SUN-494 A Case of Hyperthyroidism with Multiple Recurrences of Neutropenia After Stopping Methimazole

Background: The adverse effects of methimazole usually occur in the first 6 months of treatment and they usually are dose dependent. The most severe ones are hepatotoxicity and agranulocytosis, the frequency of the latter is 0.1-0.5% and with a high mortality rate. Clinical case: A 15-year-old female patient was sent to Endocrinology in May 2017 because of a 4-month history of tremor, palpitations and heat intolerance. Lab tests: WBC: 6,800, neutrophils: 36% (2,448/l), TSH: < 0.06 uU/ml (0.27- 4.7), T4: > 25 ug/dl (4.5 -12), FT4: >7.7 ng/dl (0.93 -1.7), TPO >1,000 UI/ml (<10), TRAb > 40 UI/L (<1.75) which confirmed Graves’ disease. Propranolol 80 mg/day and methimazole 30 mg/day were prescribed. Two months later methimazole dose was increased to 40 mg/d, hematologic lab test was normal. Seven months after starting methimazole the patient presented with febrile neutropenia, methimazole was stopped, methylprednisolone 20 mg/d was prescribed and we increased propranolol to 120 mg/d, neutropenia improved. A month after the first episode of neutropenia, she presented a second episode with a pharyngeal infection, WBC: 6,300, neutrophils: 1%. In December 2017 radioiodine therapy was performed: 15 mCi. Hyperthyroidism was not resolved, she continued with methylprednisolone 20 mg/d and propranolol 120 mg/d, and 6 drops/d of Lugol solution was prescribed. From December 2017 to July 2018, the patient presented 9 episodes of febrile neutropenia, she had a good response to Granulocyte-colony stimulating factor. Serology tests for CMV, VDRL, HIV, Epstein Barr, Toxoplasmosis, hepatitis B and C were all negative. Lab tests for rheumatologic diseases: rheumatoid factor, C3 and C4, electrophoretic proteinogram, antiestreptolysin O, anti-DNA, ANA, anti-Ro/SSA, anti-La/SSB were all negative, and immunoglobulins were normal. Bone marrow aspiration was normal. We could not perform flow cytometry of anti-neutrophil cytoplasmic antibodies (C-ANCA). Hyperthyroidism persisted and a second I-131 treatment was performed (20 mCi) in June 2018. A month later she presented hypothyroidism, levothyroxine was indicated. She continued with episodes of febrile neutropenia until March 2019, 23 months after the diagnosis of hyperthyroidism, 16 months after stopping methimazole and 8 months after having initiated levothyroxine treatment and having normal thyroid levels. Conclusion: We presented a young female patient with persistent and recurrent neutropenia despite having stopped methimazole, and regardless of her thyroid hormone levels. Although neutropenia usually appears in the first months of treatment, it seldom occurs much later and almost never after stopping the drug. We could not reach an etiological diagnosis of neutropenia, but it is probable that methimazole had triggered an immune-hematological illness associated to Graves’ disease.