methimazole ( 1-methyl-2-mercaptoimidazole , mmi ) is an effective and generally safe antithyroid drug for the treatment of graves ' disease . it has been associated with various adverse reactions , which are generally minor and include skin reactions ( usually urticaria or macular rashes ) , arthralgia , and gastrointestinal upset . major side effects such as agranulocytosis , hepatitis , and vasculitis occur rarely , but are sometimes fatal . only four cases of acute pancreatitis after mmi treatment have been reported worldwide ( 2 , 3 , 4 ) since the first report in 1999 ( 3 ) . in this report , we describe the clinical course , imaging and hla typing of a case of acute pancreatitis induced by mmi in a 51-yr - old korean male with graves ' disease and review relevant literature . a 51-yr - old korean male visited the emergency room with complaints of high fever , chills , and abdominal pain in august 2013 . he described the pain as increasing progressively in intensity , worsening after meals , and accompanied by nausea . he was diagnosed with graves ' disease 2 weeks ago , and was being treated with mmi ( 20 mg per day ) . his family history was unremarkable , and did not include thyroid disease or gastrointestinal disorders . upon admission , his vital signs were as follows : blood pressure of 100/70 mmhg , heart rate of 121 beats per minute , a respiratory rate of 21 times per minute , and a body temperature of 39.0. he had a slightly enlarged thyroid gland , but there was no pharyngeal injection . physical examination revealed tenderness in the epigastric and upper abdomen without rebound tenderness , guarding , or rigidity . the results of blood tests were as follows : white blood cell count of 5,460/l , hemoglobin of 16.3 g / dl , and platelet count of 103,000/l . biochemical parameters were glucose of 222 mg / dl , triglycerides of 113 mg / dl , blood urea nitrogen of 30.3 mg / dl , creatinine of 1.45 mg / dl , sodium of 133.8 mm / l , potassium of 3.9 mm / l , chloride of 97.3 mm / l , aspartate transaminase of 34 iu / l , alanine transaminase of 46 iu / l , alkaline phosphatase of 46 u / l , total bilirubin of 2.60 mg / dl , c - reactive protein ( crp ) of 46.7 mg / l , amylase of 86 iu / l ( normal range : 29 - 110 ) , and lipase of 86 iu / l ( normal range : 14 - 60 ) . miu / l ( normal range : 0.27 - 4.20 ) , free t4 of 3.89 ng / dl ( normal range : 0.93 - 1.70 ) , total t3 of 199.8 ng / dl ( normal range : 80 - 200 ) , anti - tpo antibody of 17.84 ( normal range : 0 - 34 ) , and tsh - receptor antibody of 8.8 iu / l ( normal range : 0.00 - 1.75 ) . in tc-99 m thyroid scan , the uptake ratio was 4.8% . there was no elevation of serum antibodies for respiratory viruses including adenovirus , influenza , parainfluenza , and rhinovirus . the following day , mmi therapy was restarted after holding 42 hr because his fever had subsided and there was no evidence of agranulocytosis . however , 5 hr after he took the second dose of mmi ( 10 mg ) , abdominal pain and fever ( 39.2 ) developed again . at that time , laboratory studies showed a white blood cell count of 5,580/l ( 72.7% neutrophils and 1.9% eosinophils ) , total bilirubin of 1.84 mg / dl , and crp of 26.0 his serum amylase and lipase levels increased to 265 iu / l and 682 iu / l , respectively . an abdominal ct revealed a swollen pancreas with peripancreatic inflammatory fat stranding , suggestive of acute pancreatitis ( fig . an abdominal ultrasound was then performed , which showed no evidence of cholelithiasis or biliary duct dilatation ( fig . after the withdrawal of mmi , his fever and abdominal pain improved , and pancreatic enzyme levels began to decrease and finally normalized ( fig . the serum levels of igg and igg subclass-4 were in the normal range ( 901.5 mg / dl , normal range : 700 - 1,600 ; and 349 mg / l , normal range : 30 - 2,010 , respectively ) . after discharge , ptu ( 50 mg t.i.d ) was prescribed for treatment of graves ' disease and his hyperthyroidism was gradually controlled without any side - effects . there have been only four reports of mmi - induced acute pancreatitis since the first report in 1999 ( 2 , 3 , 4 ) . because of the absence of cause - specific tests , the diagnosis of drug - induced pancreatitis ( dip ) is usually based on the following criteria ( 5 ) : 1 ) acute pancreatitis developed during the administration of a drug ; 2 ) resolution of symptoms upon withdrawal of the drug ; 3 ) recurrence after a rechallenge with the suspected agent ; and 4 ) exclusion of all other common causes . in this case report , acute pancreatitis occurred 14 days after starting mmi in a 51-yr - old male . dip by mmi was confirmed because there was no evidence of cholelithiasis , pancreatic and bile duct dilatation , or history of alcohol use to cause pancreatitis , normal triglyceride level , and the recurrence of pancreatitis occurred after the unintended rechallenge with mmi . the diagnosis of mmi - induced dip is commonly overlooked compared to drug - induced liver disease for several reasons ( 6 ) . first , the index of suspicion for dip is considerably lower than drug - induced hepatotoxicity . unlike transaminases , serum amylase and lipase levels are not part of the metabolic profile obtained during a routine health checkup because of the differences in the latency period between the time of exposure and the development of acute pancreatitis ; therefore , it takes an astute and motivated physician to diagnose dip . in addition , even when dip is diagnosed it is reported only rarely , and many cases might be often erroneously classified as being alcoholic or biliary in etiology by default . finally , treatment invariably includes making the patient nil - per - os ( npo ) , which results in the inadvertent discontinuation of the possibly offending medication , which can remove the opportunity to diagnose dip . although cases of acute pancreatitis after mmi with positive rechallenge have been reported previously ( 3 ) , detection of this adverse event has not been emphasized due to its low incidence . however , the accumulation of reports of such cases will encourage clinicians to suspect mmi - induced acute pancreatitis and to discontinue the use of mmi when patients taking mmi complain of abdominal pain and fever . therefore , more active and systematic efforts will be necessary to detect cases and understand the mechanism by which mmi induces a hypersensitivity reaction or injures the pancreas . four of the five cases of mmi - induced dip were asian and one was caucasian , and all were females , and thus this is the first report in a male subject . we initially suspected that genetic susceptibility or an autoimmune mechanism could be involved in mmi - induced pancreatitis in our patient . therefore , we analyzed the patient 's hla haplotype to identify the type frequently found in korean graves ' disease and confirm that it was congruous with that of autoimmune pancreatitis ( aip ) . the hla drb10405-dqb10401 haplotype was associated with aip in a japanese study ( 7 ) , but this did not correspond with the haplotype of our patient . however , the hla drb10803 and dqb10601 detected in this patient have been linked with autoimmune thyroid diseases such as graves ' disease , and have been reported to play a protective role in type 1 diabetes ( 8) . type 1 aip is more common in asian subjects and in males , and is accompanied by elevated serum igg , igg4 , and positive autoantibodies ( 9 ) . igg4 plays a major role in the pathogenesis of aip ( 10 ) , but igg4 levels were not increased in our patient . we also excluded autoimmune type 1 diabetes because of negative anti - insulin and anti - gad antibodies , which suggested that his hyperglycemia could have been caused by thyrotoxicosis . in summary , we describe a 51-yr - old korean male who developed acute pancreatitis after the administration of mmi for graves ' disease . he presented with acute pancreatitis after taking mmi for 14 days , and his fever and abdominal pain subsided after the withdrawal of mmi . when mmi was re - administered , acute pancreatitis rapidly recurred , which was confirmed by clinical , biochemical , and imaging studies . if a patient taking mmi complains of abdominal symptoms and fever without neutropenia , clinicians should consider the rare possibility of mmi - induced pancreatitis and exclude all other potential causes of acute pancreatitis during diagnosis . even after the pancreatitis has improved , mmi should not be administered again .
methimazole ( mmi)-induced acute pancreatitis is very rare but severe adverse reaction . 
 a 51-yr - old male developed a high fever , chills , and abdominal pain , two weeks after commencement on mmi for the treatment of graves ' disease . 
 there was no evidence of agranulocytosis , and fever subsided soon after stopping mmi treatment . however , 5 hr after taking an additional dose of mmi , abdominal pain and fever developed again . 
 his symptoms , biochemical , and imaging studies were compatible with acute pancreatitis . 
 after withdrawal of mmi , he showed clinical improvement . 
 this is the first case of mmi - induced acute pancreatitis in korea . 
 clinicians should be aware of the rare but possible mmi - induced pancreatitis in patients complaining of fever and abdominal pain.graphical abstract