the mainstay of antithyroid medications are the thionamides , such as methimazole ( mmi ) and propylthiouracil ( ptu ) , which usually restore euthyroidism in 1 to 3 months . when the medical treatments have failed , surgery or radioactive iodine ( rai ) therapy is generally chosen . if the patient is scheduled to undergo surgery , prompt preoperative achievement of the euthyroid state is recommended to minimize potential complications . adjunctive treatment with -blockers , corticosteroids , and iopanoic acid may also be used to control symptoms . however , literature reviews have reported a few cases of resistant thyrotoxicosis that did not respond to conventional modalities and required additional management . cholestyramine is an ion exchange resin which binds to iodothyronines in the intestines , lowering serum thyroid hormone levels when used adjunctively with thionamides and a -blocker . studies from the 1990s have shown cholestyramine to be safe and effective , but its use in clinical practice remains limited . in this paper , we report a case of one patient with thyrotoxicosis who was resistant to nearly all conventional medical therapies but successfully responded to high - dose cholestyramine prior to thyroidectomy . she was initially diagnosed with hyperthyroidism 6 years ago and treated with antithyroid medication in local clinics for 5 months . since then seven months ago , she started to present thyrotoxic symptoms of fatigue , palpitation , hand tremor , heat intolerance , and dyspnea . her blood pressure was 110/60 mm hg , heart rate was 114 beats per minute , and body temperature was 37.2. the thyroid gland was diffusely enlarged and firm . her thyroid function test revealed thyrotoxicosis with elevated thyroid stimulating hormone ( tsh ) receptor antibody ( trab ) ; free thyroxine ( ft4 ) of 3.66 ng / dl , triiodothyronine ( t3 ) of 3.65 ng / ml , tsh of 0.08 miu / l , and trab of 4.15 iu / l ( normal range : ft4 , 0.85 to 1.86 ; t3 , 0.78 to 1.82 ; tsh , 0.17 to 4.05 ; trab < 1.0 ) . the erythrocyte sedimentation rate ( esr ) and c - reactive protein ( crp ) level were 47 mm / hr and 0.36 mg / dl , respectively ( normal range , esr , 0 to 15 ; crp , 0.01 to 0.47 ) . the thyroid ultrasonography revealed mild enlargement of both thyroid lobes with heterogeneous echogenicity and no discrete nodules ( fig . based on clinical presentation and laboratory findings , the diagnosis of thyrotoxicosis due to graves ' disease was made . we started mmi and propranolol , both at 30 mg / day , but thyrotoxic signs and symptoms persisted . despite 4 months treatment , the ft4 and t3 levels increased to 4.27 ng / dl and 7.34 ng / ml , respectively . we increased the dose of mmi up to 45 mg / day but liver enzymes began to increase . potassium iodide solution 15 ml / day was added for 2 weeks but that did not decrease thyroid hormone levels . one month after the mmi dose increase , the aspartate aminotransferase and alanine aminotransferase levels had increased to 58 and 101 therefore , we changed mmi to ptu 300 mg / day and increased the dose of propranolol up to 120 mg / day . we asked if she was taking her medication during every visit and she said that she was taking it as recommended . because she was also taking topiramate , tianeptine , etizolam , and itopride for migraines , we considered the possibility of drug interactions or side effects . rarely has it been reported to the u.s . food and drug adminstration that individuals taking these medications developed hyperthyroidism , and there was nothing in the literature that demonstrated a definitive relationship between them . despite our efforts , there were no effects on hyperthyroidism and her liver enzymes remained elevated ( table 1 ) . during the treatment refractoriness to antithyroid drugs and inorganic iodides along with the subsequent hepatotoxicity led to the decision to schedule a thyroidectomy . she was admitted to our division of endocrinology and metabolism for pre - operative evaluation and close medical management of the thyrotoxicosis . we initially considered glucocorticoids but were not able to use them because she had a history of angioedema , sudden development of skin rash with pruritus , generalized edema , and dyspnea after the intravenous administration of steroids . a few cases in which high - dose cholestyramine successfully treated refractory thyrotoxicosis had been reported , so we added 12 g divided three times a day to the patient 's treatment regimen . the patient 's t3 levels began to decrease dramatically and there was a notable improvement of symptoms ( fig . there are several cases in the literature of refractory graves ' disease that resistant to conventional therapies . refractory cases have shown resistance to high - dose thionamides , -blockers , and rarely , to iodine . in an attempt to restore euthyroidism in refractory cases before surgery , several modalities have been reported . iopanoic acid , an oral cholecystographic agent , was used for rapid preoperative preparation in a patient with refractory graves ' disease but it is not available in many countries . lithium increases retention of rai in the thyroid , and therefore , it is used with rai rather than thyroidectomy in refractory cases . high dose of glucocorticoids can be used in management of thyroid crisis and for rapid preoperative preparation of resistant thyrotoxicosis . however , it is an invasive procedure and potential complications such as hypotension , hemolysis , allergic reactions , coagulopathy , vascular injury , and infection must be carefully monitored . possible mechanisms mediating resistant thyrotoxicosis have been suggested by li et al .   in 1995 are ; ( 1 ) drug malabsorption , ( 2 ) rapid drug metabolism , ( 3 ) the presence of antidrug antibodies , ( 4 ) impaired intrathyroidal drug accumulation or action , and ( 5 ) predominant elevation of t3 rather than t4 . in our patient , resistance to two different thionamides ( mmi and ptu ) and iodine was observed . also , propranolol did not improve the symptoms of thyrotoxicosis . serum and thyroid mmi levels and the presence of antidrug antibodies were not obtained in this case , but rapid drug metabolism , the existence of antidrug antibodies and impaired accumulation of mmi must be considered as possible reasons for drug resistance . however , the most probable reason for refractoriness to antithyroid medications in this case is the severity of the hyperthyroidism , particularly high t3 level . dahlberg et al .   found that the failure of carbimazole in the treatment of hyperthyroidism is primarily dependent upon the t3 level . when the t3 level is above 6 ng / ml before treatment , a higher dose of antithyroid drug was needed . because the increase of liver enzyme was mild in our patient , we could not completely rule out the possibility of uncontrolled thyrotoxicosis as the reason of the liver enzyme abnormality . but we could not administer an unconventionally high - dose of mmi because of the risk of hepatotoxicity . during preparation for surgery , we also had limitation to use of glucocorticoids , because of the possibility of anaphylactic reaction from her past history . clinical manifestations of steroid hypersensitivity range from relatively minor reactions such as urticaria to more life - threatening ones , such as bronchospasm and anaphylaxis . studies have shown that the most common steroids to which people develop hypersensitivity reactions to are hydrocortisone and methylprednisolone . cholestyramine is an anion exchange resin which binds bile in the gastrointestinal tract to prevent its reabsorption . it is mainly used to lower serum cholesterol and to treat pruritus due to cholestasis . a few rare cases of refractory thyrotoxicosis that were successfully treated with cholestyramine have been reported . thyroid hormones are metabolized mainly in liver by conjugating to glucuronides and sulphates and enter the enterohepatic circulation by excretion into bile . a fraction of conjugated products are deconjugated in the intestine , and free hormones are reabsorbed . cholestyramine has been shown to interfere with the enterohepatic circulation of endogenous thyroid hormones , which is increased in hyperthyroidism . a previous experiment showed that 50 mg of cholestyramine can bind to approximately 3,000 g of t4 . several studies have reported that combining cholestyramine with the antithyroid drug and propranolol led to a more rapid reduction in serum thyroid hormone levels compared to only antithyroid drug and propranolol treatment . solomon et al .   conducted a double - blind placebo - controlled cross - over study that included fifteen patients with thyrotoxicosis ( 14 graves ' disease , 1 toxic adenoma ) . they gave patients 16 g per day of cholestyramine with mmi , divided four times a day . levels of thyroid - stimulating immunoglobulins and hyrotrophin - binding inhibitory immunoglobulins remained unaffected . a study done by mercado et al . new clinical trials that have combined ptu and low dose of cholestyramine have been reported with positive results . despite the prior reports of therapeutic efficacy of cholestyramine , its use in clinical practice remains limited . at first , despite prior studies showed a rapid decline in thyroid hormone for about initial 4 weeks , a long - term efficacy of this drug appears to be unclear : cholestyramine had no immune - modulating effects , compared to other antithyroid drugs of which the use showed decreasing concentration of tsh receptor antibody . in our experience , second , cholestyramine is uncomfortable to eat because only available as a powder form , and of its bad taste and gastrointestinal side effect . since the introduction of statins , cholestyramine has only a minor role for lipid - lowering drug and its clinical use has been decreased . however , the aforementioned studies showed only a few minor complications like hyperdefecation and bad taste . our patient also tolerated cholestyramine without any complications . remarkably , in tsai 's study , which only included chinese individuals , no one experienced constipation . they suggested high fiber diets in chinese culture as the possible reason . also considering that the main gastrointestinal symptom of thyrotoxicosis is diarrhea , constipation as a side effect may be favorable . in conclusion , we recommend cholestyramine as an effective adjunctive therapy for preoperative preparation in patients with severe graves ' disease that is resistant to conventional therapies or when a failure of conventional therapies is expected due to high t3 level . considering the safety profiles and dramatic effects of cholestyramine , it may be the primary option for treatment of severe thyrotoxic patients , along with antithyroid drugs . also in contrast to antithyroid drugs which inhibit thyroid hormone synthesis and are used for the hyperthyroidism , cholestyramine could be an option for treatment of any condition with excessive thyroid hormone levels , including thyroiditis and factitious thyroid hormone disorder .
the three major forms of treatment for graves thyrotoxicosis are antithyroid drugs , radioactive iodine therapy and thyroidectomy . 
 surgery is the definitive treatment for graves thyrotoxicosis that is generally recommended when other treatments have failed or are contraindicated . 
 generally , thyrotoxic patients should be euthyroid before surgery to minimize potential complications which usually requires preoperative management with thionamides or inorganic iodine . 
 but several cases of refractory graves ' disease have shown resistance to conventional treatment . here 
 we report a 40-year - old female patient with graves ' disease who complained of thyrotoxic symptoms for 7 months . 
 her thyroid function test and thyroid autoantibody profiles were consistent with graves ' disease . 
 one kind of thionamides and -blocker were started to control her disease . 
 however , she was resistant to nearly all conventional medical therapies , including -blockers , inorganic iodine , and two thionamides . 
 she experienced hepatotoxicity from the thionamides . 
 what was worse is her past history of serious allergic reaction to corticosteroids , which are often used to help control symptoms 
 . a 2-week regimen of high - dose cholestyramine improved her uncontrolled thyrotoxicosis and subsequent thyroidectomy was successfully performed . in conclusion , cholestyramine could be administered as an effective and safe adjunctive agent for preoperative preparation in patients with severe hyperthyroid graves 's disease that is resistant to conventional therapies .