To differentiate ACTH-dependent from ACTH-independent Cushing syndrome, which measurement is most informative?

• A. 24-hour urinary free cortisol
• B. Plasma ACTH concentration
• C. Serum cortisol level
• D. Dexamethasone suppression test

Answer: (B)

In Cushing syndrome, the crucial question is whether the excess cortisol is driven by ACTH or produced independently by the adrenals. Measuring plasma ACTH directly answers that. If ACTH is detectable (normal or elevated) despite high cortisol, the syndrome is ACTH-dependent, meaning the pituitary or an ectopic source is stimulating cortisol production. If ACTH is suppressed or very low, cortisol is coming from an adrenal source with negative feedback shutting down ACTH.

The other tests don’t distinguish the source as clearly. A 24-hour urine free cortisol confirms that cortisol production is increased but doesn’t reveal what is driving it. Serum cortisol level alone shows elevation but not the mechanism. The dexamethasone suppression test helps differentiate pituitary from ectopic ACTH sources once ACTH is known, but it doesn’t directly identify ACTH dependence versus independence as efficiently as measuring ACTH itself.