Therapy Division, Russian Endocrinology Research Center, Moscow, Russia (D. Ulyanova str., 11, Moscow 117030).
In 1987 Glinoer et al. reported the results of a survey of European Thyroid Association (ETA) members on the management of GD. Shortly thereafter, Solomon et al. (1994) used a similar format to query members of the American Thyroid Association (ATA) on their approach to the treatment of GD. These surveys showed that ETA thyroid specialists preferred to use methimazole (MMI) in contrast to ATA specialists who more often used propylthiouracil (PT U) as initial therapy.
Numerous other investigators (Shiroozu 1986, Messina 1987, Mashio 1988) have shown that 10-15 mg starting doses of MMI may be as effective as larger doses. Reinwein et al. reported in 1993 the results of a randomized trial of either 10 or 40-mg daily dose of MMI in patients with GD. He found that the 10-mg dose achieved biochemical euthyroidism in 6 weeks, while the 40-mg dose produced remission in 3 weeks. Relapse rates did not differ between the two groups.
In 1992 a survey of the management of GD by members of the endocrine society in the former LTSSR was performed (Gerasimov 1992). The only treatment available at that time was MMI, as PTU and 131I ablation were not available. 70.2% of respondents used 3040 mg MMI daily as initial therapy; less than 5% chose an MMI dose of less than 20 mg as initial treatment.
The purpose of the study reported here was to investigate the effects of two different MMI starting doses on the clinical and biochemical course of GD and to investigate the effects of various independent factors on MMI's efficacy.
The diagnosis of GD was based upon characteristic clinical features, thyroid ultrasonography, and measurement of serum free thyroxine (FT4) and TSH levels by automated immunometric assay (IMX free T4, normal range 9,1-23,8 pmol/l; IMX ultrasensitive hTSH; Abbott Diagnostics, No. Chicago, Ill. USA).
With the exception of 8 patients as described above, patients were randomized to treatment with either 15 or 30 mg MMI daily. No other medications were administered. The clinical and laboratory data of all patients at the time of initial evaluation is shown in Table 1. There were no differences in patient age, disease duration, thyroid volume (determined by real-time ultrasonography using a 5 MHz transducer and Phillips SDR-1200 sector scanner and volume calculation by the method of Brunn et al. (1981)), FT4 or urinary iodine levels (as measured by the cerium-arsenite method of Wawschinek et al. (1985)) between the two patient groups. The time to achieve euthyroidism was defined as the duration of therapy necessary to achieve normal FT4 levels. Evaluation of serum FT4 levels and clinical examination were performed 3, 4 and 5 weeks after commencement of MMI therapy.
Data were analyzed using an unpaired Student's t-test and are presented as mean ± standard error. Results were considered significant at p<0.05.
In patients treated with 15 mg MMI daily, 26 of 30 patients (86.7%) achieved euthyroidism within 3 weeks with a mean FT4 of 15.79 ± 2.26 pmol/l. 100% of patients in this
group were euthyroid within 4 weeks of initiating therapy. 28/30 patients receiving 30 mg MMI daily were euthyroid within 3 weeks with mean FT4 levels of 13.89 ± 2.26 pmol/l. 29/30 patients were euthyroid within 4 weeks. 1/30 patients required 5 weeks to become euthyroid. This patient, however, was receiving amiodarone chronically and had urinary iodine level of 92.9 mcg/dl.
The mean time to achieve control of hyperthyroidism was 3.13 ± 0.1 weeks in patients receiving 30 mg MMI daily and 3.1 ± 0.3 weeks in patients receiving 15 mg a day. This difference was not significant (Fig. 1).
No correlation was observed between patient outcome and age, duration of disease, thyroid volume, presence of ophthalmopathy. Patients with FT4 levels > 75 pmol/l treated with 30 mg MMI (10/30) required 3.4 ± 0.3 weeks to become euthyroid while patients treated with 15 mg MMI (6/30) required 3.0 ± 0.0 weeks to become euthyroid. This difference was significant (p <0.05).
All patients were followed up for 5-20 months. During this time one patient treated with 15 mg MMI daily and two patients treated with 30 mg daily suffered a relapse. Noncompliance was the cause of the relapse in all three patients. 7/30 patients (23.3%) treated with 15 mg and 9/26 (30%) treated with 30 mg required surgery because of goiter > 40 ml or noncompliance with medication.
8 patients who had developed side effects on 30 mg MMI prior to entering this study received 15 mg doses without experiencing any adverse reactions. Side effects occurred with equal frequency in both groups. 11 episodes were noted and involved pruritus (87.5%) and rash (75%). Also, there was 1 episode of diarrhea, 1 episode of alopecia and 1 episode of myalgia and arthralgia (Fig. 2). No hematological side effects were observed. All side effects occurred between 1 and 3 weeks of therapy and more frequently affected those under age 30.
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Our results differ from those reported by Reinwein et al. (1993). One explanation for this may be dosage difference, as their study used 10 and 40 mg MMI compared to the 15 and 30 mg used in our report. Alternatively, iodine intake may account for this difference (Azizi 1985, Hilditch 1990). Our patients came from regions of Russia, including the Moscow region, North Caucasus, and Central Russia, which are known to have mild to moderate iodine deficiency (Gerasimov 1993), and exhibited relatively low urinary iodine levels. Additionally, the one patient in our study with high urinary iodine due to amiodarone therapy required a longer period to achieve remission than all other patients, despite receiving 30 mg MMI daily.
We found no significant difference in dose response. However, patients with high (>75 pmol/l) FT4 levels, receiving 15 mg MMI required a significantly longer time to become euthyroid compared to those who received 30 mg daily.
As previously reported (Cooper 1983, Romaldini 1991), MMI side effects are dosedependent. Allergic skin reactions with pruritus and rash were observed most frequently. We found no leukopenia or agranulocytosis in this study and this is consistent with the low incidence of 0.1-0.4% reported by others (Tamai 1993, Ross 1993).
We conclude that the clinical and biochemical response to MMI treatment of GD correlates primarily with the pretreatment FT4 level. Most patients with GD, particularly if they come from a region of marginal iodine deficiency and have not received iodine supplementation, can be effectively controlled by a 15-mg starting dose of MMI, and this appears to correlate with a reduced likelihood of developing MMI side effects.
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