MON-356 - When First-Line Therapy Backfires: A Case Series of Rare Methimazole-Associated Toxicities

Introduction:
Methimazole is a first-line therapy for Graves’ disease but may rarely cause immune-mediated and organ-specific toxicities. We present three cases illustrating uncommon but clinically significant methimazole-associated adverse effects.

Case 1: A women in her 70’s with Graves’ disease, long-standing T1DM, and CKD stage IIIA; developed recurrent hypoglycemia shortly after methimazole reinitiation. She had stable glycemic control, HbA1c 6.8%; using a Medtronic 780G hybrid closed-loop insulin pump in auto mode. Following methimazole exposure, frequent hypoglycemia required pump adjustments, including increasing the CR from 1:8 to 1:16 and raising the Smart Guard glucose target from 100 to 120 mg/dL. Had a positive insulin antibody 22uu/mL. Hypoglycemia resolved within weeks without methimazole discontinuation, suggesting a transient immune-mediated mechanism such as insulin autoantibody–associated hypoglycemia.

Case 2: A women in her 60’s with lung adenocarcinoma on pembrolizumab developed overt hyperthyroidism requiring urgent perioperative control. Methimazole 30 mg BID was started with normal baseline liver enzymes. She later developed a marked mixed hepatocellular–cholestatic liver injury, ALT 373 U/L, AST 246 U/L, ALP 632 U/L. Liver enzymes normalized after methimazole discontinuation but recurred within one week of low-dose rechallenge ALT 164 U/L, AST 111 U/L, ALP 229 U/L, confirming methimazole-induced drug-induced liver injury. Definitive management was achieved with thyroidectomy.

Case 3: A women in her 40’s, seven months postpartum, presented with severe Graves’ thyrotoxicosis; FT4 5.5 ng/dL, total T3 575 ng/dL and markedly elevated thyroid antibodies TSI 3.48, TRAb 6.62, TPO Ab 900. She started methimazole 10 mg BID, increased to 15 mg BID for persistent hyperthyroidism, FT4 3.2 ng/dL, FT3 9.7 pg/mL. Three weeks after initiation and eight days after dose titration, she developed acute, disabling inflammatory polyarthritis. Symptoms resolved rapidly with methimazole cessation and glucocorticoids. Serologic evaluation showed C-ANCA 1:20 (reference < 1:20) two weeks off steroids, negative RF and ANA. She transitioned to PTU for ongoing biochemical control and started on potassium iodide preoperatively. She then underwent thyroidectomy.

Conclusion:
Methimazole can cause rare but severe metabolic, hepatic, and inflammatory complications. Early recognition and individualized management are critical to minimize morbidity and guide prompt definitive therapy.

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