Endocrinol Metab.  2024 Dec;39(6):827-838. 10.3803/EnM.2024.2079.

Long-Term Antithyroid Drug Therapy in Smoldering or Fluctuating-Type Graves’ Hyperthyroidism with Potassium Iodide

• Okamura K

• KMID: 2562709
• DOI: http://doi.org/10.3803/EnM.2024.2079

Abstract

Graves’ hyperthyroidism is characterized by stimulation of the thyroid gland by thyroid-stimulating hormone receptor antibodies (TRAbs). Antithyroid drug (ATD) continuation is recommended as long as the thyroid gland is stimulated. Goiter size, thyroidal ¹²³I uptake, serum thyroglobulin level, and TRAb positivity are reliable markers of thyroid stimulation. Attention must also be paid to the responsiveness of the thyroid gland due to the high prevalence of painless thyroiditis and spontaneous hypothyroidism during treatment. TRAbs disappeared at <5 years entering remission in 36.6% of patients (smooth-type), while re-elevation of TRAb activity occurred in 37.7% (fluctuating-type) and remained positive for >5 years in 21.1% (smoldering-type). Seven percent of patients remained positive for TRAbs for >30 years, requiring life-long ATD treatment. Remission occurred after median 6.8 years (interquartile range, 4.0 to 10.9) of ATD treatment in 55% of patients. However, late relapse may occur after stressful events (dormant type). In apparently intractable Graves’ disease (GD) with a large goiter (>40 g), ¹³¹I therapy should be considered. For initial and long-term ATD treatment, we must choose effective, safe, and economical drugs such as 100 mg potassium iodide (KI), although KI sensitivity varies in patients with GD. Thionamide, which has notorious side effects, is added only during the KI-resistant period.

Keyword

Hyperthyroidism; Graves disease; Antithyroid agents; Iodides; Thyrotropin-binding inhibitory immunoglobulin

Figure

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  Fig. 1. Thyroid-stimulating hormone (TSH)-dependent increase of thyroidal radioactive iodine uptake (RAIU) in reversible hypothyroidism [27]. The latent hypothyroidism (LH; TSH <40) and reversible hypothyroidism (RH; TSH >40) groups were subdivided depending on their serum TSH levels. The correlation between serum TSH levels and RAIU values in the pituitary insufficiency (PI), euthyroid normal subjects (EU), euthyroid chronic thyroiditis (CE), LH, and RH groups was significant (r=0.6203, P<0.001) [27]. Although %/24 hours values are shown in this figure, the 1-day method measuring 5 hours uptake is more convenient and was used in later studies [12,65]. GV, thyrotoxic Graves’ disease stimulated by TRAb; TRAb, TSH receptor antibody; PT, painless thyroiditis; HG, primary hypothyroidism after 131I therapy for Graves’ disease; IH, irreversible overt primary hypothyroidism.

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  Fig. 2. Thyroid stimulation indices (TSIs) and the prognosis of the patients with treated Graves’ disease [10]. Numbers in the column are the percentage of patients in each group. Numbers in parentheses are the number of patients. Remission: the patient remained euthyroid after the withdrawal of antithyroid drugs for more than 1 year. Late relapse: relapse occurred after >1 year. Early relapse: relapse occurred within 1 year. The number of positive TSIs and the prognosis are also shown [10]. RAIU ↑, thyroidal radioactive iodine uptake (>25%/5 hours when serum thyroid-stimulating hormone [TSH] level was normal or >10% when serum TSH level was suppressed); thyroid weight ↑, estimated thyroid weight (>40 g or audible bruit); TRAb(+), positive TSH receptor antibody; serum Tg ↑, serum thyroglobulin (>100 ng/mL).

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  Fig. 3. Three factors that are important in clinical thyroidology and for considering the prognosis of Graves’ hyperthyroidism. In the thyrotoxic state, if a suppressed thyroid-stimulating hormone (TSH) level is confirmed, no further TSH measurements are necessary and free thyroxine (fT4) and free triiodothyronine measurement are useful while the patient remains thyrotoxic. TSH should be measured after the patient becomes euthyroid on treatment. TRAb, TSH receptor antibody.

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  Fig. 4. (A) Time until the first disappearance of serum thyroid-stimulating hormone binding inhibitor immunoglobulin (TBII) activity after the initiation of thionamide treatment in Graves’ hyperthyroid patients [12]. The distribution pattern was normal after logarithmic conversion. Patients who became TBII-positive again were classified as fluctuating-type (shaded). Forty-three (7.8%) of the patients remained TBII-positive during the observation period. Cases in which remission was achieved are indicated with closed circles. (B) The cumulative percentage of patients who entered remission is indicated with closed circles [12]. Similar results reported in children with Graves’ disease by Leger et al. [15] and Ohye et al. [16] are shown for comparison. SD, standard deviation.

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  Fig. 5. Changes in the serum thyroid-stimulating hormone (TSH) binding inhibitor immunoglobulin (TBII) activity during the longterm follow-up of patients with Graves’ hyperthyroidism who were initially treated with thionamide [12]. (A) Smooth-type patients in whom TBII became negative within 5 years and remained negative. Smoldering-type patients in whom TBII remained positive for more than 5 years. (B) Fluctuating-type patients in whom TBII was negative before therapy or positive TBII became negative once within 5 years, but an increase in the TBII activity was observed during the clinical course. In the fluctuating-type, only patients who did not enter remission are shown. Late relapse after 1 year was defined as the dormant type. The normal range of the serum TBII level is <15%. The median and interquartile range are shown in the smooth-type or smoldering-type. The percentage of patients in each group and the percentage of patients in remission and with spontaneous hypothyroidism (Spontan.hypo) in each group are also shown [12].

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  Fig. 6. The inhibition of organification of iodide by excess iodide in rat thyroid lobes in vitro [60]. Rat thyroid lobes were incubated in 5 mL of Eagle’s solution (0.01–100 μM 127I, 20 μCi 131I, and 5 mU/mL bovine thyroid-stimulating hormone) for 8 hours and analyzed after anaerobic digestion with pronase and ascending paper chromatography. The absolute amount of iodide incorporated into newly synthesized monoiodotyrosine (MIT), diiodotyrosine (DIT), triiodothyronine (T3), thyroxine (T4), or total organified iodine synthesized after 8 hours incubation in the presence of various amounts of iodide is shown [60].

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  Fig. 7. Changes in serum free thyroxine (fT4) levels in patients with untreated Graves’ hyperthyroidism who were initially treated with 100 mg of potassium iodide (KI) [65]. (A) A1: Patients who became hypothyroid with an elevated serum thyroid-stimulating hormone (TSH) level. When the KI dosage was reduced (tapering), the re-elevation of the serum fT4 level was frequently observed, as shown with an open circle. Therefore, the KI dosage was fixed at 100 mg and the patients were treated with KI+L-thyroxine (T4) combined therapy, avoiding a decrease in the serum iodide level below the threshold of the Wolff-Chaikoff effect (KI fixed). A2: Patients who became euthyroid with a normal TSH level. (B) B1: The serum fT4 level initially became low, but the TSH level remained suppressed. B2: The serum fT4 and free triiodothyronine (fT3) level initially became normal, but the TSH level remained suppressed. B3: The serum fT4 level initially became normal, but the fT3 level remained high (T3 toxicosis). (C) The serum fT4 level decreased, but remained above the normal range. KI-partially sensitive (B) or KI-resistant patients (C) were treated with combined KI and methylmercaptoimidazole (MMI) therapy (shown by open circles). The percent of patients in each group (upper row) and the long-term prognosis (remission and spontaneous hypothyroidism [Spont. hypo.]) in each group (lower row) are also shown [65].

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  Fig. 8. The long-term clinical course of Graves’ disease treated with antithyroid drugs (ATDs) including excess iodide, disease progression (left) and recovery (right) [12,65]. Underlined numbers indicate the percentage of patients who were expected to recover to the upper stage in this figure. T-cell abnormality includes lymphocytic infiltration in the thyroid gland and spontaneous hypothyroidism in the recovery phase, which was found in 6% of the patients. Stress includes social, economic, emotional, physical, familial stress or pregnancy. ST-ATD, short-term ATD therapy <5 years; LT-ATD, long-term ATD therapy >5 years; TRAb, thyroid-stimulating hormone receptor antibody; fT4, free thyroxine.

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