A 52-year-old man with a 2-year history of progressive hypertension (now 170/105 mmHg), central weight gain, and proximal leg weakness presents for evaluation. He has also developed new-onset diabetes mellitus and recurrent infections. Laboratory results show: morning serum cortisol 35 µg/dL (normal 5–25), 24-hour urinary free cortisol 280 µg/day (normal <50), ACTH 42 pg/mL (normal 10–50), and plasma potassium 3.2 mEq/L (normal 3.5–5.0). A low-dose dexamethasone suppression test (1 mg overnight) shows cortisol of 18 µg/dL. A high-dose dexamethasone suppression test (8 mg) shows cortisol of 8 µg/dL (>50% suppression from baseline). What is the most likely diagnosis?

Explanation

## Clinical Diagnosis: Cushing Disease (ACTH-Secreting Pituitary Adenoma) ### Diagnostic Algorithm for Cushing Syndrome ```mermaid flowchart TD A[Confirmed Hypercortisolism<br/>High UFC, High Cortisol]:::outcome --> B{ACTH Level?}:::decision B -->|Low/Suppressed| C[ACTH-Independent<br/>Primary Adrenal Disease]:::outcome B -->|Normal/Elevated| D{LDDST Result?}:::decision D -->|Suppression >50%| E[ACTH-Dependent<br/>Cushing Disease]:::outcome D -->|No Suppression| F{HDST Result?}:::decision F -->|Suppression >50%| G[Cushing Disease<br/>Confirm with Imaging]:::action F -->|No Suppression| H[Ectopic ACTH Syndrome]:::outcome ``` ### Key Diagnostic Features **Key Point:** The combination of elevated ACTH (42 pg/mL, at the upper limit of normal but inappropriately high given the hypercortisolism) with >50% suppression of cortisol on high-dose dexamethasone (HDST) is diagnostic of Cushing disease. ### Interpretation of Dexamethasone Suppression Tests | Test | Result | Interpretation | |------|--------|----------------| | LDDST (1 mg) | Cortisol 18 µg/dL (no suppression) | Rules out pseudo-Cushing; confirms true Cushing | | HDST (8 mg) | Cortisol 8 µg/dL (>50% suppression) | **Diagnostic of pituitary-dependent disease** | | ACTH level | 42 pg/mL (inappropriately normal) | Confirms ACTH-dependent disease | **High-Yield:** In Cushing disease, the pituitary adenoma produces ACTH but retains some sensitivity to feedback inhibition. High-dose dexamethasone (8 mg) suppresses the adenoma's ACTH secretion, causing >50% reduction in cortisol. This distinguishes pituitary disease from ectopic ACTH (which is autonomous and does not suppress). ### Pathophysiology of Cushing Disease 1. ACTH-secreting pituitary microadenoma (usually <10 mm) produces excess ACTH 2. ACTH stimulates adrenal cortex → excess cortisol production 3. Negative feedback is partially intact → ACTH is suppressed relative to cortisol level but remains elevated in absolute terms 4. High-dose dexamethasone can suppress the adenoma → >50% cortisol reduction 5. Clinical consequences: hypertension, hypokalemia (from mineralocorticoid excess), hyperglycemia, immunosuppression, myopathy ### Clinical Pearl: Hypokalemia in Cushing Syndrome **Clinical Pearl:** The serum potassium of 3.2 mEq/L reflects mineralocorticoid excess from high cortisol levels. Cortisol at high concentrations can activate mineralocorticoid receptors, causing sodium retention and potassium wasting. This is particularly pronounced in ectopic ACTH syndrome but also occurs in Cushing disease. ### Next Steps in Management 1. **Imaging:** MRI of the pituitary to localize the adenoma (sensitivity ~70% for microadenomas) 2. **Inferior petrosal sinus sampling (IPSS):** If MRI is negative or equivocal; demonstrates central (pituitary) source of ACTH 3. **Treatment:** Transsphenoidal adenomectomy is the first-line definitive treatment ### Mnemonic: HDST Interpretation **Mnemonic:** **SUPPRESS** — Suppression in HDST = pituitary disease (Cushing Disease); No Suppression = ectopic ACTH syndrome