Comparison of Efficacy and Adverse Effects Between Methimazole 15 mg+Inorganic Iodine 38 mg/Day and Methimazole 30 mg/Day as Initial Therapy for Graves' Disease Patients with Moderate to Severe Hyperthyroidism

Abstract

Background:

Methimazole (MMI) is usually used at an initial dose of 30 mg/day for severe Graves' disease (GD) hyperthyroidism, but adverse effects are more frequent at this dose than at MMI 15 mg/day.

Objectives:

We designed a regimen to address the lack of a primary therapeutic effect of the MMI 15 mg/day by combining it with inorganic iodine at 38.2 mg/day. Our aim was to compare the two regimens (MMI 15 mg+inorganic iodine at 38.2 mg/day (M15+I) vs. MMI 30 mg/day (M30)) in terms of therapeutic effect, adverse effects, and remission rate.

Design and Patients:

In a prospective study, 310 patients with untreated GD (serum free thyroxine (fT4) ≥5 ng/dL) were assigned to one of the two regimens. Potassium iodide was discontinued in the M15+I group as soon as the serum fT4 level was within the reference range (0.8–1.6 ng/dL).

Results:

Percentages of patients achieving an fT4 level within reference range in ≤30, ≤60, or 90 days on the study treatment regimens were 45.3%, 73.9%, and 82.0% respectively for the M15+I group, and 24.8%, 63.1%, and 75.2% respectively for the M30 group. Hence, the proportions of patients achieving this goal in ≤30 or ≤60 days were significantly larger in the M15+I group. Adverse effects that required discontinuation of MMI were more frequent in the M30-treated than in the M15+I-treated group (14.8% vs. 7.5%; p=0.0387). The remission rates in the M15+I and M30 groups were 19.9% and 14.8%—higher in the former, but the difference did not reach statistical significance.

Conclusion:

The results of this study raise the possibility that M15+I is superior to M30 as a primary treatment for moderate to severe hyperthyroidism caused by GD.

Introduction

Antithyroid drugs (ATD) are the principal method of treating Graves' disease (GD). Nakamura et al. assessed the free thyroxine (fT4) ameliorating effect of low-dose methimazole (MMI; 15 mg/day) and high-dose MMI (30 mg/day) in untreated GD patients. They observed no difference between the therapeutic effects of these two MMI regimens for mild to moderate hyperthyroidism (fT4 <7.0 ng/dL when untreated), while for severe hyperthyroidism, the therapeutic effect at the low dose was significantly weaker than that at the high dose (1). There is also a report describing a similar high dose of the MMI pro-drug carbimazole as being necessary for severe hyperthyroidism (2). However, the risk of adverse effects of MMI reportedly increases in a dose-dependent manner, and mild (including pruritus and rashes) to severe (including agranulocytosis and granulocytopenia) adverse effects have been reported at higher rates with high-dose than with low-dose MMI administration (1,3 –5). Because of these findings, from the standpoint of its therapeutic effect, high-dose MMI has been recommended as early therapy in patients with moderate to severe thyrotoxicosis, but there is concern about adverse effects. Therefore, we speculated that if there were a treatment regimen in which the adverse effects that occur with high-dose MMI in patients with moderate to severe hyperthyroidism could be reduced and for which the therapeutic effect was higher than that achieved with low-dose MMI, this might be an ideal treatment regimen. It has been known for a long time that the administration of iodide ameliorates the symptom of hyperthyroidism and decreases the serum hormone concentration to the normal range in many patients in the initial period of the treatment. Thionamide drugs inhibit uptake and organification of iodide and hormone formation, and the decrease in thyroid hormone secretion is believed to occur through the depletion of thyroid hormones within the thyroid gland, In contrast, the effect of iodide on the decrease of serum hormone levels in GD occurs earlier than that of thionamides, and the rapid decrease in hormone secretion induced by iodine is due to an abrupt decrease in the thyroid hormone release (6,7). Furthermore, the thyroidal radioactive iodine uptake rate decreases with much smaller quantities of iodide in hyperthyroid patients than in euthyroid individuals; the uptake rate remains within the euthyroid range and absolute iodine uptake (AIU, stable iodine uptake to the thyroid) increases during treatment with iodide (6,8). The mechanisms resulting in a decrease of thyroid hormones in patients with GD is different between thionamides and iodide, and the combination of these two treatments could form an optimized treatment regimen. Indeed, in the American Thyroid Association Guidelines, the combined use of inorganic iodine and an ATD is clinically recommended for the rapid control of severe thyrotoxicosis (9). No study to date has comparatively assessed therapeutic responses to and untoward effects of low dose MMI+potassium iodide (KI) versus high-dose MMI in patients with moderate to severe GD, although there have been reports comparing MMI combined with inorganic iodine and MMI alone. In the present study, we compared the therapeutic effect, adverse effects, and remission rates of a treatment regimen that compensates for the inadequate efficacy of initial treatment with low-dose MMI by combining it with inorganic iodine, that is, MMI 15 mg+inorganic iodine 38 mg/day regimen (M15+I), and the conventional treatment regimen (MMI 30 mg/day; M30).

Subjects and Methods

We enrolled 310 patients with untreated GD examined at Ito Hospital during the period from August 2008 to November 2009 as study subjects. GD was diagnosed according to Japan Thyroid Association's diagnosis guidelines (www.japanthyroid.jp/doctor/guideline/english.html#basedou), and included clinical findings, measuring fT4, free triiodothryonine (fT3), thyrotropin (TSH), and TSH receptor antibody (TRAb) levels, and/or the determination of ¹²³I thyroid uptake. Of the patients with a history of ATD use, those who had been off this therapy for at least one year were included in the present study population (17 patients). The following conditions excluded patients from the study: pregnancy or lactation; relapse after subtotal thyroidectomy or radioiodine therapy; severe complications, such as heart failure and type 1 diabetes mellitus; glucocorticoid therapy or other drugs that may influence thyroid function; and concurrent thyroid nodules. The untreated GD patients who met the above inclusion criteria and who had fT4 values ≥5 ng/dL were assigned to a group treated with M15+I or a group treated with M30.

The assignment method was as follows. In treatment-naïve GD patients with baseline serum fT4 values >5.0 ng/dL, the MMI 15 mg+KI regimen was started during the first week, depending on the day of initial examination. They then received the MMI 30 mg regimen during the second week, and this alternate regimen process was thereafter repeated weekly.

The parameters assessed before treatment were: fT4, fT3, TSH, TRAb, total bilirubin (T-Bil), aspartate aminotransferase (AST), alanine aminotransferase (ALT), hematological values, and thyroid volume as measured by ultrasonography. In order to check for adverse effects and adjust the doses, patients were scheduled to visit the hospital at 2, 4, 6, 8, and 12 weeks after initiation of their treatment. Adverse effects of the drugs were systematically identified by careful health interview and clinical examinations. T-Bil, AST, ALT, and hematological values were measured for evaluation at every outpatient clinic visit. Serum fT4 values were determined by assay at 2, 4, 6, 8, and 12 weeks, and fT3 and TSH were measured at 4, 8, and 12 weeks. Our hospital obtained the values for serum fT4 and fT3 within 50 minutes after taking blood samples at the outpatient clinics, and doctors were thus able to select the ATD dose after checking hormone values.

We explained the treatment method, adverse effects of ATDs, and follow-up examinations after the start of treatment to all patients and obtained their informed consent. The full amounts of the drugs administered in both groups were prescribed so as to be taken by mouth after the morning meal. We used KI tablets (50 mg of KI is equivalent to 38.2 mg of iodide; Nichiiko Co. Ltd, Tokyo, Japan) for inorganic iodine at a dose of 38 mg/day.

The treatment method in the M15+I group consisted of continuing MMI at the 15 mg/day dose when the fT4 value improved to within the reference range (0.8–1.6 ng/dL) after the start of treatment and discontinuing the inorganic iodine. If the fT4 value subsequently rose again, the MMI dose was increased or KI was resumed. In the M30 group, the MMI dose was tapered when the fT4 value approached the reference range after the start of treatment. MMI was discontinued when patients remained in a euthyroid state (normal fT4 and TSH) for at least six months while receiving a minimum maintenance dose (MMI 5 mg every other day). After discontinuation of MMI therapy, the patients were followed with determinations of serum fT4 and TSH levels once every three to four months during the first year and biannually thereafter. Patients remaining euthyroid for at least one year were considered to have achieved remission.

A beta blocker was prescribed concomitantly to treat patients with tachycardia, and a concomitant antihistaminic agent was used when pruritus or a rash developed after the start of MMI. We assessed the two treatment groups using intention-to-treat analysis with respect to the number of patients attaining a serum fT4 level within the reference range in ≤30, ≤60, and ≤90 days after the start of study treatment, the types and prevalence of adverse reactions, and remission rates.

fT4, fT₃, and TSH were measured employing Elecsys fT4, fT3, and TSH assays (Roche Diagnostics GmbH, Mannheim, Germany). TRAb was measured with an Elecsys TRAb assay (Roche Diagnostics GmbH). Reference ranges for fT4, fT3, TSH, and TRAb were 0.8–1.6 ng/dL, 2.2–4.3 pg/mL, 0.2–4.5 μIU/mL, and <2.0 IU/L respectively. The upper limit of the assay range of fT3 and fT4 are 32.5 pg/mL and 7.77 ng/dL. Thyroid volume was determined by measuring the length (a, in mm), width (b, in mm), and depth (c, in mm) of each lobe of the thyroid gland ultrasonographically and then calculating its volume by the formula used in our hospital: thyroid volume=(0.7365×right lobe a×b×c+0.7412×left lobe a×b×c)−0.55.

Adverse effects were defined as:

• Pruritus and rashes: Skin manifestations persisting despite the use of antihistaminic agents, eventually necessitating discontinuation of MMI.

• Hepatic dysfunction: T-Bil>3.0 mg/dL, or ≥3-fold elevation of AST and/or ALT over reference range (AST >115 IU/dL, ALT >120 IU/dL) after the start of MMI therapy, and further exacerbation of AST and ALT elevation on re-examination performed during one to two weeks of ongoing MMI therapy.

• Granulocytopenia/agranulocytosis: Agranulocytosis was diagnosed when the neutrophil count fell to 500/mm³ or less according to a measurement performed after the start of treatment, and granulocytopenia was diagnosed when the neutrophil count fell to 1000/mm³ or lower.

This study was approved by the clinical research ethics committee of our hospital, and it was conducted by full-time staff physicians of our hospital with training and experience in thyroid practice.

Statistical analysis

Because they did not show normal distributions, the parameters assessed are all presented as median values (range), and the chi-square test or Wilcoxon rank-sum test was used to test for statistically significant differences between groups. The JMP10.0 software program (SAS Institute, Inc., Cary, NC) was used to perform the statistical analyses.

Results

Background factors of the subjects in the M15+I and M30 groups and their test results before treatment

The numbers of patients in the MI15+I and M30 groups were 161 and 149 respectively. There were no significant differences between the two groups in age, sex ratio, or any of the test results before treatment (Table 1).

Table 1.

Patient Background Factors in the M15+I and M30 Groups

		M15+I group (n=161)	M30 group (n=149)
Sex	Male: female	32:129	29:120
Age (years)	Median value (range)	36 (13–74)	34 (12–72)
fT4 (ng/dL)	Median value (range)	7.77 (5.0–7.77)	7.77 (5.0–7.77)
fT3 (pg/mL)	Median value (range)	24.1 (13.1–32.5)	25.8 (13.7–32.5)
TRAb (IU/L)	Median value (range)	19.5 (2.23–40.0)	22.2 (0.6–40.0)
Thyroid volume (g)	Median value (range)	40.7 (13.4–123.8)	42.7 (14.3–178.7)
AST (IU/L)	Median value (range)	29 (14–98)	29 (15–146)
ALT (IU/L)	Median value (range)	39 (14–146)	37 (15–370)
WBC count (/mL)	Median value (range)	5390 (3050–14780)	5450 (3010–13430)
Neutrophil count (/mL)	Median value (range)	2447 (990–10789)	2238 (821–8448)

There were no significant differences between the two groups in any of the background factors.

fT4, free thyroxine; fT3, free triiodothyronine; TRAb, thyrotropin receptor antibody; AST, aspartate aminotransferase; ALT, alanine aminotransferase; WBC, white blood cell.

Course after the start of treatment

Treatment was discontinued in 26 of the 310 subjects. Of these 26 patients, 24 were withdrawn from the study because of adverse effects that occurred within 90 days of starting the study treatment and prior to achieving a serum fT4 level within the reference range, and the other two because of hepatic dysfunction suspected to be possibly caused by MMI (later diagnosed as nonattributable to MMI therapy in both cases). Because the therapeutic effect was insufficient, it was necessary to increase the MMI dose in six subjects in whom it was feasible to continue treatment. Analysis of the data was carried out using the intention-to-treat method, by regarding these 32 patients (10.3%) as nonresponders. Overall, the percentages of patients achieving a serum fT4 level within the reference range in ≤30 days and in ≤60 days after the start of study treatment were significantly greater for the MI15+I group, but there was no significant intergroup difference in the percentage achieving a serum fT4 level within the reference range in ≤90 days (Table 2). Patients who achieved a reference range level of fT3 within 30 days were significantly more frequent among those on M15+I than those on M30, though there was no significant intergroup difference in the percentage of patients achieving this goal within either 60 or 90 days (Table 3). Of the patients with severe hyperthyroidism with fT4 levels >7.77 ng/dL, the percentage achieving a serum fT4 level within the reference range in ≤30 days was 46.9% for the M15+I group, being significantly higher than the 20.5% for the M30 group (p=0.0004). There was no significant difference in the percentage of patients achieving a serum fT4 level within the reference range in ≤60 or ≤90 days between the two groups (Table 4). There were 47 patients with serum fT4 elevation after KI discontinuation. However, the serum fT4 level returned to the reference range with no particular corrective measures in 20 patients, as a result of resuming KI in 14 patients, or in response to an MMI dose increase in 13 patients.

Table 2.

Number and Percentage of Patients Attaining a Within-RR Serum fT4 Level in ≤30, ≤60, or ≤90 Days of Study Treatment

		fT4 within RR		fT4 above RR
No. of days at which within-RR fT4 was attained	Group	n	(%)	n	(%)	p-Value
≤30 days	MMI15+I	73	(45.3)	88	(54.7)	0.0001
	M30	37	(24.8)	112	(75.2)
≤60 days	MMI15+I	119	(73.9)	42	(26.1)	0.0399
	M30	94	(63.1)	55	(36.9)
≤90 days	MMI15+I	132	(82.0)	29	(18.0)	0.1427
	M30	112	(75.2)	37	(24.8)

RR, reference range; fT4 within RR, patient attaining a serum fT4 level within the reference range; fT4 above RR, patient whose serum fT4 level was above the reference range.

Table 3.

Number and Percentage of Patients Attaining a Within-RR Serum fT3 Level in ≤30, ≤60, or ≤90 Days of Study Treatment

		fT3 within RR		fT3 above RR
No. of days at which within-RR fT3 was attained	Group	n	(%)	n	(%)	p-Value
≤30 days	MMI15+I	47	(29.2)	114	(70.8)	0.0003
	M30	19	(12.8)	130	(87.2)
≤60 days	MMI15+I	85	(52.8)	76	(47.2)	0.1344
	M30	66	(44.3)	83	(55.7)
≤90 days	MMI15+I	104	(64.6)	57	(35.4)	0.5213
	M30	91	(61.1)	58	(38.9)

Table 4.

Number and Percentage of Patients with a Baseline Serum fT4 >7.77 ng/dL Who Attained a Within-RR Serum fT4 Level in ≤30, ≤60, or ≤90 Days of Study Treatment

		fT4 within RR		fT4 above RR
No. of days at which within-RR fT4 was attained	Group	n	(%)	n	(%)	p-Value
≤30 days	MMI15+I	38	(46.9)	43	(53.1)	0.0004
	M30	16	(20.5)	112	(79.5)
≤60 days	MMI15+I	58	(71.6)	23	(28.4)	0.0937
	M30	46	(59.0)	32	(41.0)
≤90 days	MMI15+I	66	(81.5)	15	(18.5)	0.1477
	M30	56	(71.8)	22	(28.2)

Differences in background factors before treatment in the sufficient and insufficient therapeutic effect groups during the course of 90-day treatment

The ratios of the number of subjects in the M15+I group to the number of subjects in the M30 group in the sufficient and insufficient therapeutic effect groups were 132:112 and 29:37, respectively, and their fT3, fT4, and TRAb values showed no significant differences. However, the poor responder group was older than the responder group (p=0.04), and thyroid volume was significantly higher in the former group (p<0.0001; Table 5).

Table 5.

Pretreatment Background Factors of the Group in Which a Therapeutic Effect Was Observed and of the Group in Which the Therapeutic Effect Was Considered to Be Insufficient

		Sufficient effect group (n=244)	Insufficient effect group (n=66)	p-Value
Treatment method	MMI15+I:M30	132:112	29:37	NS
Sex (M:F)		46: 198	15:51	NS
Age (years)	M/SD	37.1/13.7	33.5/12.2	p=0.04
fT3 (pg/mL)	Median value (range)	24.5 (11.8–32.5)	26.1 (9.7–32.5)	NS
fT4 (ng/dL)	Median value (range)	7.8 (4.2–7.8)	7.8 (3.8–7.8)	NS
TRAb (IU/L)	Median value (range)	20.8 (1.9–40.0)	20.4 (0.6–66.3)	NS
Thyroid volume (g)	Median value (range)	38.5 (13.4–123.8)	54.6 (14.7–178.6)	p<0.0001

The chi-squared test and Wilcoxon rank-sum test were used to test the data for significant differences between groups.

NS, not significant.

Relationships of fT4 changes after discontinuation of inorganic iodine with various parameters in the M15+I group

The serum fT4 level in 80 (63.0%) of the 127 patients (excluding five with temporary medication compliance failure after fT4 fell below 1.6 ng/dL) remained at or below the upper limit (1.6 ng/dL) of the reference range for two to four weeks after inorganic iodine discontinuation, whereas the serum fT4 level was >1.6 ng/dL in the other 46 (37.0%) after discontinuing iodine. There were significant differences between the improved stable group and the deterioration group with respect to age, serum fT4 level and thyroid volume at baseline, and the serum fT4 level at discontinuation of inorganic iodine (Table 6). We constructed receiver operating characteristic curves to explore the relationships of these factors with post-inorganic iodine discontinuation fT4 changes (fT4 ≤1.6 or >1.6). With age, serum fT4 level and thyroid volume at baseline, and serum fT4 level at discontinuation of inorganic iodine taken as explanatory variables, the area under the curve (AUC) was calculated with the results indicating that the most useful parameter for predicting post-inorganic iodine discontinuation fT4 changes was the serum fT4 level at discontinuation of inorganic iodine. A serum fT4 level of 1.19 ng/dL at the time of inorganic iodine discontinuation was found to be the most effective cutoff value with an AUC of 0.797, a sensitivity of 78.2%, and a specificity of 68.8%. The lowest fT4 level before discontinuation of inorganic iodine was 0.91 ng/dL in the group showing exacerbation.

Table 6.

Changes in Serum fT4 Level and Other Parameters Following Discontinuation of Inorganic Iodine in the M15+I Group Patients

		Improved-stable group (n=80)	Deterioration group (n=47)	p-Value
Sex	M:F	12:68	12:35	NS
Age (years)	Median value (range)	39.5 (14–74)	35.0 (13–57)	p=0.0278
fT3 at initial treatment (pg/mL)	Median value (range)	23.2 (13.1–32.5)	24.8 (18–32.5)	NS
fT4 at initial treatment (ng/dL)	Median value (range)	7.18 (5.01–7.77)	7.77 (5–7.77)	p=0.0326
TRAb (IU/L)	Median value (range)	22.1 (2.23–40)	19.5 (4–40)	NS
Thyroid volume (mL)	Median value (range)	34.4 (13.4–108.5)	41.5 (18.6–123.8)	p=0.0153
fT4 at inorganic iodine discontinuation (ng/dL)	Median value (range)	1.09 (0.21–1.57)	1.35 (0.91–1.6)	p<0.0001

Adverse effects

Adverse effects necessitating discontinuation of MMI occurred before (26 patients) and after (eight patients) achieving a serum fT4 level within the reference range (Table 7). The overall prevalence of adverse effects was significantly higher for the M30 group (22 patients, 14.7%) than for the M15+I group (12 patients, 7.4%; p=0.0387). In particular, pruritus and rash were nearly twice as frequent in the M30 group (11.4%) as in the M15+I group (5.6%). Two patients, both on the M30 regimen, developed agranulocytosis on day 14 (WBC 688; neutrophils (Neu) 0%) and day 57 (WBC 1700; and Neu 1%) of MMI treatment. One patient in the M15+I group experienced asymptomatic granulocytosis (WBC 2930; Neu 20%) on day 83 of study treatment. No patients developed hepatic dysfunction.

Table 7.

Adverse Effects Leading to (or Necessitating) Discontinuation of MMI

	M15+I group, n=161 n (%)	M30 group, n=149 n (%)
Pruritus or rash	9 (5.6)	17 (11.4)
Agranulocytosis	0	2 (1.3)
Neutropenia	1 (0.6)	0
Other	2 (1.2)	3 (2.0)
Total	12 (7.4)^*	22 (14.7)

“Other” includes arthralgia and myalgia in one patient each in the M15+I group, and arthralgia in two patients and fever in one patient in the M30 group.

M15+I group vs. M30 group, p=0.0387.

Comparison of remission rates

The overall median follow-up duration was 47.8 months (range 2.6–59.5 months). During the course of follow-up, the study treatment was switched to radioiodine therapy in 47 patients, to surgery in 15, and to propylthiouracil based on the patient's desire for childbearing in 13 patients. There were seven patients who had been off MMI therapy for less than one year after discontinuation of MMI, and two who experienced recurrence after achieving remission. These nine patients were subjected to intention-to-treat analysis as nonresponders. There were 32 patients (19.9%) who attained remission and 129 (80.1%) who failed to attain remission in the M15+I group, and the corresponding numbers were 22 (14.8%) and 127 (85.2%) respectively in the M30 group. Hence, there were no significant intergroup differences.

Discussion

The Japan Thyroid Association Guideline for the Medical Treatment of GD recommends the following dosage regimens for MMI depending on the serum fT4 level in the untreated state: MMI 30 mg/day for fT4 >7.77 ng/dL, MMI 15 or 30 mg/day according to the patient's condition (for fT4 ≤5 or ≤7.77 ng/dL), or MMI 15 mg/day for fT4 <5 ng/dL. These dose regimens are recommended in patients with fT4 <5 ng/dL because there was no significant difference in the duration of MMI therapy needed to attain a serum fT4 level within the reference range between the MMI dose levels of 15 mg/day and 30 mg/day. We did not assess the effect of MMI 15 mg/day+KI 38 mg/day in comparison with that of MMI 15 mg/day in patients with fT4 <5 ng/dL. The prevalence of adverse effects is rather similar for these two dose regimen groups. However, as hyperthyroidism does not seem to be particularly severe in such patients, we considered it to be unnecessary to aggressively add KI 38 mg/day to the MMI regimen in this study. We thus conducted this study in patients with serum fT4 levels ≥5 ng/dL, who are considered to have moderate to severe hyperthyroidism.

It has been found that treatment with high-dose MMI is superior in terms of efficacy, but dose-dependent adverse effects are a clinical problem, and although adverse effects are reduced with low-dose MMI, the treatment has lower efficacy. Faced with this dilemma, we hypothesized that a treatment method that adds inorganic iodine to low-dose MMI as a method has fewer adverse effects than high-dose MMI and greater efficacy than low-dose MMI. In order to evaluate its usefulness, we conducted a study of efficacy and adverse effects in comparison with those of high-dose MMI. A therapeutic effect was obtained in many of our patients, but there were few subjects in whom the therapeutic effects of each of these methods were judged to be insufficient. It is well known that the administration of iodide usually ameliorates the symptoms of hyperthyroidism and decreases serum hormone concentrations to within the respective reference ranges. At the beginning of the 1920s, Plummer (10) utilized iodine in amounts of 100–400 mg/day to prevent the postoperative death of GD patients, and this dose continued to be employed by the majority of clinics during the following decades. However, in a series of studies from Harvard, beginning in 1938, Thompson et al. (11) were able to show an inhibitory effect on thyroid function of hyperthyroid patients with doses as small as 1.5 mg of iodine or 6 mg of iodine daily, and the effects of small doses of iodide have been reviewed by Volpe et al. (12). This effect of iodide usually persists for a few weeks or a few months in approximately 70% of patients (10,12 –14). The decreases in serum hormone concentrations are usually evident sooner than those elicited by ATD, suggesting the effect of iodide to involve direct inhibition of the thyroid hormone secretion step (7). Although the thyroid radioactive iodine uptake rate decreases with much smaller quantities of iodide in hyperthyroid patients than in euthyroid individuals, the uptake rate remains within the euthyroid range and absolute iodine uptake (AIU, stable iodine uptake to the thyroid) increases during treatment with iodide (8). Thus, the effects of iodide administration in GD patients are completely different from the Wolff–Chaikoff effect, which is characterized by a decrease in AIU due to the inhibition of thyroidal iodide uptake and organification in response to a marked elevation of plasma iodide (15,16). However, the mechanism by which iodide inhibits hormone release has not yet been elucidated.

In contrast, the major effect of an ATD is inhibition of the organification and hormone synthesis within the thyroid; the decrease in thyroid hormone secretion in GD patients in response to these agents is thus believed to be due to the depletion of thyroid hormones within the thyroid gland (16). Therefore, it takes a few weeks before thyroid hormone secretion decreases. The existence of iodine-induced thyrotoxicosis, which is very resistant to treatments, and the high frequency of Amiodarone-induced thyrotoxicosis (17) generally discourages thyroid specialists from administering large amounts of iodine to patients receiving ATD treatment. However, efforts to decrease the levels of serum thyroid hormones as rapidly as possible in patients suffering from thyroid storm and attempts to prevent adverse effects of ATDs have prompted the development of combination therapies employing MMI and iodide (4,18). Combination therapies were proposed as early as 1945 in a series of studies from Yale University by Danowski and Winkler (13,19), and now combined use of inorganic iodine and an ATD is clinically recommended for rapid control of severe thyrotoxicosis in the American Thyroid Association Guidelines (9). A similar study was recently published from Japan (4).

Roti et al. reported that the combination of MMI 40 mg/day with KI was no more effective than MMI alone in restoring serum T3 and T4 to normal with 10 days of therapy (18). Takata et al. assessed percentages of patients with normalization of serum fT3 and fT4 levels with a 12-week administration of MMI 15 mg, MMI 15 mg+KI (38.2 mg of iodide), MMI 30 mg, or MMI 30 mg+KI, and reported that the groups receiving the combined regimens achieved higher rates of normalization (4). Their study results, however, encompassed treatment outcomes of patients with mild to severe GD, such that it remains unclear to what extent the monodrug and combined therapy regimens were effective in patients with severe hyperthyroidism. The present study compared therapeutic responses of MMI 15 mg+I and MMI 30 mg in patients with moderate to severe hyperthyroidism. The results demonstrate greater efficacy of M15+I than M30 even in severely hyperthyroid patients.

Since the report of Takata et al. does not contain a detailed description of adverse effects of MMI, it is not possible to compare our data with those obtained in their study regarding adverse effects (4). The prevalence of skin rashes and itching in patients receiving monodrug therapy with MMI 30 mg or MMI 15 mg were 22.3% and 6.6% respectively in a study reported by Nakamura et al. (1). In contrast, we found the prevalence of skin rashes and itching in patients receiving MMI 30 mg or MMI 15 mg+KI to be 11.4% and 5.6% respectively. Thus, the prevalence of these adverse effects was slightly lower in the present study at the MMI 30 mg dose, and this trend seen in the present series is considered to be attributable to the active use of antihistaminic agents when necessary in this study. In any event, it seems that rashes and itching necessitating discontinuation of MMI are more likely to occur at a dose level of 30 mg than at 15 mg. Agranulocytosis as an adverse effect is reportedly less frequent at MMI 15 mg than at MMI 30 mg (5). Two patients, both receiving MMI 30 mg, developed agranulocytosis, and one patient receiving MMI 15 mg showed neutropenia. However, there were no significant intergroup differences, possibly due to the small numbers of affected patients.

Wartofsky et al. reported a remarkably low remission rate of only 11.4% and raised the possibility that increased dietary inorganic iodine intake (M±SE urinary iodine 374±88 μg/day; estimated iodine requirement 150–200 μg/day) might lower the remission rate in GD cases (20). Recent studies on the urinary iodine concentration in school children in Japan have shown median values of 288 μg/L in Hokkaido (21) and 282 μg/L in Tokyo (22), but the maximum value was >3 mg/L, and 16% of the values were >1 mg/L (22). Dietary inorganic iodine intake is customarily high in Japanese communities, such that there is a possibility of high-dose administration of iodine during an early stage of treatment having an untoward influence on GD prognosis. Reported one-year remission rates are approximately 40–50% in Japan, but would presumably vary with the treatment method as well as among patients (23,24). Takata et al. reported that the remission rates after discontinuation of MMI were 34%, 44%, 33%, and 51% for groups given MMI 30 mg, MMI 30 mg+KI, MMI 15 mg, and MMI 15 mg+KI respectively in their study in which the initial MMI regimen was set at either 15 mg/day or 30 mg/day, though the group sizes were rather small, ranging from 30 to 37 patients (4). In the present study, the remission rate was 20.5% for the MMI 15 mg+KI group and 15.4% for the MMI 30 mg group, showing no significant intergroup difference and being lower than the rates in other reported studies. We consider this to be attributable to our study population being comprised of patients in very poor condition due to their GD and to the use of intention-to-treat analysis. Taking the results of the study by Takata et al. and the present investigation together, it appears that administering inorganic iodine concomitantly with an ATD early in the treatment of GD, at least in Japanese patients, is unlikely to have an unfavorable influence on disease remission.

However, the mechanism of action of this combined treatment has yet to be adequately explained. The purpose of this report is to present our actual results as precisely as possible, and to document the results of combined therapy in a country where the majority of GD patients are being treated with oral medications, not radioactive iodide or surgery.

Footnotes

Author Disclosure Statement

The authors have no competing financial interests to declare.

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