Methimazole-Induced Aplastic Anemia with Concomitant Hepatitis in a Young Filipina with Graves’ Disease

Natalia Wijaya, Celeste Ong-Ramos

Abstract

A 34-year-old Filipino with Graves’ disease on methimazole came in due to fever, sore throat and jaundice. Patient was initially diagnosed with methimazole induced agranulocytosis and drug induced liver injury. She was treated with intravenous broad spectrum antibiotic and granulocyte colony stimulating factor. On day 4 of admission, patient had pancytopenia and was managed as methimazole induced aplastic anemia and was started on steroid therapy and 1 unit of packed red blood cell was transfused. The jaundice also increased hence she was given ursodeoxycholic acid. On day 9 of admission, with the consideration of “lineage steal phenomenon,” biopsy was done and eltrompobag was started. Patient was discharged stable at 12th day of hospital admission. This case presents the 3 rarest, life threatening complication of methimazole: agranulocytosis, aplastic anemia and hepatitis. .

Keywords

anemia, aplastic, agranulocytosis, methimazole, antithyroid agents

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References

Bahn Chain RS, Burch HB, Cooper DS, et al. Hyperthyroidism and other causes of thyrotoxicosis: Management guidelines of the American Thyroid Association and American Association of Clinical Endocrinologists. Thyroid. 2011: 21(6):593-646. PMID: 21510801. https://doi.org/10.1089/thy.2010.0417.

Cooper DS. Antithyroid drugs. N Engl J Med. 2005;352:905-17. https://doi.org/ 10.1056/NEJMra042972.

Meyer-Gessner M, Benker G, Lederbogen S, Ollbricht T, Reinwein, D. Antithyroid drug-induced agranulocytosis: Clinical experience with ten patients treated at one institution and review of the literature. J Endocrinol Invest. 1994;17(1):29-36. PMID: 7516356. https://doi.org/10.1007/BF03344959.

Cooper DS, Goldminz D, Levin AA, et al. Agranulocytosis associated with antithyroid drugs. Effects of patient age and drug dose. Ann Intern Med. 1983;98(1):26-9. PMID: 6687345.

Vilchez FJ, Torres I, Garcia-Valero A, López-Tinoco C, de Los Santos A, Aguilar-Diosdado M. Concomitant agranulocytosis and hepatotoxicity after treatment with carbimazole. Ann Pharmacother. 2006;40(11):2059-63. PMID: 17077174. https://doi.org/10.1345/aph.1G720.

Escobar-Morreale HF, Bravo P, Garcia-Robles R, García-Laraña J, de la Calle H, Sancho JM. Methimazole-induced severe aplastic anemia: Unsuccessful treatment with recombinant human granulocyte-monocyte-colony-stimulating factor. Thyroid. 1997;7(1):67-70. PMID: 9086574. https://doi.org/10.1089/thy.1997.7.67.

Biswas N, Ahn YH, Goldman JM, Schwartz JM. Case report: Aplastic anemia associated with antithyroid drugs. Am J Med Sci. 1991;301(3):190-4. PMID: 2000892.

Yang J, Zhong J, Xiao XH, et al. The relationship between bone marrow characteristics and the clinical prognosis of antithyroid drug-induced agranulocytosis. Endocr J. 2013;60(2):185-9. PMID: 23117149.

Wang MT, Lee WJ, Huang TY, Chu CL, Hsieh CH. Antithyroid drug-related hepatotoxicity in hyperthyroidism patients: A population-based cohort study. Br J Clin Pharmacol. 2014;78(3):619-29. PMID: 25279406. PMCID: PMC4243912.

Chen PL, Shih SR, Wang PW, et al. Genetic determinants of antithyroid drug-induced agranulocytosis by human leukocyte antigen genotyping and genome-wide association study. Nat Commun. 2015;6:7633. PMID: 26151496. PMCID: PMC4506516. https://doi.org/10.1038/ncomms8633.

Cheung CL, Sing CW, Tang CS, et al. HLA-B*38:02:01 predicts carbimazole/methimazole-induced agranulocytosis. Clin Pharmacol Ther. 2016;99(5):555-61. PMID: 26599303. https://doi.org/10.1002/cpt.309.

He Y, Zheng J, Zhang Q, et al. Association of HLA-B and HLA-DRB1 polymorphisms with antithyroid drug-induced agranulocytosis in a Han population from northern China. Sci Rep. 2017;7(1):11950. PMID: 28931918. PMCID: PMC5607267. https://doi.org/10.1038/s41598-017-12350-2.

Thao MP, Tuan PVA, Linh LGH, et al. Association of HLA-B*38:02 with antithyroid drug-induced agranulocytosis in Kinh Vietnamese patients. Int J Endocrinol. 2018; Article ID 7965346. https://doi.org/10.1155/2018/7965346.

Hallberg P, Eriksson N, Ibañez L, et al. Genetic variants associated with antithyroid drug-induced agranulocytosis: a genome-wide association study in a European population. Lancet Diabetes and Endocrinol. 2016;4(6):507-16. PMID: 27157822. https://doi.org/10.1016/S2213-8587(16)00113-3.

Heidari R, Babaei H, Eghbal M. Mechanisms of methimazole cytotoxicity in isolated rat hepatocytes. Drug Chem Toxicol. 2013;36(4):403-11. PMID: 23256569. https://doi.org/10.3109/01480545.2012.749272.

Sundaram V, Björnsson ES. Drug-induced cholestasis. Hepatol Commun. 2017;1(8):726-35. PMID: 29404489. PMCID: PMC5678916. https://doi.org/10.1002/hep4.1088.

Thomas D, Moisidis A, Tsiakalos A, Alexandraki K, Syriou V, Kaltsas G. Antithyroid drug-induced aplastic anemia. Thyroid. 2008;18(10):1043-8. PMID: 18816182. https://doi.org/10.1089/thy.2008.0097.

Willfort A, Lorber C, Kapiotis S, et al. Treatment of drug-induced agranulocytosis with recombinant granulocyte colony-stimulating factor (rh G-CSF). Ann Hematol. 1993;66(5):241-4. PMID: 7685193.

Sheng WH, Hung CC, Chen YC, et al. Antithyroid-drug-induced agranulocytosis complicated by life-threatening infections. QJM. 1999;92(8):455-61. PMID: 10627862.

Molineaux G, Hartley C, McElroy P, McCrea C, McNiece IK. Megakaryocyte growth and development factor accelerates platelet recovery in peripheral blood progenitor cell transplant recipient. Blood. 1996;88(1):366-76. PMID: 8704197.

Bayhan T, Ünal Ş, Gümrük F, Çetin M. A rare complication of a common problem: Thrombocytopenia subsequent to iron replacement therapy in an adolescent girl with severe iron deficiency anemia. HK J Paediatr. 2016;21(2):113-5. http://www.hkjpaed.org/details.asp?id=1057&show=1234.

United States Food and Drug Administration. Eltrombopag/Promacta.fda.gov. Retrieved 18 March 2016. https://www.accessdata.fda.gov/drugsatfda_docs/label/2008/022291lbl.pdf.

Townsley DM, Scheinberg P, Winkler T, et al. Eltrombopag added to standard immunosuppression for aplastic anemia. N Engl J Med. 2017;376(16):1540-50. PMID: 28423296. PMCID: PMC5548296. https://doi.org/10.1056/NEJMoa1613878.

Desmond R, Townsley DM, Dumitriu B, et al. Eltrombopag restores trilineage hematopoiesis in refractory severe aplastic anemia that can be sustained on discontinuation of drug. Blood. 2014;123(12):1818-25. PMID: 24345753. PMCID: PMC3962161. https://doi.org/10.1182/blood-2013-10-534743.

Ross DS, Burch HB, Cooper DS, et al. 2016 American Thyroid Association Guidelines for diagnosis and management of hyperthyroidism and other causes of thyrotoxicosis. Thyroid. 2016;26(10):1343-1421. PMID: 27521067. https://doi.org/10.1089/thy.2016.0229.