Hypothyroidism During Antithyroid Drug Treatment with Methimazole is a Favorable Prognostic Indicator in Patients with Graves' Disease

Abstract

Background:

A major problem with antithyroid drug (ATD) therapy in Graves' disease is the high relapse rate. Therefore, clinicians have sought prognostic indicators of permanent remission. Suppression of serum thyrotropin (TSH) when ATD therapy is stopped carries a poor prognosis, but little is known regarding the significance of elevated serum TSH concentrations in the course of ATD therapy. The objective of this study was to determine if elevated serum TSH concentrations during methimazole (MMI) therapy is associated with a favorable long-term prognosis.

Methods:

We retrospectively studied patients with Graves' disease who were initially on MMI, in whom this drug was stopped because they had undetectable thyroid-stimulating antibodies (TSAbs) or were euthyroid after at least 24 months on MMI treatment. A strategy of high MMI doses plus T4 was not used in these patients. We identified 40 patients with elevated serum TSH concentration (>10 μIU/mL) during MMI therapy (H-TSH group). Eighty-five percent of the H-TSH group had negative tests for TSAb. The H-TSH group was sex- and age-matched with 37 patients who had similar selection criteria, but did not have elevated serum TSH concentration during MMI therapy (N-TSH group). The H-TSH and N-TSH groups were similar in gross thyroid size, percentage of patients with exophthalmos, serum free thyroxine, duration of MMI treatment, TSAb status, duration that their TSAb tests remained negative, and thyroid peroxidase antibody titers. The patients were followed for 24 months after stopping MMI.

Results:

In the H-TSH group, MMI-associated hypothyroidism typically occurred after 7–8 months of treatment with daily doses of 10–15 mg MMI. No patient had severe symptoms of hypothyroidism. The percentage of patients in remission at 6, 12, and 24 months after discontinuation of MMI was 90.0, 87.5, and 85.0, respectively, in the H-TSH group and 70.3, 67.6, and 54.1, respectively, in the N-TSH group (p < 0.05 for the comparison of groups at 6 and 12 months and p < 0.001 for comparison of the groups at 24 months).

Conclusions:

In patients with Graves' disease who are treated with MMI for at least 2 years and become euthyroid, the occurrence of elevated serum TSH concentrations during MMI treatment is a favorable indicator for long-term remission and is independent of multiple other factors including TSAb status, duration of MMI treatment, and gross parameters of goiter size.

Introduction

A ntithyroid drugs (ATDs) are one of the main therapeutic modalities for Graves' disease (1). Unlike radioactive iodine and surgery, ATD treatment is not an ablative or traumatic method. One problem with ATDs is the low remission rate. Indeed, the permanent remission rate after treatment of ATDs is less than 50% (1 –3). Thus it would be useful if one could predict which patients will have a remission with ATDs, because those who do not have much possibility of remission may better be treated with radioactive iodine or surgery.

Various clinical parameters have been tested for their ability to predict the clinical course of a patient with Graves' disease after drug withdrawal (4 –7). Abnormal suppression of serum thyrotropin (TSH) or an abnormal thyrotropin releasing hormone test at the end of ATD therapy is a poor prognostic factor (4). Delayed recovery of the pituitary–thyroid axis (8) and suppressed function of the pituitary TSH receptor (9) have been suggested as possible mechanisms of continued suppression of serum TSH. In this study, we focused on the opposite situation, that is, increased TSH during ATD therapy. In our clinical experience, a percentage of patients with Graves' disease have ATD-associated hypothyroidism during ATD therapy despite the fact that we do not use a “block-replacement” (i.e., relatively high doses of levothyroxine [L-T4] plus ATD) strategy for their treatment.

ATD-associated hypothyroidism is thought to result from overly aggressive dosing in mild hyperthyroidism or failure to adjust the ATD dosage (10). Concerning the side effects or symptoms of hypothyroidism, it has been recommended that the ATD dosage be carefully adjusted to prevent ATD-associated hypothyroidism. Thus, clinicians may reduce the dosage steeply or temporarily hold the dose when ATD-associated hypothyroidism occurs, which we believe results in worsening of drug compliance. We hypothesized that ATD-associated hypothyroidism that occurs with a usual methimazole (MMI) dose adjustment schedule is an expression of higher drug responsiveness. As ATDs are known to have some immune-modulating effects (11 –15), we postulated that ATD-associated hypothyroidism may be a favorable sign that correction of the immunologic disturbance underlying Graves' disease has occurred.

The purposes of this study were to determine the clinical characteristics of patients with Graves' disease and MMI-associated hypothyroidism and to determine if MMI-associated hypothyroidism is an indicator of favorable prospects for long-term remission.

Patients and Methods

We retrospectively analyzed the medical records of patients with Graves' diseases who were cared for at Dankook University Hospital between 2000 and 2006. Graves' disease was diagnosed on the basis of an elevated level of free T4 (>1.9 ng/dL [23 pmol/L]) and/or total triiodothyronine (>2.75 nmol/L), a decreased serum TSH level (<0.10 mU/L), a positive thyroid-stimulating antibody (TSAb) titer (>1.5 IU/L), and diffuse uptake on a technetium scintigram in the presence of clinical features of thyrotoxicosis. The inclusion criteria for the study were as follows: a new diagnosis of Graves' disease, receiving and complying with MMI treatment, and a record of a complete panel of thyroid function tests at baseline and during MMI therapy (every 4–6 weeks interval). In addition, this record had to be maintained after discontinuation of MMI at 6, 12, and 24 months to confirm relapse. None of the patients were treated with a “block-replacement” strategy. The patients with Graves' disease who also had serious nonthyroidal illnesses, pregnancy, or medications that influence pituitary–thyroid function were excluded. A total 112 Graves' patients were initially included in the study.

MMI-associated hypothyroidism was defined as an increased TSH level (>10 mU/L), regardless of the serum free T4 levels, on more than one occasion during MMI therapy. To ensure that MMI-associated hypothyroidism was not caused by failure of dose adjustment, drug compliance was monitored carefully. Eleven patients were excluded because of poor compliance with MMI and 14 were excluded for lack of complete thyroid function tests. Finally, three patients with fluctuating thyroid function tests during MMI treatment were also excluded. Thus, a total of 84 patients were eligible for the study. Among them, we found 40 patients with Graves' disease who were hypothyroid during MMI therapy. They were designated as the MMI-associated hypothyroid (H-TSH) group. Of the remaining 44 patients, 37 were sex- and age-matched to the H-TSH group and designated the N-TSH group. The study protocol was approved by the Medical Ethics Committee of the Dankook University Hospital.

The clinical features of the 77 patients in the two groups were noted at the time of diagnosis, including goiter as determined by a single observer (nonpalpable, palpable, and nonvisualized [20–30 g], visible [25–50 g], and huge [>50 g]) and presence of eye signs of Graves' ophthalmopathy. All patients were initially treated with MMI at a high dose (30–40 mg/day), followed by decreasing doses to maintenance daily doses of 5–10 mg of MMI. During the MMI treatment, patients were seen every 4–6 weeks for physical examination and assays of serum free T4, TSH, and TSAb activity. Serum free T4 and TSH were measured using commercial radioimmunoassay kits (Immunotech), TSAb kits (Brahms), and TPO-Ab kits (RADIM S.P.A.).

The decision to discontinue MMI was based on the status of TSAb and, in a minority of patients, on their thyroid function after 24 months of MMI treatment. MMI therapy was discontinued if TSAb activity became undetectable for at least three consecutive assessments during treatment with MMI. If this did not occur after 24 months of MMI therapy, the patient was counseled with respect to switching to radioactive iodine treatment or continuing drug therapy for more than 24 months. Relapse was assessed by thyroid function testing at 6, 12, and 24 months after discontinuation of MMI and defined as a suppressed serum TSH and increased free T4 levels, regardless of TSAb activity.

In patients who developed hypothyroidism during MMI treatment (TSH > 10 mU/L), we noted if there were symptoms and signs of hypothyroidism, such as weight gain, edema, constipation, changes in eye symptoms, and goiter size. If hypothyroidism developed, we reduced the MMI dosage or added L-T4 (50–100 μg/day). Thus 24 patients were treated with L-T4 in the H-TSH group.

Statistical analysis

The data were analyzed using an SPSS-PC software program (version 15.0; SPSS, Inc.). Values of p < 0.05 were considered to indicate statistical significance. Relapse rates were compared using a chi-square test between the two groups. In the case of normally distributed parameters, the mean ± standard deviation were compared using a nonpaired t-test between the two groups. To evaluate prognostic factors, logistic regression analysis was also used.

Results

Comparison of clinical parameters and remission rates between the H-TSH and N-TSH groups

The clinical features of the patients before MMI therapy and after discontinuation in the H-TSH and N-TSH groups are presented in Table 1. There were no significant differences between the two groups in pretreatment goiter size, concentrations of serum free T4, TSH, and serum anti-thyroid peroxidase (TPO) antibodies, or serum TSAb activities. The rate at which TSAb tests became negative before MMI therapy was stopped, and the duration that TSAb tests were negative before MMI therapy was stopped were similar in the H-TSH and N-TSH groups. However, the remission rate after discontinuation of MMI was significantly different between the two groups (Table 2 and Fig. 1). In the H-TSH group, four patients (10.0%) relapsed at 6 months after MMI was discontinued, one patient relapsed at 12 months after MMI was discontinued, and one patient relapsed at 24 months after MMI was discontinued. Thus, the overall remission rate at 24 months after discontinuation of MMI was 85% in the H-TSH group. In contrast, in the N-TSH group, 11 (29.7%), 1, and 5 patients relapsed at 6, 12, and 24 months, respectively, after discontinuation of MMI. Therefore, the overall remission rate at 24 months after discontinuation of MMI was 54.1% in the N-TSH group.

FIG. 1.

Comparison of remission rate at 6, 12, and 24 months after ATD discontinuation between the H-TSH and N-TSH groups.

Table 1.

Comparison of Clinical Characteristics Between the H-TSH and N-TSH Groups

Variables	H-TSH	N-TSH	p-Value
(A) Onset of ATD therapy
Sex (M/F)	11/29	7/30	NS
Age (years)	43.6 ± 16.1	39.8 ± 11.8	NS
Goiter (gm)	43.2 ± 19.6	43.3 ± 16.6	NS
Exophthalmos (%)^a	43.2 ± 19.6	43.3 ± 16.6	NS
TSH (mU/L)	0.03 ± 0.0	0.03 ± 0.0	NS
Free T4 (ng/dL)	5.2 ± 3.0	4.9 ± 2.8	NS
TSAb (IU/L)	20.1 ± 22.8	23.5 ± 35.9	NS
Anti-TPO Ab (IU/mL)	583 ± 1207	456 ± 940	NS
(B) Discontinuation of ATD therapy
Duration of therapy (months)	26.8 ± 9.3	28.7 ± 14.0	NS
Rate of negative TSAb (%)^b	85.0	81.0	NS
Duration of negative TSAb (months)^c	9.5 ± 6.7	8.4 ± 5.5	NS

Reference range: TSH, 0.25–4.00 mU/L; free T4, 0.78–1.94 ng/dL; TSAb, 0–1.5 IU/L; anti-TPO Ab, 0–100 IU/mL.

Percentage of patients with exophthalmos.

Percentage of patients whose test for TSAb was negative before ATD therapy was stopped.

Duration that TSAb tests remained negative.

TSH, thyrotropin; ATD, antithyroid drug; NS, not significant; T4, thyroxine; TSAb, thyroid-stimulating antibody; TPO, thyroid peroxidase.

Table 2.

Comparison of Remission Rate (%) at 6, 12, and 24 Months After Antithyroid Drug Discontinuation Between the H-TSH and N-TSH Groups

	H-TSH group	N-TSH group	OR (95% CI)	p-Value
After 6 months	90.0%	70.3%	3.81 (1.09–13.29)	<0.05
After 12 months	87.5%	67.6%	3.36 (1.05–10.75)	<0.05
After 24 months	85.0%	54.1%	4.32 (1.46–12.77)	<0.001

OR (odds ratio) means calculation by dividing the odds in the H-TSH group by the odds in the N-TSH group (odds are calculated as the number of events divided by the number of nonevents).

CI, confidence interval.

Clinical features of MMI-associated hypothyroidism

The characteristics of MMI-associated hypothyroidism are presented in Figure 2. The time when hypothyroidism occurred ranged from 2 to 19 months after the start of MMI treatment (mean ± standard deviation = 7.3 ± 5.5 months). The average duration of the hypothyroid state was 2.9 ± 2.3 months, with a range of 1–12 months. The range of elevated serum TSH was 10.5–40.0 μIU/mL; 21 patients had a TSH range of 10.0–20.0 μIU/mL, 8 patients had a TSH range of 20.0–30.0 μIU/mL, and 11 patients had a TSH level of >30.0 μIU/mL.

FIG. 2.

Characteristics of ATD-related hypothyroidism. (a) Onset, (b) duration of ATD-related hypothyroidism, (c) TSH, (d) free T4 levels, and (e) daily dosage of methimazole of each patient at the onset of ATD-related hypothyroidism are represented as dots. Cross bars represent means and hatched boxed are normal ranges. ATD, antithyroid drug; TSH, thyrotropin; T4, thyroxine.

During the state of hypothyroidism or subclinical hypothyroidism, 16 patients (40%) had normal and 24 patients (60.0%) had a decreased level of serum free T4. The latter had a mean serum free T4 level of 0.39 ± 0.15 ng/dL, with a range of 0.18–0.59 ng/dL. Hypothyroidism-related symptoms were observed in seven patients (17.5%), mainly edema, fatigue, and constipation. However, there were no severe symptoms necessitating a discontinuation of MMI treatment and the hypothyroidism was easily controlled with a reduction in the MMI dose (n = 9, 22.5%) or by temporarily adding T4 (n = 31, 77.5%).

The mean daily dosage of MMI when hypothyroidism developed was 12.00 ± 5.16 mg/day. Six patients were taking 5 mg, 21 were taking 10 mg, 5 were taking 15 mg, 7 were taking 20 mg, and 1 was taking 25 mg. Thus, the MMI-associated hypothyroidism usually started in the middle of MMI therapy when patients were on a maintenance dose, rather than the early phase during which there was active dosage adjustment.

TSAb activity was decreased in 24 patients and increased in 16 patients in the H-TSH group when they were taking MMI and were hypothyroid. There were no significant differences between the H-TSH group and the N-TSH group in the time-to-recovery after MMI was stopped of free T4 level (2.03 ± 1.52 months in the H-TSH group and 1.76 ± 1.01 months in the N-TSH group).

Comparison of clinical characteristics of patients in remission and patients who had relapsed in each group

Table 3 presents the subgroup analysis between patients who were in remission and patients who were not in remission in each group. The initial features or statuses with respect to sex, age, goiter size, ophthalmopathy, serum TSH level, free T4 level, anti-TPO antibody, and TSAb activity were similar in patients who remained in remission and those who did not. In the H-TSH group the time of onset or the duration of MMI-associated hypothyroidism was similar in those who remained in remission and those who did not.

Table 3.

Comparison of Clinical Characteristics at Onset, During, and After Discontinuation of Antithyroid Drug Between Relapse and Remission Cases at 24 Months After Antithyroid Drug Discontinuation

	H-TSH group (n = 40)			N-TSH group (n = 37)
	Relapse (n = 6)	Remission (n = 34)	p	Relapse (n = 16)	Remission (n = 21)	p
(A) Onset of ATD treatment
Sex (M/F)	2/4	9/25	NS	3/13	4/17	NS
Age (years)	43.8 ± 16.5	43.5 ± 16.3	NS	39.8 ± 18.8	39.7 ± 12.6	NS
Goiter (g)	50.0 ± 10.9	41.7 ± 17.4	NS	42.8 ± 16.0	41.8 ± 20.7	NS
Exophtalmos (%)^a	16.7	17.6	NS	6.3	14.2	NS
TSH (mU/L)	0.03 ± 0.0	0.03 ± 0.0	NS	0.03 ± 0.0	0.03 ± 0.0	NS
Free T4 (ng/dL)	6.6 ± 2.7	4.7 ± 2.8	NS	5.4 ± 2.1	4.5 ± 2.8	NS
TSAb (IU/L)	16.5 ± 12.5	23.5 ± 38.7	NS	22.9 ± 30.5	24.7 ± 16.7	NS
Anti-TPO Ab (IU/mL)	20.9 ± 41.7	688.6 ± 1290.1	NS	533.0 ± 1308.2	395.7 ± 542.6	NS
(B) MMI-associated hypothyroidism during ATD treatment
Onset (mo.)^b	6.4 ± 5.1	7.4 ± 5.6	NS	(−)	(−)	(−)
Duration (mo.)	3.8 ± 4.1	2.8 ± 1.8	NS	(−)	(−)	(−)
(C) Discontinuation of ATD treatment
Duration of therapy (mo.)	27.7 ± 11.2	26.6 ± 9.2	NS	28.8 ± 13.6	28.7 ± 14.6	NS
Negative TSAb (%)^c	50 (3/3)	91 (31/3)	<0.001	50 (8/8)	81 (17/4)	<0.05
Duration of negative TSAb^d	2.6 ± 3.0	10.5 ± 6.5	<0.05	4.1 ± 5.0	12.1 ± 6.1	<0.05

Reference range: TSH, 0.25–4.00 mU/L; free T4, 0.78–1.94 ng/dL; TSAb, 0–1.5 IU/L; anti-TPO Ab, 0–100 IU/mL.

Percentage of patients with exophthalmos.

Time (months) when hypothyroidism occurred after the start of MMI treatment.

Percentage of patients whose test for TSAb was negative before ATD therapy was stopped.

Duration (months) that TSAb tests remained negative.

MMI, methimazole.

In both the H-TSH and the N-TSH groups the duration of treatment with MMI was similar in patients who remained in remission and those who did not (Table 3). In the H-TSH and the N-TSH groups the percentage of patients whose test for TSAb was negative at the last determination was higher in the patients who remained in remission than in those who relapsed. Similarly, in both groups, the duration that the TSAb tests remained negative was longer in the patients who remained in remission compared with those who relapsed (Table 3). Note that the criteria for relapse was based on serum TSH and free T4, but not the TSAb test results (see Patients and Methods section).

Discussion

Our results suggest that MMI-associated hypothyroidism is an expression of favorable responsiveness to MMI or an indicator of a milder underlying disease process, rather than a clinical error in ATD dosage adjustment. We found a positive relationship between MMI-associated hypothyroidism and long-term remission. Thus, based on the usual ATD dosage adjustment schedule, MMI-associated hypothyroidism is a favorable prognostic sign. The patients who had MMI-associated hypothyroidism did not manifest any serious symptoms or signs related to the hypothyroid state. Several minor symptoms were easily controlled by reducing the dose or temporarily adding L-T4. Thus, we believe that when the hypothyroid state occurs during ATD treatment in patients with Graves' disease, it is advisable not to discontinue ATD or markedly reduce the dose. Rather, we favor patient reassurance, a moderate reduction in dose, and a consideration of adding L-T4.

In our study, we considered it most important that MMI-associated hypothyroidism is not due to inappropriate selection of the MMI dose or poor patient compliance with taking medication or maintaining follow-up. Therefore, as noted in the Patients and Methods section, some patients with Graves's disease who were taking MMI were excluded from the final study groups. The data presented in this study are an approximate index of the percentage of patients who become hypothyroid while on maintenance therapy with MMI, or at least maintenance therapy with MMI. Under our strict criteria, the H-TSH group comprised 35.7% of the initial group of 112 patients with Graves' disease. We do not know, however, the exact prevalence of Graves's disease in the population from which our patients were selected. Nevertheless, even if the percentage of patients who are likely to develop hypothyroidism on the usual doses of MMI is lower, this is likely to be a clinically important group.

The high remission rate in the MMI-associated hypothyroidism group was impressive. The remission rate was >80% up to 24 months after MMI discontinuation, which was much higher than the generally reported remission rates after ATD therapy (1 –3). We believe that it might be related not only to better ATD responsiveness but also to strict selection of patients with excellent compliance. As a prognostic factor, positive (85.0%) and negative (43.2%) predictive values of ATD-associated hypothyroidism were also superior to other previously known prognostic factors (4). However, it is not sufficient to use it as the only prognostic indicator. ATD-associated hypothyroidism could be used as one of the meaningful clinical factors to predict prognosis, along with other factors (4 –7). The status of serum TSAb tests seems to be an important factor, and in our study, a negative test for serum TSAb was predictive of a higher remission rate (Table 3).

Our study was a retrospective one and focused only on drug responsiveness in a conventional regimen of MMI. We do not know if similar results would be obtained with propylthiouracil, another ATD. Almost all previous prospective trials that examined the benefits of “block-and-replace” high-dose ATD treatment were negative (16 –18). Thus, our study is not comparable to most if not all of the previous reports regarding the prognostic implications of ATD-associated hypothyroidism. There are many studies relating to mechanisms for remission and relapse in Graves' disease and functional responses of the thyroid to ATD treatment and its discontinuation (8,9,11 –15,19 –22). However, the pathophysiology of ATD-associated hypothyroidism during maintenance treatment is not clear.

In conclusion, we suggest that if hypothyroidism develops during maintenance treatment with MMI, this should be considered a favorable prognostic indicator. This, along with other parameters, could be useful in assessing the chances of long-term remission and in deciding the most-effective strategy for using ATDs, or at least MMI, in patients with Graves' disease.

Disclosure Statement

The authors declare that no competing financial interests exist.

Footnotes

This work was presented at the 91st Annual Meeting of the Endocrine Society, June 10–13, 2009, Washington, DC.

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