A 38-year-old woman presents with progressive weight gain, proximal muscle weakness, easy bruising, and amenorrhea for 8 months. Clinical examination reveals central obesity, purple striae, and hypertension (160/100 mmHg). You suspect Cushing syndrome. Which investigation is the best initial screening test?

Explanation

## Screening for Cushing Syndrome **Key Point:** 24-hour urinary free cortisol (UFC) is the gold standard initial screening test for Cushing syndrome due to its high sensitivity (95–100%) and specificity (98%), and it avoids the stress-induced cortisol elevation seen with morning serum cortisol. ### Why UFC is Preferred **High-Yield:** UFC integrates cortisol secretion over 24 hours, eliminating the confounding effects of: - Acute stress - Diurnal variation (cortisol peaks at 6–8 AM) - Episodic ACTH secretion **Clinical Pearl:** A normal 24-hour UFC essentially excludes Cushing syndrome with >95% confidence. Elevated UFC (>2× upper limit of normal) warrants confirmatory testing. ### Diagnostic Algorithm for Cushing Syndrome ```mermaid flowchart TD A[Clinical suspicion of Cushing syndrome]:::outcome --> B[24-hour UFC or late-night salivary cortisol]:::action B --> C{Abnormal?}:::decision C -->|No| D[Cushing syndrome excluded]:::outcome C -->|Yes| E[Perform LDDST or midnight serum cortisol]:::action E --> F{Confirms hypercortisolism?}:::decision F -->|No| G[Pseudo-Cushing state]:::outcome F -->|Yes| H[Measure ACTH level]:::action H --> I{ACTH level?}:::decision I -->|Suppressed <5 pg/mL| J[Primary adrenal Cushing]:::outcome I -->|Elevated >15 pg/mL| K[ACTH-dependent Cushing]:::outcome I -->|10-15 pg/mL| L[Repeat ACTH or CRH stimulation]:::action ``` ### Comparison of Screening Tests | Test | Sensitivity | Specificity | Advantages | Limitations | |------|-------------|-------------|-----------|-------------| | **24-hour UFC** | 95–100% | 98% | Gold standard, integrates diurnal variation | Requires 24-hr collection; false positives in obesity, depression, alcohol use | | **Late-night salivary cortisol** | 92–100% | 94–96% | Non-invasive, avoids stress effect | Not widely available in India; requires patient cooperation | | **Morning serum cortisol** | 80–90% | 70–80% | Simple, rapid | High false-positive rate due to stress; not recommended as sole screening | | **LDDST** | 95–98% | 80–90% | Confirmatory, not screening | Requires overnight hospitalization; not first-line | **Warning:** Morning serum cortisol alone is NOT adequate screening because stress (hospital visit, phlebotomy) can elevate cortisol in normal individuals, leading to false positives. ACTH is a second-line test used AFTER hypercortisolism is confirmed, to distinguish ACTH-dependent from ACTH-independent causes. [cite:Harrison 21e Ch 375]