Povidone-iodine-induced transient triiodothyronine thyrotoxicosis in a Japanese patient with prolonged habitual gargling: A case report and literature review

Rationale: Iodine-induced hyperthyroidism and triiodothyronine (T3) thyrotoxicosis in patients who routinely gargle with povidone-iodine (PVP-I) gargling solution are rare in Japan. Patient concerns: A 50-year-old man presented to our hospital for a close examination of an enlarged thyroid, which was noted during a complete health checkup. The thyroid was slightly enlarged with no palpable nodules. He had an increased appetite but no weight gain. He had been routinely gargling with PVP-I gargling solution 4 times daily for >10 years. He had no history of thyroid disease. Diagnoses: Test results revealed suppressed thyroid-stimulating hormone, normal free thyroxine, and increased free triiodothyronine levels, leading to the diagnosis of T3 thyrotoxicosis. Interventions: The patient agreed to stop gargling with PVP-I gargle solution. Outcomes: The free triiodothyronine and thyroid-stimulating hormone levels returned to normal at 18 and 21 weeks, respectively, after discontinuation of PVP-I gargling. After an improvement in thyroid function, he gained 5 kg in 1 year. Lessons: To our knowledge, this is the first case report that describes PVP-I gargle-induced T3 thyrotoxicosis in a healthy individual without thyroid disease. In Japan, which is an iodine-sufficient country, considering the possibility of high-dose iodine intake-induced thyrotoxicosis due to long-term PVP-I gargling or other causes is necessary, even in individuals with no history of thyroid disease.


Introduction
Povidone-iodine (PVP-I) gargles have been commonly used in Japan and other countries for decades. [1]PVP-I gargles marketed in Japan contain 7 mg of effective iodine in 1 mL of undiluted solution. [1]Gargling with 4 mL of the solution containing 7% PVP-I results in the absorption of approximately 4.2 mg or 10% of total iodine through the oral mucosa or gastrointestinal tract. [2]While Graves' disease, multinodular disease, iodine-deficiency goiter, and Hashimoto's thyroiditis have been described as predisposing factors for hyperthyroidism caused by iodine overdose, limited reports exist on iodine-induced hyperthyroidism in the absence of thyroid disease. [3,4]Reports of triiodothyronine (T3) thyrotoxicosis are even rarer.
Here, we report a Japanese man with transient T3 thyrotoxicosis developed due to habitual gargling with a 7% PVP-I gargling solution for >10 years.The patient had no underlying thyroid disease.

Case presentation
A 50-year-old man presented to our hospital for a close examination of an enlarged thyroid gland, which was noted during a complete health checkup.He had an increased appetite but no weight gain.His social history was negative for alcohol consumption or smoking.His medical history was significant for hyperlipidemia, and family history, for hypertension and diabetes mellitus.The patient had no history of thyroid disease.The The patient provided written informed consent for the publication of this case.

The authors have no funding and conflicts of interest to disclose.
Data sharing not applicable to this article as no datasets were generated or analyzed during the current study.
Suzuki R and Suzuki S • (2023) 102:34 Medicine patient was taking antihyperlipidemic medication (statin).He had routinely gargled with 7% PVP-I gargling solution (30 mL/ bottle, Isodin Gargle) 4 times daily for >10 years.Informed consent was obtained from the patient for the publication of this case.
On examination, he was 63.9 kg and 176.1 cm tall, with a body mass index of 20.6 kg/m 2 .His blood pressure was 113/68 mm Hg, with a pulse rate of 84 beats/min.The thyroid was slightly enlarged with no palpable nodules.He had no history of ophthalmopathy.The thyroid-stimulating hormone (TSH) level was suppressed to 0.01 μIU/mL (reference range 0.46-3.50μIU/ mL), and the free triiodothyronine (FT3) level had increased to 5.1 pg/mL (reference range 2.2-4.1 pg/mL).His free thyroxine (FT4) level was 1.1 ng/dL (reference range 0.8-1.6 ng/dL).The hormonal profile indicated T3 thyrotoxicosis.The patient tested negative for antithyroid-stimulating hormone receptor (third generation), antithyroid peroxidase (anti-TPO), and antithyroglobulin (anti-TG) antibodies.Thyroid ultrasonography revealed enlarged and poorly perfused lobes.Internal echogenicity was somewhat uneven, and small cysts were observed in the lobes.He agreed to stop gargling with the 7% PVP-I gargling solution.Therefore, a non-iodine-containing gargling solution (azulene sulfonate-containing solution: Azunol) was prescribed.
Blood tests performed 18 weeks (126 days) after the discontinuation showed FT3 levels within the normal range (TSH, 0.17 μIU/mL; FT3, 3.9 pg/mL; and FT4, 0.9 ng/dL).Thyroid radioiodine scintigraphy performed 128 days after the PVP-I gargling discontinuation at another hospital showed a 5% decrease in radioiodine uptake at 24 hours.Blood tests performed 21 weeks (147 days) after the PVP-I gargling discontinuation showed TSH levels within the normal range (TSH, 0.94 μIU/mL; FT3, 3.4 pg/mL; FT4, 0.8 ng/dL; thyroglobulin, 28.6 ng/mL), indicating improvement in T3 thyrotoxicosis.Thyroid ultrasonography performed 21 weeks (147 days) after the PVP-I gargling discontinuation showed a reduction in the short axis of the lobes and a normalization of blood flow in the lobes compared to the corresponding findings immediately after gargling discontinuation.The improvement in thyroid volume was attributed to the discontinuation of high-dose iodine loading.Thereafter, the patient's thyroid autoantibody titers have been negative throughout the disease course, and he has been euthyroid for >2 years (Fig. 1).After an improvement in thyroid function, he gained 5 kg in 1 year.

Discussion
Our patient showed decreased radioiodine uptake and no increase in blood flow on color Doppler thyroid ultrasonography, suggesting the need to differentiate between painless thyroiditis, a common condition, and iodine-induced hyperthyroidism.Painless thyroiditis is generally associated with a family history of autoimmune thyroid disease and is characterized by positive thyroid autoantibodies such as anti-TPO and anti-TG antibodies. [5]In the present case, the patient tested negative for thyroid autoantibodies throughout the disease course.Moreover, painless thyroiditis occurs when the thyroid tissue is destroyed, and thyroid hormones leak into the blood, and it is usually associated with increased blood levels of both T3 and thyroxine, but not T3 alone.The patient had T3 thyrotoxicosis, with FT4 levels within the normal range throughout the disease course (Fig. 1), and the FT3/FT4 was >3.1 [5] ; these findings are inconsistent with painless thyroiditis.
Iodine-induced hyperthyroidism is observed in iodine-deficient areas and is uncommon in Japan, an iodine-sufficient country where excessive iodine intake appears to be common. [6]n Japan, iodine-induced hyperthyroidism is rare in patients without thyroid disease, [6] but thyrotoxicosis induced by the excessive consumption of Japanese kombu (kelp) has been reported. [7]T3 thyrotoxicosis is extremely rare. [8]In healthy individuals without thyroid disease, short-term gargling with PVP-I is generally safe, but long-term gargling with PVP-I has been reported to induce thyroid dysfunction. [1,2]Reported cases of PVP-I gargle-induced thyroid dysfunction in healthy individuals include hypothyroidism [1,9] ; reports of iodine-induced hyperthyroidism are rare.
0,18] To the best of our knowledge, only 2 cases of T3 thyrotoxicosis due to iodine-induced hyperthyroidism have been reported to date. Moreover, Lee et al [19] reported T3 thyrotoxicosis in 1 of 49 patients without thyroid dysfunction at baseline who received a single dose of contrast agent for computed tomography.This case is not included in Table 1 because their study was not a case report. They did not prode information on thyroid disease, such as the presence or absence of antithyroid antibodies.

Conclusion
To the best of our knowledge, this is the third case of iodine-induced T3 thyrotoxicosis and the first case of PVP-I gargle-induced T3 thyrotoxicosis in a healthy individual without thyroid disease, evaluated using thyroid scintigraphy and thyroid ultrasonography and followed up for 2 years.Even in Japan, an iodine-sufficient country, considering the possibility of highdose iodine intake-induced thyrotoxicosis due to long-term PVP-I gargling or other causes is necessary, even in individuals with no family history of autoimmune thyroid disease or negative thyroid autoantibody test results.Only FT3 increased CT = computed tomography, FT3 = free triiodothyronine, PVP-I = povidone-iodine, T3 = triiodothyronine, T4 = thyroxine.

Table 1
Cases of iodine-induced hyperthyroidism with no history of thyroid diseases.