Preoperative Ketoconazole Therapy for Primary Bilateral Adrenocorticotropic Hormone-Independent Macronodular Adrenal Hyperplasia Syndrome

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To the Editor:
Bilateral adrenocorticotropic hormone (ACTH)-independent macronodular adrenal hyperplasia (BMAH) is a rare cause of Cushing syndrome (CS). It is characterized by nodular enlargement of both adrenal glands that produce excess cortisol and features of ACTH-independent CS.1,2 Clinical presentation varies from easy bruising, fatigability, hypertension, and cognitive decline to truncal obesity, muscle wasting, and pretibial edema.3 The hypercortisolism of CS is primarily treated surgically. When surgery is delayed, contraindicated, or unsuccessful, medical therapy is often required.4 Ketoconazole has been used worldwide for more than 30 years in CS to lower circulating cortisol levels. Its use has been recently questioned after warnings from European Medicine Agencies and US Food and Drug Administration (FDA) because of potential hepatotoxicity.4 Therefore, FDA has yet not approved it for CS management. We report a rare case of paranoid psychosis and acute pulmonary embolism secondary to primary BMAH syndrome that was successfully controlled on ketoconazole while awaiting surgery.
A 49-year-old man coming from home after right knee replacement 5 days ago, with a medical history of hypertension and diabetes presented with confusion. Computed tomography (CT) and magnetic resonance imaging of the head were negative for acute stroke. A CT angiogram chest showed bilateral upper lobe pulmonary embolism. He was started on heparin drip. During hospital stay, he had multiple episodes of psychosis requiring antipsychotic medications and constant observation. Electroencephalography was performed but did not show any epileptiform activity. Hypokalemia (2.7), metabolic alkalosis (bicarbonate level of 35), and uncontrolled Hypertension indicated possibility of hyperaldosteronism. Saline infusion test was performed but was negative. Symptoms of psychosis, depression, insomnia, and emotional labiality in the setting of venous thromboembolism were concerning for hypercortisolism. Hence, 1 mg dexamethasone suppression test was performed. It showed no suppression. 24 hours urine cortisol was elevated at 1116 μg. ACTH suppression test was negative on two separate occasions. CT showed large bilateral adrenal nodules measuring 3.8–4 cm. Diagnosis of BMAH was made. Spironolactone was started for hypokalemia because of hypoaldosteronism with very good control of hypokalemia and hypertension. After getting opinion from our endocrine colleagues, we started ketoconazole 200 mg twice daily as a bridge for eventual surgical intervention. Over the course of next 2 weeks, patient clinically improved with significant reduction in hallucination, psychosis, and emotional labiality.
Mifepristone is an FDA-approved drug for elevated blood sugar control in CS. However, it is not readily available at local pharmacies that cause significant delay in treatment. But ketoconazole is easily available, and is shown to be effective for controlling hypertension, hypokalemia, and diabetes.4 Under close liver enzyme monitoring, it can be used for CS control while awaiting surgery. No fatal hepatitis is observed. Hepatotoxicity is usually mild and resolves after drug withdrawal. Ketoconazole is effective for long-term control of hypercortisolism of either pituitary or adrenal origin. It decreases cortisol in patients with CS, and may prevent adrenal overgrowth.5 Hence, we recommended early initiation of ketoconazole therapy for BMAH syndrome for symptom relief and disease control while awaiting surgery.
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