Confirm cortisol excess, then localise with ACTH and high dose suppression
Expansion
Step 1, confirm the excess, using any two of
- Overnight low dose dexamethasone suppression: 1 mg at 11 pm, cortisol at 9 am. Failure to suppress below 50 nmol/l is positive
- 24 hour urinary free cortisol, at least two collections
- Late night salivary cortisol, which detects loss of the diurnal rhythm
Step 2, measure ACTH
- Suppressed ACTH: ACTH independent, so an adrenal adenoma, carcinoma or nodular hyperplasia, or exogenous steroid. Image the adrenals
- Normal or raised ACTH: ACTH dependent, so pituitary (Cushing’s disease) or ectopic
Step 3, localise the ACTH dependent cases
| Pituitary (Cushing’s disease) | Ectopic ACTH | |
|---|---|---|
| High dose dexamethasone | Suppresses | Does not suppress |
| ACTH level | Moderately raised | Very high |
| Onset | Gradual | Rapid |
| Features | Classic Cushingoid habitus | Pigmentation, hypokalaemic alkalosis, weight loss, weakness |
| Common source | Corticotroph adenoma | Small cell lung cancer, carcinoid |
Inferior petrosal sinus sampling is the definitive test where imaging and biochemistry disagree, and it remains the gold standard for confirming a pituitary source.
Causes of a false positive suppression test: oestrogens and the combined oral contraceptive (which raise cortisol binding globulin), pregnancy, depression, alcohol, obesity, and enzyme inducing drugs that accelerate dexamethasone metabolism, such as phenytoin, carbamazepine and rifampicin.
Exogenous steroid is by far the commonest cause of Cushing’s syndrome overall, and the drug history answers the question before any test is sent.