Effects of thermal ablation on thyroid function in patients with thyrotoxicosis

To the Editor: Thermal ablation (TA) techniques have been widely used for the management of benign thyroid nodules (BTNs) and have been suggested as an alternative to surgery in some authoritative guidelines.[1] In theory, TA causes follicle destruction in the BTNs and a large release of the thyroid hormone stored in the follicles into the bloodstream; then, a dramatic change in thyroid function may occur. However, for euthyroid patients, researchers believe that TA treatment can preserve thyroid function and that these patients rarely develop thyroid dysfunction in the long term.[2] Nevertheless, for patients with pre-existing thyrotoxicosis, whether the release of thyroid hormone causes thyroid storm (TS) and how their thyroid function changes after TA are unknown. Therefore, we retrospectively summarized these cases of patients with subclinical or overt thyrotoxicosis before TA in our institute, aiming to provide more information about the effects of TA on these patients with pre-existing thyrotoxicosis. This retrospective study was approved by the Ethics Committee of the Third Affiliated Hospital of Sun Yat-sen University (No. [2015]2-215), and informed consent was obtained from each patient. We included patients who met the following criteria: (1) treated with ultrasonography (US)-guided TA of BTNs cytologically or histologically confirmed in our institution from January 2016 to November 2020; (2) had treated BTNs that measured larger than 20 mm or caused symptomatic or cosmetic problems; and (3) had subclinical or overt thyrotoxicosis before TA.[3] A total of 13 patients were included during the study period. All were female, with a median age of 41 years (range, 25–78 years). There were 3/13 patients with overt thyrotoxicosis, and the remaining 10/13 with subclinical thyrotoxicosis. The median thyrotropin (TSH) level before TA was 0.156 mU/L (range, 0.001–0.302 mU/L). One patient with thyrotoxicosis and a BTN for 1 month underwent thyroid scintigraphy to facilitate the diagnosis of an autonomously functioning thyroid nodule (AFTN) and received methimazole to control thyrotoxicosis. This patient also received potassium iodide solution for 1 week before TA. Among the remaining 12 patients, one had previous BTNs and underwent hemithyroidectomy 3 years prior; one previously had Graves' disease (GD) and underwent subtotal thyroidectomy plus 131I treatment 9 months prior; and the other 10 patients had BTNs for 1–10 years. All 12 patients had regular follow-ups in endocrinology departments and had shown stable thyroid function in the past 6 months before TA. A total of 16 BTNs were ablated, with a median maximum diameter of 38 mm (range, 20–59 mm) and a median volume of 6.5 mL (range, 1.9–49.9 mL), and all were solid or predominantly solid nodules. The median total ablated volume was 16.1 mL (range, 2.8–49.9 mL). The median initial ablation ratio (IAR) was 100% (range, 98%– 100%), and complete ablation (IAR 100%) was achieved in 15/16 of nodules. None of the patients showed symptoms related to TS during or after TA or experienced complications such as voice changes or local hematoma. The ablated nodules showed median volume reduction ratios (VRRs) of 75.6% (range, 26.3%–93.0%) at 6 months and 82.3% (range, 26.3%–94.8%) at the 12-month follow-up. There were 10/13 patients, with 11 nodules and a median total ablated volume of 6.4 mL (range, 2.8–16.9 mL), who returned to euthyroid status during follow-up: (1) this was observed in 6/13 patients as early as 1 month after TA, including one patient with thyrotoxicosis and five patients with subclinical thyrotoxicosis before the procedure; (2) 2/13 patients with preoperative thyrotoxicosis gradually recovered, showing subclinical thyrotoxicosis at 1 month, and returned to normal thyroid function at 6 months; and (3) the other 2/13 patients with preoperative subclinical thyrotoxicosis showed persistent abnormalities at 1 month but returned to normal thyroid function at 6 months. In these 10 patients, the thyroid antibody status remained the same in 9 patients, while 1 patient with both thyroid peroxidase antibody (aTPO) and thyroglobulin antibody (aTG) positivity before showed only aTPO positivity at 12 months. The remaining 3/13 patients, with five nodules and a larger total ablated volume of 27.3 mL (range, 22.4–49.9 mL), developed thyrotoxicosis at 1 month after TA [Figure 1]. One patient returned to normal thyroid function without any medication at 6 months, and the remaining two showed palpitations and underwent thyroid scintigraphy, base on which a diagnose of hyperthyroidism was established. Both took propylthiouracil or thiamazole and returned to subclinical status at 6 months. In these three patients, the thyroid antibody status remained the same in two patients, while one patient with antibody negativity before TA showed aTG positivity at 1 month posttreatment. Compared with the patients who returned to normal thyroid function, these patients had a higher body mass index (BMI) (25.0 kg/m2vs. 22.1 kg/m2, P = 0.042) and larger ablated volume (27.3 mL vs. 6.4 mL, P = 0.011).Figure 1: A case with pre-existing subclinical thyrotoxicosis showing deterioration of thyroid function after RFA on BTNs. (A) Female, 25 years old, with a BMI of 25.0 kg/m2, decreased TSH level of 0.156mU/L (normal range: 0.350–4.940 mU/L), and negative thyroid antibodies before RFA. US showed homogeneous thyroid parenchyma (white asterisk) and two BTNs (50 mm × 34 mm × 23 mm, red asterisk; and 17 mm × 8 mm × 27 mm) in the left lobe of thyroid. (B) At 1-month follow-up, the patient complained of palpitation, and the TSH level decreased to 0.081 mU/L accompanied with slightly elevated FT3 (5.79 pmol/L, normal range: 2.63–5.70 pmol/L), normal FT4, and positive aTG. US showed slightly reduction of the nodules (red asterisk) and an enlargement of thyroid parenchyma (white asterisk). The patient received thyroid scintigraphy, based on which a diagnose of hyperthyroidism was established, and took thiamazole for treatment. (C) At 6-month follow-up, the patient returned to subclinical status (decreased TSH level of 0.003 mU/L, normal FT3 and FT4), and US showed a significantly reduction of the nodules (red asterisk) but deceased, heterogeneous thyroid parenchyma (white asterisk). aTG: Thyroglobulin antibody; BMI: Body mass index; BTNs: Benign thyroid nodules; FT3: Free triiodothyronine; FT4: Free thyroxine; RFA: Radiofrequency ablation; TSH: Thyrotropin; US: Ultrasonography.Although TA causes follicle destruction and hormone release, it does not cause severe thyroid emergencies in these patients. It has also been proven by previous studies that TA can be applied in patients with AFTNs.[4] The use of preoperative antithyroid medication could partly explain this finding since most patients with AFTNs received antithyroid treatment to maintain a nearly euthyroid state before undergoing TA. However, most patients in our study did not receive any preoperative preparation. An increased but slow release of thyroid hormone, instead of an abrupt release, following ablation would be another possible reason. This is probably because TA usually causes coagulative necrosis, which rarely leads to uncontrolled release of thyroid hormone. Therefore, even in patients with pre-existing thyrotoxicosis, TA cannot trigger perioperative TS and should be safe. In addition, for these patients, TA treatment not only achieved remarkable nodule shrinkage but also had a therapeutic effect on thyroid function normalization. In our current study, 76.9% of patients returned to an euthyroid status after their BTNs were treated with TA. It is likely that these BTNs were the etiology of thyrotoxicosis in these patients, as the nodules produced redundant thyroid hormones, and the coagulative necrosis and following fibrotic changes caused by TA damaged the functional follicle structures in the nodules. This is similar to TA treatment for AFTNs in that the procedure could help normalize thyroid function in 24%–86% of patients or lower the dosage of antithyroid medicine.[4] However, the risk of developing overt thyrotoxicosis in these patients should also be noted. This complication tended to occur in patients with a larger ablated volume and higher BMI in our study. There are some possible explanations: (1) Larger ablated areas would cause a larger and longer-lasting release of functional thyroid hormone into the bloodstream. (2) Although it is believed that TA only affects the targeted nodules, some techniques, such as radiofrequency ablation, may still deliver some energy to the surrounding tissue, thus representing a risk of inducing thyrotoxicosis.[5] (3) The development of autoimmune thyroiditis after ablation may occur because TA could lead to massive release of partially denatured thyroglobulin, which could be the reason underlying immune responses. (4) Increased BMI is correlated with the presence and size of thyroid nodules and an increased risk of thyroid autoimmunity. This indicates that patients with higher BMI would have larger ablated nodules, and autoimmune thyroiditis would probably occur more easily with the combination of increased BMI and ablation, easily causing thyroid function deterioration. Therefore, for these patients, especially those with a large targeted volume, a two-step ablation plan and close monitoring of thyroid function after TA are needed. Some limitations of this study should be considered. First, thyroid scintigraphy was not performed in all patients, although regular long-term follow-ups of thyroid function were performed in these patients before TA. In addition, this study showed a possible tendency that functional deterioration may be related to a higher BMI and larger total ablated volume, but the small sample size made it difficult to draw reasonable conclusions or to identify possible risk factors. Further studies with larger sample sizes and more patient details are needed. In conclusion, TA treatment of BTNs could be considered basically safe and effective in patients with pre-existing thyrotoxicosis. TA could achieve significant nodule shrinkage and normalize thyroid function without causing perioperative TS in most of these patients. It should also be noted that developing overt thyrotoxicosis in these patients tended to be associated to a higher BMI and larger ablated volume, and so these patients should also be aware of this possible condition. Conflicts of interest None.