Managing the Total Thyroid Process

Correlation of TSH with FT4

TSH has an even weaker correlation with FT3¹⁹. Patients other than those diagnosed by high TSH and low FT4 (overt primary hypothyroidism) may still manifest typical hypothyroid symptoms for the following reasons:

1. Ranges used for diagnosis are too broad for individualized interpretation and skewed to the low end^13,20. Labs have no means other than TSH to identify and exclude from their database used to calculate ranges, other forms of hypothyroidism which typically have lower levels of FT4 and FT3²¹.
2. FT4/ FT3 levels in the lower part of their population ranges may be inadequate since each patient can have different thyroid hormone levels at which they feel normal (inter- individuality)^13,20,22

In the treatment situation, instead of the normal, continuous slow release of thyroid hormones from the gland, the daily dosage of thyroid medication is taken all at once. It has been shown that with replacement treatment there is a shift in the equilibrium between TSH and FT4 that is not recognised in current diagnostic procedures²². Furthermore, a significant dosage of thyroid hormone, taken all at once, spikes FT4 levels in the short term causing a suppressive effect on TSH for an extended period. Even with FT4/FT3 well within range, this is typically misdiagnosed as overmedication leading to a reduction in dosage and an increase in symptoms. Rather than totally relying on TSH, both FT4 and FT3 should be tested and prioritised¹³. This was also the conclusion of a carefully conducted meta-analysis by Fitzgerald et al.²³.

Supply of Thyroid Hormone

Upon entering the bloodstream, the hormones produced by the thyroid gland are bound to protein, only a small proportion of serum T4 and T3 remaining unbound as FT4 and FT3. The ratio is largely dependent on Thyroxine-Binding Globulin (TBG) levels¹⁶. Serum levels of thyroid hormone merely indicate availability to the tissues.

Transport of Thyroid into Cells

Transport of thyroid hormone across the plasma membrane into cells is not simply a matter of diffusion, as previously assumed. A number of variables affect their active transport across the plasma membrane and cellular thyroid levels²⁴.

Conversion of T4 to T3

Most serum FT3 results from conversion of the pro-hormone T4 to the biologically active T3 in tissues throughout the body²⁵. Contrary to common belief, the quantity of T4 converted into T3 is not always adequate^26,27. Conversion is affected by numerous variables, including iodine, selenium, ferritin, zinc, and others^16,26. Importantly, conversion also occurs within the thyroid gland itself, this being TSH-dependent and therefore severely compromised in the absence of a functioning thyroid gland^28,29. This is evidenced by reduced conversion rates during treatment with L-T4^13,26. The achievement of adequate FT3 levels may consequently require the addition of liothyronine (L-T3), especially in athyreotic patients^13,30. However, FT3 is seldom tested and basically ignored in both diagnosis and treatment, despite its vital role for achieving adequate T3 genomic effect in tissue^3–5.

T3 Genomic Effect in Tissue

As mentioned, a comprehensive definition of hypothyroidism includes “inadequate T3 genomic effecting tissue throughout the body”. This definition goes beyond the standard Hypothalamus/Pituitary/Thyroid (HPT) interpretation and recognizes the effect of all the steps within the total thyroid process and their numerous confounding variables. This definition also focuses on the desired end result of the total thyroid process, not just the controller TSH, and enables diagnosis of all forms of hypothyroidism. After all, FT3 is the biologically active thyroid hormone that essentially regulates metabolic activity in cells. Cellular levels of FT4 and FT3 are determined by all the preceding steps and their numerous confounding variables which comprise the total thyroid process. The response to thyroid hormone at the cellular level is affected by numerous variables, especially TSH, Vitamin D, cortisol, and sometimes impaired by Thyroid Hormone Resistance (THR)^16,17.

Statistically the variance in the outcome from a process is the sum of the variance of each variable within the process. In view of the number of different process steps and their inherent confounding variables, we cannot logically assume that the controller variable (TSH) is an accurate surrogate measure of the outcome from the total thyroid process: “T3 genomic effect in tissue”. This is confirmed by both the weak correlation with thyroid hormones and the subjective “prominent dissatisfaction" among hypothyroid patients^1,18,19. It is also evident in the negligible correlation between TSH and a clinical score of symptoms, as compared to that between the concentrations of FT4 and FT3 and symptoms^23,31. For diagnostic purposes, there is no direct measure of the extent of T3 genomic effect in tissue available, requiring the use of indirect measures including symptoms and the levels of FT4 and FT3, as discussed below^6,13.

Summary

Diagnostic and treatment practices are clearly ineffective for many hypothyroid patients and should be reconsidered and amended in the light of recent advances in our understanding of thyroid regulation. The following suggestions more adequately address the needs of both patients and doctors and are supported by extensive scientific evidence as cited in the link given in section 1 above and the following selected references.

1. The current diagnostic protocol based on tests for TSH followed by FT4 as needed is only effective in diagnosing overt primary hypothyroidism, and should be amended to enable effective diagnosis of the numerous other forms of hypothyroidism, which are currently overlooked¹³.
2. The diagnostic process must always include a review of the full medical history of the patient¹³.
3. There are no reliable direct measures of a patient’s thyroid status at the cellular level. The diagnostic process must include an evaluation of the patient’s signs/symptoms, which reflect both tissue thyroid responses and the patients’ well-being^13,14. Typical symptoms have been identified by numerous sources. One study reported that symptoms correlated best with 24-hour urine FT3³². Signs can include resting metabolic rate, body temperature, body mass index, and cholesterol level. It is also interesting to note that the ATA Guidelines state, “Early as well as recent studies strongly correlate the degree of hypothyroidism with ankle reflex relaxation time, a measure rarely used in clinical practice today”³.
4. Symptomatic testing and case finding should include TSH, the thyroid hormones FT4 and FT3, arguably RT3, TPO ab, TG ab (only if TPO ab is negative and TSH is high), cortisol, vitamin D, B12 and ferritin. Interpretation of test results is discussed in the Recommended Diagnostic and Treatment Procedures section on page 9 of the linked article². The ATA has recommended the blood draw for thyroid hormone tests conducted during treatment should be done before the morning dose of thyroid medication, to avoid false high results^3,4.
5. If symptoms of hypothyroidism are present, an ultrasound examination of the thyroid gland should be carried out, irrespective of the severity of biochemical abnormalities.
6. Since symptomatic change has been shown to be strongly associated with serum thyroid hormone levels but not TSH levels²³, the current treatment protocol based on L-T4, titrated to just return TSH within range, cannot guarantee that FT4 and FT3 levels are adequate for clinical euthyroidism and patient satisfaction¹³. A TSH test alone cannot reliably determine that medication dosage is adequate to restore the clinical euthyroid state^6,13. Instead, when hypothyroid symptoms persist, the patient’s FT4 and FT3 levels should both be increased enough to relieve symptoms of hypothyroidism without creating symptoms of hyperthyroidism¹³.

Implementation of these suggestions would individualize diagnostic and treatment regimens, address pervasive patient dissatisfaction with the current standard of care and empower physicians to more effectively use their extensive knowledge, experience and judgment. This is consistent with the following directives in the AACE/ATA Guidelines, which have been generally disregarded.

“The guidelines are not inclusive of all proper approaches or methods, or exclusive of others, the guidelines do not establish a standard of care and specific outcomes are not guaranteed. Treatment decisions must be based on independent judgment of health care providers and each patient’s circumstances. A guideline is not intended to take the place of physician judgment in diagnosis and treatment of particular patients. We encourage medical professionals to use this information in conjunction with their best clinical judgment.”For a PDF version of this article, click here.