ESSENTIALS OF DIAGNOSIS
Central obesity, muscle wasting, hirsutism, purple striae.
Osteoporosis, hypertension, poor wound healing.
Hyperglycemia, leukocytosis, lymphocytopenia, hypokalemia.
Elevated serum cortisol and urinary free cortisol. Lack of normal suppression by dexamethasone.
The term Cushing “syndrome” refers to the manifestations of excessive corticosteroids, commonly due to supraphysiologic doses of corticosteroid drugs and rarely due to spontaneous production of excessive cortisol by the adrenal cortex. Cases of spontaneous Cushing syndrome are rare, with an incidence of 2.6 new cases yearly per million population in the United States.
A. Cushing Disease with Elevated ACTH Levels
About 68% of cases are due to Cushing “disease,” caused by a benign ACTH-secreting pituitary adenoma that is typically smaller than 5 mm and usually located in the anterior pituitary (94%); however, about 6% of such adenomas are ectopic in locations such as the cavernous sinus, sphenoid sinus, ethmoid sinus, or posterior pituitary. Cushing disease is at least three times more frequent in women than men.
About 7% of cases are due to nonpituitary ACTH-secreting neuroendocrine neoplasms that produce ectopic ACTH. Ectopic locations include the lungs (55%), pancreas (9%), mediastinum-thymus (8%), adrenal (6%), gastrointestinal tract (5%), thyroid (4%), and other sites (13%). About 15% of cases are due to ACTH from a source that cannot be initially located.
B. Cushing Disease with Normal or Low ACTH
About 25% of cases are due to excessive autonomous secretion of cortisol by the adrenals. Cortisol secretion is independent of ACTH, and plasma ACTH levels are usually low or low-normal. Most such cases are due to a unilateral adrenal tumor. Benign adrenal adenomas are generally small and produce mostly cortisol; adrenocortical carcinomas are usually large when discovered and can produce excessive cortisol as well as androgens but may be nonsecretory. ACTH-independent macronodular adrenal hyperplasia can also produce hypercortisolism due to the adrenal cortex cells’ abnormal stimulation by hormones such as catecholamines, arginine vasopressin, serotonin, hCG/LH, or gastric inhibitory polypeptide; in the latter case, hypercortisolism may be intermittent and food-dependent, and plasma ACTH levels may not be completely suppressed. Bilateral primary pigmented adrenal macronodular adrenocortical disease is a rare cause of Cushing syndrome in children and young adults. Bilateral primary pigmented adrenal macronodular adrenocortical disease may be an isolated condition or part of the Carney complex, an autosomal dominant condition with additional features consisting of myxomas of the heart and skin with spotty skin pigmentation and facial freckles.
The manifestations of Cushing syndrome vary considerably. Early in the course of the disease, patients frequently complain of nonspecific symptoms, such as fatigue or reduced endurance but may have few, if any, of the physical stigmata described below. On average, patients with Cushing syndrome have seen four clinicians with a delay in diagnosis of 5 years ...