Redefinition of Successful Treatment of Patients With Hypothyroidism. Is TSH the Best Biomarker of Euthyroidism?

Abstract

In recent years evidence has accumulated supporting a revised view of the nature of euthyroidism and the biomarkers of thyroid function. Within the normal range, variations in thyroid hormone levels are associated with variations in clinical parameters and outcomes. There are therefore no readily identified individually specific optimum levels of thyroid hormones for any individual. Levels around the middle of the normal population range may best reflect euthyroidism. These levels may have evolutionary advantages on the basis that adverse outcomes often increase with divergence from such levels, and physiological processes tend to minimise such inter-individual and intra-individual divergence. In populations of predominantly untreated individuals, levels of thyroid hormones and in particular levels of free thyroxine (FT4) correlate more often with clinical parameters than do levels of thyrotropin (TSH). Levels of thyroid hormones may therefore be regarded as the best available biomarkers of euthyroidism and dysthyroidism. It follows that ‘subclinical hypothyroidism’ (normal FT4/raised TSH levels), rather than being an accurate marker of peripheral tissue hypothyroidism is more a marker of decreased thyroid reserve and prognosis. The recent evidence suggests that treatment of hypothyroxinemia, regardless of the TSH level, and monitoring therapy using FT4 and/or triiodothyronine levels, depending on the replacement regime, may result in more successful treatment of hypothyroidism than relying on thyrotropin levels for patient selection and subsequent treatment monitoring. The equivalents of mid-range levels of thyroid hormones (especially FT4), adjusted by individual comorbidity concerns, may be rational general replacement targets. These implications of the new evidence may create opportunities for novel trials of thyroid replacement therapy.

Editorial: Thyroid hormones and cardiac arrhythmia

“…According to the available evidence, even slight deviations of thyroid hormones confer significant risks for MACE, including malignant arrhythmia. Advanced diagnostical strategies should address the whole feedback loop to avoid misinterpretation by allostatic load, hysteresis and other effects, and modern therapeutic measures should involve multimodal approaches ( 21 – 23 , 33 – 37 ). This is of particular importance due to the biological potency and relatively long plasma half-life of thyroid hormones.…”

The application of new concepts of the assessment of the thyroid state to pregnant women

“…It followed from this that on account of the sensitivity of TSH levels to primary changes in thyroid hormone levels, TSH levels were the best guide to any deviation from the individual set point and thereby the best guide to the thyroid state of peripheral tissues ( 60 ). The evidence now indicates that as well as the concept of such a set point being flawed ( 5 ), all levels of thyroid hormones within the normal range are associated with risks and benefits ( 61 ). Thus, though TSH levels may provide evidence of a change in thyroid function, there is no rationale to consider such a change to be necessarily disadvantageous, and though TSH levels may provide prognostic information, there is no reason to consider them to be the best guide to the thyroid state of peripheral state in general ( 8 , 61 ).…”

“…The evidence now indicates that as well as the concept of such a set point being flawed ( 5 ), all levels of thyroid hormones within the normal range are associated with risks and benefits ( 61 ). Thus, though TSH levels may provide evidence of a change in thyroid function, there is no rationale to consider such a change to be necessarily disadvantageous, and though TSH levels may provide prognostic information, there is no reason to consider them to be the best guide to the thyroid state of peripheral state in general ( 8 , 61 ). As a maternal TSH level thereby cannot be assumed to be the best biochemical marker of the thyroid state of even maternal tissues, it is difficult to sustain the argument that a maternal TSH level can be the best marker of the thyroid state of maternal and placental/fetal tissues given that they have different DNA and thereby potentially different sensitivities to thyroid hormones and different physiologies.…”

“…We have previously indicated that although clinical parameters appear to associate most robustly with FT4 levels, free and total T3 levels also associate with these parameters more often than do TSH levels and that further studies to determine the idiosyncrasies of each organ/tissue are indicated ( 61 ). Analogously, in the perhaps unlikely circumstances that TT4 levels were found to be the best guide to the pregnancy thyroid state, the fundamental principle would remain that thyroid hormone measurement is preferable to TSH measurement.…”

“…With regard to the non-pregnant state, there is now a model of physiology coherent with empirical data ( 61 ). There is good evidence that FT4 is generally superior to TSH in defining the thyroid state, and there would appear to be good prospects for proceeding with new intervention trials using FT4 levels for subject selection and treatment targets.…”