Re: “Thyroid Stimulating Hormone and Thyroid Hormones (Triiodothyronine and Thyroxine): An American Thyroid Association-Commissioned Review of Current Clinical and Laboratory Status” by Van Uytfanghe et al.

Dear Editor:

The American Thyroid Association-Commissioned review of the clinical and laboratory status of measurement of thyrotropin (TSH) and thyroid hormones concentrations provides an excellent text with regard to laboratory and technical considerations. Nevertheless, it appears that the authors did not incorporate evidence from recent research when providing support for the longstanding recommendation that the TSH concentration is the best blood test of the thyroid status of peripheral tissues. ¹ Similarly supported is the usual rationale for this recommendation, that is, the log-linear relationship between concentrations of TSH and thyroid hormones. ¹

To the best of our knowledge, there is no robust empirical evidence that TSH concentrations are superior to thyroid hormone concentrations. To the contrary, there is abundant accumulating evidence that thyroid hormone (especially free thyroxine [fT4]) concentrations are superior to TSH concentrations in terms of correlation with clinical outcomes. ^{2 –4} It would thus appear that any technical advantages of the TSH assay are outweighed by the fact of the direct exposure of tissues to thyroid hormones, and the greater biological variation in TSH levels. ¹

Furthermore, the evidence suggests that the clinical state changes continuously with the fT4 concentration, even within the normal range, rather than there being discrete thyroid states. ⁵ The evidence suggests that any relationship between clinical outcomes and TSH concentrations reflects predominantly the population correlation between the concentrations of thyroid hormones and TSH.

Though fT4 concentrations appear to be the best single indicators of the thyroid status of peripheral tissues, additional information nevertheless may be provided by the consideration of simultaneous concentrations of TSH and triiodothyronine. ⁶

Furthermore, the underlying logic of the theoretical basis for the putative superiority of TSH concentrations, that is, that concerning the log-linear relationship between fT4 and TSH, has been addressed from differing perspectives and found to be flawed. ^5,6 For example, an extrapolation of this logic would imply that calcium and hemoglobin concentrations might be better estimated by parathyroid hormone and erythropoietin concentrations, respectively, there being similar log-linear relationships at play.

Notably, prevalent psychosocial and other forms of stress (obesity, aging) act to primarily raise the TSH concentrations, independently of lower fT4 concentrations as in hypothyroidism. ⁶ This is a strong mechanism, which could, for example, lead to an exaggeration of the apparent effect of thyroid failure, as judged by TSH concentrations, on clinical complications such as cardiovascular disease.

Furthermore, despite claims to the contrary, ⁷ the sensitivity of TSH concentrations to minor primary alterations in thyroid function from putative individual set point levels does not imply the superiority of TSH concentrations for the assessment of the thyroid state. Rather, evidence suggests that individual euthyroidism and thyroid set points do not exist, ⁵ and that moderate changes to TSH concentrations related to changes in concentrations of thyroid hormones might reflect adequate compensation for a primary drop in thyroid hormone concentrations, ⁶ be a driver of changes to thyroid hormone concentrations, ⁶ or reflect a change in thyroid hormone concentrations that is not detrimental for peripheral tissues. ⁵

We suggest that recommendations regarding the places of thyroid hormone and TSH concentrations in the assessment of the thyroid state be brought into line with the recent strong evidence. We hope that this suggestion might be considered by the committees, and at the conferences, of the major thyroid associations.