Thyroid diseases are the most common endocrine diseases in children; they are characterized by impaired synthesis or functions of thyroid hormones due to genetic aberrations during growth and development¹⁾. Thyroid dysfunction leads to impairment in growth and development during childhood and metabolic dysfunction in adults²⁾.

Hyperthyroidism is characterized by the overproduction of thyroid hormone, and its incidence is lower in children compared with adults, i.e., pediatric thyroidism accounts for approximately 5% of all diagnosed cases^3,4,5). In contrast, more than 95% of pediatric hyperthyroidism evolves from Graves disease (GD), also known as diffuse toxic goiter⁶⁾. Currently, antithyroid medications are considered the first-line treatment for pediatric hyperthyroid GD^7,8). However, it remains problematic because treatment occurs over a long period of time and high compliance is required from children^9,10). It has been suggested that children with GD should receive long-term antithyroid medications, such as methimazole (MMI), which are essential for achieving complete remission. It would therefore be mandatory to predict the response to initial treatment with MMI in such children. Consequently, we conducted this study to identify factors associated with response to initial treatment with MMI in children with GD.

Hyperthyroidism is a disease involving hyperactivity of the thyroid gland. Excessive secretion of thyroid hormones can produce symptoms of thyrotoxicosis. In children, the incidence of hyperthyroidism is lower than that of hypothyroidism⁶⁾. The major cause of hyperthyroidism is GD, and other causes include neonatal thyrotoxicosis, thyroiditis, or McCune-Albright syndrome¹²⁾. In most pediatric and pubescent patients, symptoms of hyperthyroidism are easily detectable but TF tests are required to confirm diagnosis¹³⁾. The diagnosis is confirmed when TF shows a decrease in TSH levels and an increase in T4 and T3 levels commensurate with the patient's age¹⁴⁾. The treatment methods used include medicines to directly reduce the excessive production and secretion of thyroid hormones, surgical methods, and radioisotope therapy. However, these all have the potential to cause complications^15,16). Because of antithyroid drugs, the low remission rate, complications, and decreased longitudinal compliance, several studies contended that radioactive iodine therapy or thyroidectomy is needed^9,17,18).

Of all the treatment methods, antithyroid drugs should remain the first-line therapy for the treatment of thyrotoxicosis in children^3,13). PTU and MMI, which are antithyroid drugs, interfere with the production of thyroid hormones alleviating symptoms, rather than actually treating the cause of the disease¹⁹⁾.

The predictive factors of remission with medical therapy have been studied in children with thyrotoxicosis and have yielded variable results. Allahabadia et al.²⁰⁾ reported that prognosis was poor for younger, male patients. Benker et al.²¹⁾ stated that patients with high thyroid hormone levels, high thyroid autoantibody levels, and a larger sized thyroid gland prior to treatment had an unfavorable prognosis. Furthermore, pretreatment serum T3 levels were the main factor behind the therapeutic response to MMI in GD. In other studies, the remission rates are higher in those patients with low AMA levels at diagnosis than in those patients who have high serological titers²²⁾. AMA can be used as a diagnostic method and high titers of AMA in hyperthyroidism patients represent the immune-mediated disease process. Fine needle aspiration cytology evidence of lymphocytic infiltration in patients with hyperthyroidism is well known^3,23).

Therefore, we assumed that the AMA level before treatment might correlate with the degree of TF responsiveness. Indeed, we found that there was a relationship between the T3 recovery time and the AMA level at diagnosis. The higher AMA titer group developed a normalized T3 earlier than the lower AMA titer group. Consequently, we think that more studies are required to truly ascertain treatment progression in GD patients with higher AMA titers before treatment.

Kim et al.²⁴⁾ showed that prepubertal patients had more severe symptoms and complications than pubertal ones at diagnosis but this conflicts with other studies^25,26). We were concerned about the relationship between age or other factors at diagnosis, and the normalization time of TF. We found a tendency for fT4 and TSH normalization times to be longer in those more than 16 years old, although there was no statistical correlation. Moreover, the normalization time of T3, fT4, and TSH were not significantly different by sex or family history of thyroid disease.

Our results have several limitations. First, our research was carried out retrospectively and at a single center institution. Second, almost half of the patients dropped out from the original cohort. These drop-out patients could introduce a form of selection bias. Third, we were not able to analyze confounding factors such as drug compliance.

Therefore, serum AMA titers at diagnosis could be used as a predictive factor for the degree of response to initial treatment with MMI in children with hyperthyroidism. To confirm this observation, there is a requirement for further large-scale and multi-institution studies in the future to evaluate the treatment effects of antithyroid drugs in a larger number of children and adolescent patients.