In the latest Case Record of the Massachusetts General Hospital, a 52-year-old man was admitted to this hospital because of weakness, leg swelling, and hypokalemia. During the hospital course, multiple infections were diagnosed and imaging studies revealed enlarged adrenal glands. A diagnostic procedure was performed.
Once excess cortisol is suspected, laboratory testing is advisable for the detection of pathologic hypercortisolism from other conditions. Laboratory tests for Cushing’s syndrome are conducted in cases of excessive cortisol secretion (which leads to increased excretion in the urine, as measured by 24-hour urine free cortisol), blunted normal circadian rhythm of cortisol secretion (which leads to high nocturnal cortisol in the blood or saliva), and diminished sensitivity to negative feedback regulation of cortisol secretion by glucocorticoids (which leads to lack of suppression of early- morning serum cortisol levels after the oral administration of dexamethasone, known as the dexamethasone suppression test).
• What clinical features are consistent with a diagnosis of Cushing’s syndrome?
Classical features include weight gain, facial rounding, hyperglycemia, ecchymoses, wide striae, edema, muscle weakness, hypokalemia, thrombotic events, and multiple infections. Osteopenia and osteoporosis are often seen given prolonged glucocorticoid exposure.
• What laboratory finding is pathognomonic of Cushing’s syndrome?
A measured urine free cortisol level that is at least four times as high as the upper end of the normal range is pathognomonic of Cushing’s syndrome. Cortisol excess of a lesser magnitude may be present in other conditions, such as pregnancy, severe obesity, or poorly controlled diabetes mellitus, which need to be distinguished from Cushing’s syndrome.
Morning Report Questions
Q: What medical therapy may be offered to patients with symptoms associated with Cushing’s syndrome?
A: Inhibitors of steroidogenesis, including ketoconazole and metyrapone can be used to treat symptoms associated with Cushing’s syndrome. Ketoconazole inhibits the first step in cortisol synthesis as well as inhibiting the conversion of 11-deoxycortisol to cortisol. Metyrapone works by blocking the conversion of 11-deoxycortisol to cortisol.
Q: What is Nelson’s syndrome?
A: Nelson’s syndrome is estimated to affect 8 to 38% of patients with Cushing’s disease after bilateral adrenalectomy. The first reports of Nelson’s syndrome described the onset of cutaneous manifestations, such as the development of diffuse skin pigmentation, which may be more prominent in scars or in skin areas subject to friction and may affect the buccal mucosa. These manifestations occur as a result of rising plasma corticotropin levels, despite adequate glucocorticoid replacement, which stimulates melanocortin 1 receptors in the skin. The onset of Nelson’s syndrome occurs from a few months to 24 years after adrenalectomy. Patients may present with large, locally aggressive corticotroph tumors, leading to mass effect (headache, visual-field defects, ophthalmoplegia, or hypopituitarism). The precise pathogenesis of Nelson’s syndrome has not been elucidated, but presumably, after bilateral adrenalectomy, the absence of the negative feedback by glucocorticoids may lead to stimulation of an undetected small pituitary tumor and uncontrolled corticotropin secretion.