Methimazole-Induced Pancytopenia with ANCA Positivity: Diagnostic and Management Challenges

Introduction

Agranulocytosis is a rare adverse effect of antithyroid medications such as propylthiouracil and methimazole, with a prevalence of 0.1–0.5%, while pancytopenia is even less common [1,2]. This condition is distinct from Graves’ disease-induced pancytopenia, which typically resolves with antithyroid medication [3]. Fewer than 20 cases of methimazole-induced aplastic anemia have been reported, with resolution occurring after discontinuation of the medication within a few weeks [4,5]. There have also been a handful of case reports of ANCA-associated vasculitis induced by antithyroid medications, including methimazole [6,7]. We present the case of a 36-year-old woman who developed pancytopenia 2 months after starting methimazole and was found to have positive ANCA serology.

Case Report

Our patient was a 36-year-old woman who was initially diagnosed with Graves’ disease 2 months prior to admission. At the time of diagnosis, her thyroid serologies showed free T4 at 3.76 ng/dL (reference range 0.7–1.5 ng/dL), free T3 at 15.1 pg/mL (reference range 1.7–3.7 pg/mL), and TSH receptor antibody at 31 IU/L (reference range 0.00–1.75 IUnits/L) (Table 1). She was subsequently started on methimazole 20 mg BID and atenolol 25 mg daily by her endocrinologist.

Two months later, she was admitted to an outside hospital with right axillary and right buttock abscesses (Figure 1), accompanied by symptoms of nausea, dizziness, and fevers. She was found to be significantly pancytopenic, with elevated liver function test results (Table 1). Blood cultures were positive for Serratia marcescens and Candida albicans. Methimazole was held, and she was started on vancomycin, meropenem, and micafungin for her neutropenic fever. At this point, her mental status worsened significantly, leading to intubation and transfer to our hospital for a higher level of care due to her pancytopenia.

Upon transfer, her laboratory results showed significant leukopenia, anemia, and thrombocytopenia, with an absolute neutrophil count (ANC) of 0.01×109/L. Repeat blood cultures continued to grow Candida albicans and Serratia marcescens. She developed bloody stools and worsening skin lesions. A skin biopsy revealed nonspecific superficial and deep dermal perivascular lymphocytic infiltrate. Endoscopic evaluations, including esophagogastroduodenoscopy (EGD) and sigmoidoscopy (Figures 2, 3), showed diffuse bleeding gastric and non-bleeding duodenal ulcerations, along with ulcers in the colon. Stomach ulcer pathology revealed yeast with small vascular necrosis and calcification. She was then found to have pneumoperitoneum on computed tomography angiogram (CTA), prompting an exploratory laparotomy (Figure 4). During surgery, a liver abscess was found and Gram stain and culture grew Candida albicans. She underwent surgical repair for a cecal perforation.

An ANCA panel, ANA, and ENA panel were checked by the primary team, revealing positive c-ANCA at 1: 640 and positive p-ANCA at 1: 640, with negative MPO/PR3 antibodies on ELISA. Rheumatology was consulted, and it was determined that the ANCAs were due to methimazole-induced immunogenicity rather than primary ANCA-associated vasculitis.

A bone marrow biopsy performed to evaluate the pancytopenia was inconclusive due to an inadequate marrow sample. Throughout hospitalization, the patient required multiple platelet and red blood cell transfusions for thrombocytopenia and anemia. Her marrow finally responded to Filgrastim colony-stimulating factor. All cell lines improved back to baseline. She was transitioned to IV fluconazole and later to oral fluconazole.

Our patient survived and, in outpatient follow-up, had her tracheostomy and PEG tube removed. She continues to require antifungal therapy with fluconazole for chronic hepatosplenic candidiasis and ongoing wound care for several slowly healing ulcers.

Discussion

Antithyroid medications, such as propylthiouracil and methimazole, are known to cause agranulocytosis, an uncommon yet significant adverse effect, with an incidence ranging from 0.1% to 0.5% [1,2,5]. While agranulocytosis is relatively rare, pancytopenia and aplastic anemia, which encompass anemia, thrombocytopenia, and leukopenia, are even less frequently observed [8,9]. These conditions are present in only about one-tenth of the patients who develop agranulocytosis, translating to an estimated morbidity rate of 0.05% [5].

The pathogenesis of pancytopenia induced by antithyroid medications remains poorly understood and is a subject of ongoing research. Several factors are believed to contribute to the development of this severe condition [5]. Genetic predispositions may play a crucial role, making certain individuals more susceptible to adverse reactions from these medications [5]. Additionally, immune-mediated mechanisms could be involved, in which the body’s immune system mistakenly targets and destroys hematopoietic cells in the bone marrow [5]. Direct bone marrow suppression caused by the drug’s toxicity is another important factor, leading to replacement of the bone marrow with fibrous tissue and subsequent loss of its hematopoietic capability [5]. This results in a marked decrease in blood cell production, including red blood cells, white blood cells, and platelets.

When our patient initially presented to the ED, she had severe pancytopenia. Aplastic anemia is characterized by pancytopenia and a bone marrow biopsy, which show decreased nucleated cells and fat replacement [4]. Our patient’s bone marrow biopsy was inconclusive due to the insufficient sample (Table 1), so an official diagnosis of aplastic anemia was not given. The clinical presentations of aplastic anemia and agranulocytosis can be quite similar, adding to the diagnostic complexity [5,6]. This overlap in clinical manifestations necessitates careful evaluation and differentiation to ensure accurate diagnosis and appropriate management.

Methimazole is known to frequently cause elevations in liver function tests (LFTs) in patients being treated for hyperthyroidism [10]. These elevations, although concerning, are generally expected to normalize with continued treatment and careful monitoring [10]. In the context of our patient, a 36-year-old woman with methimazole-induced pancytopenia, we observed significant elevations in liver enzyme levels (Table 1). This abnormality is likely multi-factorial. While methimazole itself can contribute to hepatic dysfunction, the patient’s prolonged use of antifungal medications throughout her hospital stay further complicated the clinical picture. Antifungal agents exert hepatotoxic effects, potentially exacerbating liver enzyme abnormalities. Also, severe infections with candidemia and Serratia bacteremia may have also played a role in hepatic stress and enzyme elevation. Understanding the interplay of these various factors is essential in managing the patient’s condition and highlights the need for a comprehensive approach in monitoring and treating liver function abnormalities in patients undergoing complex medical treatments.

Our patient’s positive serologies were difficult to interpret in the setting of infection. However, +C-ANCA/+P-ANCA without concordant MPO/PR3 is classic of drug-induced immunogenicity due to antithyroid drugs [6,7,11]. Our patient did not have kidney or pulmonary involvement, as seen in other cases of ANCA-associated vasculitis (AAV) caused by antithyroid medications [6,7,10]. During follow-up, she did not develop clinical manifestations of ANCA-associated vasculitis. There was no evidence of diffuse alveolar hemorrhage or glomerulonephritis, as usually seen in AAV. The sequence of events for our patient, with pancytopenia following 2 months of methimazole treatment with bacteremia/fungemia, points to drug-induced complications.

Conclusions

This case highlights the potential for severe hematologic complications, such as pancytopenia and ANCA positivity, associated with methimazole therapy. Our 36-year-old female patient presented with significant pancytopenia 2 months after initiating methimazole for Graves’ disease, complicated by severe candidemia and Serratia bacteremia.

Despite the rarity of such adverse effects, this case underscores the importance of vigilant monitoring and early detection of hematologic abnormalities in patients receiving antithyroid medications. The positive ANCA serology observed in this patient adds a layer of complexity, suggesting a possible autoimmune mechanism triggered by the drug. Prompt discontinuation of methimazole and appropriate treatment of the infections were crucial in the patient’s recovery.

This case serves as a reminder for healthcare providers to consider iatrogenic causes when encountering pancytopenia in patients on antithyroid medications and to ensure thorough counseling and follow-up to prevent morbidity and mortality. Further research is needed to elucidate the underlying mechanisms and to develop strategies for early identification and management of these rare but serious adverse effects. Counseling and managing these patients and avoiding further immunosuppression is key to reducing morbidity and mortality.