A 52-year-old man with a 10-year history of hypertension and type 2 diabetes presents with progressive fatigue, proximal muscle weakness, and recurrent infections over 4 months. On examination, he has central obesity, facial plethora, and multiple bruises on his arms and legs. Investigations reveal: morning serum cortisol 32 µg/dL (normal <10), 24-hour urinary free cortisol 520 µg/24 h (normal <50), ACTH 65 pg/mL (normal 10–50), and low-dose dexamethasone suppression test (1 mg overnight) shows cortisol of 18 µg/dL. High-dose dexamethasone suppression test (8 mg overnight) shows cortisol of 8 µg/dL. MRI pituitary shows a 6 mm hypodense lesion in the anterior pituitary. What is the most likely diagnosis?

Explanation

## Diagnosis: ACTH-Secreting Pituitary Microadenoma (Cushing Disease) ### Clinical Presentation Classic Cushing syndrome features: - Central obesity, proximal myopathy, easy bruising, facial plethora - Hypertension and hyperglycemia (cortisol antagonizes insulin) - Recurrent infections (immunosuppression from excess cortisol) - Gradual onset over months (typical of pituitary adenoma) ### Laboratory Interpretation & Dexamethasone Suppression Tests | Test | Result | Interpretation | |------|--------|----------------| | Morning cortisol | 32 µg/dL | Elevated | | 24-h UFC | 520 µg/24 h | Markedly elevated | | ACTH | 65 pg/mL | **Elevated** (pituitary-driven) | | LDDS (1 mg) | 18 µg/dL | **No suppression** | | HDDS (8 mg) | 8 µg/dL | **Suppression achieved** — KEY finding | | Pituitary MRI | 6 mm lesion | Microadenoma (<10 mm) | ### Diagnostic Algorithm: ACTH-Dependent Cushing ```mermaid flowchart TD A[Cushing Syndrome Confirmed]:::outcome --> B{ACTH Level?}:::decision B -->|Elevated/Normal| C[ACTH-Dependent]:::outcome C --> D{LDDS Suppression?}:::decision D -->|Yes| E[Pituitary Adenoma]:::action D -->|No| F{HDDS Suppression?}:::decision F -->|Yes| G[Cushing Disease]:::outcome F -->|No| H[Ectopic ACTH]:::action E --> I[Cushing Disease]:::outcome ``` ### Why This Patient Has Cushing Disease **Key Point:** The **suppression of cortisol with high-dose dexamethasone (8 mg) from 18 to 8 µg/dL** is the hallmark of pituitary adenoma. The tumor's ACTH secretion is still partially sensitive to very high glucocorticoid feedback. **High-Yield:** The classic dexamethasone suppression pattern: - **LDDS (1 mg): NO suppression** → Rules out normal pituitary - **HDDS (8 mg): YES suppression** → Confirms pituitary source (not ectopic) **Mnemonic: HDDS Rule** — High-Dose Dexamethasone Suppression: If cortisol drops >50% from baseline or to <5 µg/dL, the source is **pituitary adenoma** (Cushing disease). If no suppression, think **ectopic ACTH**. ### Imaging Correlation MRI pituitary shows a **6 mm hypodense lesion** — consistent with a **microadenoma** (<10 mm). Microadenomas are: - Often difficult to visualize on standard MRI (30% may be radiographically occult) - Confirmed by biochemical suppression pattern - Treated with transsphenoidal surgery ### Differential: Why Not Ectopic ACTH? **Clinical Pearl:** Ectopic ACTH syndrome typically presents with: - **Very high ACTH** (often >100 pg/mL; this patient has 65) - **Severe hypokalemia** and metabolic alkalosis (this patient not mentioned) - **NO suppression with HDDS** (this patient suppresses) - Rapid, aggressive course (this patient has 4-month history, gradual) The **suppression with HDDS is the key discriminator** — ectopic ACTH-producing tumors (lung carcinoid, medullary thyroid, pheochromocytoma) are autonomous and do NOT respond to dexamethasone at any dose. ### Management 1. **Transsphenoidal pituitary surgery** — first-line for Cushing disease 2. **Perioperative glucocorticoid and mineralocorticoid coverage** 3. **Post-operative cortisol monitoring** — remission if cortisol <2 µg/dL on POD 1 4. **Bilateral adrenalectomy** if surgery fails (rare) [cite:Harrison 21e Ch 375]