Cushing Syndrome (Hypercortisolism)

Key Features

Essentials of Diagnosis

• Central obesity, muscle wasting, thin skin, psychological changes, hirsutism, purple striae

• Osteoporosis, hypertension, poor wound healing

• Hyperglycemia, leukocytosis, lymphocytopenia, hypokalemia, glycosuria

• Elevated serum cortisol and urinary free cortisol. Lack of normal suppression by dexamethasone

General Considerations

• Cushing "syndrome" refers to manifestations of excessive corticosteroids

  • Commonly due to supraphysiologic doses of corticosteroid drugs

  • Rarely due to excessive spontaneous corticosteroid production

  • ~68% of such cases are due to ACTH hypersecretion by a pituitary adenoma (so-called Cushing "disease"), which is usually small and benign

  • ~25% are due to excessive autonomous secretion of cortisol

  • Cortisol secretion is independent of ACTH, and plasma ACTH levels are usually low or low-normal

  • ~7% are due to nonpituitary ACTH-secreting neuroendocrine neoplasms that produce ectopic ACTH

  • ~15% are due to ACTH from a source that cannot be initially located

  • May result from excessive ingestion of gamma-hydroxybutyric acid; resolves when drug is stopped

• Impaired glucose tolerance from insulin resistance

Demographics

• Spontaneous Cushing syndrome is rare: 2.6 new cases yearly per million population in the United States

• ACTH-secreting pituitary adenoma (Cushing "disease") > 3 times more common in women than men

Clinical Findings

Symptoms and Signs

• Fatigue and reduced endurance

• Central obesity with plethoric "moon face," "buffalo hump," supraclavicular fat pads, protuberant abdomen, and thin extremities

• Muscle atrophy causes weakness, with difficulty standing up from a seated position or climbing stairs

• Oligomenorrhea or amenorrhea in women (or erectile dysfunction in men)

• Backache, headache

• Hypertension

• Osteoporosis or avascular bone necrosis

• Skin

  • Acne

  • Superficial skin infections

  • Purple striae (especially around the thighs, breasts, and abdomen)

  • Easy bruising, impaired wound healing

• Thirst and polyuria (with or without glycosuria); renal calculi

• Glaucoma

• Unusual bacterial or fungal infections occur more commonly

• Mental symptoms range from diminished concentration to increased mood lability to psychosis

• Increased susceptibility to opportunistic infections

Differential Diagnosis

• Chronic alcoholism (alcoholic pseudo-Cushing syndrome)

• Diabetes mellitus

• Depression (may have hypercortisolism)

• Osteoporosis due to other cause

• Obesity due to other cause

• Primary hyperaldosteronism

• Anorexia nervosa (high urine free cortisol)

• Striae distensae ("stress marks") seen in adolescence and in pregnancy

• Lipodystrophy from antiretroviral agents

Diagnosis

Laboratory Tests

• Hyperglycemia

• Leukocytosis; relative granulocytosis and lymphopenia

• Hypokalemia (not hypernatremia), particularly with ectopic ACTH secretion

• Easiest screening test involves dexamethasone suppression test

  • 1 mg is given orally at 11 PM and serum is collected for cortisol determination at 8 AM the next morning

  • Cortisol level < 1.8 mcg/dL (50 nmol/L, high-performance liquid chromatography [HPLC] assay) excludes Cushing syndrome with some certainty

• If hypercortisolism is not excluded, measure 24-hour urine for free cortisol and creatinine

  • High 24-hour urine free cortisol (or free ...