A 52-year-old man with a 3-month history of hypertension, proximal myopathy, and weight gain undergoes investigation for suspected Cushing syndrome. His 24-hour urinary free cortisol is elevated at 250 μg/24h (normal <50), and plasma ACTH is 8 pg/mL (normal 10–50). High-dose dexamethasone suppression test (HDDST) shows no suppression of cortisol. Which of the following is NOT consistent with the diagnosis of adrenocorticotropic hormone (ACTH)-independent Cushing syndrome?

Explanation

## Diagnostic Approach to ACTH-Independent Cushing Syndrome ### Case Analysis The patient has: - Elevated 24-hour UFC (autonomous cortisol production) - Suppressed ACTH (8 pg/mL, well below normal 10–50) - No suppression on HDDST (primary adrenal disease, not pituitary) This pattern is diagnostic of ACTH-independent Cushing syndrome. ### Diagnostic Features of ACTH-Independent Cushing **Key Point:** ACTH-independent Cushing syndrome is characterized by autonomous adrenal cortisol secretion with suppressed ACTH and resistance to both low-dose and high-dose dexamethasone suppression. | Diagnostic Test | ACTH-Independent | ACTH-Dependent (Cushing Disease) | |-----------------|------------------|----------------------------------| | Low-dose dex (2 mg) | No suppression | No suppression | | High-dose dex (8 mg) | **No suppression** | **Suppression** (>50% fall) | | Plasma ACTH | Suppressed (<5 pg/mL) | Elevated (20–200 pg/mL) | | 24h UFC | Elevated | Elevated | | Metyrapone test | **No rise in 17-OHS** | **Rise in 17-OHS** | ### Why Metyrapone Response is NOT Consistent **High-Yield:** Metyrapone is a 11β-hydroxylase inhibitor that blocks the final step of cortisol synthesis. In ACTH-dependent disease, the blocked cortisol causes a compensatory rise in ACTH (via loss of negative feedback), which drives increased precursor (11-deoxycortisol and 17-hydroxycorticosteroids). In ACTH-independent disease, the adrenal tumor/hyperplasia does not respond to ACTH stimulation, so metyrapone produces little or no rise in 17-OHS. **Clinical Pearl:** A positive metyrapone test (rise in 17-OHS and ACTH) indicates an intact hypothalamic-pituitary-adrenal (HPA) axis and is seen in ACTH-dependent Cushing (Cushing disease), not ACTH-independent disease. **Mnemonic:** **ACTH-I = Dex-resistant + Metyrapone-silent** — the adrenal tumor ignores both suppression (dexamethasone) and stimulation (metyrapone/ACTH). ### Consistent Features in This Case 1. **No suppression on HDDST** — confirms primary adrenal pathology (not pituitary) 2. **Suppressed ACTH** — confirms autonomous cortisol production 3. **Unilateral adrenal mass** — typical imaging finding in adrenal adenoma (most common ACTH-independent cause) 4. **Elevated 24h UFC** — confirms cortisol excess ### Metyrapone Test Interpretation ```mermaid flowchart TD A[Metyrapone Test:<br/>Blocks 11β-hydroxylase]:::action --> B{HPA Axis Intact?}:::decision B -->|Yes: ACTH-Dependent| C[ACTH rises<br/>17-OHS rises]:::outcome B -->|No: ACTH-Independent| D[ACTH stays low<br/>17-OHS minimal rise]:::outcome C --> E[Cushing Disease<br/>or Ectopic ACTH]:::outcome D --> F[Adrenal Adenoma<br/>or Carcinoma]:::outcome ``` [cite:Harrison 21e Ch 375]