A 45-year-old man with a 6-month history of fatigue, orthostatic dizziness, and recurrent episodes of hypoglycemia is referred to the endocrinology clinic. He reports a 4 kg weight loss and denies fever or respiratory symptoms. On examination, blood pressure is 98/62 mmHg (supine) and 82/50 mmHg (standing). Skin examination reveals diffuse hyperpigmentation of the palms and knuckles. Serum sodium is 132 mEq/L, potassium 5.9 mEq/L, and fasting glucose is 58 mg/dL. Morning cortisol is 2.8 µg/dL and ACTH is 198 pg/mL. An abdominal CT scan shows bilateral adrenal atrophy with no masses or calcifications. Which of the following is the most likely underlying etiology?

Explanation

## Diagnosis: Autoimmune Adrenalitis (Autoimmune Addison Disease) ### Clinical and Radiological Clues **Key Point:** The combination of **bilateral adrenal atrophy** (not enlargement, calcification, or masses) on imaging in a patient with confirmed primary adrenal insufficiency strongly suggests **autoimmune adrenalitis**. ### Differential Diagnosis of Addison Disease by Etiology | Etiology | Imaging Finding | Clinical Clue | Prevalence in Developed Countries | |----------|-----------------|---------------|----------------------------------| | **Autoimmune adrenalitis** | **Bilateral atrophy** | No systemic disease, adrenal antibodies | 70–80% | | Tuberculosis | Bilateral enlargement + calcification | Fever, weight loss, TB risk factors, calcification | 10–15% | | Metastatic cancer | Bilateral enlargement ± masses | Known primary malignancy, rapid onset | 5–10% | | Lymphoma | Bilateral enlargement | Lymphadenopathy, systemic symptoms | <5% | | Adrenoleukodystrophy | Bilateral atrophy + calcification | Young male, neurological symptoms | Rare in adults | ### Why Autoimmune Adrenalitis? 1. **Bilateral adrenal atrophy** (not enlargement or calcification) is the classic imaging finding 2. **No masses or calcifications** rules out TB, malignancy, and lymphoma 3. **Insidious onset** (6 months) with gradual weight loss is typical of autoimmune disease 4. **Confirmed primary adrenal insufficiency** (elevated ACTH, low cortisol, electrolyte abnormalities) 5. **No systemic symptoms** (no fever, no respiratory symptoms) makes TB less likely **High-Yield:** Autoimmune adrenalitis is the **most common cause of Addison disease in iodine-sufficient countries** (70–80% of cases). ### Pathophysiology **Mnemonic: AUTOIMMUNE ADDISON — A.A.A.** = Autoimmune Adrenalitis with Atrophy and Antibodies - Autoimmune destruction of adrenocortical cells - Antibodies against 21-hydroxylase (CYP21A2) are present in ~90% of cases - Gradual loss of cortical tissue → atrophy - Often associated with other autoimmune conditions (thyroiditis, vitiligo, pernicious anemia) ### Clinical Pearl **Orthostatic hypotension** (BP drop from supine to standing) is a hallmark of adrenal insufficiency and reflects loss of both cortisol and aldosterone. The patient's BP drop from 98/62 to 82/50 mmHg is diagnostic. ### Diagnostic Confirmation - **Adrenal antibodies** (21-hydroxylase antibodies) would be positive in ~90% of autoimmune cases - **Short Synacthen test** would show failure of cortisol response - **Screening for associated autoimmune diseases** (TSH, tissue transglutaminase antibodies, B12 level) is recommended [cite:Harrison 21e Ch 375]