Cushing Syndrome
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Direct answer
Glucocorticoid excess from any cause — commonest overall from exogenous steroid therapy, commonest endogenous from an ACTH-secreting pituitary adenoma (Cushing disease) — produces the central obesity, moon face, wide purple striae and proximal myopathy of Cushing syndrome. Screening uses any one of the 1 mg overnight dexamethasone suppression test (serum cortisol below 1.8 micrograms per dL excludes), 24-hour urinary free cortisol or late-night salivary cortisol, confirmed by a second test. A suppressed ACTH then points to the adrenal gland, a high ACTH to pituitary or ectopic disease, localised by MRI, inferior petrosal sinus sampling or adrenal CT in that order.
What you must remember
- Clinical cluster: central obesity with thin limbs, moon face, wide purple striae (over 1 cm), easy bruising, proximal myopathy — the single most discriminating sign — plus hypertension, glucose intolerance, osteoporotic fractures, hirsutism, menstrual irregularity, depression and recurrent infections.
- Hyperpigmentation with hypokalaemic metabolic alkalosis suggests very high ACTH, typically ectopic secretion from small-cell lung carcinoma.
- Screening tests: 1 mg overnight dexamethasone suppression (cutoff 1.8 micrograms per dL), 24-hour urinary free cortisol, late-night salivary cortisol; diagnose only after two abnormal results.
- Step two — plasma ACTH: low or suppressed ACTH means adrenal (adenoma, carcinoma, bilateral macronodular hyperplasia); high ACTH means ACTH-dependent disease.
- Step three — ACTH-dependent: high-dose dexamethasone suppression and pituitary MRI favour Cushing disease, but incidental microadenomas are common, so inferior petrosal sinus sampling with a central-to-peripheral ACTH gradient is the definitive pituitary-versus-ectopic discriminator; ectopic sources are sought with chest and abdominal imaging.
- Treatment: trans-sphenoidal adenomectomy for Cushing disease, adrenalectomy for adrenal adenoma, and cortisol synthesis blockers such as metyrapone or ketoconazole before or after failed surgery; bilateral adrenalectomy risks Nelson syndrome (pituitary corticotroph tumour growth with hyperpigmentation), demanding lifelong follow-up.
- Pseudo-Cushing states — alcohol misuse, depression, obesity and poorly controlled diabetes — elevate cortisol marginally and need careful repeat testing; cyclical Cushing genuinely exists.
Two vignettes, two steps of the algorithm
The first vignette: a 42-year-old woman with central obesity, moon face, wide purple striae, easy bruising and — the single most discriminating sign — proximal myopathy, needing help to rise from a chair. The best initial test is a screen: her cortisol after dexamethasone is 6.2 micrograms per dL (above the 1.8 cutoff that excludes), and a second abnormal test confirms hypercortisolism before anything is localised. The second vignette continues: her plasma ACTH is high, so the disease is ACTH-dependent — pituitary or ectopic. High-dose dexamethasone suppression and pituitary MRI follow; a microadenoma appears, but incidental microadenomas are common, so the definitive discriminator is inferior petrosal sinus sampling after corticotropin-releasing hormone — a clear central-to-peripheral ACTH gradient confirming Cushing disease; without it, chest and abdominal imaging hunt the ectopic source. Had her ACTH been suppressed, the answer would have been an adrenal CT for adenoma, carcinoma or bilateral macronodular hyperplasia — and a history of inhaled or topical steroids might have made the work-up unnecessary, since exogenous steroids in any route remain the commonest cause. Treatment follows the source: trans-sphenoidal adenomectomy for Cushing disease, adrenalectomy for the adrenal adenoma, metyrapone or ketoconazole to block synthesis around surgery, and — after bilateral adrenalectomy specifically — lifelong vigilance for Nelson syndrome, pituitary corticotroph tumour growth with rising ACTH and hyperpigmentation.
Where students slip
Syndrome versus disease heads the list: the syndrome is the clinical state from any cause, the disease strictly the ACTH-secreting pituitary adenoma, and options blur them deliberately. Screening is confused with localisation: dexamethasone tests and urinary cortisol establish hypercortisolism, whereas the ACTH level and imaging determine its source — and skipping the confirmation step produces false positives from pseudo-Cushing states, though cyclical Cushing genuinely exists. Two discriminators are worth overlearning: hyperpigmentation with hypokalaemic metabolic alkalosis means very high ACTH, typically ectopic;
Frequently asked questions
What is the difference between Cushing syndrome and Cushing disease?
Syndrome is glucocorticoid excess from any cause — exogenous steroids, adrenal tumours, ectopic ACTH — whereas disease strictly means the pituitary ACTH-secreting adenoma.
Which tests screen for hypercortisolism?
Any one of the 1 mg overnight dexamethasone suppression test, 24-hour urinary free cortisol or late-night salivary cortisol; a positive screen is confirmed with a second test.
How is an ACTH level interpreted?
Suppressed ACTH indicates a primary adrenal source; a normal or high ACTH indicates pituitary or ectopic ACTH-dependent disease.
What is inferior petrosal sinus sampling?
Sampling ACTH from the petrosal veins draining the pituitary after corticotropin-releasing hormone; a clear central-to-peripheral gradient confirms Cushing disease when MRI is equivocal.
What is Nelson syndrome?
Enlargement of a pituitary corticotroph adenoma after bilateral adrenalectomy removes negative feedback — rising ACTH, hyperpigmentation, mass effects.
Which features separate Cushing syndrome from simple obesity?
Proximal myopathy, wide purple striae, easy bruising and unprovoked osteoporotic fractures.