A 38-year-old woman from rural Maharashtra presents with a 6-month history of progressive fatigue, weight loss (8 kg), and postural dizziness. On examination, she is hypotensive (BP 95/58 mmHg), has diffuse hyperpigmentation of the skin and oral mucosa, and mild generalized weakness. Laboratory investigations reveal: Na⁺ 128 mEq/L, K⁺ 5.8 mEq/L, fasting glucose 68 mg/dL, and morning cortisol 2.2 µg/dL (normal >10 µg/dL). ACTH level is 285 pg/mL (normal 10–50 pg/mL). What is the most likely diagnosis?

Explanation

## Clinical Diagnosis: Primary Adrenal Insufficiency (Addison Disease) ### Key Diagnostic Features **Key Point:** The constellation of hyperpigmentation, hyponatremia, hyperkalemia, hypoglycemia, elevated ACTH with low cortisol is pathognomonic for primary adrenal insufficiency. ### Pathophysiology In primary adrenal insufficiency, destruction of the adrenal cortex (>90% loss required for clinical symptoms) leads to: 1. Loss of cortisol and aldosterone production 2. Loss of negative feedback on the anterior pituitary 3. Compensatory elevation of ACTH and renin ### Laboratory Interpretation | Parameter | Finding | Interpretation | |-----------|---------|----------------| | Morning cortisol | 2.2 µg/dL (very low) | Adrenal failure | | ACTH | 285 pg/mL (markedly elevated) | Pituitary attempting to drive failed gland | | Na⁺ | 128 mEq/L (hyponatremia) | Aldosterone deficiency + SIADH | | K⁺ | 5.8 mEq/L (hyperkalemia) | Aldosterone deficiency | | Glucose | 68 mg/dL (hypoglycemia) | Cortisol deficiency | **High-Yield:** The **elevated ACTP with low cortisol** is the biochemical hallmark that distinguishes primary from secondary adrenal insufficiency. ### Clinical Features Explained - **Hyperpigmentation:** ACTH stimulates melanocyte-stimulating hormone (MSH) receptors on melanocytes; elevated ACTH → increased melanin deposition in skin and mucosa - **Hyponatremia:** Loss of aldosterone → sodium wasting; also SIADH from cortisol deficiency - **Hyperkalemia:** Loss of aldosterone-mediated K⁺ excretion in collecting duct - **Hypoglycemia:** Loss of cortisol's gluconeogenic and glycogenolytic effects - **Hypotension:** Loss of both cortisol (vascular tone) and aldosterone (intravascular volume) ### Differential Diagnosis ```mermaid flowchart TD A[Suspected adrenal insufficiency]:::outcome --> B{ACTH level?}:::decision B -->|Elevated| C{Cortisol low?}:::decision B -->|Low/normal| D[Secondary adrenal insufficiency]:::outcome C -->|Yes| E[Primary adrenal insufficiency]:::outcome C -->|No| F[Ectopic ACTH syndrome]:::outcome E --> G{Pigmentation?}:::decision G -->|Present| H[Addison disease]:::action G -->|Absent| I[Acute adrenal crisis/recent onset]:::action ``` **Clinical Pearl:** Hyperpigmentation is a clinical clue that distinguishes primary from secondary insufficiency — it is absent in secondary insufficiency because ACTH is low. ### Etiology in India Most common causes in Indian population: 1. **Tuberculosis** (most common, ~60–80% of cases) — chronic granulomatous destruction 2. Autoimmune (Addison disease proper) — ~10–15% 3. Fungal infections (histoplasmosis, coccidioidomycosis) — endemic areas 4. Adrenal hemorrhage (sepsis, anticoagulation, trauma) [cite:Harrison 21e Ch 379]