**7. Management**

The three cornerstones of management of pediatric GD are antithyroid drugs (ATDs), radioiodine (RAI) therapy and surgical management. Age of the patient, likelihood of remission, availability of expertise and facilities, patient preferences determine the choice of modality. The choice of initial therapy also depends on the prevailing practices in different geographic regions of the world. For instance, antithyroid drug therapy remains overwhelmingly the most popular choice in Japan, with >90% of children with newly diagnosed GD being instituted on ATDs, whereas the proportion is >80% in Europe, Asia, Oceania and South America. RAI therapy is more commonly used in the United States of America, with >70% of newly diagnosed pediatric GD patients being treated with I-131 previously. However, the use has been declining, with current estimates of 40% of patients being instituted on ATDs [22].

#### **7.1 Medical management**

Antithyroid medications still remain the modality of choice in most pediatric patients with GD, despite lower remission rates as compared to adults. Methimazole (MMI) or carbimazole (CBZ) are the drugs of choice, with the former used commonly in the United States and Japan, and the latter being used in Europe.

All the drugs act by inhibition of the critical enzyme thyroid peroxidase, effectively inhibiting the organification of iodine by inhibiting its binding to the tyrosyl residues on thyroglobulin. They also inhibit thyroglobulin synthesis, coupling of iodotyrosine residues, and secretion of thyroid hormones. PTU additionally inhibits type 1 deiodinase enzyme, decreasing the conversion of T4 to the peripherally active T3. Carbimazole is a prodrug and it get converted to methimazole completely after hepatic metabolism. 10 mg CBZ is equivalent to 7.5 mg MMI and 100 mg PTU. Besides the differences in potencies, the drugs differ in their pharmacokinetics, with MMI having a half-life of 6–8 hours, whereas PTU has a much shorter half-life of 30 minutes, necessitating 3 times a day dosing [22].

#### *7.1.1 Dosing considerations*

The starting dose of MMI is typically 0.2–0.5 mg/kg/day, ranging from 0.1-1 mg/ kg/day. French guidelines suggest a dose of 0.4 mg/kg/day in moderate thyrotoxicosis (FT4 < 50 pmol/L), and doses of 0.8 mg/kg/day in severe thyrotoxicosis (FT > 70 pmol/L). As MMI is usually available in the form of 5 or 10 mg tablets, ATA guidelines also put forth a simplified guideline to ease administration, suggesting doses of 1.25 mg/day, 2.5–5 mg/day, 5–10 mg/day and 10–20 mg/day in the age groups of infancy, 1–5 years, 5–10 years and 10–18 years respectively, with dose escalation of 50–100% above the suggested doses in cases of severe hyperthyroidism. The doses are typically administered in a single dose or divided into two or three doses a day in the initial stages. Single dose therapy may result in better patient compliance.

PTU may be considered in doses of 2–7.5 mg/kg/day in three divided doses. But it is strictly avoided in pediatric patients due to concerns of severe hepatotoxicity, except in cases of thyroid storm and patients with adverse reactions to MMI requiring short-term control of thyrotoxicosis prior to definitive therapy. French guidelines contraindicate PTU use in children, and Japanese guidelines advocate caution with PTU use [22, 31, 36].

Symptoms of sympathetic overactivity including tremors, tachycardia, muscle weakness, neuropsychological disturbances are treated with beta blockers, propranolol at 1–2 mg/kg/day in 2–3 divided doses, or atenolol at 0.5–1.2 mg/kg/day as a once daily dose. Selective beta blockers like atenolol and metoprolol are preferred in children with reactive airway disease [22, 31, 36].

#### *7.1.2 Adverse effects*

Most adverse reactions to antithyroid drugs emerge within 3 months of initiating treatment. PTU was widely used for medical management of pediatric GD until it fell out of favour in early 2000s, due to multiple reports of serious hepatotoxicity. PTU is associated with idiosyncratic hepatocellular necrosis, leading to hepatic dysfunction ranging from reversible injury to acute liver failure requiring transplantation, and rarely leading to death. PTU was the third most common cause of drug-induced liver failure, accounting for approximately 10% of drug-related liver transplantations in the United States [41].

The risk of hepatotoxicity is considerably higher in children than in adults, with children accounting for almost half of the patients in case reports of PTU-induced liver failure. Rivkees et al. estimated that the risk of reversible liver injury in children taking PTU was atleast 1 in 200, and the risk of liver failure requiring transplantation was atleast 1 in 2000–4000. It was also noted that PTU-induced liver failure was rapidly progressive and with low chances of reversibility, and there were no meaningful biochemical markers to predict the risk of hepatotoxicity [42]. FDA issued a boxed warning for PTU use in 2010, noting that 22 adult and 10 pediatric cases of serious liver injury were associated with PTU use, and limited its use to patients intolerant to other modalities and in first trimester of pregnancy [43].

MMI can also be associated with hepatotoxicity, although it is typically milder and of the cholestatic pattern. No cases of liver failure or transplantation have been reported in association with MMI use in children, in contrast to adults in whom hepatocellular toxicity has been described.

PTU is also associated with a 40 times higher risk of antineutrophil cytoplasmic antibody (ANCA) vasculitis than with MMI use. The positivity rate of ANCA in pediatric users is higher, approximately 64%, approximately 20% of whom can develop vasculitis. The antibodies tend to develop at or after 1 year of treatment. Usually asymptomatic, it can occasionally manifest as polyarthritis, dermatologic involvement in the form of purpuric skin lesions, pulmonary and renal involvement. There exist few case reports of renal failure in children due to vasculitis. Majority of the cases resolve with discontinuation of the offending medication, but severe involvement may require glucocorticoid and other immunosuppressive therapy.

MMI is more commonly associated with minor adverse events in upto 25% of the children being treated with MMI, most commonly involving mucocutaneous adverse events like urticaria, rash, oral ulcers and arthralgias, myalgias. The risk of agranulocytosis appears to be similar for MMI and PTU, affecting 0.3% of treated adults, with possibly lower prevalence in children. The risk appears to be dosedependent with MMI use, with most of the cases occurring with daily MMI doses exceeding 20 mg/day.

Minor allergic reactions are usually managed with antihistamines, while continuing the drug under watchful guidance. On the other hand, occurrence of serious adverse reactions warrant drug discontinuation and consideration of alternative therapies. PTU and MMI exhibit significant cross-reactivity, hence use of either drugs should be avoided with the occurrence of a serious adverse reaction to the other drug [22, 31, 36].

#### *7.1.3 Monitoring and dose titration*

Patients should be monitored clinically for symptoms and signs of thyrotoxicosis. Weight and height should be checked periodically during clinic visits and

#### *Graves' Disease in Childhood DOI: http://dx.doi.org/10.5772/intechopen.97569*

charted in appropriate growth charts. Parents should also be counselled about possible weight gain in the first few months of therapy, which can persist.

ATA guidelines suggest a complete hemogram and liver function testing prior to initiating ATDs. Routine monitoring of WBC counts and liver function tests is not advocated due to sudden onset of agranulocytosis and rapidly progressive nature of PTU-related hepatotoxicity. WBC counts should be ordered in the presence of febrile illnesses or pharyngitis. Similarly, liver functions should be obtained when patients develop symptoms of hepatotoxicity like jaundice, pruritus, anorexia, light-coloured stools or dark urine, drug should be discontinued if transaminases are elevated upto 2–3 times the upper limit of normal. Subsequently, liver function tests should be monitored till normalization. Japanese guidelines also advocate annual urinalysis and MPO-ANCA measurement for early detection of ANCAassociated vasculitis in children on PTU [22, 36].

Thyroid function tests should first be obtained after 2–6 weeks of initiation of therapy, every 4–6 weeks till dose is stabilized and every 3 months thereafter. MMI dose can be reduced by 50% once thyroid hormones normalize. The usual maintenance doses range from 5 mg every alternate day to 10 mg a day [22, 36].

Alternatively, "block and replace" strategy has been used, where replacement levothyroxine is added so that ATDs can be continued at higher doses. A 2010 metanalysis by Abraham et al. showed that block and replace regimens had similar efficacy to titration regimens, but had higher risk of treatment withdrawal due to adverse effects [44]. This is especially true for MMI as most adverse effects of MMI are dose-related. However, some authors attributed these findings to the unconventionally higher doses of MMI in the studies using block-and-replace regimens in the meta-analysis, and hence maintain that block-and-replace can be a worthwhile strategy, especially in patients who are sensitive to minor increases in doses of MMI and become hypothyroid [36, 45].

#### *7.1.4 Duration of therapy*

Multiple prognostic factors determine the response to antithyroid drugs. It is usually assessed by remission rates, defined as the proportion of patients who remain euthyroid 1 year after cessation of ATD. Remission rates in children after 1–2 years of ATD therapy are typically 20–30%, lower than in adults.

In contrast to older studies which suggested a 25% chance of remission for every 2 years of continued treatment, longer duration of therapy has not translated into significant improvements in remission rates in more recent studies. For example, treatment beyond 2 years has been seen to associated with remission rates of 23–37% after 4 years, and only 15% after 4–10 years of therapy. Relapse can occur in as many as 36–47% of patients after initial remission. Additionally, longer treatment durations carry the risk of non-compliance and drug toxicities. However, more recent studies have shown encouraging data on relapse rates. In a retrospective study involving 1138 pediatric GD patients by Ohye et al., remission rate was 46% after a median duration of 3.8 years of ATD therapy, with no significant predictors for remission identified. The cumulative rates of remission increased with duration of anti-thyroid medication till 5 years of therapy. Similar findings were seen in the prospective study by Leger et al., in which remission rates were 20, 37, 45 and 49% after 4, 6, 8 and 10 year of ATD therapy respectively, suggesting a plateau of remission after 8–10 years of ATD therapy [36, 46, 47].

Evidence for prognostic factors predicting remission and relapse in pediatric GD have been mostly derived from many retrospective and few prospective studies. Older age and pubertal onset of disease, higher BMI, lower levels of thyroid hormone levels at presentation, early achievement of euthyroidism within 3 months of institution of ATDs and smaller goitres, have all been associated with early remission. Pre-pubertal children also tend to require longer duration of therapy to achieve remission vis-à-vis pubertal children [25, 32, 33, 48]. Non-Caucasian origin, higher TRAb levels additionally have also been associated with increased risk of relapse in treated patients [49]. In a study by Smith et al., TRAb antibodies decreased with duration of antithyroid therapy, but normalized only in 18% of children even after 24 months of therapy, with no further significant decreases with prolonged therapy. This points to a persistence of autoimmunity in pediatric age groups in contrast to adults, in whom TRAb levels tend to decline with anti-thyroid therapy, and may be used to guide decision-making for stopping anti-thyroid medication [50].

ATA guidelines suggest 1–2 years of ATD therapy before considering definitive modalities of RAI or surgery, depending on age of the child. Japanese guidelines suggest a duration of atleast 18–24 months, extending upto 5–10 years for better remission rates. They also suggest utility of TRAb assays in deciding duration of therapy.

#### *7.1.5 Other drug therapies*

Patients of thyrotoxicosis intolerant to MMI, awaiting surgery can be treated with inorganic iodine, either with 3–7 drops thrice a day of saturated solution of potassium iodide (SSKI) containing 50 mg iodide per drop, or 3–4 drops a day of Lugol's solution, containing 6.3 mg of iodine per drop, for 10 days prior to surgery. Inorganic iodine can also be used in the management of thyroid storm. It acts by inhibiting organification of iodine and thyroid hormone release, termed the "Wolff-Chaikoff effect". Caution has to be exercised for potential development of escape phenomenon, or exacerbation of thyrotoxicosis after drug withdrawal.

Alternatively, other drugs like lithium carbonate can be used, which acts by inhibiting the synthesis and release of thyroid hormones, but needs watchful care for any adverse effects. Some of the other medications that have been used are perchlorate, cholestyramine, corticosteroids and rituximab [22, 36].

#### **7.2 Radioiodine therapy**

The target of I-131 therapy is to achieve hypothyroidism by thyroid ablation with a single optimal dose of I-131 rather than euthyroidism. This is particularly relevant in pediatric age groups due to sensitivity of the thyroid gland to radiation.

The concerns over increased risk of malignancy with radioiodine were born after the Chernobyl incident, where increased risk of thyroid malignancies was attributed to low doses of I-131 and other radionuclides, in the presence of a dietary iodine deficiency in the population. Importantly, the maximum risk appeared to occur in children less than 5–6 years of age, decreasing gradually through 12 years of age. However, the highest risk of thyroid malignancy is seen with low levels of radiation exposure of about 0.09–30 μCi/g, and not with the higher activities administered in treatment of GD.

In a retrospective study by Read et al. involving 36 years follow up of 116 patients who had received RAI therapy between the ages of 3–19 years, there were no cases of thyroid malignancy or leukemia. There was also no increase in congenital anomalies in the offspring or rate of spontaneous abortions in the cohort [51]. Similarly, no significant increase in risk of non-thyroid malignancies has been observed in recipients of I-131 treatment.

Hence, ATA guidelines suggest avoiding RAI therapy in children less than 5 years of age, and considering RAI therapy in children between 5 and 10 years of age when the

required activity for treatment is <10 mCi, while emphasizing that these restrictions are based on theoretical concerns of malignancy [18, 22, 31, 36].
