A 38-year-old woman presents to the emergency department with a 3-month history of progressive fatigue, weight loss of 8 kg, and recurrent episodes of syncope. On examination, she is hypotensive (BP 88/54 mmHg), has generalized hyperpigmentation over the knuckles, elbows, and buccal mucosa, and appears chronically ill. Laboratory investigations reveal: sodium 128 mEq/L, potassium 5.8 mEq/L, fasting glucose 62 mg/dL, and elevated ACTH 850 pg/mL with cortisol 2.2 µg/dL (8 AM). A chest X-ray shows bilateral hilar lymphadenopathy. What is the most likely diagnosis?

Explanation

## Clinical Diagnosis: Primary Adrenal Insufficiency (Addison Disease) ### Key Clinical Features Present **High-Yield:** The combination of hyperpigmentation, hyponatremia, hyperkalemia, hypoglycemia, elevated ACTH with low cortisol, and bilateral hilar lymphadenopathy is pathognomonic for primary adrenal insufficiency with tuberculosis as the underlying etiology. **Key Point:** Hyperpigmentation in Addison disease occurs due to elevated ACTH stimulating melanocytes via the melanocyte-stimulating hormone (MSH) pathway. This is a distinguishing feature of primary (not secondary) adrenal insufficiency. ### Laboratory Interpretation | Parameter | Finding | Significance | |-----------|---------|---------------| | Sodium | 128 mEq/L (low) | Loss of aldosterone → sodium wasting | | Potassium | 5.8 mEq/L (high) | Loss of aldosterone → potassium retention | | Cortisol (8 AM) | 2.2 µg/dL (low) | Adrenal failure | | ACTH | 850 pg/mL (high) | Pituitary attempting to drive failed adrenals | | Glucose | 62 mg/dL (low) | Loss of cortisol's gluconeogenic effect | **Clinical Pearl:** The elevated ACTH with low cortisol is the hallmark of primary adrenal insufficiency. In secondary insufficiency, both ACTH and cortisol would be low. ### Why Tuberculosis is the Likely Cause 1. Bilateral hilar lymphadenopathy on chest X-ray is classic for TB 2. TB accounts for ~80% of Addison disease in endemic countries (including India) 3. TB causes caseating granulomas that destroy the adrenal cortex 4. Slow, progressive presentation over months fits TB pathology **Mnemonic: CAUSES OF ADDISON (Primary Adrenal Insufficiency)** — **A**utoimmune (60% in developed countries), **T**uberculosis (80% in endemic regions), **H**IV/AIDS, **M**etastases (lung, breast), **F**ungal (histoplasmosis, coccidioidomycosis), **A**myloidosis, **D**rugs (mitotane, ketoconazole) ### Diagnostic Confirmation Next steps would include: - Short Synacthen test (ACTH stimulation) → blunted cortisol response in primary insufficiency - Adrenal imaging (CT/MRI) → bilateral adrenal enlargement or calcification suggests TB - TB culture from sputum/gastric aspirate if suspected [cite:Harrison 21e Ch 375]