A 38-year-old woman from Delhi presents with progressive fatigue, weight loss of 8 kg over 3 months, and recurrent hypoglycaemic episodes. On examination, she has hyperpigmentation of the buccal mucosa and palmar creases, blood pressure 95/60 mmHg, and mild postural dizziness. Laboratory investigations show: sodium 128 mEq/L, potassium 5.8 mEq/L, fasting glucose 65 mg/dL, and ACTH 850 pg/mL (normal <50). A morning cortisol is 2.2 μg/dL (normal 10–20). The dexamethasone suppression test shows no suppression of cortisol. What is the primary pathophysiological defect?

Explanation

## Clinical Diagnosis: Primary Adrenal Insufficiency (Addison's Disease) ### Key Clinical Features **Key Point:** The combination of low cortisol (2.2 μg/dL) with markedly elevated ACTH (850 pg/mL) is pathognomonic for primary adrenal failure. The adrenal gland cannot respond to ACTH stimulation, so the pituitary increases ACTH secretion in a futile attempt to raise cortisol — this is the hallmark of primary adrenal insufficiency. ### Pathophysiology of the Feedback Loop **High-Yield:** In primary adrenal insufficiency, the negative feedback loop is INTACT but the target organ (adrenal cortex) is non-functional. ACTH rises because there is insufficient cortisol to suppress the pituitary corticotroph cells. | Feature | Primary Adrenal Insufficiency | Secondary (Pituitary) Insufficiency | Ectopic ACTH | |---------|-------------------------------|--------------------------------------|---------------| | **Cortisol** | Low | Low | High | | **ACTH** | Very high (>200) | Low/normal | Very high (>200) | | **Dexamethasone suppression** | No suppression | Suppression at high dose | No suppression | | **Feedback mechanism** | Intact but target organ fails | Intact but pituitary fails | Ectopic source ignores feedback | | **Hyperpigmentation** | Yes (ACTH stimulates melanocytes) | No | Possible | ### Why This Is Primary Adrenal Insufficiency 1. **Low cortisol** — adrenal gland is failing 2. **Very high ACTH** — pituitary is responding appropriately to low cortisol, but the adrenal cannot respond 3. **Hyperpigmentation** — elevated ACTH stimulates melanocytes via ACTH receptors 4. **Electrolyte abnormalities** — hyponatremia and hyperkalaemia reflect loss of aldosterone (also produced by adrenal cortex) 5. **Dexamethasone non-suppression** — the adrenal is too damaged to produce cortisol even with ACTH stimulation ### Clinical Pearl **Clinical Pearl:** Hyperpigmentation in the setting of hypotension and hyponatremia is a red flag for Addison's disease. The ACTH level is the key discriminator: in primary disease it is markedly elevated; in secondary disease it is low or normal. ### Mnemonic: ACTH Feedback Logic **Mnemonic:** **PRIMARY = ACTH UP, Cortisol DOWN** (gland fails, pituitary tries harder) vs. **SECONDARY = ACTH DOWN, Cortisol DOWN** (pituitary fails, no stimulus to gland). **Key Point:** The negative feedback system is functioning correctly in primary adrenal insufficiency — it is the adrenal gland itself that has failed.