Ken Okamura

doi:10.3803/EnM.2024.2079

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Review Article Thyroid Long-Term Antithyroid Drug Therapy in Smoldering or Fluctuating-Type Graves’ Hyperthyroidism with Potassium Iodide Keypoint - In Graves' hyperthyroidism, antithyroid drugs may be required as long as the thyroid gland is stimulated, especially in the smoldering or fluctuating types of the condition. - Potassium iodide is safe and useful for initial and long-term treatment of Graves' hyperthyroidism, especially to induce remission in patients with Graves’ disease who exhibit thionamide-associated side effects.: Ken Okamura; Endocrinology and Metabolism 2024;39(6):827-838.
DOI: https://doi.org/10.3803/EnM.2024.2079
Published online: October 16, 2024

Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

Corresponding author: Ken Okamura. Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Higashi-ku, Fukuoka 812-8582, Japan Tel: +81-92-642-5256, Fax: +81-92-642-5271, E-mail: ken.okamura.439@m.kyushu-u.ac.jp

• Received: July 1, 2024 • Revised: July 9, 2024 • Accepted: July 14, 2024

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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ABSTRACT
INTRODUCTION
HOW TO EVALUATE THYROID STIMULATION BY THYROIDSTIMULATING HORMONE IN REVERSIBLE HYPOTHYROIDISM
HOW TO EVALUATE THYROID STIMULATION BY TRAb IN GRAVES’ DISEASE
THE RESPONSIVENESS OF THE THYROID GLAND ITSELF TO STIMULATION
THE CLASSIFICATION OF SMOOTH, FLUCTUATING, AND SMOLDERING GRAVES’ DISEASE
DRUGS USED FOR LT-ATD
WOLFF-CHAIKOFF EFFECT
KI THERAPY IN GRAVES’ DISEASE
STRATEGY FOR KI-PARTIALLY SENSITIVE OR KI-RESISTANT GRAVES’ DISEASE
THE RE-CLASSIFICATION OF GRAVES’ DISEASE: KI-SENSITIVE VERSUS KI-RESISTANT WITH TSH SUPPRESSION
ENLARGING GOITER VERSUS SHRINKING GOITER
LT-ATD: HOW LONG?
LT-ATD OR RI THERAPY?
LT-ATD IN CHILDREN
CONCLUSIONS
Article information
References

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

INTRODUCTION

Graves’ hyperthyroidism (also known as Graves’ disease [GD]) is characterized by a stimulated thyroid gland, with small follicles containing tall stimulated epithelial cells. Most colloids are hydrolyzed and depleted. It is reasonable to suggest that antithyroid drugs (ATDs) may be required as long as the thyroid gland is stimulated. After the introduction of thioureylene [1], an ATD that reversibly or irreversibly blocks thyroid peroxidase (TPO) [2], the efficacy of relatively long-term (LT) treatment without limiting the treatment period has been suggested [3-14], especially in children [15,16] or patients with ophthalmopathy as a complication [17,18]. However, for ATD treatment of GD, a relatively short-term course has been recommended [19,20], probably because of the low reported incidence of lasting remission [21], as short-term treatment avoids unnecessary delays and expenses in patients who will eventually require ablative therapy. Recently, Azizi et al. [22-24] stressed the significance of LT-ATD treatment for 5 to 10 years. In this review, I will introduce our ATD therapy strategy depending on the pathophysiology of the thyroid gland and the different reactions of each patient to initial treatment namely, individualized strategies for GD treatment. The pathophysiology of goitrous reversible hypothyroidism (RH) is highly indicative of the stimulation of the thyroid gland [25-30].

HOW TO EVALUATE THYROID STIMULATION BY THYROIDSTIMULATING HORMONE IN REVERSIBLE HYPOTHYROIDISM

RH was initially reported after excessive ingestion of seaweed in a male patient who became strongly positive for antithyroid autoantibody after an episode of hypothyroidism, suggesting the exacerbation of Hashimoto thyroiditis [25]. A potassium iodide (KI) challenge test with a dose of 100 mg induced RH again, but a 10 mg dose did not. Subsequently, many patients with RH have been reported [26-30]. The characteristics of RH are (1) a large goiter [25,26]; (2) increased thyroidal radioactive iodine uptake (RAIU) [25-27]; (3) elevated serum thyroglobulin (Tg) levels [28]; and (4) a high prevalence of renal dysfunction [29]. Interestingly, goiter enlargement, high RAIU (Fig. 1) [27], and elevated serum Tg [28] have been found to be thyroid-stimulating hormone (TSH) dependent, and these markers become almost normal when patients spontaneously become euthyroid. Therefore, these are reliable markers of thyroid gland stimulation by endogenous TSH.

Evaluating thyroid gland stimulation in treated euthyroid GD patients was difficult. After the introduction of the sensitive TSH assay [31], high RAIU values in patients with suppressed TSH levels (Fig. 1) suggested that the thyroid gland might be stimulated by other signaling molecules, which were later found to include TSH binding inhibitor immunoglobulin (TBII) or TSH receptor antibody (TRAb) [32,33]. Although the clinical significance of the measurement of TRAb was initially debated [34], it is now considered useful for the diagnosis and follow-up of GD [35,36].

HOW TO EVALUATE THYROID STIMULATION BY TRAb IN GRAVES’ DISEASE

In 1991, Ikenoue et al. [10] evaluated the utility of the presence of (1) a large goiter, (2) high RAIU, (3) elevated serum Tg levels, and (4) TRAb positivity in predicting the relapse of GD after ATD withdrawal (Fig. 2). Elevated serum Tg levels had been reported in GD [37]. If one of these thyroid stimulation indices (TSIs) was positive, the relapse rate after ATD withdrawal was as high as 70% to 95%. The most sensitive index was the estimated thyroid weight. However, even if the index was negative, there was still a high risk of GD relapse (20% to 50%). The relapse of GD in TRAb-negative patients was later shown to involve a fluctuating-type TRAb pattern [12], as discussed later.

The combined evaluation of these TSIs was more useful in predicting relapse. If more than three indices were positive, the relapse rate was 100%. However, even if all the indices were negative, the risk of early relapse within 1 year was still approximately 10%, and the risk of late relapse after 1 year was approximately 4%, suggesting “dormant GD” resembling a dormant volcano. The estimated thyroid weight and TRAb measurements are simple and convenient markers of GD relapse.

We experienced (1) a severe exacerbation of ophthalmopathy when a patient became hypothyroid after an ATD overdose and (2) the onset of atrial fibrillation after the relapse of GD. Therefore, our policy is to avoid iatrogenic hypothyroidism and the exacerbation of GD during ATD treatment as much as possible.

THE RESPONSIVENESS OF THE THYROID GLAND ITSELF TO STIMULATION

We have reported several cases of primary hypothyroidism with strong TRAb positivity, sometimes blocking-type (TSBAbs) and other stimulating-type (TSAb) [38]. Severe hypothyroidism was observed in some goitrous patients in whom the thyroid gland was replaced with infiltration of many lymphocytes, severely damaged epithelial cells, and fibrosis, despite extremely elevated serum TSH levels and the presence of TSAb [38]. It was then suggested that the morphological changes and responsiveness of the thyroid gland to the stimulator are important.

Recently, we reported a high incidence of painless thyroiditis (PT) mimicking the relapse of GD during the clinical course of GD [39]. Interestingly, most patients achieved remission after an episode of PT. Our preliminary data suggested that the incidence of PT during the treatment of GD might be higher than expected, similar to the incidence of spontaneous hypothyroidism (6%) [12], suggesting the importance of immunological perturbation within the thyroid gland itself in the same patient during the long clinical course of GD. In complicated cases, RAIU remains a useful marker for evaluating changes in the thyroid gland (Fig. 1). The remission of GD has been reported to be associated with histological changes in the thyroid gland in patients with chronic thyroiditis [40].

Therefore, when evaluating the prognosis of GD, we must consider three factors: (1) function, (2) morphology, and (3) immune mechanisms (Fig. 3). Immunological disorders usually persist. Most patients with systemic lupus erythematosus or rheumatoid arthritis may require LT persistent treatment.

THE CLASSIFICATION OF SMOOTH, FLUCTUATING, AND SMOLDERING GRAVES’ DISEASE

It is rather difficult to consider the general prognosis of GD and it is challenging to initially classify the type of GD, because even persistent intractable GD may show only mild thyrotoxicosis at the onset. Therefore, one possibility for classification is to consider the clinical course of treatment.

In 2019, Bandai et al. [12] reported a LT (5 to 30 years) follow-up study of GD patients initially treated with thionamide. The median time to the first disappearance of serum TRAb was 1.5 years (Fig. 4), but in approximately half of the patients, re-elevation of TRAb activity was observed, suggesting “fluctuating-type” GD (Figs. 4, 5). Remission was observed after median 6.8 years (interquartile range, 4.0 to 10.9) of treatment. The cumulative remission rate was 54.8%. The other patients were treated with ablative therapy or LT-ATD. Approximately 8% of patients remained TRAb-positive during the entire observation period (Fig. 4).

GD was then classified into three types depending on the TRAb response pattern: (1) smooth (TRAb became negative within 5 years and remained negative afterward, suggesting remission); (2) fluctuating (TRAb became negative once within 5 years but later became positive again); and (3) smoldering (TRAb remained positive over 5 years, requiring LT-ATD or ablation) (Figs. 4, 5).

Remission or spontaneous hypothyroidism was observed in 89% and 6.0% of patients with smooth-type GD, 37% and 6.0% of those with fluctuating-type GD, and 20% and 6.0% of those with smoldering-type GD, respectively (Fig. 5). Ablation therapy was performed in 20% of cases, mainly in smoldering-type cases involving a large goiter, and in fluctuating-type cases because there is a Japanese saying that “what happens twice will happen three times.”

DRUGS USED FOR LT-ATD

As a medical treatment for GD, iodide therapy proposed by Plummer [41], thionamide therapy proposed by Astwood [42], and ¹³¹I therapy (radioactive iodine [RI]) proposed by Hertz and Roberts [43] have shown monumental progress. When we began to treat patients with GD around 1980, we soon realized that methylmercaptoimidazole (MMI) was more effective than propylthiouracil [44], and a small single daily dose of MMI (15 mg) was as effective as a divided dose of MMI (30 mg) [45], providing evidence by the perchlorate (KClO₄) discharge test. Thereafter, a single daily dose of MMI (15 mg) became the standard initial treatment for GD at our clinic. However, this strategy was established more than 40 years ago.

In this era of evidence-based medicine and randomized controlled trials, individualized therapy remains important. When patients have severe conditions such as thyroid storm or atrial fibrillation, a large dose of ATD might be required. However, in patients with mild GD who lead ordinary daily lives, there is a risk of ATD overdose due to the high prevalence of side effects and the exacerbation of ophthalmopathy by iatrogenic hypothyroidism.

Thionamide ATDs contain an S=C-N structure, resembling that of K-C≡N or potassium cyanide. Cyanide is also a potent inhibitor of TPO [46]. Thionamides have a high risk of various side effects [47-52]. Fatal cases of agranulocytosis have been reported every year in Japan [53]. Unexpected side effects, including anti-insulin antibody production [54], uveitis in human T-cell leukemia virus type 1 (HTLV-1)-positive patients [55], and pancreatitis [56], have been reported. By contrast, KI has a simple structure without significant severe side effects.

WOLFF-CHAIKOFF EFFECT

The blocking of the organification of iodide by excess iodide, the so-called Wolff-Chaikoff effect, was reported in 1948 [57] and clearly shown in the rat thyroid in vivo by Nagataki and Ingbar [58] and Inoue and Taurog [59], and in vitro using rat thyroid lobes [60]. It was also demonstrated in a model system of Tg iodination using purified TPO [46]. 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. Inoue, who received the Van Meter Award in 1967 for his outstanding research on the effects of iodide in the iodine-deficient thyroid gland, returned to Japan in 1973, we began to treat mild GD patients with KI, which is associated with extremely rare side effects. The only significant side effect may be the induction of hypothyroidism in patients with autoimmune thyroid disorders, which may be troublesome in cases of euthyroid Hashimoto thyroiditis, as mentioned previously [25-30], but may be beneficial in hyperthyroid GD. The problem may be the different sensitivities to excess iodide in each patient, probably due to the complicated autoregulation system in the thyroid gland [61], including the inhibition of the Na-iodide symporter by excess iodide [62] or the presence of renal dysfunction [29].

In 2014, we reported the effectiveness of KI in inducing remission in patients with GD who exhibited thionamide-associated side effects [63]. The average duration until remission was 7 years, which was comparable to that observed in patients treated with thionamide [12]. Administration of ≥100 mg of KI resulted in a serum iodide concentration exceeding 2.5 µM. The clear relationship between iodine intake and urinary iodide excretion suggests that excess iodide that does not enter the thyroid gland is promptly excreted into the urine [63].

We then tried KI therapy for untreated GD complicated with malignancy, avoiding the risk of thionamide-associated neutropenia [64]. KI (100 mg) promptly reduced serum free thyroxine (fT4) levels in elderly patients and could be continued despite severe neutropenia during chemotherapy.

In 2022, we reported the effect of KI (100 mg) in 504 patients with untreated GD [65]. As shown in Fig. 7, 33.6% or one-third of the patients (A1 and A2 groups) were KI-sensitive and did not require thionamide ATD treatment. It was important not to reduce the KI dosage when the patients became hypothyroid and to treat them with KI and L-thyroxine combined therapy.

STRATEGY FOR KI-PARTIALLY SENSITIVE OR KI-RESISTANT GRAVES’ DISEASE

Although the interaction between the antithyroid effect of KI and MMI is very complicated, especially in iodine deficiency [66,67], the clinical effect of MMI and KI was additive when a large dose of KI was administered to KI-resistant patients (Fig. 7). After combined KI+MMI therapy, KI-resistant patients become euthyroid within 2 months [65]. After GD becomes less active, MMI can be withdrawn, and the patients can be managed with KI alone.

RI was performed as usual in persistent cases during KI therapy. Excess iodide is promptly excreted into the urine [63], and KI therapy does not interfere with the efficacy of RI [65]. The RAIU after withdrawal of KI for 4 to 7 days was 60.0%/5 hours, and 86.1% of patients became hypothyroid or euthyroid. The high RAIU values found in most patients suggested that RI was appropriately recommended for extremely stimulated active GD.

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 be required. These results support our “KI first,” “KI main,” and “KI or RI” strategies. Thionamide is only required by KI-resistant patients during the KI-resistant period.

ENLARGING GOITER VERSUS SHRINKING GOITER

Since the introduction of thionamide ATDs, it has been suggested that prolonged remission is more likely with a small goiter or with a decrease in goiter size during treatment [68,69]. Goiter size was also included in the Graves’ Recurrent Events After Therapy (GREAT) score [70]. 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?

Greer reported that short-term ATD therapy was useful for about one-third of patients with GD, and ATD could be stopped when the patient becomes euthyroid on ATD [71]. This may be the case for smooth-type GD. However, we have to recognize that LT-ATD may be required in another two-thirds of patients, and that remission can only be expected in about one-third of these patients. The next question is for how long the LT-ATD therapy should be administered. It may be more than 5 years, 10 years, or life-long [5]. All thyroidologists who lend an ear to patient complaints may realize that GD is a psychosomatic immunological disorder frequently triggered and aggravated by stress [72]. Life is full of stress. There is a Japanese saying that “10 years can bring a lot of changes.” Ten years may be required to overcome stress or for the stressful circumstances of patients to change. Psychiatric care may be required, and the doctor-patient relationship is important. Thyroid crisis most often occurs after self-interruption or inadequate interruption of ATD treatment.

LT-ATD OR RI THERAPY?

Our data suggest that more than 20% of patients with GD may require life-long ATD. An unsolved problem is the strategy for persistent GD “LT-ATD or RI?” This decision may depend on the patient’s choice. In our experience, it is almost 50:50 [12,65].

Regarding RI, concerns have been raised about the possibility of substituting a permanent disease requiring life-long treatment for a probably self-limited disease [8,73]. However, the treatment of hypothyroidism is usually simple. Most elderly patients in modern countries may have lifestyle diseases that require regular medical examinations. Therefore, stabilizing thyroid function using RI is a good alternative to LT-ATD treatment in patients with intractable GD and a large goiter.

LT-ATD IN CHILDREN

LT-ATD in children and adolescents is a bumpy road to follow [74]. Special attention must be paid to future pregnancy, especially in young female GD patients. It is recommended that KI be withdrawn in the latter half of pregnancy, when the amelioration of GD activity is observed [75]. KI may affect the fetal thyroid gland after the onset of iodothyronine secretion, which may occur at 18 to 22 weeks of gestation. However, the administration of large amounts of iodine during any stage of pregnancy seems to be much better than iodine deficiency [76]. The avoidance of hypothyroxinemia rather than hypothyroidism is most important during pregnancy, especially in the first trimester [76]. In young women with apparently intractable GD and a large goiter, our policy is to give the patients a chance to consider RI after they become >18 years of age, before marriage. TRAb activity should be monitored until its disappearance to avoid fetal thyrotoxicosis in future pregnancies.

CONCLUSIONS

The clinical course of GD suggested in our study is shown schematically in Fig. 8. LT-ATD may be required in two-thirds of patients with smoldering, fluctuating, or KI-resistant GD as long as the thyroid gland is stimulated. TRAb and the change in goiter size are useful for evaluating thyroid gland stimulation. KI is inexpensive, safe, effective, and suitable for initial and LT-ATD therapies. KI+MMI or RI is useful for KI-resistant GD, and a “KI first,” “KI main,” or “KI or RI” strategy may be useful for avoiding the notorious side effects of thionamide as much as possible. The doctor-patient relationship is the most important factor in LT-ATD therapy to keep GD dormant.

Article information

CONFLICTS OF INTEREST

No potential conflict of interest relevant to this article was reported.

Acknowledgements

The author thanks Dr. Brian Quinn for correcting the English language of the manuscript. This research did not receive any specific grants from any funding agency in the public, commercial, or not-for-profit sectors.

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.

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).

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.

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. (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].

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].

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].

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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Figure

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

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.

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).

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.

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. (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].

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].

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].

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