graves ' disease is the most common cause of hyperthyroidism in the pediatric population [ 1 , 2 ] . treatment options for graves ' disease include antithyroid medications , radioactive iodine , and surgery [ 1 , 2 ] . antithyroid medications used in children and adults include propylthiouracil ( ptu ) and methimazole ( mmi ) , and carbimazole , which is metabolized to mmi , and is available in europe but not the united states . recently , a significant safety concern related to hepatotoxicity risk associated with ptu use in children was brought to attention [ 4 , 5 ] . it is thus now recommended that ptu not be used in children , except in special circumstances [ 4 , 5 ] , and mmi should be used for antithyroid drug therapy in children . to date , the majority of publications related to medical therapy for graves ' disease have focused on children treated with ptu [ 614 ] . the description of the nature of adverse events that are associated with methimazole use in the pediatric population is modest , as well . at our center , we have routinely used mmi for graves ' disease therapy for many years . to provide insights into adverse events that can be associated with mmi use , we reviewed the adverse events associated with mmi use in our last one hundred consecutive pediatric patients treated with this medication . this review of treatment practice outcomes was conducted with the approval of the yale university human investigation committee . all adverse events were reported to the united states food and drug administration via the medwatch program . patients with the diagnosis of graves ' disease were identified from icd-9 coding ( 242.0 or 242.9 ) . the diagnosis of graves ' disease was made if there were elevated total and/or free thyroxine [ t4 ] and/or triiodothyronine [ t3 ] concentrations , subnormal thyrotropin levels , and evidence of thyroid autoimmunity not thought to be consistent with hashitoxicosis . the presence of goiter and ophthalmopathy supported the diagnosis of graves ' disease ; however eye disease was present in only 60% of the patients . in situations where there was a question of the diagnosis patients were diagnosed with graves ' disease in this setting only if the i uptake was elevated . the medical records of the last 100 consecutively treated patients with the diagnosis of graves ' disease were reviewed . medical records were reviewed to determine if adverse events occurred , and the length of time from initiating therapy until when adverse events developed . for those patients receiving treatment with either surgery or radioactive iodine , this was noted . initial thyroid function tests at diagnosis along with levels of thyroid stimulating immunoglobulin ( tsi ) or thyrotropin binding inhibitory immunoglobulin ( tbii ) were collected . 70% of patients were from the new haven ct area ; 30% of patients were from outside of the new haven area . 62% of the individuals were caucasian , 16% were hispanic , 16% were asian , and 6% were african american . at diagnosis , tsh levels were 0.01    0 the initial total t4 levels were 18.3    2.0  mcg / dl . the initial free t4 levels were 4.9    2.4  ng / dl . tsi levels were available in 73% of the individuals and were 180    70% . the patients were treated with average daily dose of mmi of 0.3    0.2  mg / kg / day . medication was given once a day in 60% of patients and twice daily in 40% of patients . adverse events attributed to the use of mmi , were seen in 19 patients ( table 1 ) . the most common side effects included pruritus and hives , which were seen in eight patients . two patients developed neutropenia with absolute neutrophil counts of 500 and 750 counts per cubic ml . three patients developed stevens - johnson syndrome with diffuse cutaneous eruption and mucous membrane involvement . u / l , the alanine aminotransferase ( alt ; sgpt ) was 379  u / l , the alkaline phosphatase was 355 u / l ; the bilirubin was 0.18  mg / dl ; and the gamma - glutamyl transpeptidase , ( ggt ) was 193 the age , methimazole dose , and length of time from initiation of treatment until development of adverse events for each patient are shown in table 1 . when clinical characteristics were compared in individuals who developed adverse events to methimazole with those who did not develop such reactions , no differences were detected as related to age , gender , dose , or ethnicity . there was no relationship to initial thyroid hormone levels , or circulating levels of immunoglobulins . of those individuals who developed adverse events to mmi , thyroidectomy was performed in three patients ( ages 34 years ) . radioactive iodine was administered to thirteen individuals ( age range 818 years ) , and three patients were changed to ptu , as treatment with radioactive iodine or surgery was refused by the families . adverse events to mmi occurred within one month of therapy in 20% of the patients , within three months of therapy in 50% of patients , and within six months of therapy in 90% of patients . in three patients , adverse events occurred after one and a half years of treatment . published reports related to the treatment of children with graves ' disease have generally involved cohorts of children treated with ptu [ 614 ] . these studies reveal an incidence of minor adverse events between 1%   and 15% . within reports in which the use of mmi has been described , there has been little description of adverse events associated with this medication . our data suggest that methimazole can be associated with a risk of adverse events in up to 19% of individuals . if one excludes the eight patients with pruritus and hives , which are minor side effects , the more serious adverse events were found in 11% of patients . based on published reports describing outcomes for children treated with antithyroid medications for graves ' disease , up to 10 years ago , ptu was more widely used than mmi [ 1113 ] . more recent data however , suggest that two thirds of children in the united states treated with antithyroid medications are now being treated with mmi , and one - third are treated with ptu . recently , a concerning risk of hepatotoxicity resulting in liver failure in children and adults and in pregnant women treated with ptu has been brought to attention [ 4 , 16 ] . based on the incidence of reported cases of acute liver failure and liver transplantation associated with ptu , it is estimated that up to 1 in 2,000 children will sustain acute liver injury in response to ptu [ 4 , 16 ] . as the result , it is recommended that ptu not be used in children except in special circumstances , such as when an individual has had a toxic reaction to methimazole , and antithyroid medication is needed until definitive treatment either in the form of surgery or radioactive iodine can be performed . as such , mmi use in the pediatric population we observed one child who had cholestatic liver injury associated with methimazole . in the adult population , mmi associated liver injury is most typically seen in individuals who are older rather than younger , and in those who are treated with higher rather than lower mmi doses . in the individual who developed modest transaminase and alkaline phosphatase elevations , this condition reversed fully within one month after discontinuation of the medication . of concern was the development of stevens - johnson syndrome in three of the children , one of which required hospitalization . in each child , the condition reversed without long - term sequelae . of note , the three patients who developed stevens - johnson syndrome were receiving large doses of mmi ( 30  mg ) . at present we do not know , though , if the risk of stevens - johnson syndrome is dose - related . whereas most of the adverse events associated with mmi occurred within the first half year of the treatment onset , we observed adverse events after one and a half years of therapy in three children . these observations show that children treated with mmi warrant close follow - up for the development of potential toxic events . our observations raise the question about the utility of routine monitoring of hematological profiles or liver function tests or transaminase levels in patients on antithyroid medications . at present there is little evidence to support the notion that routine monitoring of these parameters is effective in minimizing the risk of antithyroid drug related adverse events [ 3 , 18 , 19 ] . if ptu is used , it is recommended that ptu should be stopped immediately and liver function and hepatocellular integrity be 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 fatigue [ 19 , 20 ] . in addition , ptu and mmi should be stopped immediately and white blood counts be measured in children who develop fever , mouth sores , pharyngitis , or feel ill . while routine monitoring of white blood counts may detect early agranulocytosis , it is not recommended because of the rarity of the condition and the lack of cost - effectiveness [ 3 , 18 ] . agranulocytosis has been reported in about 0.3% of adult patients taking mmi or ptu [ 3 , 18 , 19 ] . data of the incidence of agranulocytosis in children is not available , but is estimated to be very low . in adults , agranulocytosis is dose - dependent with mmi , and rarely occurs at low doses [ 3 , 18 ] . when it develops , agranulocytosis typically occurs within the first 100 days of therapy in 95% of individuals [ 3 , 18 ] . we recognized that a potential limitation of our study is that our referral patterns may bias our outcomes , as some of the patients coming for second opinions may have been treated beforehand with mmi doses higher than we typically use . the demographics of self - referred patients may also differ from that seen in a typical cross - section of children with graves ' disease . our patients are also not typically treated beyond two years with mmi , which influences our ability to observe long - term side effects . at present , ptu and mmi are the only antithyroid drugs available for graves ' disease in the united states . although mmi is less hepatotoxic than ptu , our data show that mmi use is indeed associated with potential adverse events , which can be serious . considering the hepatotoxicity risk associated with ptu , and the other minor and major adverse events associated with both ptu and mmi , strong consideration should be given to the development of less toxic antithyroid medications for use in children and adults .
objective . graves ' disease is the most common cause of hyperthyroidism in the pediatric population . 
 antithyroid medications used in children and adults include propylthiouracil ( ptu ) and methimazole ( mmi ) . at our center 
 we have routinely used mmi for graves ' disease therapy . 
 our goals are to provide insights into adverse events that can be associated with mmi use . methods . 
 we reviewed the adverse events associated with mmi use in our last one hundred consecutive pediatric patients treated with this medication . 
 results . 
 the range in the patient age was 3.5 to 18 years . 
 the patients were treated with an average daily dose of mmi of 0.30.2  mg / kg / day . 
 adverse events attributed to the use of the medication were seen in 19 patients at 177 weeks of therapy . 
 the most common side effects included pruritus and hives , which were seen in 8 patients . 
 three patients developed diffuse arthralgia and joint pain . 
 two patients developed neutropenia . 
 three patients developed stevens - johnson syndrome , requiring hospitalization in 1 child . 
 cholestatic jaundice was observed in 1 patient . 
 no specific risk - factors for the development of adverse events were identified . 
 conclusions . 
 mmi use in children is associated with a low but real risk of minor and major side effects .