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Managing the Total Thyroid Process

Authors: Mel Rowe, Rudolf Hoermann, Peter Warmingham

Address correspondence to: peter.warmingham@outlook.com

Introduction

This paper was written to examine the current standard of care for hypothyroidism, underlying causes for the prominent dissatisfaction expressed by thyroid patients1, and opportunities for improvement. This paper is intended to include a strong patient’s perspective. It expands on previous work 2, and reviews the total thyroid process.

Current Standard of Care

When hypothyroid patients see their doctors with unwanted signs/symptoms (hereafter called symptoms) doctors usually diagnose in accordance with a standard of care (SOC) interpreted from the American Association of Clinical Endocrinologists (AACE) / American Thyroid Association (ATA) Guidelines for Hypothyroidism3–5. For decades, it has been assumed that hypothyroidism is the result of inadequate thyroid hormone production from a diseased or damaged thyroid gland3–5 . It was further assumed that any inadequacy in thyroid function would be correctly sensed by the patient’s pituitary gland and be accurately reflected in secreted levels of the controller variable, thyroid stimulating hormone (TSH)3–5. The pituitary hormone TSH was therefore adopted as the surrogate marker for the thyroid functional state provided there is no pituitary or hypothalamic failure (central hypothyroidism)3–6.

Although considered as a sensitive biochemical marker, the guidelines3 recognize that “TSH levels vary diurnally by up to approx. 50% of mean values and with more recent reports indicating up to 40% variation on specimens performed serially during the same time of day.” With the availability of a sensitive test for TSH, a remarkable shift was made to the clinical diagnostic process: the evaluation of patient symptoms was largely superseded by thyroid function testing3–6. A TSH test within range became synonymous with the assumption of euthyroidism in all cases3–6. Accordingly, a patient is diagnosed as overtly hypothyroid and recommended for treatment only if TSH is above range and FT4 is below range, or if TSH is greater than 103–9. If FT4 is still within range in the presence of a confirmed elevated TSH the patient is classified as subclinically hypothyroid4. The diagnosis of subclinical hypothyroidism is applied to the majority of patients (up to 10% in a population with a preponderance of older females)10–12.

The standard treatment is levothyroxine (L-T4) dosed as needed to return TSH within range3–5,7. The important biologically active thyroid hormone Free T3 (FT3) is seldom tested and essentially ignored in both diagnosis and treatment13.

Results from SOC

The problem arising from this approach is that patients expect more than biochemical euthyroidism as defined by a TSH within range. Rather they expect clinical euthyroidism – the relief of their hypothyroid symptoms. The current SOC, including its TSH-centred definition of hypothyroidism, has left many thyroid patients dissatisfied1,6,14,15. This has been documented by recent surveys conducted by the ATA and other organisations1. It is also evident from the numerous patient advocacy sites that have reported continual negative feedback from around the world15.

For example, “prominent dissatisfaction” was reported by the ATA from their 2018 survey of 12,146 hypothyroid patients1. On a scale of 1 – 10, the average rating for both their treatment and their doctor’s knowledge about treatment was 51. They had changed doctors numerous times seeking help and rated the need for new treatments as 10 (strong need). Inadequately diagnosed or treated hypothyroidism results in an extensive array of symptoms and frequently develops into more serious medical issues1. The current SOC is expedient, but does not facilitate effective individualised diagnosis and treatment13. Patient feedback and extensive current scientific evidence clearly confirm the need for improvement.

The Total Thyroid Process

Improved diagnosis and treatment requires a more comprehensive definition of hypothyroidism: “Insufficient T3 genomic effect in tissue throughout the body due to inadequate supply of, or response to, the hormones”. As discussed in the following, this definition goes beyond the current focus on the TSH response, which has been recently found to be much less diagnostically reliable than originally supposed6,13. It recognises that the subsequent steps in the total thyroid process (as discussed in the following paragraphs), along with numerous confounding variables, have a substantial effect on the outcome16,17.

TSH/FT4/FT3 Control Loop

For a given TSH signal, the response from the thyroid gland can be affected by many variables along the path, including genetic variability, multiple afferent influences from various brain regions, iodine, gender, aging, body mass and the gland’s condition13,16,17. These processes are expressed differently among individuals (inter-individuality), causing a weak correlation of TSH with FT4 within their population ranges as shown by the data scatter in the following graph from a group database18.

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 end13,20. 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 adequate26,27. Conversion is affected by numerous variables, including iodine, selenium, ferritin, zinc, and others16,26. Importantly, conversion also occurs within the thyroid gland itself, this being TSH-dependent and therefore severely compromised in the absence of a functioning thyroid gland28,29. This is evidenced by reduced conversion rates during treatment with L-T413,26. The achievement of adequate FT3 levels may consequently require the addition of liothyronine (L-T3), especially in athyreotic patients13,30. However, FT3 is seldom tested and basically ignored in both diagnosis and treatment, despite its vital role for achieving adequate T3 genomic effect in tissue3–5.

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 patients1,18,19. 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 symptoms23,31. 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 below6,13.

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-being13,14. 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 results3,4.
  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 state6,13. 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.

References

1. Peterson SJ, Cappola AR, Castro MR, Dayan CM, Farwell AP, Hennessey JV, Kopp PA, Ross DS, Samuels MH, Sawka AM, Taylor PN, Jonklaas J, Bianco AC. An online survey of hypothyroid patients demonstrates prominent dissatisfaction. Thyroid. 2018;28:707-721. doi:10.1089/thy.2017.0681

2. Rowe M, Hoermann R, Warmingham P. The Diagnosis and Treatment of Hypothyroidism: A Patient’s Perspective.
Available here.

3. Garber JR, Cobin RH, Gharib H, Hennessey JV, Klein I, Mechanick JI, Pessah-Pollack R, Singer PA, Woeber KA for the American Association of Clinical Endocrinologists and American Thyroid Association Taskforce on Hypothyroidism in Adults. Clinical practice guidelines for hypothyroidism in adults: Cosponsored by the American Association of Clinical Endocrinologists and the American Thyroid Association. Thyroid. 2012;22:1200-1235. doi:10.1089/thy.2012.0205

4. Jonklaas J, Bianco AC, Bauer AJ, Burman KD, Cappola AR, Celi FS, Cooper DS, Kim BW, Peeters RP, Rosenthal MS, Sawka AM. Guidelines for the treatment of hypothyroidism: Prepared by the American Thyroid Association task force on thyroid hormone replacement. Thyroid. 2014;24:1670-1751. doi:10.1089/thy.2014.0028

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13. Hoermann R, Midgley JEM, Larisch R, Dietrich JW. Individualised requirements for optimum treatment of hypothyroidism: Complex needs, limited options. Drugs Context. 2019;8:212597. doi:10.7573/dic.212597

14. Winther KH, Cramon P, Watt T, Bjorner JB, Ekholm O, Feldt-Rasmussen U, Groenvold M, Rasmussen ÅK, Hegedüs L, Bonnema SJ. Disease-specific as well as generic quality of life is widely impacted in autoimmune hypothyroidism and improves during the first six months of levothyroxine therapy. PLoS One. 2016;11:e0156925. doi:10.1371/journal.pone.0156925

15. Wiersinga WM. Therapy of endocrine disease: T4 + T3 combination therapy: Is there a true effect. Eur J Endocrinol. 2017;177:R287-R296. doi:10.1530/EJE-17-0645

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17. Chatzitomaris A, Hoermann R, Midgley JEM, Hering S, Urban A, Dietrich B, Abood A, Klein HH, Dietrich JW. Thyroid allostasis-adaptive responses of thyrotropic feedback control to conditions of strain, stress, and developmental programming. Front Endocrinol (Lausanne). 2017;8:163. doi:10.3389/fendo.2017.00163

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19. Hoermann R, Midgley JEM, Giacobino A, Eckl WA, Wahl HG, Dietrich JW, Larisch R. Homeostatic equilibria between free thyroid hormones and pituitary thyrotropin are modulated by various influences including age, body mass index and treatment. Clin Endocrinol (Oxf). 2014;81:907-915. doi:10.1111/cen.12527 Page 6 of 7

20. Andersen S, Pedersen KM, Bruun NH, Laurberg P. Narrow individual variations in serum T4 and T3 in normal subjects: A clue to the understanding of subclinical thyroid disease. J Clin Endocrinol Metab. 2002;87:1068-1072. doi:10.1210/jcem.87.3.8165

21. Wayne PA. Clinical and Laboratory Standards Institute. Defining, Establishing, and Verifying Reference Intervals in the Clinical Laboratory; Approved Guideline. CLSI document C28-A3. Clinical and Laboratory Standards Institute. 2008.

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24. Meier C, Trittibach P, Guglielmetti M, Staub JJ, Müller B. Serum thyroid stimulating hormone in assessment of severity of tissue hypothyroidism in patients with overt primary thyroid failure: cross sectional survey. BMJ 2003;326:311-312.

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26. Groeneweg S, Van Geest FS, Peeters RP, Heuer H, Visser WE. Thyroid hormone transporters. Endocr Rev. 2020;41doi:10.1210/endrev/bnz008

27. Bianco AC, Dumitrescu A, Gereben B, Ribeiro MO, Fonseca TL, Fernandes GW, Bocco BMLC. Paradigms of dynamic control of thyroid hormone signaling. Endocr Rev. 2019;40:1000-1047. doi:10.1210/er.2018-00275

28. Hoermann R, Midgley JEM, Larisch R, Dietrich JW. Relational stability in the expression of normality, variation, and control of thyroid function. Front Endocrinol (Lausanne). 2016;7:142. doi:10.3389/fendo.2016.00142

29. Hoermann R, Midgley JEM, Larisch R, Dietrich JW. Lessons from randomised clinical trials for triiodothyronine treatment of hypothyroidism: Have they achieved their objectives. J Thyroid Res. 2018;2018:3239197. doi:10.1155/2018/3239197

30. Berberich J, Dietrich JW, Hoermann R, Müller MA. Mathematical modeling of the pituitary-thyroid feedback loop: Role of a TSH-T3-shunt and sensitivity analysis. Front Endocrinol (Lausanne). 2018;9:91. doi:10.3389/fendo.2018.00091

31. Hoermann R, Pekker MJ, Midgley JEM, Larisch R, Dietrich JW. Triiodothyronine secretion in early thyroid failure: The adaptive response of central feedforward control. Eur J Clin Invest. 2020;50:e13192. doi:10.1111/eci.13192

32. Midgley JEM, Larisch R, Dietrich JW, Hoermann R. Variation in the biochemical response to L-thyroxine therapy and relationship with peripheral thyroid hormone conversion efficiency. Endocr Connect. 2015;4:196-205. doi:10.1530/EC-15-0056

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