[O] If antithyroid drugs are chosen as initial management of GD in children, how should the therapy be managed?

[O1] Initiation of antithyroid drug therapy for the treatment of GD in children

    Methimazole should be used in virtually every child who is treated with antithyroid drug therapy. 1/++0

Technical remarks: MMI comes in 5 or 10mg tablets and can be given once daily, even in patients with severe hyperthyroidism. Although many practitioners give MMI in divided doses, data in adults do not support a need for such and show that compliance with once-daily MMI therapy is superior to multiple daily doses of PTU (83% vs. 53%) (196). The MMI dose typically used is 0.2–0.5 mg/kg daily, with a range from 0.1–1.0 mg/kg daily (197–204). One approach is to prescribe the following whole tablet or quarter to half-tablet doses: infants, 1.25 mg/day; 1–5 years, 2.5–5.0 mg/day; 5–10 years, 5– 10 mg/day; and 10–18 years, 10–20 mg/day. With severe clinical or biochemical hyperthyroidism, doses that are 50%– 100% higher than the above can be used.

When thyroid hormone levels normalize, MMI doses can be reduced by 50% or more to maintain a euthyroid state (205). Alternatively, some physicians elect not to reduce the MMI dose and add levothyroxine to make the patient euthyroid, a practice referred to as ”block and replace.” However, because meta-analyses suggest a higher prevalence of adverse events using block-and-replace regimens than dose titration (81,84,206), and there may be dose-related complications associated with MMI (207), we suggest that this practice in general be avoided.

    Pediatric patients and their caretakers should be informed of side effects of antithyroid drugs and the necessity of stopping the medication immediately and informing their physician if they develop pruritic rash, jaundice, acolic stools or dark urine, arthralgias, abdominal pain, nausea, fatigue, fever, or pharyngitis. 1/+00

    Prior to initiating antithyroid drug therapy, we suggest that pediatric patients have, as a baseline, complete blood cell count, including white blood cell count with differential, and a liver profile including bilirubin, transaminases, and alkaline phosphatase. 2/+00

PTU is associated with an unacceptable risk of hepatotoxicity in children, with a risk of liver failure of 1 in 2000–4000 children taking the medication (208–210). PTU can cause fulminant hepatic necrosis that may be fatal; liver transplantation has been necessary in some patients taking PTU (91). It is for this reason that the FDA recently issued a safety alert regarding the use of PTU, noting that 32 (22 adult and 10 pediatric) cases of serious liver injury have been associated with PTU use (92,93).

Because PTU-induced liver injury is of rapid onset and can be rapidly progressive, biochemical monitoring of liver function tests and transaminase levels is not expected to be useful in managing the hepatotoxicity risk in a PTU-treated patient (210). However, when neither prompt surgery nor 131I therapy are options, and ATD therapy is necessary in a patient who has developed a minor toxic reaction to MMI, a short course of PTU use can be considered. When surgery is the planned therapy and MMI cannot be administered, if the patient is not too thyrotoxic (and the hyperthyroidism is due to GD), the hyperthyroid state can be controlled before surgery with beta blockade and SSKI (50mg iodide/ drop) 3–7 drops (0.15–0.35 mL) by mouth, given three times a day for 10 days before surgery). Alternatively, if the surgery cannot be performed within a few weeks, a short course of PTU may be administered with the child closely monitored.

Technical remarks: It is advisable to provide information concerning side effects of ATDs to the patient in writing. This information can be found on the UpToDate Web site (99). See Technical remarks following Recommendation 15 for a discussion regarding the utility of obtaining complete blood count and liver profile before initiating methimazole therapy.

[O2] Symptomatic management of Graves’ hyperthyroidism in children

    Beta adrenergic blockade is recommended for children experiencing symptoms of hyperthyroidism, especially those with heart rates in excess of 100 beats per minute. 1/+00

In children in whom the diagnosis of Graves’ hyperthyroidism is strongly suspected or confirmed, and who are showing significant symptoms, including, but not limited to, tachycardia, muscle weakness, tremor, or neuropsychological changes, treatment with atenolol, propranolol, or metoprolol leads to a decrease in heart rate and symptoms of GD. In those with reactive airway disease, cardioselective beta-blockers can be used (211), with the patient monitored for exacerbation of asthma.

[O3] Monitoring of children taking methimazole

After initiation of MMI therapy, thyroid function tests (estimated free T4, total T3, TSH) are obtained monthly at first, and then every 2–4 months. Depending on the severity of hyperthyroidism, it can take several months for elevated thyroid hormone levels to fall into the normal range on ATDs.

    Antithyroid medication should be stopped immediately, and white blood counts measured in children who develop fever, arthralgias, mouth sores, pharyngitis, or malaise. 1/+00

Although MMI has a better overall safety profile than PTU, MMI is associated with minor adverse events that may affect up to 20% of children (212). MMI-related adverse events include allergic reactions, rashes, myalgias, and arthralgias (188,213,214), as well as hypothyroidism from overtreatment. Side effects to MMI usually occur within the first 6 months of starting therapy, but adverse events can occur later. In children, the risks of cholestasis and hepatocellular injury appear to be much less than that observed in adults.

Agranulocytosis has been reported in about 0.3% of adult patients taking MMI or PTU (81,207,215). Data on the prevalence of agranulocytosis in children are unavailable, but it is estimated to be very low. In adults, agranulocytosis is dose dependent with MMI, and rarely occurs at low doses (207,215). When agranulocytosis develops, 95% of the time it occurs in the first 100 days of therapy (207,215). The overall rate of side effects to ATDs (both major and minor) in children has been reported to be 6%–35% (214,216).

Technical remarks: While routine monitoring of white blood counts may occasionally detect early agranulocytosis, it is not recommended because of the rarity of the condition and its sudden onset, which is generally symptomatic. It is for this reason that measuring white cell counts during febrile illnesses and at the onset of pharyngitis has become the standard approach to monitoring.

[O4] Monitoring of children taking propylthiouracil

    When propylthiouracil is used in children, the medication should be stopped immediately and liver function and hepatocellular integrity assessed in children who experience anorexia, pruritis, rash, jaundice, light-colored stool or dark urine, joint pain, right upper quadrant pain or abdominal bloating, nausea, or malaise. 1/+00

Technical remarks: PTU should be discontinued if transaminase levels (obtained in symptomatic patients or found incidentally) reach 2–3 times the upper limit of normal and fail to improve within a week with repeat testing. After discontinuing the drug, liver function tests (i.e., bilirubin, alkaline phosphatase, and transaminases) should be monitored weekly until there is evidence of resolution. If there is no evidence of resolution, referral to a gastroenterologist or hepatologist is warranted.

[O5] Management of allergic reactions in children taking methimazole

    Persistent minor cutaneous reactions to methimazole therapy in children should be managed by concurrent antihistamine treatment or cessation of the medication and changing to therapy with radioactive iodine or surgery. In the case of a serious allergic reaction to an antithyroid medication, prescribing the other antithyroid drug is not recommended. 1/+00

If children develop serious allergic reactions to MMI, radioactive iodine or surgery should be considered because the risks of PTU are viewed to be greater than the risks of radioactive iodine or surgery. PTU may be considered for short-term therapy in this setting to control hyperthyroidism in preparation for surgery.

[O6] Duration of methimazole therapy in children with GD

    If methimazole is chosen as the first-line treatment for GD in children, it should be administered for 1–2 years and then discontinued, or the dose reduced, to assess whether the patient is in remission. 1/++0

The issue of how long ATDs should be used in children before considering either radioactive iodine or surgery is a topic of controversy and warrants further study. Prospective studies in adults show that if remission does not occur after 12–18 months of therapy, there is little chance of remission occurring with prolonged therapy (217). In children, when ATDs are used for 1–2 years, remission rates are generally 20%–30%, with remission defined as being euthyroid for 1 year after cessation of therapy (187,199,214,218,219). Retrospective studies have suggested that the chance of remission after 2 years of ATDs is low if the thyroid gland is large (more than 2.5 times normal size for age), the child is young (<12 years) (214,219) or not caucasian, serum TRAb levels are above normal on therapy, or FT4 estimates are substantially elevated at diagnosis (>4 ng/dL; 50 pmol/L) (214). One prospective study suggested that likelihood of remission could best be predicted by the initial response to antithyroid medication, with achievement of euthyroid state within 3 months, suggesting higher likelihood. Younger children and those with high initial thyroid hormone levels were also found to be less likely to achieve remission within 2 years in the prospective study (214).

Remission rates in children treated with ATDs for longer than 2 years have been reported. Although two decades ago it was suggested that 25% of children with GD go into remission with every 2 years of continued treatment (220), other studies of larger cohorts of pediatric patients with GD treated with ATDs for extended periods have not revealed similar remission rates (213,216,221). Of 120 pediatric patients treated with ATDs at one center, after 1 year of therapy with ATDs, 25% were in remission; after 2 years, 26%; after 4 years, 37%; and after 4–10 years, 15%. Importantly, 30% of the children who went into remission eventually relapsed (213). In another large cohort of 184 medically treated children, after 1 year of therapy with ATDs, 10% were in remission; after 2 years, 14%; after 3 years, 20%; and after 4 years, 23% (221).

Data also suggest that there are age-related differences in responsiveness to ATDs. In one study that compared outcomes of 32 prepubertal and 68 pubertal children, remission occurred in only 17% of prepubertal children treated 5.9 + 2.8 years, compared with 30% of pubertal individuals treated 2.8 + 1.1 years (219). In another report, the course of GD was compared in 7 prepubertal, 21 pubertal, and 12 postpubertal children (216). Remission was achieved in 10 patients (28%) with similar rates among the three groups, whereas the time to remission tended to be longer in the small proportion of prepubertal children (median age, 6 years) (216).

Persistence of GD in children is correlated with the persistence of TRAbs. A recent study found that TRAb levels normalized after 24 months in only 18% of pediatric patients on ATDs (204). There were no data showing that there was normalization of TRAb levels when patients were on ATDs for a longer time. Therefore, it appears that TRAb levels persist longer in children than in adults (204). Whereas monitoring of TRAb levels while on ATDs has been shown to be useful in adult patients for predicting the likelihood of remission or relapse of GD after stopping the medication (222), this approach has yet to be validated in children.

    Pediatric patients with GD who are not in remission following 1–2 years of methimazole therapy should be considered for treatment with radioactive iodine or thyroidectomy. 1/+00

If after stopping MMI after 1 or 2 years’ remission is not achieved, 131I or surgery should be considered, depending on the age of the child. Alternatively, practitioners can continue MMI for extended periods, as long as adverse drug effects do not occur and the hyperthyroid state is controlled. This approach can be used as a bridge to 131I therapy or surgery at a later age if remission does not occur. In selected situations where it might not be suitable or possible to proceed with 131I or surgery, low-dose MMI can be continued, although the likelihood of remission is not great.