Diagnosis of Hypothyroidism:
Are we getting what we want from TSH testing?
Hypothyroidism is a common disorder where there is inadequate cellular thyroid effect to meet the needs of the tissues. Typical symptoms of hypothyroidism include fatigue, weight gain, depression, cold extremities, muscle aches, headaches, decreased libido, weakness, cold intolerance, water retention, premenstrual syndrome (PMS) and dry skin. Low thyroid causes or contributes to the symptoms of many conditions but the deficiency is often missed by standard thyroid testing. This is frequently the case with depression, hypercholesterolemia (high cholesterol), menstrual irregularities, infertility, PMS, chronic fatigue syndrome (CFS), fibromyalgia, fibrocystic breasts, polycystic ovary syndrome (PCOS), hyperhomocysteinuria (high homocystine), atherosclerosis, hypertension, obesity, diabetes and insulin resistance.
The TSH is thought to be the most sensitive marker of peripheral tissue levels of thyroid, and it is erroneously assumed by most endocrinologists and other physicians that, except for unique situations, a normal TSH is a clear indication that the person’s tissue thyroid levels are adequate (symptoms are not due to low thyroid) (see why doesn’t my doctor know this). A more thorough understanding of the physiology of hypothalamic-pituitary-thyroid axis and tissue regulation of thyroid hormones demonstrates that the widely held belief that the TSH is an accurate marker of the body’s overall thyroid status is clearly erroneous.
The TSH is inversely correlated with pituitary T3 levels but with physiologic stress (1-32), depression (33-38), insulin resistance and diabetes (28,39,116,117), aging (30,40-49), calorie deprivation (dieting)(27, 50-57), inflammation (5-8,22,108,109-111), PMS (58,59), chronic fatigue syndrome and fibromyalgia (60,61), obesity (112,113,114) and numerous other conditions (1-32), increasing pituitary T3 levels are often associated with diminished cellular and tissue T3 levels and increased reverse T3 levels in the rest of the body (1-62) (see pituitary diagram). The pituitary is both anatomically and physiologically unique, reacting differently to inflammation and physiologic stress than every other tissue in the body (1-20,50-52,62,63)(see deiodinase). The conditions above stimulate local mechanisms to increase pituitary T3 levels (reducing TSH levels) while reducing T3 levels in the rest of the body (1-63). Thus, with physiologic or emotional stress, depression or inflammation, the pituitary T3 levels do not correlate with T3 levels in the rest of the body, and thus, the TSH is not a reliable or sensitive marker of an individual’s true thyroid status (see deiodinase).
Serum levels of thyroid hormones
Due to the differences in the pituitary’s response to physiological stress, depression, dieting, aging and inflammation as discussed, most individuals with diminished tissue levels of thyroid will have a normal TSH (1-63). Doctors are taught that if active thyroid (T3) levels drop, the TSH will increase. Thus, endocrinologists and other doctors tell patients that an elevated TSH is the most useful marker for diminished T3 levels and that a normal TSH indicates that their thyroid status is “fine”. The TSH is, however, merely a marker of pituitary levels of T3 and not of T3 levels in any other part of the body. Only under ideal conditions of total health do pituitary T3 levels correlate with T3 levels in the rest of the body, making the TSH a poor indicator of the body’s overall thyroid status. The relationship between TSH and tissue T3 is lost in the presence of physiologic or emotional stress (1-32), depression (33-38), insulin resistance and diabetes (28,39), aging (30,40-49)(see thyroid hormones and aging graph), calorie deprivation (dieting)(50-57), inflammation (5-8,22), PMS (58,59), chronic fatigue syndrome and fibromyalgia (60,61), obesity (112,113,114) and numerous other conditions (1-63). In the presence of such conditions, the TSH is a poor marker of active thyroid levels and thyroid status of an individual, and a normal TSH cannot be used as a reliable indictor that a person is euthyroid (normal thyroid) in the overwhelming majority of patients.
Value of Serum T4
The suppression of TSH with physiologic and emotional stress and illness suppresses the production of T4 (1,2,9,64-68), which would tend to lower serum T4 levels. In the presence of such conditions, there are, however, competing effects that result in an increase in serum T4 while further reducing tissue levels of T3 levels, making serum T4 (or free T4) a poor marker of tissue thyroid level, as is the case with the TSH. Such effects include a suppression of tissue T4 to T3 conversion (misleadingly increasing serum T4 levels) (1-68,76) with an increased conversion of T4 to reverse T3 (12,14,18,35,36,41,59,69-74,85) and an induced thyroid resistance with reduced uptake of T4 into the cells (misleadingly increasing serum T4 levels) (16,1976-84) in all tissues except for the pituitary (84). Although all such effects reduced intracellular T3 in all tissues except for the pituitary, the serum T4 level can be increased, decreased or unchanged. Consequently, serum T4 levels oftentimes do not correlate with tissue T3 levels and, as with the TSH, the serum T4 level is often misleading and an unreliable marker of the body’s overall thyroid status (see serum thyroid levels in stress and illness).
Current best method to diagnosis
With increasing knowledge of the complexities of thyroid function at the cellular level, it is becoming increasingly clear that TSH and T4 levels are not the reliable markers of tissue thyroid levels as once thought, especially with chronic physiologic or emotional stress, illness, inflammation, depression and aging. It is common for an individual to complain of symptoms consistent with hypothyroidism but have normal TSH and T4 levels. While there are limitations to all testing and there is no perfect test, obtaining free triiodothyronine, reverse triiodothyronine, and triiodothyronine/reverse-triiodothyronine ratios can be helpful to obtain a more accurate evaluation of tissue thyroid status and may be useful to predict those who may respond favorably to thyroid supplementation (1,11,12,14,18,35,36,41,59,69-74,85) (see serum thyroid levels in stress and illness). Many symptomatic patients with low tissue levels of active thyroid hormone but normal TSH and T4 levels significantly benefit from thyroid replacement, often with significant improvement in fatigue, depression, diabetes, weight gain, PMS, fibromyalgia and numerous other chronic conditions (86-99).
With an understanding of thyroid physiology, it becomes clear why a large percentage of patients treated with T4 only preparations continue to be symptomatic. Thyroxine (T4) only preparations should not be considered the treatment of choice and are often not effective in conditions associated with reduced T4 to T3 conversion, reduced uptake of T4 or increased T4 to reverse T3 conversion. As discussed above, with any physiologic stress (emotional or physical), inflammation, depression, inflammation, aging or dieting, T4 to T3 conversion is reduced and T4 will be preferentially converted to reverse T3 (12,14,18,35,36,41,53,69-74,85), which acts a competitive inhibitor of T3 (blocks T3 at the receptor) (100-104), reduces metabolism (100,103,104), suppresses T4 to T3 conversion (101,103) and blocks T4 and T3 uptake into the cell (105).
While a normal TSH cannot be used as a reliable indicator of global tissue thyroid effect, even a minimally elevated TSH (above 2) demonstrates that there is diminished intra-pituitary T3 level and is a clear indication (except in unique situations such as a TSH secreting tumor) that the rest of the body is suffering from inadequate thyroid activity because the pituitary T3 level is always significantly higher than the rest of the body and the most rigorously screened individuals for absence of thyroid disease have a TSH below 2 to 2.5 (106). Thus, treatment should likely be initiated in any symptomatic person with a TSH greater than 2. Additionally, many individuals will secrete a less bioactive TSH so for the same TSH level, a large percentage of individuals will have reduced stimulation of thyroid activity, further limiting the accuracy of TSH as a measure of overall thyroid status. Reduced bioactivity of TSH is not detected by current TSH assays used in clinical practice.
Due to the lack of correlation of TSH and tissue thyroid levels, as discussed, a normal TSH should not be used as the sole reason to withhold treatment in a symptomatic patient. A symptomatic patient with an above average reverse T3 level and a below average free T3 (a general guideline being a free T3/reverse T3 ratio less than 2) should also be considered a candidate for thyroid supplementation (13,14,18,69-76,85-106). A relatively low sex hormone binding globulin (SHBG) and slow reflex time can also be useful markers for low tissue thyroid and levels and can aid in the diagnosis of tissue hypothyroidism (93,107,115).
A study published in the Journal of Clinical Endocrinology and Metabolism assessed the level of hypothyroidism in 332 female patients based on a clinical score of 14 common signs and symptoms of hypothyroidism and assessments of peripheral thyroid action (tissue thyroid effect). The study found that the clinical score and ankle reflex time correlated well with tissue thyroid effect but the TSH had no correlation with the tissue effect of thyroid hormones (118). The ankle reflex itself had a specificity of 93% (93% of those with slow relaxation phase of the reflexes had tissue hypothyroidism) and a sensitivity of 77% (77% of those with tissue hypothyroidism had a slow relaxation phase of the reflexes) making both the measurement of the reflex speed and clinical assessment a more accurate measurement of tissue thyroid effect than the TSH.
A combination of the serum levels of TSH, free T3, free T4, reverse T3, anti-TPO antibody, antithyroglobulin antibody and SHBG should be used in combination of with clinical assessment and measurement of reflex speed and basal metabolic rate to most accurately determine the overall thyroid status in a patient. Forgoing treatment based on a normal TSH without further assessment will result in the misdiagnosis of mismanagement of a large number of hypothyroid patients that may greatly benefit with treatment. Simply relying a TSH to determine the thyroid status of a patient demonstrates a lack of understanding of thyroid physiology and is not evidence based medicine (see Why my Endocrinologist Doesn’t Know All of This). In patients with elevated or high normal reverse T3 levels, T4 only preparations should not be considered adequate and T3 containing preparations, in particular timed released T3, should be considered the treatment of choice.
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