Methimazole-Induced Agranulocytosis: A Clinical Case Report Open Access

Antithyroid drugs (ATDs) are widely used in the treatment of hyperthyroidism [1‒4]. They are generally safe and well tolerated [2, 5, 6]. However, major side effects such as hepatotoxicity and agranulocytosis may occur, so patients should be informed about the symptoms of these conditions [7, 8]. Although rare, with an estimated incidence of 0.1–0.5% [8‒10], agranulocytosis appears to be more likely with propylthiouracil (PTU) at any dose than with low-dose methimazole (MMI) [3] and cross-reactivity may occur [2, 3]. We report a case of a woman with persistent low thyroid-stimulating hormone (TSH) levels compatible with subclinical hyperthyroidism (SH), previously treated with PTU with no major adverse effects, who developed agranulocytosis after starting MMI. This case also highlights the importance of early symptom recognition and treatment.

A 70-year-old woman was referred to our endocrinology clinic for SH diagnosed 20 years before, managed with PTU for at least 12 years, which was suspended due to an alteration in the white blood cells she could not specify. A later review of her primary care medical records revealed a mild transitory leukopenia. Her past medical history also included dyslipidemia treated with simvastatin 40 mg/day. There was no history of other adverse reactions to medication. She had no history of iodine supplements or exams requiring iodinated-based contrast.

On presentation to our clinic, she reported worsening anxiety with no other symptoms. On examination, her blood pressure was 141/73 mm Hg, her heart rate was 75/min, and she had a body temperature of 36.6°C. Her thyroid was not enlarged, and no signs of Graves’ ophthalmopathy, Graves’ dermopathy, or fine tremors were present. A thyroid ultrasound revealed an enlarged thyroid with diffuse heterogeneous echogenicity and no hyperemia, suggestive of thyroiditis, and a 5-mm cystic node classified as ACR-TIRADS 1. Thyroid function tests revealed low TSH 0.252 μUI/mL (ref. 0.35–4.94) and normal free thyroxine (fT4) 1.12 ng/dL (ref. 0.7–1.48). Antithyroid peroxidase antibodies, antithyroglobulin antibodies, and anti-TSH receptor antibodies were negative (<0.2 UI/mL [ref. <5.6], 0.7 mUI/mL [ref. <4.1], and <0.5 U/L [ref. 0–1.8], respectively). MMI 2.5 mg daily was started.

After 2 months, analytical work-up showed persistent SH (TSH 0.33 μUI/mL, fT4 1.05 ng/dL, free tri-iodothyronine [fT3] 3.25 pg/mL [ref. 1.71–3.71]) and a decrease in the white blood cell count from 3.92 × 10⁹/L to 2.28 × 10⁹/L (ref. 4.0–11.0), with normal levels of neutrophils. Due to leukopenia, MMI was suspended while awaiting thyroid scintigraphy for a potential radioactive iodine treatment.

Six days later, the patient presented to the emergency room with a 2-day history of sore throat, right-sided pleuritic chest pain, fever, headache, nausea, and vomiting. On examination, she had a body temperature of 37.4°C, heart rate of 104 bpm, arterial blood pressure of 103/52 mm Hg, peripheral oxygen arterial saturation of 95%, and slightly diminished breath sounds and fine crackles on the right lung base on auscultation, with no other relevant findings. A chest radiography revealed a right lower lobe consolidation with air bronchogram. Blood tests showed worsened leukopenia 0.16 × 10⁹/L with severe neutropenia (“0 cells”) and elevated C-reactive protein (243 mg/L). The diagnosis of pneumonia and agranulocytosis was made. Peripheral blood and sputum samples were collected for microbiological studies, broad-spectrum antibiotherapy with piperacillin/tazobactam 4.5 g every 6 h and weight-adjusted vancomycin were started, and she was admitted in an intensive care unit.

Agranulocytosis was further characterized with bone marrow biopsy, which revealed a severe hypocellularity, with few myeloid precursors and rare neutrophils, with no presence of blasts. No schizocytes or dysmorphic erythrocytes were observed. Other causes for agranulocytosis were excluded, namely, renal or hepatic impairment, no folic acid or cyanocobalamin deficits, viral or zoonotic infections. Antinuclear antibodies, rheumatoid factor, and anti-cyclic citrullinated peptide antibodies were negative. Testing for anti-myeloperoxidase peripheral neutrophil cytoplasmic antibodies (pANCA:AntiMPO) was positive, but there was no clinical evidence of vasculitis. No microbiological agents were isolated in the collected blood and sputum samples.

Granulocyte colony-stimulating factor (filgrastim) 5 μg/kg/day was administered for 6 days, and the patient was discharged after 12 days with a normal leukocyte (7.5 × 10⁹/L) and neutrophil (5.8 × 10⁹/L) count, with the diagnosis of MMI-induced agranulocytosis. On follow-up visits, the patient continued to exhibit SH (TSH 0.16 μUI/mL, fT4 0.96 ng/dL, fT3 3.31 pg/mL) and a mild leukopenia (3.4 × 10⁹/L). Thyroid scintigraphy revealed a normofunctioning thyroid with normal radioiodine uptake. The patient reported occasional anxiety with no other symptoms, and propranolol 10 mg was prescribed for symptomatic control as needed. On a follow-up visit 18 months after the agranulocytosis, her SH had remitted spontaneously (TSH 0.47 μUI/mL, fT4 0.93 ng/dL, fT3 3.05 pg/mL).

Albeit rare, agranulocytosis, which is defined as a granulocyte count below 500 cells/μL [8], is one of the most feared adverse reactions of ATDs. ATD-induced agranulocytosis most commonly occurs within the first 90 days after starting treatment (in up to 85% of cases). However, it may occur months to years after initiation, and it can also develop during reexposure after a period of discontinuation, months to years after the first course of treatment [8, 10]. ATD-induced agranulocytosis is more likely to occur in females and older people [8, 11]. Additionally, agranulocytosis risk is dose dependent with MMI, but not with PTU [3, 4, 10, 12], and cross-reactivity may occur [2, 3].

In the present case, there are some atypical features when comparing it with previous literature, namely, the fact that there had been no major adverse reaction with PTU, which our patient had been taking for a prolonged period, but agranulocytosis ensued shortly after starting MMI. Additionally, this adverse reaction happened with a very low dose of MMI, which seems atypical, considering that the risk is higher with higher doses of medication. Although not completely established, there are currently two mechanisms that could explain the development of this life-threatening condition: (1) ATDs have been demonstrated to accumulate inside neutrophils and can be oxidized to reactive metabolites (in a reaction mediated by myeloperoxidase or cytochrome P450), which may induce apoptosis by direct toxicity or through an immune reaction by activating inflammasomes [2, 13, 14]; (2) an immune-mediated mechanism may occur through antibodies against granulocytes, which can be responsible for ATDs-induced agranulocytosis, specifically with antineutrophil cytoplasmic antibodies [2, 15].

The presence of antineutrophil cytoplasmic antibodies in our patient seems consistent with the latter mechanism. Additionally, it highlights the risk of cross-reactivity when using different ATDs, since the presence of these antibodies might have been triggered by the previous use of PTU. This would also explain why only a low dose of MMI was required to trigger an agranulocytosis.

While reviewing our approach in this patient, it seemed appropriate at the time to start an ATD. She had a diagnosis of SH, with no accompanying symptoms. Elderly people with SH have an increased risk of atrial fibrillation, osteoporotic fractures, coronary heart disease, and excess risk of total mortality, and current guidelines [4] recommend treating persistent grade 1 SH (TSH between 0.1 and 0.39 mU/L), in older people (e.g., >65 years) according to its etiology and risk factors. Considering the long-term persistence of grade 1 SH in our patient, treatment was started with the ATD with the least risk of adverse reactions, while undergoing etiologic studies to plan for a definitive solution.

Although the abrupt onset of agranulocytosis may render routine monitoring of blood cell counts ineffective, Nakamura et al. [16] proposed periodic monitoring of blood cell count in Graves’ patients, especially in the first 3 months of ATD therapy, as some cases may exhibit a slower progression of neutropenia secondary to the toxic effects of ATDs on the bone marrow. Additionally, there have been reported cases of asymptomatic agranulocytosis [11] and cases with a progressive decline in white blood cell count prior to the onset of agranulocytosis [8]. Despite this, the ATA guidelines [3] did not find sufficient evidence to recommend routine white blood cell count monitoring. Nevertheless, monitoring blood cell counts in our patient allowed for the detection of decreasing leukocyte levels before the onset of the agranulocytosis, enabling a prompt suspension of the ATD.

If there had been an evident cause for our patient’s subclinical thyrotoxicosis, a definitive treatment could have been planned. However, no evidence of increased radioiodine uptake was found on scintigraphy and no anti-TSH receptor antibodies were identified.

In conclusion, this case highlights the importance of recognizing possible life-threatening adverse reactions to ATDs, even in patients with prior exposure to these medications, and in low ATD doses. A thorough medical history, including a detailed history of previous medication and any associated adverse reactions, is fundamental in risk assessment and patient management. Clinicians should be aware of possible cross-reactivity and atypical presentation features. Patients should be advised to discontinue the medication if signs or symptoms of agranulocytosis, such as fever and sore throat, occur, particularly within the first 90 days of starting an ATD. This case report was written in accordance with the CARE guidelines (the CARE Checklist is available as online suppl. material; for all online suppl. material, see https://doi.org/10.1159/000546313).

This study was performed in accordance with the Declaration of Helsinki. This human study was approved by Comissão de Ética da Unidade Local de Saúde de São João – approval: 24 April 2025. Written informed consent was obtained from the individual for publication of the details of their medical case and any accompanying images.

The authors have no conflicts of interest to declare.

This case report was presented at ECE2023 and was supported by a scientific presentation grant from the Portuguese Society of Endocrinology, Diabetes and Metabolism (SPEDM). Other funders had no role in the design, data collection, data analysis, and reporting of this case study. This case report was not supported by any sponsor or funder.

J.M. and I.M.: wrote this case report. J.G. and S.R.: helped in the writing of this case report. J.P.: involved in the patient care and revised the draft. J.Q.: critical revision of the draft.

All data generated or analyzed during this study are included in this article and its online supplementary material files. Further inquiries can be directed to the corresponding author.