Concomitant methimazole-induced agranulocytosis and cholestatic jaundice in a young woman
- Chris Alcorn ,
- Prathayini Subarajan and
- Jay Anderson
- Medical Education, OhioHealth Riverside Methodist, Columbus, Ohio, USA
- Correspondence to Dr Jay Anderson; jay.anderson@ohiohealth.com
Abstract
A woman in her 30s presented to the emergency department with new-onset sore throat and fever. She had recently been diagnosed with Graves’ disease 3 months prior. As a result, she was initiated on atenolol and methimazole for management. Her methimazole dosing had been stable at 15 mg daily for the month prior to presentation. Investigation revealed severe neutropenia and jaundice. She was found to have concomitant agranulocytosis and cholestatic jaundice secondary to methimazole.
Methimazole was discontinued on admission and the patient received granulocyte colony-stimulating factor for an absolute neutrophil count (ANC) of zero. She was placed on broad-spectrum antibiotics and intravenous steroids for epiglottic and supraglottic oedema noted on bedside laryngoscopy. ANC and bilirubin improved over a 2-week hospital course. She was discharged on a temporary regimen of propranolol, dexamethasone and potassium iodide until she was able to undergo successful thyroidectomy for definitive management of Graves’ disease outpatient.
Background
Thionamide therapy, specifically methimazole (MMI), is the cornerstone for medical management of Graves’ disease. Though this medication is generally well tolerated, there are rare but serious side effects that can be seen, notably agranulocytosis and cholestatic jaundice. Independently, each of these adverse effects is infrequent. The prevalence of agranulocytosis with thionamide therapy is only 0.1%–0.5%.1 MMI-induced cholestatic jaundice occurs in an even lower percentage of patients at 0.1%–0.2%.1 The presentation of concomitant MMI-induced agranulocytosis and cholestatic jaundice is exceedingly rare and has only been reported in the literature a handful of times.2–5 We share a case of a woman in her 30s who arrived with such a presentation.
Case presentation
A Caucasian woman in her 30s with a medical history of depression, essential hypertension and recently diagnosed Graves’ disease presented to the emergency department with acute-onset sore throat and fever. On arrival, she was febrile with a temperature of 38.33°C, neutropenic and had elevated liver function tests. Initial white cell count (WCC) 0 cells x109/L, absolute neutrophil count (ANC) 0, total bilirubin 7.3 mg/dL, direct bilirubin 3.8 mg/dL, aspartate aminotransferase (AST) 28 U/L, alanine transaminase (ALT) 51 U/L and alkaline phosphatase 179 U/L. Serum concentration of MMI was not obtained. She was noted to have significant cervical adenopathy and jaundice on physical examination.
She was diagnosed 3 months prior with new-onset Graves’ disease with palpitations, tremors, anxiety and weight loss. At that time, she was initiated on atenolol 25 mg two times per day and MMI 10 mg daily. Her baseline laboratory analysis demonstrated a normal WCC, ALT, AST, alkaline phosphatase and total bilirubin 1 month prior to presentation. The MMI dose was increased to 15 mg daily (0.21 mg/kg dose) after 1 month due to persistently elevated free T3. She was compliant with the medication and had no complications prior to this hospitalisation.
A workup for other aetiologies for agranulocytosis including peripheral smear, HIV, parvovirus B-19, Epstein-Barr virus (EBV), blood cultures, strep A culture were performed and found to be non-significant. She was on no other potentially offending home medications. Bone marrow biopsy was offered but deferred by the patient. Evaluation of jaundice with lactate dehydrogenase(LDH), haptoglobin and right upper quadrant (RUQ) ultrasound were also non-significant. She was admitted and diagnosed with agranulocytosis, neutropenic fever and cholestatic jaundice secondary to MMI.
Treatment
During the admission, she was followed by endocrinology, haematology, otolaryngology, infectious disease and critical care. MMI was discontinued and haematology then initiated granulocyte colony-stimulating factor (G-CSF) due to the severity of agranulocytosis. She was placed on broad-spectrum antibiotics for neutropenic fever and severe pharyngitis.
Intravenous steroids were initiated for epiglottic and supraglottic oedema noted on CT neck and bedside laryngoscopy. Right upper quadrant ultrasound was benign on admission. HIV screening and haemolysis screening were negative. Her ANC began to increase on day 7 of hospitalisation, it completely normalised on day 10. Liver function tests and bilirubin slowly trended towards normal after admission with total bilirubin reaching normal range on day 11 of hospitalisation.
Outcome and follow-up
The patient was discharged without further thionamide therapy. She was temporarily managed with propranolol, dexamethasone and potassium iodide (SSKI) in the outpatient setting. She was ultimately able to undergo a successful total thyroidectomy for definitive management of her Graves’ disease 2 weeks after discharge.
Discussion
Thionamides, specifically MMI, are first-line pharmacological therapy for the management of Graves’ disease. MMI, also known as thiamazole, acts by preventing the oxidation of iodine in the thyroid gland, preventing the formation of thyroid hormone. Though rare, agranulocytosis and cholestatic jaundice are known potential side effects of MMI.
Agranulocytosis is defined by severe neutropenia with an ANC <500. It is reported in approximately 0.1%–0.5% of patients taking MMI.6 Typically, onset occurs within the first 2–3 months of initiating MMI. A national database review in Japan indicated that 85% of reported events occurred within 9 days of medication initiation.6 A separate review showed that the median duration of medication use prior to the onset of MMI-induced agranulocytosis was 36 days.7 The risk of agranulocytosis with MMI appears to be dose-dependent, with increased risk at increased doses of the medication. This is not true in other thionamides therapies such as propylthiouracil where risk appears to be independent of total dose. In the same review, the average patient MMI dose at the onset of agranulocytosis was 25 mg per day.6 Our patient demonstrates that agranulocytosis can still be seen at lower doses as she was only on 15 mg daily at the time of diagnosis.
The underlying mechanism of MMI-induced agranulocytosis remains unclear. Within the limited literature, proposed mechanisms suggest both an immune-mediated and non-immune-mediated pathogenesis. Immune-mediated mechanisms include humoral immunity via the formation of granulocyte-specific autoantibodies such as antineutrophil cytoplasmic antibodies. These react to neutrophils inducing apoptosis or with myeloid progenitor cells inducing compliment-mediated opsonisation of neutrophils.8
Direct neutrophil toxicity by MMI is the proposed aetiology of non-immune-mediated agranulocytosis. In this pathway, MMI is oxidised by cytochrome P450 and myeloperoxidase into reactive metabolites within the neutrophil, leading to inflammatory damage and apoptosis of the neutrophil.8 There is also evidence that individuals with particular HLA alleles, such as DRB1*08032 in Japanese patients, are predisposed to develop MMI-induced agranulocytosis.9 Formal HLA allele evaluation was not performed in this patient.
Current guidelines by the American Thyroid Association (ATA) recommend an initial WCC with differential prior to initiation of the drug, however, does not recommend routine WCC screening in patients initiated on MMI.10 Commonly, agranulocytosis presents as a sudden fever or pharyngitis in patients on MMI. The ATA does recommend patients on thionamide therapy obtain a WCC with differential at the first sign of sore throat, fever or other potential infection. MMI should be held until lab results are reviewed. If a patient develops agranulocytosis, then MMI should be discontinued immediately and all future thionamide therapy is contraindicated.10 Supportive care is required as there is a risk of mortality in these patients.
Though randomised-controlled trials are not available, utilisation of G-CSF is generally recommended in these patients. Evidence supports that G-CSF therapy can decrease the length of hospitalisation, duration of antibiotic treatment and expedite WCC normalisation, though there is no proven mortality benefit.11 Time of recovery after development of agranulocytosis varies but is typically within 1 month. While awaiting recovery, particular caution for the development of severe infection is necessary due to underlying severe immunosuppression. Broad-spectrum antibiotics are typically indicated for neutropenic fever, such as in our patient.
Cholestatic jaundice secondary to MMI is extremely rare on its own, noted in approximately 30 prior case reports.12 It is one of two types of hepatic injury that have been reported with MMI. There is typically a latent period between 2 days and 3 months until the development of jaundice, and the reaction is dose-dependent. Several mechanisms have been proposed as possible explanations for the physiology behind this phenomenon but none have been clearly proven. An allergic or immunologic aetiology is believed to be the most likely explanation.12 Recovery has been noted to occur quickly after withdrawal of MMI therapy. Steroids have been inconsistently shown to accelerate recovery. The definitive treatment for Graves’ disease after this complication is radioactive iodine (RAI) or thyroidectomy.12
As discussed, patients with Graves’ disease who cannot tolerate thionamide medications require urgent, definitive therapy with either RAI or thyroidectomy. Typically, in those undergoing thyroidectomy, thionamide therapy is used for 1–3 months prior to the procedure to ensure a euthyroid state and reduce the risk of severe complications such as thyroid storm.13 In patients with thyrotoxicosis where thionamide therapy is contraindicated, a variety of medications are used in combination to minimise side effect risk. Preoperative medical therapy with beta-blockers, SSKI and dexamethasone has been recommended as a multimodal approach to managing thyrotoxicosis.13
Beta-blocker therapy is effective at mitigating cardiac side effects of thyrotoxicosis. Propranolol is often used first line as it has a small added effect inhibiting the conversion of T4 –T3 peripherally. Atenolol and esmolol are also commonly used alternatives. SSKI therapy at supraphysiologic doses can inhibit the creation of thyroxine by the thyroid gland. Steroids, such as dexamethasone, also inhibit the peripheral conversion of T4–T3 while also assisting with vasomotor stability. Medical management is often required up to a week postoperatively as the half-life of circulating thyroxine typically lasts 7 days.14
Reports of concomitant agranulocytosis and hepatotoxicity in patients receiving thionamide therapy (including MMI, propylthiouracil and carbimazole) are infrequently documented in the literature. On review, only four separate cases of concomitant MMI-induced agranulocytosis and hepatotoxicity have been reported.2–5 Including our case, four of the five reported cases were seen in young females in their thirties. They each occurred within the first 3 months of initiating MMI therapy, with onset ranging from 6 days to 3 months. MMI doses among these five cases ranged from a total of 15–60 mg per day (table 1).
Comparison of reported concomitant agranulocytosis and hepatoxicity cases on MMI
| Case | Age | Sex | Methimazole dose | Time on medication | ANC on admission | Total bilirubin on admission | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| ANC, absolute neutrophil count; MMI, methimazole. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Our case | 30s | Female | 15 mg daily | 3 months | 0 | 7.3 mg/dL | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Abegunde et al2 | 31 years | Female | 30 mg daily | 2 months | 24 (0.02) | 3.1 mg/dL | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Wijaya et al5 | 34 years | Female | 60 mg daily | 1 month | 0.58 | 3.1 mg/dL | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Yang et al3 | 38 years | Female | 20 mg daily | 6 days | 0.03 | 26.4 mg/dL | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Yang et al4 | 51 years | Male | 20 mg daily | 1 month | 0 | 22.5 mg/dL | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Ethics statements
Patient consent for publication
Footnotes
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Contributors CA is the primary author. He contributed the majority of the discussion, learning objectives, background and formatting. PS is the secondary author. She contributed the majority of the case presentation and summary. JA provided work in the presentation and editing throughout the manuscript.
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Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
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Case reports provide a valuable learning resource for the scientific community and can indicate areas of interest for future research. They should not be used in isolation to guide treatment choices or public health policy.
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Competing interests None declared.
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Provenance and peer review Not commissioned; externally peer reviewed.
- © BMJ Publishing Group Limited 2022. No commercial re-use. See rights and permissions. Published by BMJ.
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