**6. Treatment of hyperthyroidism**

In most common type of hyperthyroidism in children with Graves' Disease causal treatment is unknown. The management involves pharmacotherapy (thyrostatics, β-adrenolitics), although sometimes radical radioiodine I131 therapy or surgical treatment is necessary. Some world literature reports indicate the application of immunotherapy in Graves ophtalmopathy in adults using rituximab (monoclonal anti-CD20 antibodies) to delete B cells. Thorough knowledge of the structure of human antibodies stimulating (M22) and blocking (Ki-70) TSHR has given great hope for their immunotherapeutic use in humans, including possible administration of blocking antibodies (TBI) to treat severe thyroid ophthalmopathy in the course of Graves' Disease. In children, conservative treatment with thyrostatics is most frequently used.

In clinical practice, two basic methods are used:


## **6.1 Thyrostatics**

It is assumed that treatment with thyrostatics until eutyreosis is obtained usually lasts a few weeks (2–6 weeks), and complete treatment with gradually decreasing doses should be conducted for 24–36 months (**Figure 11A**). When Graves' Disease occurs in the prepubertal period the time of therapy prolons to 3–6 years (**Figure 11B**). In children thiamazoles are administered, namely imidazole, thiamazole (administered in one or two doses; 0.3–0.6 mg/kg/24 h, max. 30 mg/24 h), carbimazole (two or three doses daily; 0.4–0.8 mg/kg/24 h.

Propylothiouracyl, which 12–15 years ago used to be the most commonly administered medicine in the USA in the therapy of Graves' Disease, currently is not recommended and even contraindicated due to increased risk of severe liver damage. FDA reports have indicated that 1:2000 children may develop severe liver failure that will require transplantation as a consequence of propylothiouracyl administration. In 1:200 children reversible propylothiouracyl-dependent liver damage will occur. The only way to avoid liver injury is to withdraw this drug, limiting its use only to patients who are allergic to thiamazole and who have to be prepared to surgery or in children sensitive to thiamazole whose parents do not give their consent to radical treatment, as well as in the first trimester of pregnancy.

A -adrenolitic drug (athenolol 1–2 mg/kg in one dose or propranolol 1–2 mg/kg in 2–3 doses) is also administered for the first 2–4 weeks until euthyreosis is achieved to monitor hyperactivation of the cardiovascular system. Serum levels of fT3 and fT4 get normalized after 2–6 weeks, whereas TSH can be inhibited for a few months (3–6 on average). Therefore, in the initial phase of the treatment peripheral hormones should be monitored. Thyroid hormones usually need to be measured after 2 weeks, one month and then every month until TSH normalization. When f T3 and f T4 become normal the thyrostatic dose is

#### **Figure 11.**

*(A) Schemes of Graves' Disease treatment strategies: A option (Figure 11A) and B option (Figure 11B). (B) Schemes of Graves' Disease treatment strategies: A option (Figure 11A) and B option (Figure 11b). Based on: Léger et al. [1].*

decreased by 30–50%, and then after the subsequent 3–6 weeks depending on the level of the hormones to the maintenance dose of 5–15/24 h. The persistence of antireceptor antibodies and difficulty in obtaining euthyrosis indicate high risk of relapse. Thus, remission is strictly related to the titer of TSI antibodies. When the titer is high, the chance of remission is 15%, and with a low titer approximately 50% of patients enter remission. Therefore, already at the start of the therapy, determination of TSI antibodies may help predict which patients are likely to achieve long-term remission of the disease.

#### *Hyperthyroidism in Children DOI: http://dx.doi.org/10.5772/intechopen.97444*

The incidence of side-effects depends on the thyrostatic dose. All antithyroid drugs may cause goiter. Other undesirable effects include skin disorders, such as pruritus, urticarial or erythematosus exanthema, dyspepsia, arthralgia or transitory granulocytopenia (<1500 granulocytes/mm3 ).

Agranulocytosis is rare (approximately 0.2% of cases). It should be remembered that as hyperthyreosis may lead to moderately increased neutropenia, complete blood cell count should be done prior to treatment and in any case of fever or strep throat. When the level of neutrophils is <1000/mm3 , the treatment should be discontinued or the dose decreased; at <500/mm3 – further treatment is contraindicated.

In turn, the level of transaminases should be assessed prior to treatment implementation and possibly when a thyrostatic is introduced. Regular control of liver function is not justified. If symptoms of jaundice, gastrointestinal dysfunction or pruritis appear, measurements should include liver enzymes (ASPAT, ALT), total and bound bilirubin and ALP. Cholestatic jaundice, hepatitis or lupus-like syndrome are rare.

Other side-effects after propylothiouracyl administration include hepato-, neuro- and myelotoxic effects (with thrombocytopenia and agranulocytosis <250 granulocytes/mm3 ) and vasculitis with the presence of ANCA antibodies. Thus, in the light of the current knowledge, children should not be treated with propylothiouracyl, and the recommended therapy should be based on thiamazole, radioactive iodine or surgery [19–22].

#### **6.2 Radioiodine therapy**

Radioiodine therapy is usually restricted to patients who are resistant to pharmacological treatment and who do not enter remission, or when they develop toxic reaction to a drug or have not complied with doctor's recommendations. The aim of the therapy is total destruction of the thyroid parenchyma by applying an ablative dose and in consequence obtaining permanent hypothyroidism. The advantages include easy application, lack of long-term side-effects and high efficacy of the first dose (approximately 95%). In the relapse of hyperthyroidism the subsequent dose of radioiodine can be administered 6 months after the first dose.

Young age (>5 years) is not a contraindication for this therapy, although much caution is required in children younger than 10. The risk of thyroid cancer in children exposed to I131 is the highest in those younger than 5 years due to increased vulnerability of the thyroid tissue to proliferative effects of ionizing radiation and gradually decreases in older age groups. Thus, children receive higher doses of radioiodine, i.e. a constant dose of 15 mCi, or doses dependent on the gland mass and its iodine uptake potential (150–200 μCi/g of thyroid tissue; 5.5–7.4 Mq/g; 12 000–16 000 cGy/g), so that to minimize the risk of secondary neoplasms. The radioiodine therapy should be followed by thyroxin substitution to manage hypothyroidim and avoid TSH increase. There is also no evidence that in the offspring of patients treated with I131 due to hyperthyreosis or thyroid cancer the risk of genetic defects is elevated (it is comparable to the risk noted in the general population).

Iodine (I131) is usually administered after a break of 5–7 days in the application of the thyrostatic. Some suggest that antithyroid therapy should not be disrupted and the I131 dose needs to be increased by 20% to avoid the risk of an overactive thyroid storm. Otherwise, the use of -adrenolites and antiinflammatory non-steroids should be recommended to attenuate the symptoms of postradiation thyroiditis. Moreover, less common are nausea, pruritis of the neck skin, hypoparathyroidism or exacerbation of Graves ophthalmopathy. In this latter case, even though enhanced opthalmopathy in children is not frequent, protective treatment with glycocorticosteroids

for 6–8 weeks should be considered (some recommend 3 months after radioiodine administration). Prolonged steroid therapy may have an effect on growth cartilage and body mass, and shows immunosuppresive action. Contraindications to radioiodine therapy are at the same time indications for surgery: large goiter >80 g, pressure symptoms, severe thyrotoxicosis with accompanying neurological symptoms, lack of iodine uptake of the thyroid, suspicion of a neopastic lesion, severe ophthalmopathy, age < 5 years, pregnancy and lactation, and also lack of consent to I131 treatment.
