A 38-year-old woman presents with progressive central obesity, proximal muscle weakness, amenorrhea, and easy bruising. On examination, she has facial plethora, hirsutism, and purple striae. Initial screening with 24-hour urinary free cortisol is elevated at 250 µg/day (normal <50). What is the most appropriate next investigation to confirm the diagnosis of Cushing syndrome?

## Diagnostic Algorithm for Cushing Syndrome **Key Point:** The low-dose dexamethasone suppression test (LDDST) is the gold standard confirmatory test for Cushing syndrome after elevated 24-hour urinary free cortisol screening. ### Why LDDST is the Answer The diagnostic pathway for suspected Cushing syndrome follows this sequence: 1. **Screening tests** (elevated in Cushing syndrome): - 24-hour urinary free cortisol (already abnormal here) - Midnight serum cortisol or late-night salivary cortisol 2. **Confirmation test** (next step): - **Low-dose dexamethasone suppression test (1 mg overnight)** — this is the confirmatory test - Normal individuals suppress cortisol to <1.8 µg/dL after 1 mg dexamethasone - Cushing syndrome patients fail to suppress (cortisol remains >5 µg/dL) 3. **Differentiation tests** (after confirmation): - Plasma ACTH level (to differentiate ACTH-dependent from ACTH-independent) - High-dose dexamethasone suppression test (8 mg) — used to differentiate pituitary from ectopic ACTH **High-Yield:** The sequence is **Screen → Confirm → Differentiate**. You do not jump to differentiation tests before confirmation. ```mermaid flowchart TD A[Clinical suspicion of Cushing]:::outcome --> B[24-hour UFC or midnight cortisol]:::action B --> C{Elevated?}:::decision C -->|No| D[Cushing excluded]:::outcome C -->|Yes| E[Low-dose DST 1 mg]:::action E --> F{Cortisol suppresses?}:::decision F -->|Yes| G[Cushing excluded]:::outcome F -->|No| H[Cushing confirmed]:::outcome H --> I[Measure plasma ACTH]:::action I --> J{ACTH level?}:::decision J -->|Low/undetectable| K[ACTH-independent Cushing]:::outcome J -->|Elevated| L[ACTH-dependent Cushing]:::outcome L --> M[High-dose DST 8 mg]:::action M --> N{Suppression?}:::decision N -->|Yes| O[Pituitary Cushing]:::outcome N -->|No| P[Ectopic ACTH]:::outcome ``` **Clinical Pearl:** In this patient, the elevated 24-hour UFC already suggests Cushing syndrome; the LDDST is needed to confirm it before proceeding to ACTH measurement for differentiation. ### Timing and Interpretation of LDDST | Parameter | Normal | Cushing Syndrome | |-----------|--------|------------------| | **Baseline cortisol (8 AM)** | 5–25 µg/dL | Often >25 µg/dL | | **Post-1 mg dexamethasone cortisol** | <1.8 µg/dL | >5 µg/dL (fails to suppress) | | **Sensitivity** | — | 95–98% | | **Specificity** | — | 80–90% | **Warning:** False positives in LDDST can occur in depression, anxiety, obesity, and with medications (phenytoin, rifampicin) that induce dexamethasone metabolism. However, in a patient with classic clinical features and elevated UFC, LDDST is still the confirmatory test of choice.