Which test result best distinguishes ACTH-dependent Cushing syndrome from ACTH-independent forms?

• A. Plasma ACTH concentration
• B. Dexamethasone suppression test
• C. 24-hour cortisol
• D. DHEA-S level

Answer: (A)

Distinguishing ACTH-dependent from ACTH-independent Cushing syndrome hinges on measuring ACTH levels. When cortisol is elevated due to ACTH-dependent causes (pituitary ACTH overproduction or ectopic ACTH), ACTH is inappropriately normal or elevated despite high cortisol. In contrast, when cortisol excess comes from an adrenal source (an adrenal adenoma or hyperplasia producing cortisol), the negative feedback from the high cortisol lowers ACTH production, so plasma ACTH is suppressed. Thus a single ACTH measurement directly tells you whether the excess cortisol is driven by ACTH or by an adrenal source.

The other tests aren’t as definitive for this specific distinction. The dexamethasone suppression test helps differentiate cortisol-secreting states and can hint at pituitary vs ectopic sources, but it doesn’t reliably separate ACTH-dependent from ACTH-independent etiologies in all cases. Total or 24-hour cortisol confirms hypercortisolism but doesn’t identify the driving ACTH source. DHEA-S can reflect ACTH stimulation of adrenal androgens, but its levels vary with age, sex, and other factors and aren’t a reliable discriminator on their own.