A 52-year-old man from Delhi presents with a 10-month history of progressive proximal muscle weakness, easy bruising, and recurrent infections. On examination, he has marked central obesity with supraclavicular fat pads, a dorsocervical fat pad ('buffalo hump'), and multiple purple striae on his abdomen and thighs. Blood pressure is 162/104 mmHg. Investigations reveal: 24-hour urinary free cortisol 420 µg/day (normal <50), morning plasma cortisol 38 µg/dL (normal 5–25), ACTH 68 pg/mL (normal 10–50). Low-dose dexamethasone suppression test (1 mg overnight) shows cortisol of 32 µg/dL. High-dose dexamethasone suppression test (8 mg overnight) shows cortisol of 8 µg/dL. What is the most likely diagnosis?

Explanation

## Clinical Diagnosis: ACTH-Secreting Pituitary Adenoma (Cushing Disease) ### Key Diagnostic Features **Key Point:** The **elevated ACTH (68 pg/mL)** combined with **suppression of cortisol on high-dose dexamethasone suppression test (HDDST)** is pathognomonic for **ACTH-dependent Cushing syndrome originating from the pituitary** — i.e., Cushing disease. ### Diagnostic Algorithm ```mermaid flowchart TD A[Clinical features of Cushing syndrome]:::outcome --> B[24-hr UFC elevated + Morning cortisol elevated]:::outcome B --> C{ACTH level?}:::decision C -->|Elevated| D[ACTH-Dependent Cushing]:::outcome C -->|Suppressed| E[ACTH-Independent Cushing]:::outcome D --> F{HDDST suppression?}:::decision F -->|Yes - Cortisol drops >50%| G[Pituitary ACTH adenoma - Cushing Disease]:::action F -->|No suppression| H[Ectopic ACTH syndrome]:::action ``` ### Why This Is Cushing Disease (Pituitary Adenoma) 1. **Elevated ACTH (68 pg/mL):** Indicates ACTH-dependent hypercortisolism. The pituitary is autonomously secreting ACTH. 2. **Suppression on HDDST (cortisol 8 µg/dL):** This is the **gold-standard discriminator**. High-dose dexamethasone suppresses the pituitary ACTH-secreting adenoma because it retains some sensitivity to glucocorticoid feedback (albeit at higher doses). Cortisol dropped from 32 to 8 µg/dL — a >75% reduction, well above the 50% threshold for suppression. 3. **No suppression on LDDST:** The adenoma is resistant to physiologic doses of dexamethasone but responds to pharmacologic doses — a hallmark of pituitary Cushing disease. **High-Yield:** **Cushing disease** (pituitary ACTH adenoma) accounts for ~70% of all Cushing syndrome cases. The HDDST suppression test is the critical test that separates pituitary from ectopic ACTH sources. ### Differential Diagnosis Table | Feature | Pituitary ACTH Adenoma | Ectopic ACTH | Adrenal Adenoma | | --- | --- | --- | --- | | **ACTH level** | **Elevated (20–100)** | Very elevated (>200) | Suppressed (<5) | | **24-hr UFC** | Elevated | Very elevated | Elevated | | **LDDST suppression** | No | No | No | | **HDDST suppression** | **Yes (>50% drop)** | No | No | | **Frequency** | ~70% of Cushing | ~15% of Cushing | ~15% of Cushing | **Mnemonic:** **HDDST = Pituitary; No HDDST = Ectopic** - **H**igh-**D**ose **D**examethasone **S**uppression **T**est suppresses pituitary adenomas (they retain some feedback sensitivity). - Ectopic ACTH-secreting tumors do NOT suppress even at high doses (they are autonomous and insensitive to dexamethasone). ### Clinical Correlates **Clinical Pearl:** Cushing disease typically presents insidiously over months to years with progressive central obesity, proximal weakness, hypertension, and metabolic complications. The severe hypercortisolism (UFC 420 µg/day) and clinical severity (muscle weakness, recurrent infections, hypertension) are consistent with a pituitary adenoma. ### Next Steps 1. **MRI pituitary:** To visualize the ACTH-secreting adenoma. ~50% of microadenomas are visible on standard MRI; smaller adenomas may require high-resolution sequences or inferior petrosal sinus sampling (IPSS). 2. **Inferior petrosal sinus sampling (IPSS):** If MRI is negative or equivocal. A central-to-peripheral ACTH ratio >2 (or >3 after CRH stimulation) confirms pituitary source. 3. **Treatment:** Transsphenoidal pituitary surgery is the first-line definitive treatment. **Warning:** Do not confuse HDDST suppression with cure — suppression on HDDST confirms the pituitary source but does not indicate remission. Remission requires normalization of cortisol after surgery or medical therapy. [cite:Harrison 21e Ch 375]