4-T3 hormone conversion is within the normal range, but is significantly below the mean level found in patients with healthy thyroid glands.
The researchers found that GD increased as thyroid gland capacity (GT) decreased, but there was a breaking point. “FT3 concentrations were maintained over a wide
capacity range, before beginning to fall at a GT threshold below 1.5 pmol/s.”
This patient’s GT is below 1.5. Their GD therefore reveals this fall in T3 production and conversion.
What is the clear result of this analysis?
It shows the patient has much less Free T3 than they need, even though their Free T3 is within reference range. They require thyroid hormone supplementation.
Because the GD can drop significiantly below 20.0 within T4 monotherapy, it is important to measure GD after therapy begins.
If GD drops further on therapy, it means this patient may not fare well with only the substitution of T4 hormone and may require T3 hormone included within therapy.
When all three parameters are included in diagnosis, Free T3, Free T4 and TSH, the SPINA-GT program could distinguish untreated autoimmune thyroid patients from healthy controls who merely had an elevated TSH.
The researchers explain that the scientific understanding of thyroid disease has evolved past the simplistic TSH-T4 relationship that defines the hypothalamus-pituitary-thyroid axis (HPT axis) in the untreated state.
We now understand that living thyroid gland tissue plays an essential role in maintaining Free T3 levels during health and during the early phases of autoimmune thyroid disease, before Free T3 levels fall and symptoms appear.
We also understand now that TSH secretion itself, as well as TSH receptor antibodies, play a key role in increasing and decreasing the pituitary gland’s TSH secretion.
In addition, the sensitivity of the pituitary gland’s thyroid hormone receptors, which can only be activated by the T3 hormone, varies from patient to patient.
Autoimmune thyroid disease causes the “breaking point” to occur when Free T3 drops below the level at which it should be given the patient’s Free T4 and TSH.
The breaking point is NOT when TSH rises above 10.
TSH is insensitive to the onset of true autoimmune hypothyroidism.
In technical terms, “Progressive loss of system stability [loss of living thyroid tissue] thus results in higher variability [of TSH], thereby considerably increasing the uncertainty of measured TSH values.” (3)
The authors’ further comments are also revealing of the importance of continued Free T3 measurement after treatment:
“Consequently, measurement of pituitary TSH is not merely a reflective mirror image of thyroid hormone status. The role of TSH is rather part of a dynamically adjustable controlling circuit. Treatment indication in subclinical hypothyroidism and LT4 dose finding may be highly misleading when guided by TSH measurements alone.”
“This includes monitoring disease progression in subclinical hypothyroidism, identifying conversion inefficiency in LT4‐treated patients who may potentially benefit from T3 addition, and differential diagnosis of pituitary disease, thyroid hormone resistance and
the nonthyroidal illness syndrome.”
(1) 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
(2) 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
(3) Hoermann, R., Midgley, J. E. M., Larisch, R., & Dietrich, J. W. (2018). 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
(4) Koulouri, O., Moran, C., Halsall, D., Chatterjee, K., & Gurnell, M. (2013). Pitfalls in the measurement and interpretation of thyroid function tests. Best Practice & Research. Clinical Endocrinology & Metabolism, 27(6), 745–762. https://doi.org/10.1016/j.beem.2013.10.003
(5) Jansen, S. W., Roelfsema, F., van der Spoel, E., Akintola, A. A., Postmus, I., Ballieux, B. E., … van Heemst, D. (2015). Familial Longevity Is Associated With Higher TSH Secretion and Strong TSH-fT3 Relationship. The Journal of Clinical Endocrinology and Metabolism, 100(10), 3806–3813. https://doi.org/10.1210/jc.2015-2624
(6) 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
(7) 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: Official Journal, German Society of Endocrinology [and] German Diabetes Association, 126(9), 546–552. https://doi.org/10.1055/s-0043-125064
(8) Dietrich, J. W. (2018, April 26). SPINA: Structure parameter inference approach. Retrieved February 4, 2019, from http://spina.sourceforge.net/
(9) 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