A 38-year-old woman presents with progressive weakness, weight loss, and hyperpigmentation. Clinical examination reveals postural hypotension and generalized hyperpigmentation. Serum sodium is 128 mEq/L and potassium is 5.8 mEq/L. Which investigation is most appropriate to confirm the diagnosis of primary adrenal insufficiency?

## Diagnostic Approach to Primary Adrenal Insufficiency **Key Point:** Morning serum cortisol and ACTH levels are the first-line investigations for suspected adrenal insufficiency. In primary adrenal insufficiency (Addison's disease), cortisol is LOW while ACTH is ELEVATED (due to loss of negative feedback). ### Clinical Features in This Case The patient presents with the classic triad of Addison's disease: - Weakness and weight loss - Hyperpigmentation (due to elevated ACTH stimulating melanocytes) - Hyponatremia and hyperkalemia (due to aldosterone deficiency) ### Why Morning Cortisol + ACTH? 1. **Simple and direct:** Measures the fundamental defect—inability of adrenal glands to produce cortisol 2. **Diagnostic pattern:** Low cortisol (<5 µg/dL) + HIGH ACTH (>100 pg/mL) = Primary adrenal insufficiency 3. **No stimulation needed:** Unlike secondary insufficiency, primary disease shows this pattern at baseline 4. **Morning sampling:** Cortisol follows diurnal rhythm; morning values are most reliable ### Interpretation Table | Test | Primary AI | Secondary AI | Normal | | --- | --- | --- | --- | | Morning cortisol | Low (<5 µg/dL) | Low | Normal (10–20 µg/dL) | | ACTH | Elevated (>100 pg/mL) | Low/normal | Normal (10–50 pg/mL) | | Response to ACTH stimulation | No response | May respond | Responds | **Clinical Pearl:** Hyperpigmentation is pathognomonic for primary AI because elevated ACTH (which shares sequence homology with melanocyte-stimulating hormone) directly stimulates melanin production. This feature is absent in secondary AI. **High-Yield:** Once low cortisol + high ACTH is confirmed, the next step is ACTH stimulation test (Synacthen test) to differentiate primary from secondary insufficiency, but the DIAGNOSTIC test for primary disease is the basal cortisol-ACTH pair. [cite:Harrison 21e Ch 375]