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Emphasis on the early diagnosis of antithyroid drug-induced agranulocytosis: retrospective analysis over 16 years at one Chinese center

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Abstract

Purpose

Antithyroid drug (ATD)-induced agranulocytosis is a rare but life-threatening adverse drug reaction that occurs in patients during the treatment of Graves’ disease. We aimed to comprehensively examine data for patients with this rare complication and to improve the clinical safety of ATDs.

Methods

We retrospectively reviewed the medical records of 64 hospitalized patients diagnosed with ATD-induced agranulocytosis between 2000 and 2015.

Results

Agranulocytosis occurred in 52 (81.3%) patients within the first 3 months after initiation of ATD therapy. Fever (84.4%) and sore throat (82.8%) were the most common symptoms. Although they experienced symptoms, 30 (46.9%) patients did not seek treatment immediately and delayed their diagnosis of agranulocytosis. The minimum granulocyte count was lower in the patients diagnosed after the appearance of symptoms than in those diagnosed before the appearance of symptoms (0.01 × 109/L (0 × 109/L − 0.06 × 109/L) versus 0.26 × 109/L (0.05 × 109/L − 0.40 × 109/L), P < 0.001). The interval days from the appearance of symptoms to the diagnosis of agranulocytosis were negatively correlated with the minimum granulocyte count (r = −0.348, P = 0.005). In addition, a lower minimum granulocyte count was associated with a longer recovery time (β = −11.899, 95% CI −15.304 to −8.496).

Conclusions

Our findings have demonstrated that delayed diagnosis of ATD-induced agranulocytosis is common in our population. Delayed diagnosis is associated with severe agranulocytosis and may prolong the recovery time from agranulocytosis. Monitoring of the white blood cell and granulocyte counts may be an effective way to establish an early diagnosis and prevent progression to severe agranulocytosis.

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References

  1. Bartalena L, Chiovato L, Vitti P (2016) Management of hyperthyroidism due to Graves’ disease: frequently asked questions and answers (if any). J Endocrinol Invest 39:1105–1114. doi:10.1007/s40618-016-0505-x

    Article  CAS  PubMed  Google Scholar 

  2. Burch HB, Burman KD, Cooper DS (2012) A 2011 survey of clinical practice patterns in the management of Graves’ disease. J Clin Endocrinol Metab 97:4549–4558. doi:10.1210/jc.2012-2802

    Article  CAS  PubMed  Google Scholar 

  3. Tajiri J, Noguchi S (2004) Antithyroid drug-induced agranulocytosis: special reference to normal white blood cell count agranulocytosis. Thyroid 14:459–462. doi:10.1089/105072504323150787

    Article  CAS  PubMed  Google Scholar 

  4. Cooper DS (2005) Antithyroid drugs. N Engl J Med 352:905–917. doi:10.1056/NEJMra042972

    Article  CAS  PubMed  Google Scholar 

  5. Tajiri J, Noguchi S (2005) Antithyroid drug-induced agranulocytosis: how has granulocyte colony-stimulating factor changed therapy? Thyroid 15:292–297. doi:10.1089/thy.2005.15.292

    Article  CAS  PubMed  Google Scholar 

  6. Watanabe N, Narimatsu H, Noh JY, Yamaguchi T, Kobayashi K, Kami M, Kunii Y, Mukasa K, Ito K, Ito K (2012) Antithyroid drug-induced hematopoietic damage: a retrospective cohort study of agranulocytosis and pancytopenia involving 50,385 patients with Graves’ disease. J Clin Endocrinol Metab 97:E49–E53. doi:10.1210/jc.2011-2221

    Article  CAS  PubMed  Google Scholar 

  7. Nakamura H, Miyauchi A, Miyawaki N, Imagawa J (2013) Analysis of 754 cases of antithyroid drug-induced agranulocytosis over 30 years in Japan. J Clin Endocrinol Metab 98:4776–4783. doi:10.1210/jc.2013-2569

    Article  CAS  PubMed  Google Scholar 

  8. Andersen SL, Olsen J, Laurberg P (2016) Antithyroid drug side effects in the population and in pregnancy. J Clin Endocrinol Metab 101:1606–1614. doi:10.1210/jc.2015-4274

    Article  PubMed  Google Scholar 

  9. Roeloffzen WW, Verhaegh JJ, van Poelgeest AE, Gansevoort RT (1998) Fever or a soar throat after start of antithyroidal drugs? A medical emergency. Neth J Med 53:113–117. doi:10.1016/S0300-2977(98)00065-5

    Article  CAS  PubMed  Google Scholar 

  10. Sheng WH, Hung CC, Chen YC, Fang CT, Hsieh SM, Chang SC, Hsieh WC (1999) Antithyroid-drug-induced agranulocytosis complicated by life-threatening infections. QJM 92:455–46112

    Article  CAS  PubMed  Google Scholar 

  11. Rivkees SA (2016) Controversies in the management of Graves’ disease in children. J Endocrinol Invest 39:1247–1257. doi:10.1007/s40618-016-0477-x

    Article  CAS  PubMed  Google Scholar 

  12. Marino M, Latrofa F, Menconi F, Chiovato L, Vitti P (2014) An update on the medical treatment of Graves’ hyperthyroidism. J Endocrinol Invest 37:1041–1048. doi:10.1007/s40618-014-0136-z

    Article  CAS  PubMed  Google Scholar 

  13. Yang J, Zhu YJ, Zhong J, Zhang J, Weng WW, Liu Z, Xu Q, Dong M (2016) Characteristics of antithyroid drug-induced agranulocytosis in patients with hyperthyroidism: a retrospective analysis of 114 cases in a single institution in China involving 9690 patients referred for radioiodine treatment over 15 years. Thyroid 26:627–633. doi:10.1089/thy.2015.0439

    Article  CAS  PubMed  Google Scholar 

  14. Kim HK, Yoon JH, Jeon MJ, Kim TY, Shong YK, Lee MJ, Kim BH, Kim IJ, Joung JY, Kim SW, Chung JH, Kang HC (2015) Characteristics of Korean patients with antithyroid drug-induced agranulocytosis: a multicenter study in Korea. Endocrinol Metab 30:475–480. doi:10.3803/EnM.2015.30.4.475

    Article  Google Scholar 

  15. Kobayashi S, Noh JY, Mukasa K, Kunii Y, Watanabe N, Matsumoto M, Ohye H, Suzuki M, Yoshihara A, Iwaku K, Sugino K, Ito K (2014) Characteristics of agranulocytosis as an adverse effect of antithyroid drugs in the second or later course of treatment. Thyroid 24:796–801. doi:10.1089/thy.2013.0476

    Article  CAS  PubMed  Google Scholar 

  16. Meyer-Gessner M, Benker G, Lederbogen S, Olbricht T, Reinwein D (1994) Antithyroid drug-induced agranulocytosis: clinical experience with ten patients treated at one institution and review of the literature. J Endocrinol Invest 17:29–36. doi:10.1007/BF03344959

    Article  CAS  PubMed  Google Scholar 

  17. Yang J, Zhong J, Zhou LZ, Hong T, Xiao XH, Wen GB (2012) Sudden onset agranulocytosis and hepatotoxicity after taking methimazole. Intern Med 51:2189–2192. doi:10.2169/internalmedicine.51.7845

    Article  CAS  PubMed  Google Scholar 

  18. Mutharasan P, Oatis W, Kwaan H, Molitch M (2012) Delayed anithyroid drug-induced agranulocytosis. Endocr Pract 18:e69–e72. doi:10.4158/EP11339.CR

    Article  PubMed  Google Scholar 

  19. Tajiri J, Noguchi S, Murakami T, Murakami N (1990) Antithyroid drug-induced agranulocytosis. The usefulness of routine white blood cell count monitoring. Arch Intern Med 150:621–624. doi:10.1001/archinte.1990.00390150107020

    Article  CAS  PubMed  Google Scholar 

  20. Fukata S, Kuma K, Sugawara M (1999) Granulocyte colony-stimulating factor (G-CSF) does not improve recovery from antithyroid drug-induced agranulocytosis: a prospective study. Thyroid 9:29–31. doi:10.1089/thy.1999.9.29

    Article  CAS  PubMed  Google Scholar 

  21. Andres E, Kurtz JE, Perrin AE, Dufour P, Schlienger JL, Maloisel F (2001) Haematopoietic growth factor in antithyroid-drug-induced agranulocytosis. QJM 94:423–428. doi:10.1093/qjmed/94.8.423

    Article  CAS  PubMed  Google Scholar 

  22. Takata K, Kubota S, Fukata S, Kudo T, Nishihara E, Ito M, Amino N, Miyauchi A (2009) Methimazole-induced agranulocytosis in patients with Graves’ disease is more frequent with an initial dose of 30 mg daily than with 15 mg daily. Thyroid 19:559–563. doi:10.1089/thy.2008.0364

    Article  CAS  PubMed  Google Scholar 

  23. Bahn Chair RS, Burch HB, Cooper DS, Garber JR, Greenlee MC, Klein I, Laurberg P, McDougall IR, Montori VM, Rivkees SA, Ross DS, Sosa JA, Stan MN (2011) Hyperthyroidism and other causes of thyrotoxicosis: management guidelines of the American Thyroid Association and American Association of Clinical Endocrinologists. Thyroid 21:593–646. doi:10.1089/thy.2010.0417

    Article  PubMed  Google Scholar 

  24. Huang CH, Li KL, Wu JH, Wang PN, Juang JH (2007) Antithyroid drug-induced agranulocytosis: report of 13 cases. Chang Guang Med J 30:242–248

    Google Scholar 

  25. Balkin MS, Buchholtz M, Ortiz J, Green AJ (1993) Propylthiouracil (PTU)-induced agranulocytosis treated with recombinant human granulocyte colony-stimulating factor (G-CSF). Thyroid 3:305–309. doi:10.1089/thy.1993.3.305

    Article  CAS  PubMed  Google Scholar 

  26. Sun MT, Tsai CH, Shih KC (2009) Antithyroid drug-induced agranulocytosis. J Chin Med Assoc 72:438–441. doi:10.1016/S1726-4901(09)70402-2

    Article  PubMed  Google Scholar 

  27. Dai WX, Zhang JD, Zhan SW, Xu BZ, Jin H, Yao Y, Xin WC, Bai Y (2002) Retrospective analysis of 18 cases of antithyroid drug (ATD)-induced agranulocytosis. Endocr J 49:29–33. doi:10.1507/endocrj.49-29

    Article  PubMed  Google Scholar 

  28. Li KL, Huang HS, Wang PW, Lin JD, Juang JH, Liu RT, Huang BY, Huang MJ. (1991) Agranulocytosis associated with anti-thyroid drug in patients with Graves’ thyrotoxicosis–report of 11 cases. Chang Guang Med J 14:168–173.

    CAS  Google Scholar 

  29. Abalovich M, Amino N, Barbour LA, Cobin RH, De Groot LJ, Glinoer D, Mandel SJ, Stagnaro-Green A (2007) Management of thyroid dysfunction during pregnancy and postpartum: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 92:S1–S47. doi:10.1210/jc.2007-0141

    Article  CAS  PubMed  Google Scholar 

  30. Yamashita S, Amino N, Shong YK (2011) The American Thyroid Association and American Association of Clinical Endocrinologists hyperthyroidism and other causes of thyrotoxicosis guidelines: viewpoints from Japan and Korea. Thyroid 21:577–580. doi:10.1089/thy.2011.2106.ed1

    Article  PubMed  Google Scholar 

  31. Ross DS, Burch HB, Cooper DS, Greenlee MC, Laurberg P, Maia AL, Rivkees SA, Samuels M, Sosa JA, Stan MN, Walter MA (2016) 2016 American Thyroid Association guidelines for diagnosis and management of hyperthyroidism and other causes of thyrotoxicosis. Thyroid 26:1343–1421. doi:10.1089/thy.2016.0229

    Article  PubMed  Google Scholar 

  32. Chinese Endocrinology Association (2007) Management guideline of thyroid disease in China: hyperthyroidism. Zhonghua Nei Ke Za Zhi 46:876–882 (in Chinese)

    Google Scholar 

  33. Robinson J, Richardson M, Hickey J, James A, Pearce SH, Ball SG, Quinton R, Morris M, Miller M, Perros P (2014) Patient knowledge of antithyroid drug-induced agranulocytosis. Eur Thyroid J 3:245–251. doi:10.1159/000367990

    PubMed  PubMed Central  Google Scholar 

  34. Tamai H, Mukuta T, Matsubayashi S, Fukata S, Komaki G, Kuma K, Kumagai LF, Nagataki S (1993) Treatment of methimazole-induced agranulocytosis using recombinant human granulocyte colony-stimulating factor (rhG-CSF). J Clin Endocrinol Metab 77:1356–1360. doi:10.1210/jcem.77.5.7521347

    CAS  PubMed  Google Scholar 

  35. Jakucs J, Pocsay G (2006) Successful treatment of methimazole-induced severe aplastic anemia with recombinant human granulocyte colony-stimulating factor and high-dosage steroids. J Endocrinol Invest 29:74–77. doi:10.1007/BF03349180

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by General project, Institutional science foundation of the First Affiliated Hospital of Xi’an Jiaotong University (2014YK23). We thank American Journal Experts (AJE) for English language editing.

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Correspondence to B. Shi.

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All authors have no conflicts of interest to disclose.

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Our study had been approved by the Ethics Committee of the First Affiliated Hospital of Xi’an Jiaotong University School of Medicine.

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As a retrospective study, formal consent is not required.

Additional information

This work was supported by General project, Institutional science foundation of the First Affiliated Hospital of Xi’an Jiaotong University (2014YK23).

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He, Y., Li, J., Zheng, J. et al. Emphasis on the early diagnosis of antithyroid drug-induced agranulocytosis: retrospective analysis over 16 years at one Chinese center. J Endocrinol Invest 40, 733–740 (2017). https://doi.org/10.1007/s40618-017-0626-x

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