A 38-year-old woman presents with progressive weakness, hyperpigmentation, and hypotension. Serum sodium is 128 mEq/L and potassium is 5.8 mEq/L. Morning cortisol is 3 μg/dL (normal >10 μg/dL). Which investigation is most appropriate to confirm the diagnosis of primary adrenal insufficiency?

## Diagnostic Approach to Primary Adrenal Insufficiency **Key Point:** The **ACTH stimulation test (short Synacthen test)** is the gold-standard confirmatory investigation for primary adrenal insufficiency. It directly assesses adrenal cortical reserve by measuring cortisol response to exogenous ACTH. ### Why the ACTH Stimulation Test (Short Synacthen Test) is the Best Confirmatory Test The clinical picture — weakness, hyperpigmentation, hypotension, hyponatremia (128 mEq/L), hyperkalemia (5.8 mEq/L), and low morning cortisol (3 μg/dL) — is strongly suggestive of **primary adrenal insufficiency (Addison's disease)**. However, a single low morning cortisol is not sufficient to confirm the diagnosis; dynamic testing is required. **Short Synacthen Test (SST) Protocol:** - Administer 250 μg synthetic ACTH (tetracosactide) IV/IM - Measure serum cortisol at 0, 30, and 60 minutes - **Normal response:** Peak cortisol >18–20 μg/dL - **In primary AI:** Adrenal cortex is destroyed/non-functional → cortisol fails to rise (blunted response) This test **directly confirms** that the adrenal glands cannot produce cortisol, establishing primary adrenal insufficiency. | Test | Primary AI Result | Role | |------|------------------|------| | **ACTH stimulation test** | **No cortisol rise (blunted)** | **Confirmatory — Gold Standard** | | Plasma ACTH | Markedly elevated (>100 pg/mL) | Supportive; differentiates primary from secondary | | Low-dose DST | Not applicable | Used for Cushing syndrome | | CRH stimulation | Not applicable | Differentiates secondary vs tertiary AI | ### Why Other Options Are Incorrect **Plasma ACTH level (Option B):** - A markedly elevated ACTH (>100 pg/mL) with low cortisol is highly suggestive of primary AI and helps differentiate it from secondary AI - However, it is a **supportive/differentiating** test, NOT the confirmatory gold standard - Per Harrison's Principles of Internal Medicine (21st ed.), the SST is the definitive confirmatory test for adrenal insufficiency **Low-dose dexamethasone suppression test (Option C):** - Used exclusively for diagnosing **Cushing syndrome** (hypercortisolism) - Completely inappropriate in this context of suspected adrenal insufficiency **CRH stimulation test (Option D):** - Used to differentiate **secondary (pituitary)** from **tertiary (hypothalamic)** adrenal insufficiency - Not useful in primary AI; not a first-line confirmatory test **Clinical Pearl:** In acute adrenal crisis (suggested by hypotension, hyponatremia, hyperkalemia), **do not delay treatment** with IV hydrocortisone while awaiting test results. Draw blood for cortisol and ACTH before administering steroids if clinically feasible. Hydrocortisone does not interfere with the cortisol assay if the SST is performed within a short window. **High-Yield:** Per Harrison's and Endocrine Society guidelines, the **short Synacthen test is the gold standard** for confirming adrenal insufficiency. Plasma ACTH differentiates primary from secondary but does not confirm the diagnosis on its own.