Effects of glucocorticoid pulse therapy on thyroid function and thyroid antibodies in children with graves’ disease

Hyperthyroidism is a relatively rare disease in children compared to adults [1]. The incidence rate of hyperthyroidism in children is increasing over the last decades [2]. The most common cause of hyperthyroidism in children is Graves’ disease (GD). GD is more common in children with Down or Turner syndrome (TS) than in the general population [3‐5]. A wide variety of clinical manifestations in GD have been described. Some individuals even progress from Hashimoto’s thyroiditis (HT) to GD [6]. GD has serious adverse effects on children’s growth and development [7].

The purpose of treatment for GD is not only to reduce the excess production of thyroid hormone and maintain normal thyroid function but also to prevent recurrence of hyperthyroidism. Seeking the most appropriate therapy for children is very important and urgent. Antithyroid drugs (ATD) therapy is usually the initial treatment for children with GD at present. However, uncontrolled symptoms, long-term remission, and high recurrence rate are often presented in children with GD who only use antithyroid drugs. How to correct thyrotoxicosis promptly and maintain euthyroidism stably for children with GD should be solved. Glucocorticoid treatment is used in children with GD only in cases of exophthalmos [8, 9] A novel use has been explored in this study. The purpose of this study was to observe the effects of intravenous methylprednisolone pulse therapy (MPT) followed by oral prednisolone administration on thyroid function and thyroid antibodies in children with GD.

Fasting serum samples were collected in the morning from all subjects. Serum FT3, FT4, TSH, TPOAb, TGAb, and TRAb concentrations were measured by an automated chemiluminescence immunoassay system (Advia Center, Siemens, Munich, Germany). Normal ranges were 2.27–4.22 pg/mL for FT3, 0.88–1.75 ng/dL for FT4, 0.35–5.5 μIU/mL for TSH, 0–60 IU/mL for TPOAb, 0–60 IU/mL for TGAb, and 0–1.22 IU/L for TRAb. TPOAb, TGAb, and TRAb values above the normal ranges were defined as positive. The intra- and inter-assay coefficients of variation were all < 5.0 and < 4.0%, respectively. The sensitivity of FT3, FT4, TSH, TPOAb, TGAb, and TRAb were 0.19 pg/mL, 0.1 ng/dL, 0.001 μIU/mL, 0.1 IU/mL, 10 IU/mL, and 0.01 IU/L, respectively.

Grading of goiter was performed by inspection and palpation, and was classified according to the World Health Organization (WHO) criteria: grade 0, no goiter; grade 1, goiter palpable but not visible; grade 2, goiter visible with neck in normal position [12]. Degree of proptosis was measured with a Hertel exophthalmometer. Physical examination of all subjects was done by one experienced investigator.

Thyroid ultrasound was performed with a 5–12 MHz linear-array transducer on a LOGIQ 9 scanner (GE Medical Systems, Milwaukee, WI, USA). Echocardiography was performed with a 2–5 MHz transducer using an IU-22 ultrasound scanner (Philips Medical System, Bothell, WA, USA). All ultrasound examinations were carried out by the same trained sonographer. ECG was recorded with an electrocardiograph (1550p; Nihon Kohden, Tokyo, Japan) at paper speed of 25 mm/s and 10 mv/mm.

In this study, the effects of intravenous MPT followed by oral prednisolone administration on thyroid function and thyroid antibodies were observed in children with GD. We found that no significant differences in FT3, FT4, TSH, TPOAb, and TGAb levels between the pulse group and the control group. On the 30th day, the TRAb level in the pulse group was significantly lower than that in the control group. However, the level of TRAb rose on the 60th day, and there was no difference between the pulse group and the control group. The results indicated that the intravenous MPT followed by oral prednisolone administration had a transient mitigation effect on TRAb level in children with GD.

GD is an autoimmune thyroid disease. Genetic predisposition and environmental factors contribute to the development of autoimmune thyroid disease. Polymorphism of genes occurs in genetically predisposed individuals [13]. Deficiency in suppressor T cells and loss of self-tolerance are mainly involved in the pathogenesis of GD [14]. Both cell-mediated and humoral responses lead to high levels of TRAb [15]. TRAb binds to TSH receptor (TSHR) to activate thyroid gland, leading to hyperthyroidism and goiter. Excess circulating thyroid hormone causes a wide range of clinical symptoms. However, many patients have antibodies against TSHR and thyroid peroxidase, and about 50% of them have antibodies against thyroglobulin [16]. In this study, most of children showed positive TRAb, TGAb and TPOAb.

Glucocorticoids have immunoregulatory effects. It could decrease aggregation of macrophage, interfere with function of T cells and B cells, reduce the activity of immune cells, inhibit the release of inflammatory mediators (i.e. cytokines and prostaglandins), lower the concentration of thyroid-stimulation immunoglobulins, and prevent antibodies from binding to receptors [17, 18]. In addition, glucocorticoids have non-specific anti-inflammatory effects. It could reduce interstitial capillary dilatation, exudation and edema, inhibit the proliferation of vascular endothelial cells, alleviate interstitial congestion, and decrease thyroid gland volume. Therefore, glucocorticoids could control hyperthyroidism to some extent.

The mechanism for glucocorticoids used in GD is their immunosuppressive and anti-inflammatory effects. Glucocorticoids could be given orally, intravenously and locally [19]. Retrobulbar injection of glucocorticoids may be considered under circumstances of absolute contraindications to systemic glucocorticoids [20]. Therefore, intravenous and oral glucocorticoids were used in this study.

The effect of glucocorticoids therapy on Graves’ orbitopathy has been studied in most studies. A meta-analysis of 14 clinical trials showed that glucocorticoids were more effective than other treatments for Graves’ orbitopathy, especially the intravenous glucocorticoid pulse therapy [21]. A prospective, randomized, and placebo-controlled study also reported that MPT effectively improved diplopia, eye movement and proptosis for active and moderately severe Graves’ orbitopathy. It was well tolerated and safe. However, the proptosis of one eye worsened in 1 patient. The effect of treating proptosis with MPT was not so obvious for overall outcome of both eyes [22]. A small number of paediatricians recommended the use of glucocorticoids in children with moderate-to-severe and active Graves’ orbitopathy. Glucocorticoids are the choice of treatment [8]. Based on this recommendation, GD children associated with orbitopathy were treated with MPT treatment in this study. However, the difference of proptosis in children with GD was not noted after MPT treatment. This may be due to our short-term follow-up.

Few studies have been conducted on the effects of glucocorticoids therapy on thyroid function and thyroid antibodies. A study found that the level of TSH binding inhibitor immunoglobulin (TBII) in some adult patients with GD decreased significantly after 3 to 6 months of pulse therapy, but increased again at 12 to 24 months. The effect of pulse therapy on autoimmune antibody was transient. The pulse therapy did not improve remission rate of GD [23]. However, studies of the effects of glucocorticoids therapy on thyroid function and thyroid antibodies in GD children are few. Therefore, glucocorticoids therapy on thyroid function and thyroid antibodies in GD children is our main observation. There is no clinical evidence on the optimal dosage and regimen of intravenous and oral glucocorticoids for children. Prolonged glucocorticoid administration will lead to Cushing’s syndrome, hyperglycemia, hypertension, gastrointestinal ulcer, infection, osteoporosis, growth retardation, etc. [24]. Therefore, based on the above considerations, intravenous MPT followed by oral prednisolone administration was used in this study. After 9 days of MPT, oral prednisolone was administered. The dosage of prednisolone was gradually tapered off over a period of 3 weeks. Increased appetite, hyperglycemia, and hypertension were found in some of children in the pulse group. After ceasing glucocorticoid therapy, these symptoms returned to normal. It could reduce the side effects of prolonged glucocorticoid administration to some extent.

In this study, the TRAb level on the 30th day in the pulse group was significantly lower than that in the control group. It was due to the immunosuppressive effect of glucocorticoids. The level of TRAb rose on the 60th day, and there was no difference between the pulse group and the control group. It was due to the discontinuation of glucocorticoids after 30 days. In addition, the rate of positive TGAb in the pulse group was lower than that in the control group also due to the immunosuppressive effect of glucocorticoids. There was no difference in the level of TGAb between the pulse group and the control group. It may be due to our small sample size.

There are two main limitations in this study. On one hand, different dosage and regimen of glucocorticoid administration may result in different therapeutic effects. There are no literatures which clearly specify the dosage and regimen of glucocorticoid administration for children. Considering the side effects of glucocorticoids on children, we adopted small dosage of intravenous MPT followed by oral glucocorticoids. On the other hand, this is a retrospective cohort study based on clinical practice with consents of parents and ethics committee. The clinical practice provided initial exploration for follow-up prospective study. The sample size was small and the observation time was short in this study. In fact, GD is relatively rare in children. The half-life of glucocorticoid is relatively short.

In conclusion, the effect of intravenous MPT followed by oral prednisolone on TRAb level was temporary in children with GD. Glucocorticoid pulse therapy was not beneficial for the sustained recovery of thyroid function. In the future, the dosage and regimen of glucocorticoid administration, as well as new treatments which could reduce the recurrence rate and restore thyroid function promptly need to be further explored for children with GD.