Clinical Pearls & Morning Reports
Cushing’s syndrome due to the exogenous administration of glucocorticoids is much more common than endogenous Cushing’s syndrome, which has an estimated frequency of fewer than 5 cases per 1 million patient-years. Read the latest NEJM Case Records of the Massachusetts General Hospital here.
Q: What are some of the causes of corticotropin-independent Cushing’s syndrome?
A: The causes of endogenous Cushing’s syndrome are defined according to corticotropin level. Corticotropin-independent causes account for approximately 20% of cases of endogenous Cushing’s syndrome. Any disorder in the adrenal gland that causes excess cortisol production will lead to suppression of corticotropin in the pituitary gland. Adrenal adenoma and bilateral micronodular adrenal hyperplasias cause corticotropin-independent Cushing’s syndrome. Adrenocortical carcinoma is another important cause of corticotropin-independent Cushing’s syndrome.
Q: What are some of the causes and features of corticotropin-dependent Cushing’s syndrome?
A: In corticotropin-dependent Cushing’s syndrome, unregulated corticotropin production drives excess secretion of cortisol and androgens from the adrenal gland. Pituitary corticotroph adenomas that cause excess corticotropin production (Cushing’s disease) account for approximately 70% of cases of endogenous Cushing’s syndrome, and nonpituitary tumors that cause ectopic secretion of corticotropin account for approximately 10% of cases. In rare cases, tumors that cause ectopic secretion of corticotropin-releasing hormone (CRH) can drive excess corticotropin production in the pituitary gland. When a pituitary adenoma causes Cushing’s disease, the tumor tends to be responsive to some of the regulatory controls that can suppress corticotropin production. Nonpituitary tumors with ectopic corticotropin secretion generally lack this mechanism for regulatory control, and therefore, they are typically associated with higher levels of corticotropin, serum cortisol, and 24-hour urinary free cortisol and with more severe metabolic alkalosis, muscle weakness, and thromboembolic events.
A: Hypokalemia and weight loss are particularly suggestive of a nonpituitary tumor with ectopic corticotropin secretion. Hypokalemia is present in most patients with Cushing’s syndrome due to a nonpituitary tumor with ectopic corticotropin secretion, but it is present in only 10% of patients with Cushing’s disease (pituitary adenoma). Weight loss is common in patients with Cushing’s syndrome due to a nonpituitary tumor with ectopic corticotropin secretion, whereas weight gain and obesity is present in 90% of patients with Cushing’s disease.
A: Ectopic corticotropin secretion is most commonly caused by lung tumors, namely small-cell lung cancer and bronchial carcinoid. Other common sources are thymic tumors and pancreatic neuroendocrine tumors. Somewhat less common sources are medullary thyroid cancer and pheochromocytoma, which can occasionally result in the production of CRH. Many other occult tumors, ranging from parotid tumors to lymphosarcoma, can cause ectopic corticotropin secretion and lead to Cushing’s syndrome.