ACTH dependent or independent, with exogenous steroids the commonest of all
Mnemonic
Divide by ACTH:
- ACTH dependent, so ACTH normal or raised: pituitary adenoma (Cushing’s disease, about 70 per cent of endogenous cases), ectopic ACTH (small cell lung cancer, carcinoid)
- ACTH independent, so ACTH suppressed: adrenal adenoma, adrenal carcinoma, nodular hyperplasia, and exogenous steroids
“Cushing’s disease is the pituitary; Cushing’s syndrome is everything.” That distinction is the one most often muddled.
Exogenous corticosteroid is by far the commonest cause overall, so the drug history answers the question before any test.
Features pointing to ectopic ACTH are rapid onset, pigmentation, hypokalaemic alkalosis, weight loss and profound weakness, rather than the classic cushingoid habitus, because there is no time for the phenotype to develop.
The features most specific for the syndrome are proximal myopathy, easy bruising, purple striae over 1 cm and facial plethora, rather than obesity or hypertension, which are common in the general population.
Expansion
Exogenous (by far the commonest): glucocorticoid therapy. ACTH is suppressed and the adrenals atrophy.
ACTH dependent (ACTH high or inappropriately normal)
- Cushing disease: pituitary adenoma, about 70 per cent of endogenous cases
- Ectopic ACTH: small cell lung carcinoma, carcinoid. Rapid onset, marked hypokalaemic alkalosis and pigmentation, with fewer classical body habitus changes
ACTH independent (ACTH suppressed)
- Adrenal adenoma or carcinoma
- Bilateral adrenal hyperplasia
Investigation proceeds in two stages. First confirm excess with an overnight or low-dose dexamethasone suppression test, late-night salivary cortisol or 24-hour urinary free cortisol. Then localise with ACTH: suppressed points to an adrenal source, and if raised, a high-dose dexamethasone test plus inferior petrosal sinus sampling separates pituitary from ectopic, since pituitary adenomas retain partial feedback and suppress while ectopic sources do not.
Pseudo-Cushing states (alcohol, depression, obesity) are the main diagnostic trap.