A 52-year-old man with hypertension, central obesity, proximal muscle weakness, and easy bruising is suspected of having Cushing syndrome. His 24-hour urinary free cortisol is elevated at 180 μg/day (normal <50 μg/day), and late-night salivary cortisol is elevated. Which investigation is most appropriate as the NEXT step to determine the etiology (ACTH-dependent vs. ACTH-independent)?

Explanation

## Diagnostic Algorithm for Cushing Syndrome Etiology **Key Point:** Once Cushing syndrome is confirmed (elevated 24-hour UFC and late-night salivary cortisol), the NEXT step is plasma ACTH measurement. ACTH level determines whether the syndrome is ACTH-dependent (pituitary or ectopic) or ACTH-independent (adrenal). ### Diagnostic Flowchart for Cushing Syndrome ```mermaid flowchart TD A[Cushing syndrome confirmed<br/>High UFC + High late-night salivary cortisol]:::outcome --> B[Measure plasma ACTH]:::action B --> C{ACTH level?}:::decision C -->|Low/Suppressed<br/>ACTH-independent| D[Adrenal pathology<br/>Adrenal CT/MRI]:::action C -->|Elevated<br/>ACTH-dependent| E[ACTH-dependent Cushing]:::outcome E --> F[High-dose dexamethasone<br/>suppression test]:::action F --> G{Cortisol suppression?}:::decision G -->|Yes| H[Pituitary Cushing<br/>Pituitary MRI]:::action G -->|No| I[Ectopic ACTH syndrome<br/>Imaging for source]:::action ``` ### Why Plasma ACTH is the First Discriminator **ACTH-Dependent Cushing (80% of cases):** - Pituitary adenoma (Cushing disease) — 70% - Ectopic ACTH secretion (small cell lung cancer, carcinoid) — 10% - ACTH level: **elevated (>20 pg/mL)** **ACTH-Independent Cushing (20% of cases):** - Adrenal adenoma or carcinoma - Nodular adrenal hyperplasia - ACTH level: **suppressed (<5 pg/mL)** **High-Yield:** ACTH level is the **single most important test** that determines the entire subsequent diagnostic pathway. ### Why Other Tests Are Not First **High-dose dexamethasone suppression test:** - Used AFTER ACTH level is known to be elevated - Differentiates pituitary Cushing (suppresses) from ectopic ACTH (does not suppress) - NOT the first test — must know ACTH status first - Premature use wastes time and resources **Inferior petrosal sinus sampling (IPSS):** - Gold standard for confirming pituitary source of ACTH - Invasive procedure; reserved for when high-dose dexamethasone test is inconclusive - NOT a first-line test - Only performed if ACTH is elevated AND high-dose dex test is equivocal **Adrenal CT scan:** - Appropriate ONLY if ACTH is suppressed (ACTH-independent) - Premature imaging in ACTH-dependent cases delays diagnosis - Not indicated until ACTH status is established **Clinical Pearl:** The mnemonic for Cushing syndrome workup is **"Confirm → Classify → Localize."** ACTH measurement is the **Classify** step — it determines whether you then localize the pituitary (high-dose dex, MRI) or the adrenal gland (CT/MRI).