A 38-year-old woman presents with progressive fatigue, weight loss, and hyperpigmentation of skin and mucous membranes. Laboratory investigations reveal hyponatremia (Na+ 128 mEq/L), hyperkalemia (K+ 5.8 mEq/L), and elevated ACTH (450 pg/mL). A diagnosis of primary adrenal insufficiency (Addison disease) is suspected. Which of the following is NOT a recognized cause of Addison disease?

## Causes of Addison Disease (Primary Adrenal Insufficiency) ### Pathophysiology Addison disease results from destruction or dysfunction of the adrenal cortex, leading to deficiency of cortisol, aldosterone, and adrenal androgens. The condition is characterized by elevated ACTH (due to loss of negative feedback) and low cortisol. ### Recognized Causes of Primary Adrenal Insufficiency | Cause | Mechanism | Frequency | |-------|-----------|----------| | Autoimmune adrenalitis | Lymphocytic infiltration and antibodies to 21-hydroxylase and other enzymes | 70–90% in developed countries | | Tuberculosis | Caseating granulomas destroying adrenal parenchyma | Most common worldwide; 10–15% in developed countries | | Adrenoleukodystrophy | X-linked peroxisomal disorder causing adrenal atrophy and demyelination | Rare; presents in childhood or adulthood | | Fungal infections | Histoplasmosis, coccidioidomycosis, blastomycosis (especially in immunocompromised) | Uncommon | | Metastatic malignancy | Bilateral adrenal infiltration (lung, breast, lymphoma) | Rare | | Hemorrhage/infarction | Meningococcemia (Waterhouse-Friderichsen), anticoagulation, trauma | Acute presentation | | Medications | Mitotane, ketoconazole, etomidate | Iatrogenic | ### Why Pituitary Adenoma Secreting ACTH is NOT a Cause of Primary Addison Disease **Key Point:** A pituitary adenoma secreting ACTH causes **secondary adrenal insufficiency** (central hypogonadism), NOT primary Addison disease. - In a pituitary ACTH-secreting tumor (Cushing disease), ACTH levels are **elevated** and cortisol is **elevated** — the opposite of Addison disease. - Primary Addison disease is defined by **adrenal gland pathology** (destruction, infiltration, or dysfunction). - A non-functioning pituitary adenoma or a tumor causing pituitary stalk compression would cause **low ACTH and low cortisol** (secondary insufficiency), not the high ACTH + low cortisol pattern of Addison disease. **Clinical Pearl:** The key distinguishing feature of primary vs. secondary adrenal insufficiency is the ACTH level: - **Primary (Addison):** Low cortisol + **HIGH ACTH** (loss of negative feedback) - **Secondary (pituitary/hypothalamic):** Low cortisol + **LOW ACTH** **High-Yield:** Pituitary adenomas causing adrenal insufficiency do so by **destroying normal pituitary tissue** (leading to low ACTH), not by secreting ACTH. An ACTH-secreting pituitary tumor causes Cushing disease (excess cortisol), which is the opposite of Addison disease. **Mnemonic — Addison Disease Causes (MATCH):** - **M**alignancy (metastatic) - **A**utoimmune - **T**uberculosis - **C**ongenital (adrenoleukodystrophy, CAH) - **H**emorrhage/Histoplasmosis