Abstract
The frequency, predisposing factors and course of agranulocytosis (granulocytes <250/µl) 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 appers 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±19.7 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.
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References
Orgiazzi J. Management of Graves’ hyperthyroidism. Endocr. Metab. Clin. North Am. 76: 365, 1987.
Astwood E.B. Treatment of hyperthyroidism with thiourea and thiouracil. JAMA 122: 78, 1943.
Fedotin M.S., Lefer L.G. Liver disease caused by propylthiouracil. Intern. Med. 735: 319, 1975.
Mihas A.A., Holley P., Koff K.S, Hirschowitz B.J. Fulminant hepatitis and lymphocyte sensitisation due to propylthioracil. Gastroenterology 70: 770, 1976.
Safan M.M., Tatro D.S., Rudd P. Fatal propylthiouracil-induced hepatitis. Arch. Int. Med. 142: 838, 1982.
Vitug A.C., Goldman J.M. Hepatotoxicity from antithyroid drugs. Horm. Res. 24: 229, 1985.
Blom. H., Stalk J., Schreuder M.B., von Blomberg-van der Flier M. A case of carbimazole-induced intrahepatic cholestasis. An immune-mediated reaction? Arch. Int. Med. 745: 1513, 1985.
McGravack T.H., Chevalley J. Untoward hemathologic responses to the antithyroid compounds. Am. J. Med. 77: 36, 1954.
Bilezekian S.B., Laleli Y., Tsan M.F., Hodgkinson B.A., Lee S., McIntyre P.A. Immunological reactions involving leukocytes: III agranulocytosis induced by antithyroid drugs. John Hopkins Med. J. 138: 124, 1976.
Resove M.H. Agranulocytosis and antithyroid drugs. West Med. J. 726: 339, 1977.
Cooper D.S., Goldminz D., Levin A.A., Ladenson P.W., Daniels G.H., Molich M.E., Ridgeway E.C. Agranulocytosis associated with antithyroid drugs. Effects of patient age and drug dose. Ann. Int. Med. 98: 26, 1983.
Tajiri J., Noguchi S., Murakami T., Murakami N. Antithyroid drug-induced agranulocytosis. The usefullness of routine white blood cell count monitoring. Arch. Int. Med. 750: 621, 1990.
Meyer-Geßner M., Benker G., Olbricht T., Windeck R., Reiners C., Reinwein D. Nebenwirkungen der antithyreoidalen Therapie der Hyperthyreose. Eine Untersuchung an 1256 fortlaufend betreuten Patients. Dtsch. Med. Wschr. 114: 166, 1989.
Rosien U., Benker G., Brittinger G., Reinwein D. Agranulozytose-Behandlung mit rhGH-CSF. Dtsch. Med. Wschr. 114: 1861, 1989.
Waller P.C. Measuring the frequency of adverse drug reactions. Br. J. Clin. Pharmac. 33: 249, 1992.
Burrell C.D., Fraser R., Doniach D. The low toxicity of Carbimazole — a survey of 1046 patients. Brt. Med. J. 1: 1453, 1956.
Krüskemper H.L. Nebenwirkungen thyreostatischer Arzneimmittel. Der. Internist. 9: 436, 1960.
Trotter W.R. The relative toxicity of antithyroid drugs. The Journal of New Drugs 333, 1962.
Wiberg J.J., Natall F.Q. Methimazole toxicity from high doses. Ann. Int. Med. 77: 414, 1972.
Le Guerrier A.M., Lorcy Y., Allanic H. Les accidents imputables au Carbimazole dans le traitment de la maladie de Basedow. Ann. Endocrinol. (Paris) 45: 381, 1984.
Retsagi J., Kelly J.P., Kaufman D.W. Risk of agranulocytosis and asplastic anemia in relation to use of antithyroid drugs. Brit. Med. J. 297: 262, 1988.
Werner M.C., Romaldini J.H., Bromberg N., Werner R.S., Farah C.S. Adverse effects related to thionamide drugs and their dose regimen. Am. J. Med. Sc. 297: 216, 1989.
Edell S.L, Bartuska D.G. Aplastic anemia secondary to methimazole-a case report and review of the hematologic side effects. J. Am. Med. Wom. Assoc. 30: 412, 1975.
Tamai H. Takaichi Y., Morita T., Komaki G., Mutsubayashi S., Kuma K., Walter jr. R.M., Kumagai L.F., Nataki S. Methimazole-induced agranulocytosis in Japanese patients with Graves’ disease. Clin. Endocrinol. (Oxf.) 30: 525, 1989.
Hirata Y., Tasaka Y., Ogadiri R., Takei M., Kenbo T., Horino M. A new type of hypoglycemia with spontaneous insulin autoantibodies. Diabetes 26: 401, 1977.
Tahayama S., Hirata Y. Incidence of insulin autoimmune hypoglycemia in Japan during the three-year period from 1971–1981. Diabetes 32: Suppl. 150A, 1983.
Sanke T., Kondo M., Moriyama Y., Nanjo K., Iwo K., Miyamura K. Glucagon binding autoantibodies in a patient with hyperthyroidism treated with methimazole. J. Clin. Endocrinol. Metab. 57: 1140, 1983.
Melander A., Hallergren B., Rosendal-Helgesen S., Sjöberg A-K., Wahlin-Boll E. Comparative in-vitro effects and in vivo kinetics of antithyroid drugs. Eur. J. Clin. Pharmacol. 77: 295, 1980.
Wing S.S., Fantus G. Adverse immunologic effects of antithyroid drugs. Can. Med. Assoc. J. 121, 1987.
Cooper D.S., Daniels G.H., Ridgewayn E.C. Agranulocytosis and dose of methimazole. Ann. Int. Med. 101: 283, 1984.
Haynes R.C. Thyroid and antithyroid drugs. In: Goodman Gilman A., Rall T.W., Nies A.S., Taylor P. (Eds.) The Pharmacologicical Basis of Therapeutics. 8 ed. Pergamon press, New York 1990, p. 1361.
Heinrich B., Gross M., Goebel F.D. Methimazole-induced agranulocytosis and Granulocyte-colony stimulating factor. Ann. Int. Med. 111: 621, 1989.
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Meyer-Geßner, M., Benker, G., Lederbogen, S. et al. Antithyroid drug — induced agranulocytosis: Clinical experience with ten patients treated at one institution and review of the literature. J Endocrinol Invest 17, 29–36 (1994). https://doi.org/10.1007/BF03344959
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DOI: https://doi.org/10.1007/BF03344959