A 38-year-old woman presents with progressive proximal muscle weakness, easy bruising, central obesity, and hirsutism for 6 months. Clinical suspicion of Cushing syndrome is high. Which investigation is most appropriate to confirm the diagnosis?

Explanation

## Diagnostic Approach to Cushing Syndrome **Key Point:** The 24-hour urinary free cortisol (UFC) is the gold standard screening test for Cushing syndrome because it reflects integrated cortisol secretion over 24 hours and is not affected by circadian variation or stress-induced cortisol spikes. ### Why UFC is the Investigation of Choice **High-Yield:** UFC measurement is: - Non-invasive and repeatable - Highly sensitive (95%) and specific (98%) for Cushing syndrome - Unaffected by stress, sleep, or acute illness (unlike random serum cortisol) - Recommended as the first-line confirmatory test by all major endocrine societies ### Diagnostic Algorithm for Cushing Syndrome ```mermaid flowchart TD A[Clinical suspicion of Cushing]:::outcome --> B[24-hour UFC or late-night salivary cortisol]:::action B --> C{Elevated?}:::decision C -->|Yes| D[Low-dose dexamethasone suppression test]:::action C -->|No| E[Cushing ruled out]:::outcome D --> F{Cortisol suppressed?}:::decision F -->|No suppression| G[Confirmed Cushing syndrome]:::outcome G --> H[Determine etiology: ACTH level]:::action H --> I{ACTH level?}:::decision I -->|Suppressed| J[ACTH-independent: adrenal source]:::outcome I -->|Elevated/normal| K[ACTH-dependent: pituitary or ectopic]:::outcome ``` ### Role of Other Tests | Investigation | Timing | Purpose | |---|---|---| | **24-hour UFC** | **First-line screening** | **Confirm hypercortisolism** | | Low-dose DST (1 mg) | After UFC elevated | Confirm autonomous cortisol secretion | | Serum ACTH | After Cushing confirmed | Differentiate etiology (ACTH-dependent vs independent) | | High-dose DST (8 mg) | After ACTH elevated | Distinguish pituitary from ectopic ACTH | **Clinical Pearl:** A single normal 24-hour UFC has ~95% negative predictive value; two normal UCFs essentially exclude Cushing syndrome. **Tip:** Late-night salivary cortisol (>2.5 ng/mL) is an equally sensitive alternative screening test and is gaining popularity because it is easier to perform at home.