A 48-year-old man from Mumbai presents with progressive muscle weakness, polyuria, and polydipsia for 6 months. On examination, he has central obesity, purple striae on the abdomen, and proximal muscle weakness (hip and shoulder girdle). Blood pressure is 162/98 mmHg. Laboratory findings: fasting glucose 185 mg/dL, serum potassium 3.1 mEq/L, 8 AM cortisol 28 µg/dL (normal 5–25 µg/dL), and ACTH 68 pg/mL (normal 10–50 pg/mL). A low-dose dexamethasone suppression test (1 mg overnight) shows cortisol 24 µg/dL (normal <1.8 µg/dL). What is the most likely diagnosis?

Explanation

## Diagnostic Approach to Cushing Syndrome **Key Point:** This patient has Cushing syndrome (high cortisol with clinical features). The elevated ACTH (68 pg/mL) indicates ACTH-dependent Cushing syndrome. The CRITICAL finding is that the low-dose dexamethasone suppression test (LDST) FAILS to suppress cortisol, but the clinical context and modest ACTH elevation point to a pituitary source. ### Step-by-Step Diagnosis ```mermaid flowchart TD A[High cortisol + Clinical features]:::outcome --> B{ACTH level?}:::decision B -->|High ACTH| C[ACTH-dependent Cushing]:::action B -->|Low/undetectable ACTH| D[ACTH-independent Cushing]:::action C --> E{Low-dose dexamethasone<br/>suppression test}:::decision E -->|Suppresses cortisol| F[Pituitary Cushing<br/>Corticotroph adenoma]:::outcome E -->|Does NOT suppress| G{High-dose dexamethasone<br/>suppression test}:::decision G -->|Suppresses cortisol| H[Pituitary Cushing]:::outcome G -->|Does NOT suppress| I[Ectopic ACTH or<br/>Adrenal carcinoma]:::urgent D --> J[Adrenal adenoma or<br/>carcinoma]:::action ``` **High-Yield:** In pituitary Cushing syndrome, the corticotroph adenoma retains some sensitivity to dexamethasone feedback. Although the low-dose test fails (because the tumor is relatively autonomous), a HIGH-DOSE dexamethasone suppression test (8 mg) WILL suppress cortisol by >50% in most pituitary cases. This is the key differentiator. ### Why Pituitary Cushing? | Feature | Pituitary Cushing | Ectopic ACTH | Adrenal Carcinoma | |---------|-------------------|--------------|-------------------| | ACTH level | Mildly elevated (usually 20–100) | Very high (>200) | LOW/undetectable | | Cortisol | Elevated | Very high (often >50) | Elevated | | Low-dose DST | No suppression | No suppression | N/A (ACTH low) | | High-dose DST | **Suppresses >50%** | No suppression | N/A | | Clinical severity | Moderate | Severe, acute | Variable | | Imaging | Pituitary MRI shows adenoma | Chest/abdomen CT for primary tumor | Adrenal CT shows mass | **Clinical Pearl:** The ACTH level of 68 pg/mL is in the "mildly elevated" range typical of pituitary Cushing. Ectopic ACTH (from small cell lung cancer) usually produces ACTH >200 pg/mL and cortisol >50 µg/dL, with severe hypokalemia and metabolic alkalosis. This patient's ACTH is only moderately elevated. ### Clinical Features Present - **Central obesity + purple striae** → cortisol excess - **Proximal muscle weakness** → hypokalemia (K 3.1) and cortisol-induced myopathy - **Hypertension** → cortisol's mineralocorticoid effect - **Hyperglycemia** → cortisol antagonizes insulin - **Polyuria/polydipsia** → hyperglycemia-induced osmotic diuresis **Mnemonic:** **CUSHINGS** = **C**entral obesity, **U**nusual fat deposition, **S**triae, **H**ypertension, **I**mmunosuppression, **N**euromuscular weakness, **G**lucose intolerance, **S**kin changes. ### Confirmatory Test Needed To definitively diagnose pituitary Cushing, perform a **high-dose dexamethasone suppression test (8 mg overnight)**. If cortisol suppresses to <50% of baseline, pituitary Cushing is confirmed. Then obtain **pituitary MRI** to visualize the corticotroph adenoma. [cite:Harrison 21e Ch 397; Robbins 10e Ch 24]