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. 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 123 I 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. In rat thyroid lobes in vitro , the absolute amount of thyroid hormone synthesis was inhibited in the presence of iodide at a concentration of >2.5 µM. In the presence of 100 µM iodide, the organification of iodide was almost completely inhibited ( Fig. 6 ) [ 60 ], whereas in the model iodinating system, iodination was inhibited in the presence of >1 mM iodide [ 46 ]. The inhibitory effect of excess iodide is complicated in comparison to the apparent inhibitory effect of TPO by thionamide, and is best explained by competition between iodide and tyrosyl residues of the protein for active iodine or for a site or sites on the enzyme [ 46 ]. KI THERAPY IN GRAVES’ DISEASE After Dr. THE RE-CLASSIFICATION OF GRAVES’ DISEASE: KI-SENSITIVE VERSUS KI-RESISTANT WITH TSH SUPPRESSION The second type of GD classification may be (1) KI-sensitive and (2) KI-resistant, including KI-partially sensitive with suppressed TSH, which could be diagnosed early in the treatment of GD. If GD patients are KI-sensitive, they may not require thionamide, and the remission rate, including spontaneous hypothyroidism, is expected to be 70% or approximately two-thirds ( Fig. 7 ). The pituitary gland is a wise organ, and if serum TSH levels are suppressed, even when fT4 and free triiodothyronine levels are normal, the prognosis is poor ( Fig. 7 ). KI-resistant patients require combined KI and MMI therapy, and the prognosis may be poor. There may still be an approximately 30% chance of remission; however, LT persistent treatment may Our unpublished data suggest that when the thyroid gland is >100 g, the chance of remission is only 8%. Regarding the thyroid weight in the smoldering-type, the median estimated thyroid weight before and after treatment was 31 g (interquartile range, 22 to 41) and 10 g (interquartile range, 10 to 19), respectively, in the remission group ( n =30), and 33 g (interquartile range, 24 to 46) and 49 g (interquartile range, 20 to 71) in the non-remission group ( n =86), suggesting that goiter size may be associated with the stimulating effect of TRAb in predicting a poor prognosis. LT-ATD: HOW LONG? TSH should be measured after the patient becomes euthyroid on treatment. TRAb, TSH receptor antibody. 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. 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. hypo.]) in each group (lower row) are also shown [ 65 ]. 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.