Original Article
Administration of Thyroxine in Treated Graves' Disease — Effects on the Level of Antibodies to Thyroid-Stimulating Hormone Receptors and on the Risk of Recurrence of Hyperthyroidism
N Engl J Med 1991; 324:947-953April 4, 1991
- Abstract
- Abstract
Background.
Antibodies to thyroid-stimulating hormone (TSH) receptors that stimulate the thyroid gland cause hyperthyroidism in patients with Graves' disease, and their production during antithyroid drug treatment is an important determinant of the course of the disease. One factor that might contribute to the persistent production of antibodies to TSH receptors is stimulation of the release of thyroid antigens by TSH during antithyroid drug therapy. We therefore studied the effect of the suppression of TSH secretion by thyroxine on the levels of antibodies to TSH receptors after thyroid hormone secretion had been normalized by methimazole.
Methods and Results.
The levels of antibodies to TSH receptors were measured during treatment with methimazole, either alone or in combination with thyroxine, in 109 patients with hyperthyroidism due to Graves' disease. The patients first received 30 mg of methimazole daily for six months. All were euthyroid after six months, and their mean (±SD) level of antibodies to TSH receptors decreased from 64±9 percent to 25±15 percent (P<0.01; normal, 2.9±1.4 percent). Sixty patients then received 100 μg of thyroxine and 10 mg of methimazole and 49 received placebo and 10 mg of methimazole daily for one year. In the thyroxine-treated group, the mean serum thyroxine concentration increased from 108±16 nmol per liter to 145±11 nmol per liter (P<0.01), and the level of antibodies to TSH receptors decreased from 28±10 percent to 10±3 percent after one month of combination therapy. In the patients who received placebo and methimazole, the mean serum thyroxine concentration decreased and the level of antibodies to TSH receptors did not change. Methimazole, but not thyroxine or placebo, was discontinued in each group 1 1/2 years after the beginning of treatment. The level of antibodies to TSH receptors further decreased (from 6.6±3.2 percent at the time methimazole was discontinued to 2.1±1.2 percent one year later) in the patients who continued to receive thyroxine, but it increased (from 9.1±4.8 percent to 17.3±5.8 percent during the same period) in the patients who received placebo. One patient in the thyroxine-treated group (1.7 percent) and 17 patients in the placebo group (34.7 percent) had recurrences of hyperthyroidism within three years after the discontinuation of methimazole.
Conclusions.
The administration of thyroxine during antithyroid drug treatment decreases both the production of antibodies to TSH receptors and the frequency of recurrence of hyperthyroidism. (N Engl J Med 1991; 324: 947–53.)
Article Activity
- Article
HYPERTHYROIDISM in patients with Graves' disease is due primarily, if not solely, to the production of autoantibodies that bind to receptors for thyroid-stimulating hormone (TSH) on thyroid cells.1 2 3 4 These anti—TSH-receptor antibodies are formed because of undefined disturbances in immune homeostasis.5 6 7 8 9 10 11 The treatment of hyperthyroidism with an antithyroid drug such as propylthiouracil or methimazole may be accompanied by remission of Graves' disease.12 13 14 These drugs may also have immunosuppressive actions, which may contribute to their ability to induce permanent remissions of Graves' disease.15 Even so, the rate of remission varies widely in different reports, for reasons that remain unclear.16 17 18 In a previous study, we found that the level of antibodies to TSH receptors decreased significantly in a group of patients treated with methimazole for five to six months, but in several patients it did not change even after long-term treatment.19
Thyroid stimulators, such as TSH, cyclic AMP, and antibodies to TSH receptors, stimulate the release of thyroid cell-surface components, including TSH receptors, from preparations of thyroid-cell plasma membranes in vitro.20 Although a defect in the fail-safe mechanism in immune homeostasis may contribute to the development of Graves' hyperthyroidism,21 , 22 stimulator-induced activation of the thyroid gland could also have a role in perpetuating hyperthyroidism by stimulating the release of thyroid antigens.20 With these issues in mind, we undertook to determine whether the administration of thyroxine, which inhibits the secretion of TSH, could decrease the levels of antibodies to TSH receptors in patients with Graves' disease after they had become euthyroid during methimazole therapy. We found that the administration of thyroxine decreased the level of antibodies to TSH receptors during and after methimazole therapy and, furthermore, that it decreased the rate of recurrence of hyperthyroidism after methimazole was discontinued.
Methods
Patients
One hundred nine patients with untreated hyperthyroidism caused by Graves' disease were enrolled in this study. There were 85 women and 24 men, ranging in age from 17 to 58 years (mean [±SD], 39±11). All the patients had symptoms and signs of hyperthyroidism, diffuse goiter, an increased basal metabolic rate, increased thyroidal uptake of 123I, and increased serum levels of thyroxine, triiodothyronine, and antibodies to TSH receptors. The patients were treated initially with 10 mg of methimazole every eight hours for six months (mean dose, 0.63±0.02 mg per kilogram of body weight per day; range, 0.48 to 0.71 ). The patients were then divided into two groups on the basis of their levels of antibodies to TSH receptors at that time. Group A (n = 56) was composed of patients whose antibody level was 15 percent or more, and group B (n = 53) of those whose antibody level was less than 15 percent. Each group was further randomly divided into two subgroups (the subgroups were stratified according to age and sex). Patients in subgroups A1 (n = 29) and B1 (n = 31) were given 100 μg of thyroxine once a day (subgroup A1: mean dose, 1.8±0.2 μg per kilogram per day; range, 1.7 to 2.2; subgroup B1: mean dose, 1.8±0.3 μg per kilogram per day; range, 1.6 to 2.2) and 10 mg of methimazole once daily (subgroups A1 and B1: mean dose, 0.21±0.02 mg per kilogram). In 15 normal subjects, a 100-μg daily dose of thyroxine decreased the mean (±SD) serum concentration of TSH from 2.8±0.6 to 1.7±0.3 mIU per liter (P<0.01) in one week, and the 10-mg daily dose of methimazole, given for a week, decreased the mean serum thyroxine concentration to 58.4±9.8 percent of the initial value (P<0.01) in a different group of 15 normal subjects. The patients in subgroups A2 (n = 27) and B2 (n = 22) received placebo instead of thyroxine along with 10 mg of methimazole daily (both subgroups: mean dose, 0.21±0.02 mg per kilogram; range, 0.16 to 0.24). The clinical characteristics of these subgroups at base line (before they received any treatment) are shown in Table 1Table 1
Clinical Characteristics of the Patients before Treatment.*. One year after the beginning of the combination treatment, methimazole therapy was discontinued. The patients continued to take thyroxine or placebo alone for three years thereafter. During the study, the patients knew they were taking methimazole but not whether they were taking thyroxine or placebo, whereas the treating physicians were aware of both.The patients were examined and serum levels of thyroxine, triiodothyronine, TSH, thyroxine-binding globulin, and antibodies to TSH receptors were measured at regular intervals for a total of up to 4.5 years. For comparison, we also measured the serum level of antibodies to TSH receptors and the concentrations of TSH, thyroxine, and thyroxine-binding globulin in normal subjects (n = 1882).
During the three-year period after the discontinuation of methimazole therapy, 18 patients (1 patient in subgroup A1, 10 patients in subgroup A2, and 7 patients in subgroup B2) had recurrences of hyperthyroidism. These 18 patients were treated by the discontinuation of thyroxine, if the patient was taking it, and the reinstitution of methimazole; subsequent data on these patients were excluded from our analyses. During the study, no patient had any side effects from the study medications. The study protocol was approved by a human studies review committee at our institution, and informed consent was obtained from all study subjects.
Measurement of Serum Concentrations of Thyroxine, Triiodothyronine, TSH, Thyroxine-Binding Globulin, and Antibodies to TSH Receptors
Commercially available radioimmunoassay kits were used to measure the serum concentrations of thyroxine and triiodothyronine (Boehringer–Mannheim, Mannheim, Germany), TSH (Dinabot, Tokyo, Japan), and thyroxine-binding globulin (Behringwerke, Marburg, Germany). The minimal detectable concentrations were as follows: thyroxine, 20 nmol per liter; triiodothyronine, 0.30 nmol per liter; TSH, 0.02 mIU per liter; and thyroxine-binding globulin, 2574 nmol per liter (2.0 rag per liter). The interassay and intraassay coefficients of variation for each assay were as follows: thyroxine, 1.8 and 1.2 percent; triiodothyronine, 2.8 and 3.5 percent; TSH, 2.4 and 1.5 percent; and thyroxine-binding globulin, 1.2 and 0.7 percent. The levels of antibodies to TSH receptors were determined by radioreceptor assay, with use of kits obtained from the Endocrine Immunology Unit, Department of Medicine, Welsh National School of Medicine (Cardiff, United Kingdom).23 According to the manufacturer's instructions, the test result was considered positive when the test serum sample inhibited the binding of [125I]TSH to the thyroid-membrane preparation by more than 15 percent. We found, however, that the mean antibody level was 2.9±1.4 percent (range, 0 to 7.0) in serum samples from 1882 normal subjects (men: n = 578; mean age, 39±11 years; range, 22 to 68; women: n = 1304; mean age, 38±12 years; range, 18 to 70) (Table 1). Therefore, we considered the test positive when the level of antibodies to TSH receptors was more than 7.0 percent. The mean serum levels of TSH, thyroxine, triiodothyronine, and thyroxine-binding globulin in these normal subjects are also shown in Table 1. The serum level of thyroxine-binding globulin increased in proportion to the increase in age in these subjects (P<0.05).
Statistical Analysis
Student's unpaired and paired t-tests and Wilcoxon two-sample tests were used in the statistical analysis. P values of less than 0.05 were considered to indicate statistical significance. The results are given as means ±SD. Linear regression analysis was used to assess the relation between two variables, and the slopes of the regression lines for two different groups were compared.
Results
Changes in Serum Levels of Antibodies to TSH Receptors and Levels of Thyroxine, TSH, and Thyroxine-Binding Globulin during Initial Methimazole Therapy
During the initial six-month period of treatment with 30 mg of methimazole per day, all the patients became euthyroid. The mean serum thyroxine concentration decreased from 449±77 to 119±16 nmol per liter in the patients later assigned to group A and from 421±59 to 116±11 nmol per liter in those later assigned to group B (Fig. 1Figure 1
Mean Serum Concentrations of Thyroxine (T4) during Treatment in Patients with Hyperthyroidism Due to Graves' Disease.). Neither the initial nor the six-month mean values differed significantly between the two groups, although the rate of decrease was faster in group B than group A. Similarly, the mean serum triiodothyronine concentration decreased during this treatment period in both groups, and the decrease was more rapid in group B. The mean initial and six-month values were 11.11±1.76 and 1.74±0.21 nmol per liter in group A, and 10.51±1.66 and 1.73±0.19 nmol per liter in group B. During the same period, the mean level of antibodies to TSH receptors decreased from 64±9 to 25±15 percent (P<0.01) in the study group as a whole; the levels decreased from 66±10 to 35±11 percent in group A and from 61±9 to 11±3 percent in group B (Fig. 2Figure 2
Mean Levels of Antibodies to Thyroid-Stimulating Hormone Receptors (TRAb) during Treatment in Patients with Hyperthyroidism Due to Graves' Disease.). All the patients in both groups had undetectable serum TSH concentrations (less than 0.02 mIU per liter) before and for the first four months of treatment, after which the levels were detectable but low in many patients (Fig. 3Figure 3
Mean Serum Thyroid-Stimulating Hormone (TSH) Concentrations during Treatment in Patients with Hyperthyroidism Due to Graves' Disease.). The serum concentrations of thyroxine-binding globulin increased in both groups (Fig. 4Figure 4
Mean Serum Thyroxine-Binding Globulin (TBG) Concentrations during Treatment in Patients with Hyperthyroidism Due to Graves' Disease.). Although the values in the two groups were similar before treatment, the mean serum concentration of thyroxine-binding globulin in group A (14.5±0.9 mg per liter) was significantly lower than that in group B (19.0±2.9 mg per liter; P<0.01) after six months of methimazole treatment (Fig. 4).Effect of Thyroxine on the Level of Antibodies to TSH Receptors
After six months of treatment with methimazole, the patients were divided into two groups according to their level of antibodies to TSH receptors; each group was then subdivided, with one subgroup in each group receiving thyroxine and the other placebo, as described in the Methods section. The dose of methimazole was lowered to 10 mg daily for all patients. In the patients who received thyroxine (subgroups A1 and B1), the mean serum thyroxine concentration increased from 108±16 to 145±11 nmol per liter (P<0.01) after 1 month, and remained at 116 nmol per liter or higher throughout the 12-month period of combined therapy. The mean serum thyroxine concentration in the patients who received placebo and methimazole (subgroups A2 and B2) decreased during the same period from 104±11 to 81±6 nmol per liter, and the concentrations in these two subgroups were significantly lower (P<0.01) than those in the patients in subgroups A1 and B1, who received thyroxine and methimazole throughout the period of combined treatment (Fig. 1).
During the six months after methimazole was discontinued, however, the mean serum thyroxine concentration increased significantly in subgroups A2 and B2 (P<0.01 for both comparisons, by paired t-test), whereas the discontinuation of methimazole did not result in any change in the mean serum thyroxine concentration in subgroup A1 or B1. Six to nine months after methimazole was discontinued, the mean serum thyroxine concentrations in subgroups A2 and B2 did not differ significantly from those in subgroups A1 and B1, respectively. The thyroxine concentration increased further in subgroups A2 and B2 during the next two years. Thus, the mean serum thyroxine concentrations were significantly higher in subgroup A2 than in subgroup A1 and in subgroup B2 than in subgroup B1 (P<0.01 for both comparisons) on several occasions one or more years after the discontinuation of methimazole (Fig. 1). The changes in the serum concentrations of triiodothyronine were similar (data not shown).
The mean serum TSH concentration began to increase after six months of treatment with methimazole both in group A and in group B. During the period of combined treatment, the serum TSH concentrations in subgroups A2 and B2 were significantly higher than those in subgroups A1 and B1, respectively (P<0.01 for both comparisons). The rate of increase in the serum TSH level was more rapid in subgroup B2 than in subgroup A2 during this period (P<0.05). After the discontinuation of methimazole, the serum TSH levels in subgroups A1 and B1 initially decreased. They then increased again in both subgroups and did not differ substantially from those in subgroups A2 and B2, respectively, three years after the discontinuation of methimazole. The increase in the serum TSH concentration was more rapid in subgroup B1 than in subgroup A1 (P<0.05) after the discontinuation of methimazole (Fig. 3).
Although the serum concentration of thyroxine-binding globulin decreased during the administration of thyroxine in subgroup B1, it continued to increase in subgroups A1, A2, and B2 even after the beginning of combination treatment. The serum concentration of thyroxine-binding globulin then decreased after the discontinuation of methimazole in both subgroup A1 and subgroup B1 but began to increase again two months later. In contrast, the serum concentrations of thyroxine-binding globulin decreased continuously after the discontinuation of methimazole in subgroups A2 and B2, and one year later the levels in subgroup A2 and B2 were significantly lower than those in subgroups A1 and B1, respectively (Fig. 4).
The levels of antibodies to TSH receptors, which were not significantly different in subgroups A1 and A2 or in subgroups B1 and B2 during the first six months of methimazole therapy (Fig. 2), decreased during treatment with thyroxine and methimazole in subgroups A1 and B1. The mean serum level of such antibodies in the two groups decreased from 28±10 to 10±3 percent after one month of combination therapy and fell to 6.6±3.2 percent at the end of this period. In contrast, the level did not change during the first month in subgroups A2 and B2 (22±12 and 19±12 percent) and was 9.1±4.8 percent at the end of this period. The levels in subgroups A1 and B1 were significantly lower than those in subgroups A2 and B2, respectively (P<0.01 for both comparisons), during combination treatment. The mean value in subgroups A2 and B2 increased to 17.3±5.8 percent one year after the discontinuation of methimazole, whereas the mean value in subgroups A1 and B1 decreased to 2.1±1.2 percent. The levels in subgroups A1 and B1 were significantly lower than those in subgroups A2 and B2, respectively (P<0.01 for both comparisons), on all occasions during the following three years (Fig. 2).
Frequency of Recurrence of Hyperthyroidism
As Table 2Table 2
Frequency of Recurrence of Hyperthyroidism.* shows, hyperthyroidism recurred more frequently in subgroup A2 (10 of 27 patients, 37.0 percent) and subgroup B2 (7 of 22, 31.8 percent) than in subgroup A1 (1 of 29, 3.4 percent) or subgroup B1 (none of 31) during the three years after the discontinuation of methimazole. The differences between subgroups A1 and A2 and between subgroups B1 and B2 were significant at the 95 percent level as determined by analysis of variance. However, the differences between subgroups A1 and B1 and between subgroups A2 and B2 were not significant. Most of the recurrences in subgroup A2 occurred between 2 1/2 and 3 years after the discontinuation of methimazole, whereas those in subgroup B2 were more evenly distributed over the 3-year follow-up period.Discussion
We found in this study that the levels of antibodies to TSH receptors were low in patients with hyperthyroidism due to Graves' disease who received thyroxine after an initial period of treatment with methimazole, during which their serum thyroxine concentrations fell to normal. The thyroxine-treated patients had lower serum TSH concentrations than the patients who received placebo during the period of combination therapy and for at least 1 1/2 years after the discontinuation of methimazole. These results suggest that a relatively high serum concentration of TSH contributed to maintaining the production of antibodies to TSH receptors. As mentioned previously, TSH can stimulate the release of certain molecules, including TSH receptors, that might be antigenic.20 , 24 25 26 On the basis of this finding, we speculate that the higher levels of antibodies to TSH receptors in the patients who did not receive thyroxine were due in part to their higher serum TSH concentrations during methimazole treatment and for several years thereafter. The serum TSH concentration, however, also increased after the discontinuation of methimazole in the patients treated with thyroxine and methimazole, indicating that TSH is not the only determinant of the production of antibodies to TSH receptors.
Thyroxine might also act directly on the B lymphocytes that produce antibodies to TSH receptors. However, we have no data regarding the regulation of immune function by thyroid hormones. Another possibility is that thyroxine directly inhibits the production of antigenic substances by the thyroid gland. Thyroxine is known to modify the activity of enzymes that stimulate the synthesis of phospholipids in cell-surface membranes in several tissues.27 28 29 30 The thyroid gland contains thyroid hormone nuclear receptors,31 indicating that it could be a target tissue for thyroid hormone. If so, there might be differences in thyroid-membrane structure in patients given thyroxine and those given placebo, so that the production or release of antigenic substances would be inhibited in the former group. We have not found, however, that thyroid hormone inhibits the release of TSH receptors from thyroid plasma membranes in vitro.20 , 32
The decrease in the serum level of antibodies to TSH receptors during the initial period of treatment with methimazole might be related to the immunosuppressive action of methimazole.15 Yet the level of antibodies to TSH receptors decreased further rather than increased after the cessation of methimazole therapy in the patients given thyroxine — an observation that suggests that methimazole did not contribute to inhibiting the production of antibodies to TSH receptors.
We divided the patients into two groups (A and B) according to the level of antibodies to TSH receptors after the normalization of the serum thyroxine concentrations. This meant that the decrease in the level of antibodies to TSH receptors was slower in group A than in group B during the first six months of treatment with methimazole, as was the decline in the serum thyroxine concentration. The serum level of thyroxine fell below 128 nmol per liter within two to three months in the patients in group B, whereas this level was not reached until six months after the beginning of treatment in group A. The discrepancy in the decrease in serum triiodothyronine concentrations was similar. The increase in the serum TSH concentrations was slower in subgroup A2 than in subgroup B2 during the period of combination therapy. The increase in the serum TSH concentration was slower in subgroup A1 than in subgroup B1 after the cessation of methimazole therapy. Thus, the patients whose level of antibodies to TSH receptors remained high had subclinical hyperthyroidism — that is, subnormal TSH concentrations in the presence of normal serum thyroxine and triiodothyronine concentrations.33
Although groups A and B differed in terms of their serum TSH concentrations after the normalization of their serum thyroxine concentrations, we found no difference between the two groups in the frequency of recurrent hyperthyroidism after the discontinuation of methimazole. Thus, the detection of subnormal TSH concentrations appears not to be helpful in predicting the long-term outcome of the disease in an individual patient. On the other hand, the frequency of recurrence was reduced by the administration of thyroxine both in group B and in group A. Since the thyroxine-induced decrease in the level of antibodies to TSH receptors occurred in both groups, it may be related to the frequency of recurrence of hyperthyroidism.
The mean serum thyroxine levels were low in the patients who did not receive thyroxine (subgroups A2 and B2) during the period of combination therapy, but these levels gradually increased after the discontinuation of methimazole, and the increase was associated with a decrease in the serum levels of thyroxine-binding globulin. These results suggest that the serum free thyroxine concentrations were higher after the cessation of methimazole therapy in these subgroups. Nevertheless, their levels of antibodies to TSH receptors remained high. The increase in the serum free thyroxine concentration in these patients might have been induced by thyroid stimulation in response to the high levels of antibodies to TSH receptors. In the patients who were receiving thyroxine, in contrast, these changes (increasing serum levels of thyroxine, decreasing levels of thyroxine-binding globulin, and increasing levels of antibodies to TSH receptors) did not occur even after the discontinuation of methimazole. On the basis of these findings, it appears that a relatively high level of antibodies to TSH receptors accelerates the recurrence of hyperthyroidism.
Romaldini and his coworkers reported that the frequency of negative tests for antibodies to TSH receptors was higher in patients treated with large doses of an antithyroid drug with the later addition of triiodothyronine than in patients treated with a low dose of an antithyroid drug alone.34 Although the design of our study differed from that of Romaldini et al., we also found that the administration of thyroid hormone (thyroxine) was associated with a decrease in the level of antibodies to TSH receptors in patients with Graves' disease. Furthermore, we found that recurrent hyperthyroidism was infrequent among the patients who were given thyroxine. Since the level of antibodies to TSH receptors is related to the frequency of recurrence of hyperthyroidism,35 the administration of thyroxine may contribute to a delay in the reappearance of hyperthyroidism in Graves' disease.
Source Information
From the Department of Geriatrics, Endocrinology, and Metabolism, Shinshu University School of Medicine, Matsumoto 390, Japan, where reprint requests should be addressed to Dr. Hashizume.
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