A 22-year-old woman comes to the emergency department due to fatigue and sore throat for the past few days. The throat discomfort has caused her to be unable to eat or drink without significant pain. Acetaminophen improves the pain slightly, but her oral intake has been poor. The patient recently started taking antithyroid medication for Graves disease. She has no other medical conditions and does not use tobacco, alcohol, or recreational drugs. Weight is 67 kg (148 lb), decreased from 68.5 kg (151 lb) a week ago. Temperature is 38.9 C (102 F), blood pressure is 102/68 mm Hg, and pulse is 130/min. Physical examination shows an erythematous pharynx with shallow mucosal ulcerations and a normal-sized thyroid. Mucous membranes appear dry. The abdomen is soft and nontender. No tremor is seen with outstretching of the hands. Which of the following is the most likely cause of this patient's current condition?
Medications associated with drug-induced neutropenia | |
Antithyroid |
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Anti-inflammatory |
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Psychotropic or |
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Cardiovascular |
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Antimicrobial |
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This patient has a sore throat, fever, and pharyngeal ulcers. Although this constellation of symptoms often occurs as a consequence of viral upper respiratory tract infection, the recent initiation of antithyroid medication for Graves disease should raise strong suspicion for drug-induced neutropenia.
Patients with Graves disease are often treated initially with thionamide medications such as methimazole or propylthiouracil (PTU) to achieve a euthyroid state prior to radioiodine therapy or surgery. However, these medications cause severe neutropenia (absolute neutrophil count <500/mm3) in approximately 1 in 200 individuals. This side effect of therapy is thought to occur due to the interaction of the thionamide with reactive oxidative products (eg, myeloperoxidase, hydrogen peroxide), leading to generation of drug metabolites (eg, propyl thioester, sulfonic acid) that covalently attach to the neutrophil surface. Antibodies then form against these new antigens (haptens), resulting in antibody-dependent cellular cytotoxicity.
Drug-induced neutropenia most often presents with oropharyngeal ulcers and fever (ie, mucus membrane infection). Laboratory evaluation usually shows isolated leukopenia (eg, no anemia or thrombocytopenia). Because patients with drug-induced neutropenia are at risk for severe infections, the offending drug should be immediately discontinued. This usually resolves the neutropenia within 1-3 weeks.
(Choice A) Patients with autoimmune thyroid disease (eg, Graves disease) are at risk for other autoimmune endocrinopathies, including adrenal insufficiency. However, acute adrenal insufficiency typically presents with refractory hypotension, vomiting, abdominal pain, and weakness. Pharyngitis would be atypical.
(Choice C) Excessive suppression of thyroid function by antithyroid drugs can lead to a hypothyroid state, which can present with fatigue. However, patients with hypothyroidism demonstrate weight gain, not weight loss; other symptoms (eg, cold intolerance, hair and skin changes) are also usually present.
(Choice D) Undertreatment of this patient's hyperthyroidism could result in a residual hyperthyroid state (ie, thyroid hormone–induced severe hypermetabolism), which can present with fever, tachycardia, and dehydration. However, hypertension and tremor would likely be present; pharyngeal infection is unexpected.
(Choice E) Several viral infections (eg, HIV) can cause virus-induced lymphocyte destruction. Although the loss of lymphocytes from viral infection can lead to pharyngeal infection, the presence of fever and pharyngitis shortly after initiation of antithyroid medication is more suggestive of drug-induced neutropenia.
Educational objective:
Drug-induced neutropenia is the major side effect of the first-line medications used to treat Graves disease. Initial manifestations usually include fever and oropharyngeal ulcers.