ANTITHYROID DRUG-INDUCED AGRANULOCYTOSIS - CLINICAL-EXPERIENCE WITH 10 PATIENTS TREATED AT ONE INSTITUTION AND REVIEW OF THE LITERATURE

The frequency, predisposing factors and course of agranulocytosis (granulocytes <250/mu l) secondary to antithyroid drugs were studied in a cohort of 1256 continously treated outpatients with hyperthyroidism during the 15 year period from 1973 to 1987. Two cases of agranulocytosis were detected; the frequency was 0.18% (95%-confidence intervals, 0.0-0.44%). This prevalence appears to be lower than reported in previous studies (up to 1.8%). For other adverse drug reactions, there was a clear-cut relationship to initial thiyonamide dose and to the body mass index; most reactions occurred during the first weeks of treatment. In addition, eight patients referred for thionamide drug- induced agranulocytosis were studied, and the following results obtained: Methimazole dose in patients with agranulocytosis was almost twice as in other patients (63.3+/-9.7 vs 34.3+/-29.7 mg daily) suggesting that this complication was related to dose. The interval between start of antithyroid drug treatment and first symptoms of agranulocytosis was 33 days (median; range 23-55 days); hence, prolonged treatment beyond this period would appear relatively safe. Withdrawal of the causative agent and treatment of infection led to recovery of leukocyte counts within 15 days (median; range, 5-31 days). Two fatal outcomes were seen in referred patients. In one severely hyperthyroid patient with methimazole-induced agranulocytosis, recombinant human granulocyte/macrophage colony stimulating factor induced clinical and hematologic recovery within a few days of administration. In conclusion, agranulocytosis is the most severe side effect of antithyroid drugs. According to our results and a literature review, it occurs almost exclusively during the first ten weeks of treatment and is probably related to the drug dose. Physicians should be aware of this potentially serious complication particularly during this period. A reduction of traditionally prescribed thionamide doses seems quite possible and might lead to considerable reduction of adverse reactions. In severe cases, a trial of recombinant human granulocyte/macrophage colony stimulating factor should be considered.