Response to Xiang and Zhang re: “Active Surveillance Outcomes of Patients with Low-Risk Papillary Thyroid Microcarcinoma According to Levothyroxine Treatment Status”

Dear Editor:

We appreciate the opportunity to respond to the letter to the editor by Xiang J. and Zhang H. ¹ We also thank them for their interest in our recent article on active surveillance management of patients with low-risk papillary thyroid microcarcinoma (PTMC) with levothyroxine. ² Their important comments will deepen the reader's understanding of this new management modality.

Xiang J. and Zhang H. argued that the effect of thyrotropin (TSH) levels on thyroid cancer outcomes during active surveillance is controversial. ¹ However, Kim et al. reported that high serum TSH was associated with disease progression in 126 patients with PTMC, ³ as cited in our article. ² Furthermore, in our study of 2705 patients with PTMC at Kuma Hospital, multivariate analysis revealed that a time-weighted detailed TSH score of 3 or higher was an independent predictor of tumor enlargement. ⁴ We also showed that the tumor-volume doubling rate significantly decreased after levothyroxine (LT4) in patients with PTMC who started taking LT4 during active surveillance. ² The 2015 ATA guidelines recommend keeping low serum TSH levels postoperatively for well-differentiated thyroid cancer patients, depending on their risk of recurrence. ⁵ The guidelines recommend maintaining TSH at or slightly below the lower limit of normal for low-risk patients. Therefore, we believe that considering LT4 for patients with PTMC to achieve such TSH level is reasonable if the side effects of thyrotoxicosis are avoided.

They argued that excessive intake of LT4 might increase the risk of side effects, such as cardiovascular problems, osteoporosis, and psychological instability. ¹ This comment is appropriate and important, and we completely agree with their comments. We carefully avoided “TSH suppressive therapy” and used “lowering serum TSH level.” ² Our intended management with LT4 is to lower serum TSH levels to a lower half of the normal range (detailed TSH score 3) or to a high subnormal range (>0.05 mIU/L and <lower limit of the normal range; detailed TSH score 2.5), while avoiding thyrotoxicosis. ² The time-weighted detailed TSH score in our patients who started LT4 at diagnosis and those who started LT4 during active surveillance were 3.17 and 3.05, respectively. ²

When prescribing LT4, we carefully asked and observed the patients for possible mild thyrotoxicosis symptoms and signs, alongside with periodic monitoring of serum TSH, free thyroxine (fT4), and free triiodothyronine (fT3) levels. None of the patients showed symptoms or signs of thyrotoxicosis, with fT4 levels slightly elevated above the upper normal range and TSH levels slightly below the lower normal range. However, fT3, indicating a biologically active thyroid hormone status, remained within the normal range, and none of the patients had fT3 levels above the upper normal range. In patients undergoing total thyroidectomy, we reported that those with moderately suppressed TSH had fT3 equivalent to their native values, accompanied with mildly elevated fT4 values. ⁶ Our data on biochemical markers of thyroid function suggested that the combination of these indicated euthyroid status. ⁷

We agree that more studies are needed to examine the efficacy and safety of LT4 treatment in active surveillance of patients with PTMC.

Author's Contribution

A.M.: Conceptualization and writing.