Endocrinology and Metabolism

Original Article

Clinical Study
Characteristics of Korean Patients with Antithyroid Drug-Induced Agranulocytosis: A Multicenter Study in Korea: Hee Kyung Kim, Jee Hee Yoon, Min Ji Jeon, Tae Yong Kim, Young Kee Shong, Min Jin Lee, Bo Hyun Kim, In Joo Kim, Ji Young Joung, Sun Wook Kim, Jae Hoon Chung, Ho-Cheol Kang; Endocrinol Metab. 2015;30(4):475-480. Published online December 31, 2015; DOI: https://doi.org/10.3803/EnM.2015.30.4.475

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Background

Antithyroid drugs (ATDs) can lead to the development of agranulocytosis, which is the most serious adverse effect. Characteristics of ATD-induced agranulocytosis (AIA) have seldom been reported due to the rarity. In this study, we characterized the clinical features for AIA in Korean patients.

Methods

We retrospectively reviewed data from patients with AIA diagnosed between 1997 and 2014 at four tertiary hospitals. Agranulocytosis was defined as an absolute neutrophil count (ANC) below 500/mm³.

Results

The mean age of the patients (11 males, 43 females) was 38.2±14.9 years. Forty-eight patients (88.9%) with AIA had fever and sore throat on initial presentation, 20.4% of patients developed AIA during the second course of treatment, and 75.9% of patients suffered AIA within 3 months after initiation of ATD. The patients taking methimazole (n=39) showed lower levels of ANC and more frequent use of granulocyte-macrophage colony-stimulating factor than propylthiouracil (n=15) users. The median duration of agranulocytosis was 5.5 days (range, 1 to 20). No differences were observed between the long (≥6 days) and short recovery time (≤5 days) groups in terms of age, gender, ATDs, duration of ATDs, or initial ANC levels. Four patients (7.4%) who were taking ATDs for less than 2 months died of sepsis on the first or second day of hospitalization.

Conclusion

The majority of AIA incidents occur in the early treatment period. Considering the high fatality rate of AIA, an early aggressive therapeutic approach is critical and patients should be well informed regarding the warning symptoms of the disease.

Citations

Citations to this article as recorded by

Novel Association of KLRC4-KLRK1 Gene Polymorphisms with Susceptibility and Progression of Antithyroid Drug-Induced Agranulocytosis
Yayi He, Pan Ma, Yuanlin Luo, Xiaojuan Gong, Jiayang Gao, Yuxin Sun, Pu Chen, Suliang Zhang, Yuxin Tian, Bingyin Shi, Bao Zhang
Experimental and Clinical Endocrinology & Diabetes.2024; 132(01): 17. CrossRef
A Disproportionality Analysis of the Adverse Effect Profiles of Methimazole and Propylthiouracil in Patients with Hyperthyroidism Using the Japanese Adverse Drug Event Report Database
Masanori Arai, Takahiro Tsuno, Hiromi Konishi, Kuniyuki Nishiyama, Yasuo Terauchi, Ryota Inoue, Jun Shirakawa
Thyroid®.2023; 33(7): 804. CrossRef
The Current Status of Hyperthyroidism in Korea
Hyemi Kwon
Endocrinology and Metabolism.2023; 38(4): 392. CrossRef
Clinical characteristics of neutropenic patients under antithyroid drug: Twelve-year experience in a medical center
Chih-Hsueh Tseng, Chi-Lung Tseng, Harn-Shen Chen, Pei-Lung Chen, Chun-Jui Huang
Journal of the Chinese Medical Association.2023; 86(9): 826. CrossRef
Association of MICA gene polymorphisms with thionamide-induced agranulocytosis
P. Ma, P. Chen, J. Gao, H. Guo, S. Li, J. Yang, J. Lai, X. Yang, B. Zhang, Y. He
Journal of Endocrinological Investigation.2021; 44(2): 363. CrossRef
Efficacy and adverse events related to the initial dose of methimazole in children and adolescents with Graves’ disease
Hyun Gyung Lee, Eun Mi Yang, Chan Jong Kim
Annals of Pediatric Endocrinology & Metabolism.2021; 26(3): 199. CrossRef
MICA polymorphisms associated with antithyroid drug‐induced agranulocytosis in the Chinese Han population
Xiaojuan Gong, Pu Chen, Pan Ma, Jiayang Gao, Jingsi Yang, Hui Guo, Chunxia Yan, Bao Zhang, Yayi He
Immunity, Inflammation and Disease.2020; 8(4): 695. CrossRef
The Management of Thyroid Disease in COVID-19 Pandemic
Won Sang Yoo, Hyun-Kyung Chung
International Journal of Thyroidology.2020; 13(2): 65. CrossRef
Increased Risk of Antithyroid Drug Agranulocytosis Associated with Amiodarone-Induced Thyrotoxicosis: A Population-Based Cohort Study
Michal Gershinsky, Walid Saliba, Idit Lavi, Chen Shapira, Naomi Gronich
Thyroid.2019; 29(2): 193. CrossRef
A Case of Acute Supraglottitis Following Anti-Thyroid Drug-Induced Agranulocytosis
Jung Jun Lee, Dong Young Kim, Jeon Yeob Jang
Journal of The Korean Society of Laryngology, Phoniatrics and Logopedics.2019; 30(2): 128. CrossRef
Association of HLA-B∗38:02 with Antithyroid Drug-Induced Agranulocytosis in Kinh Vietnamese Patients
Mai Phuong Thao, Pham Vo Anh Tuan, Le Gia Hoang Linh, Lam Van Hoang, Phan Huu Hen, Le Tuyet Hoa, Hoang Anh Vu, Do Duc Minh
International Journal of Endocrinology.2018; 2018: 1. CrossRef
Severe Gingival Ulceration and Necrosis Caused by an Antithyroid Drug: One Case Report and Proposed Clinical Approach
Ying‐Ying Chang, Chih‐Wen Tseng, Kuo Yuan
Clinical Advances in Periodontics.2018; 8(1): 11. CrossRef
Emphasis on the early diagnosis of antithyroid drug-induced agranulocytosis: retrospective analysis over 16 years at one Chinese center
Y. He, J. Li, J. Zheng, Z. Khan, W. Qiang, F. Gao, Y. Zhao, B. Shi
Journal of Endocrinological Investigation.2017; 40(7): 733. CrossRef
Association of HLA-B and HLA-DRB1 polymorphisms with antithyroid drug-induced agranulocytosis in a Han population from northern China
Yayi He, Jie Zheng, Qian Zhang, Peng Hou, Feng Zhu, Jian Yang, Wenhao Li, Pu Chen, Shu Liu, Bao Zhang, Bingyin Shi
Scientific Reports.2017;[Epub] CrossRef
Use of granulocyte colony‐stimulating factor in the treatment of methimazole‐induced agranulocytosis: a case report
Asha Birmingham, Carissa Mancuso, Craig Williams
Clinical Case Reports.2017; 5(10): 1701. CrossRef
2016 American Thyroid Association Guidelines for Diagnosis and Management of Hyperthyroidism and Other Causes of Thyrotoxicosis
Douglas S. Ross, Henry B. Burch, David S. Cooper, M. Carol Greenlee, Peter Laurberg, Ana Luiza Maia, Scott A. Rivkees, Mary Samuels, Julie Ann Sosa, Marius N. Stan, Martin A. Walter
Thyroid.2016; 26(10): 1343. CrossRef

Case Reports

A Case of Methimazole-induced Agranulocytosis and Kikuchi's Disease in a Patient with Graves' Disease.: Seung Eun Lee, Jihyun Ahn, Jaetaek Kim, Yeon Sahng Oh, Yun Jae Chung; J Korean Endocr Soc. 2008;23(6):420-424. Published online December 1, 2008; DOI: https://doi.org/10.3803/jkes.2008.23.6.420

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Abstract PDF: Methimazole-induced agranulocytosis is a rare, but critical side effect that should be recognized as soon as possible since it may induce a life-threatening condition when it was overlooked. Histiocytic necrotizing lymphadenitis is also called Kikuchi's lymphadenitis, and this is a rare form of lymphadenitis with a self-limited clinical course and this illness is accompanied by cervical lymph node enlargement, fever and malaise. We recently experienced a patient with methimazole-induced agranulocytosis and Graves' disease, and this was accompanied by Kikuchi's disease; the patient presented with sore throat and multiple enlarged cervical lymph nodes. To the best of our knowledge, there is no previous report on methimazole-induced agranulocytosis combined with Kikuchi's disease. Therefore, we report here on this very rare case along with a brief review of the relevant literature.

A Case of Neutropenic Enterocolitis Complicating Methimazole-induced Agranulocytosis.: Sang Hyun Park, In Sung Cho, Hyun Jin Kim, Soo Jung Gong, Nae You Kim, Jung Ae Lee; J Korean Endocr Soc. 2007;22(4):282-286. Published online August 1, 2007; DOI: https://doi.org/10.3803/jkes.2007.22.4.282

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Abstract PDF: Agranulocytosis is a rare complication of antithyroid drug therapy. Neutropenic enterocolitis is characterized by neutropenia plus cecal and ascending colon inflammation, and this is the most feared side effect of agranulocytosis. This is a rare complication of chemotherapy for treating hematological malignancies and less commonly, of the medication used for treating other diseases (e.g., hyperthyroidism). The mortality rate varies from 50 to 100%, with most deaths being due to bowel perforation and sepsis. Therefore, early recognition and proper medical management of neutropenic enterocolitis is important. Recently, early recognition and progress in the management have probably reduced the mortality of this malady, yet there have been no prospective randomized trials or high-quality retrospective studies on the treatment of neutropenic enterocolitis. Therefore, standardized recommendations concerning the indications for surgery cannot be made, but most of these patients are probably not candidates for surgical intervention. Non-surgical management may be a reasonable initial approach for those patients presenting without significant complications such as peritonitis, perforation or bleeding. We report here on a case that was treated with successful medical management for neutropenic enterocolitis that occurred when administering methimazole therapy as an antithyroid drug.

A case of Methimazole-Induced Cholestatic Jaundice With Agranulocytosis.: Sang Gu Kang, Jong Oh Bae, Eun Young Lee, Seong Min Lim, Sang Kun Cho, Ji Hye Kim, Sun Kyung Song; J Korean Endocr Soc. 2005;20(5):519-523. Published online October 1, 2005; DOI: https://doi.org/10.3803/jkes.2005.20.5.519

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Abstract PDF

Methimazole is a widely used and generally well-tolerated antithyroid agent. Adverse reactions occur in 1~5% of patients taking methimazole medication, but these are most commonly transient, benign leukopenia and a skin rash. Severe cholestatic jaundice, combined with agranulocytosis, has been known as a rare complication. Herein, a case of methimazole induced cholestatic jaundice, with agranulocytosis, is reported.

Citations

Citations to this article as recorded by

A Case Report of Methimazole-Induced Acute Liver Failure Successfully Treated with Liver Transplantation
Sung Jin Jeon, Tae Yong Kim, Seung-Hoon Lee, Jong Sik Kang, Gwang Hyeon Choi, Seung-Gyu Lee, Hee Sang Hwang
Korean Journal of Medicine.2012; 83(3): 363. CrossRef
A Case of Methimazole-induced Pancytopenia: Successful Treatment with Recombinant Human Granulocyte Colony-stimulating Factor
Joo Hyoung Lee, Jihyun Lee, Sang Hun Sung, Sung Hwa Bae, Sang Gyung Kim, Hoon Kyu Oh
Journal of Korean Endocrine Society.2006; 21(6): 548. CrossRef

A Case of Transient Granulocytopenia during Treatment of a Patient with Graves' Disease and Type 1 Diabetes Mellitus - Differential Diagnosis from Agranulocytosis by a Single Injection of G-CSF.: Jin Kyeong Park, Jeong Hun Seong, Jun Lee, Seon Nyo Chu, Hun Jeong, Yoo Lee Kim, Seok Won Park, Yong Wook Cho, Sang Jong Lee; J Korean Endocr Soc. 2002;17(2):280-285. Published online April 1, 2002

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Abstract PDF: Granulocytopenia, which can be seen in patients with Graves' disease during treatment with antithyroid agents, could be a self resolving transient episode or can imply the beginning of life threatening agranulocytosis requiring a change in treatment modality. Transient granulocytopenia could be a manifestation of hyperthyroidism itself, or a mild side effect of antithyroid drugs. Aganulocytosis is a rare, but major complications of the termination drug, propylthiouracil (PTU), requiring prompt termination of the medication, and intensive care. Therefore, differentiation of agranulocytosis and transient granulocytopenia, is important, but is not practically easy. We introduce a case of transient granulocytopenia, which was detected in a patient with Graves'Disease, accompanied by underlying type 1 diabetes mellitus, during treatment with PTU. Diagnosis of transient granulocytopenia was made by a normal granulocyte count following a single injection of G-SCF, and the patient was treated with conservative therapy. This case confirms a diagnostic tool for differentiating transient granulocytopenia and PTU-induced agranulocytosis.

A Case of Methimazole Induced Agranulocytosis Complicated with Deep Neck Abscess.: Kwan Woo Lee, Sung Kyu Lee, Yun Suk Chung, Hyun Man Kim, Yoon Jung Kim, Eun Kyung Hong, Bong Nam Chae, Jin Ho Lee, Chang Young Ha, Joon Sung Park; J Korean Endocr Soc. 1998;13(4):617-621. Published online January 1, 2001

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Abstract PDF: The thiourea derivatives, propylthiouracil and methimazole are in widespread use for the treatment of hyperthyroidism. The untoward side effects of these drugs are not infrequent and agranulocytosis is the most serious side effect them. We observed one case of methimazole induced agranulocytosis complicated by deep neck abscess. A 54-year-old woman was admitted because of fever, chilling and sore throat for 1 week. The symptom was developed after receiving methimazole 30mg daily day due to hyperthyroidism during last 3 months. Physical examination revealed hyperemic, enlarged tonsils and tender swelling of the right lower neck The peripheral blood total leukoeyte count was 1,500/mm' (absolute neutrophil count, ANC 9) and a peripheral blood smear revealed few neutrophil. The patient was administered G-CSF 2 mg/kg daily, and on the fifth day of hospitalization, fever subsided and ANC increased to 3,431. On the 11th day, fever developed again and the tenderness and swelling in both lower neck area were aggrevated. Computed tomography of the neck was performed, and revealed a large deep neck abscess. After pus aspiration and antibiotics therapy, the neck abscess was disappeared.

A Case of Methimazole Induced Agranulocytosis Treated with Granulocyte Colony Stimulating Factor ( G-CSF ).: Kwan Woo Lee, Yoon Sok Chung, Hyeon Man Kim, So Yeon Choi, Min Kyung Song, Hyun Soo Kim, Hee Sun Jeon; J Korean Endocr Soc. 1997;12(1):68-74. Published online January 1, 2001

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Abstract PDF: A 31-year-old woman admitted because of fever, chilling and sore throat for 4 days. The symptom was developed after receiving methimazole 20mg per day and carteolol 10mg per day due to Graves disease during last 4 weeks. Physical examination revealed hyperemic enlarged tonsils with whitish plaque. The peripheral blood total neutrophil count was 1,400/mm3 (absolute neutrophil count, ANC 36) and a peripheral blood smear revealed rare neutrophil with lymphocytosis. On the first day of hospitalization, the patient was severely ill with ANC 0, it was decided to administer G-CSF 2ug/kg daily. On the fifth day of hospitalization, ANC in peripheral blood count was persistently zero and bone marrow aspiration and biopsy were performed, which revealed hypocellularity and myeloid hypoplasia. G-CSF given daily for 7days, it was discontinued when the ANC reached 1,539/mm3. The availability of G-CSF may help to shorten the course of agranulocytosis and to reduce its mortality rate.

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