A 52-year-old man with a known history of hypertension presents to the emergency department with acute onset severe headache, confusion, and generalized seizures. His wife reports he has had progressive weight gain, easy bruising, and proximal weakness over the past 4 months. On examination: BP 185/110 mmHg, temperature 38.2°C, proximal myopathy (grade 3/5), and purple striae. Laboratory results: serum sodium 128 mEq/L, serum potassium 2.8 mEq/L, pH 7.52, HCO~3~^−^ 32 mEq/L, 24-hour UFC 680 µg/day, morning ACTH 185 pg/mL (normal 10–50), morning cortisol 38 µg/dL. CT chest shows a 3 cm left hilar mass. What is the most likely diagnosis?

Explanation

## Diagnosis: Ectopic ACTH Syndrome from Small-Cell Lung Cancer ### Clinical Presentation This patient presents with: - **Cushing syndrome features**: weight gain, easy bruising, proximal myopathy, hypertension - **Acute metabolic derangement**: severe hyponatremia (128 mEq/L), hypokalemia (2.8 mEq/L), metabolic alkalosis (pH 7.52, HCO~3~^−^ 32) - **Neurological emergency**: seizures, confusion, headache (from hyponatremia and hypokalemia) - **Lung mass on imaging**: 3 cm left hilar lesion (classic for small-cell lung cancer) ### Laboratory Interpretation: The ACTH-Dependent Pattern | Finding | Value | Interpretation | |---------|-------|----------------| | Morning ACTH | 185 pg/mL | **Markedly elevated** (normal 10–50) | | Morning cortisol | 38 µg/dL | Severely elevated | | 24-hr UFC | 680 µg/day | Markedly elevated (>10× normal) | | Serum Na^+^ | 128 mEq/L | **Severe hyponatremia** | | Serum K^+^ | 2.8 mEq/L | **Severe hypokalemia** | | pH / HCO~3~^−^ | 7.52 / 32 | **Metabolic alkalosis** | **Key Point:** The **markedly elevated ACTH** with severe cortisol excess and a **lung mass** is diagnostic of ectopic ACTH syndrome. The acute electrolyte derangement (hyponatremia, hypokalemia, alkalosis) is a hallmark of **ectopic ACTH**, not typical pituitary Cushing. ### Why Ectopic ACTH Causes Severe Electrolyte Abnormalities ```mermaid flowchart TD A[Ectopic ACTH from SCLC]:::outcome --> B[Massive cortisol production]:::action B --> C[Activation of mineralocorticoid receptor]:::action C --> D[Sodium reabsorption + potassium wasting]:::action D --> E[Hyponatremia + Hypokalemia]:::urgent B --> F[H+ secretion + HCO3- reabsorption]:::action F --> G[Metabolic alkalosis]:::urgent E --> H[Seizures, Confusion, Cardiac arrhythmias]:::urgent ``` **High-Yield:** Ectopic ACTH typically produces **extreme cortisol levels** (often >50 µg/dL) that overwhelm the mineralocorticoid receptor, causing: - Severe **hypokalemia** (often <3.0 mEq/L) - Severe **hyponatremia** (from volume expansion + SIADH-like effect) - **Metabolic alkalosis** (from H^+^ loss and HCO~3~^−^ retention) This triad is **rare in pituitary Cushing** (which produces moderate cortisol) and **absent in adrenocortical adenoma** (which has suppressed ACTH). ### Differential Diagnosis | Feature | Pituitary Cushing | Ectopic ACTH | Adrenocortical Adenoma | |---------|-------------------|--------------|------------------------| | ACTH | Elevated (50–200) | **Markedly elevated (>150)** | Suppressed (<10) | | Cortisol | Moderate–high | **Extreme (>40 µg/dL)** | High | | Hypokalemia | Mild–moderate | **Severe (<3.0)** | Mild | | Hyponatremia | Absent | **Present** | Absent | | Alkalosis | Mild | **Severe** | Absent | | Imaging | Pituitary MRI shows adenoma | **Lung/other malignancy** | Adrenal mass | | LDDST | Partial suppression | No suppression | No suppression | ### Clinical Pearl: Why Seizures Occur **Warning:** The seizures and confusion are due to **acute hyponatremia** (128 mEq/L) and **severe hypokalemia** (2.8 mEq/L), not the Cushing syndrome itself. These electrolyte abnormalities are a **medical emergency** requiring: 1. Careful sodium repletion (avoid overcorrection → central pontine myelinolysis) 2. Aggressive potassium repletion 3. Treatment of the underlying ectopic ACTH source (chemotherapy, surgery, or mitotane) ### Why Not the Other Options? **Mnemonic: ACES** — **A**cute adrenal insufficiency, **C**arcinoma, **E**ctopic ACTH, **S**IADH (in ectopic ACTH). 1. **Acute adrenal insufficiency from bilateral metastases**: Would present with **low cortisol** and **elevated ACTH**, not this extreme cortisol excess. Also, metastases to both adrenals are rare at presentation. 2. **Pituitary apoplexy**: Would present with **low cortisol** (acute loss of ACTH drive), not elevated. Also, no pituitary mass mentioned on imaging. 3. **Adrenocortical carcinoma**: Would have **suppressed ACTH** (primary adrenal disease), not elevated. Also, carcinoma typically presents with virilization and elevated DHEA-S, not a lung mass. ### Next Steps 1. **Immediate**: IV potassium and careful sodium repletion; seizure management 2. **Diagnostic**: LDDST (no suppression in ectopic ACTH) and high-dose DST (no suppression in ectopic ACTH) 3. **Definitive**: Chemotherapy for small-cell lung cancer; consider mitotane or ketoconazole for rapid cortisol control