Response to Michalaki et al . re: “Levothyroxine Replacement Therapy and Overuse: A Timely Diagnostic Approach”

Dear Editor:

We have read the letter by Michalaki et al. (1) concerning the article by Livadas et al. entitled “Levothyroxine Replacement Therapy and Overuse” published in Thyroid (2).

We thank the authors for their suggestion to further analyze the thyrotropin (TSH) kinetics recorded before and after withdrawal of levothyroxine (LT4) treatment in our 291 patients. Based on their comments on the relatively high standard deviation of serum TSH observed in our patients, Michalaki et al. suggest that a longer period of follow-up beyond eight weeks post-LT4 withdrawal might be recommended. However, it is important to note that none of the patients had an abnormally low or high basal TSH. We thus analyzed and compared the serum TSH of the 114 patients who developed overt hypothyroidism after LT4 treatment withdrawal with those of the 77 patients with low-normal TSH, and with those of the 100 euthyroid patients who were euthyroid prior and after withdrawal of LT4.

Eighty-six subjects had TSH values ranging from 0.4 to 1.5 IU/mL. Thirty-three of them (38%) were found to have TSH values >4.5 IU/mL after discontinuation of treatment. The mean TSH value in this group was 7.51 + 1.65 IU/mL and this value did not differ significantly from that of subjects who ultimately became hypothyroid post-LT4Rx withdrawal (mean 8.21 ± 2.35 IU/mL).

In addition, patients with suppressed TSH were excluded from the study, as has been clearly stated in the Subjects and Methods section: “Only patients with normal TSH levels (0.4–4.5 IU/mL) and normal free T4 (FT4) levels (0.58–1.60 ng/dL), according to the institutional reference ranges, were evaluated” (2). In the case of borderline low TSH values, due to endogenous or exogenous subclinical hyperthyroidism, the thyrotrophs recover quickly and TSH normalizes within a few weeks after treatment modifications or spontaneously in some cases. The usual timeframe in clinical practice to evaluate treatment changes and adjust LT4 dosage is six to eight weeks. Of note, the use of the word “hysteresis” by the authors is, in our opinion, not appropriate because it refers to a phenomenon denoting a delayed input into a system due to a time lag, for example, persistent TSH suppression or elevation with consequent lagging of thyrotroph recovery secondary to severe thyrotoxicosis and hypothyroidism (3). Hysteresis is a homeostatic concept that may be affected by a number of confounding factors, such as obesity, aging, and therapy (4).

It was the aim of the study of Livadas et al. to define a reliable timepoint for re-evaluation of those patients in whom LT4 therapy would be interrupted for the needs of the proposed periodic re-evaluation of all patients on chronic LT4 treatment. The results suggest that an eight-week timeframe is appropriate; eight weeks after withdrawal, hypothyroidism may be reliably diagnosed and LT4 treatment reintroduced if needed. In the absence of prior long-term suppressive therapy, a longer interval is not necessary.