A 38-year-old woman from rural Maharashtra presents with a 3-month history of progressive weakness, weight loss (8 kg), and darkening of skin over sun-exposed areas and palmar creases. She reports orthostatic dizziness and has been unable to work as a farm labourer. On examination: BP 92/58 mmHg (lying), 78/50 mmHg (standing), HR 104/min, skin hyperpigmentation over knuckles and buccal mucosa. Serum sodium 128 mEq/L, potassium 5.8 mEq/L, fasting glucose 68 mg/dL. ACTH level is 890 pg/mL (normal <46). What is the most likely diagnosis?

Explanation

## Clinical Diagnosis: Primary Adrenal Insufficiency (Addison Disease) ### Key Clinical Features Present **Key Point:** The triad of hyperpigmentation + hyponatremia + elevated ACTH is pathognomonic for primary adrenal insufficiency. 1. **Hyperpigmentation** — melanin stimulation by elevated ACTH acting on melanocortin-1 receptors in skin; occurs over sun-exposed areas, palmar creases, buccal mucosa, and nipples. 2. **Hyponatremia (128 mEq/L)** — loss of aldosterone → sodium wasting; combined with ADH stimulation from volume depletion. 3. **Hyperkalemia (5.8 mEq/L)** — aldosterone deficiency → potassium retention. 4. **Hypoglycemia (68 mg/dL)** — cortisol deficiency → impaired gluconeogenesis. 5. **Orthostatic hypotension** — loss of both cortisol and aldosterone → intravascular volume depletion. 6. **Markedly elevated ACTH (890 pg/mL)** — loss of negative feedback from cortisol; pituitary responds with maximal ACTH secretion in attempt to stimulate failing adrenal glands. ### Pathophysiology ```mermaid flowchart TD A[Adrenal cortex destruction<br/>TB, autoimmune, fungal]:::urgent --> B[Loss of cortisol<br/>and aldosterone]:::outcome B --> C[Loss of negative feedback<br/>on pituitary ACTH]:::outcome C --> D[ACTH levels rise markedly]:::action D --> E[Melanin stimulation<br/>Hyperpigmentation]:::outcome B --> F[Sodium wasting<br/>Hyponatremia]:::outcome B --> G[Potassium retention<br/>Hyperkalemia]:::outcome B --> H[Impaired gluconeogenesis<br/>Hypoglycemia]:::outcome ``` ### Laboratory Pattern in Primary vs Secondary Adrenal Insufficiency | Feature | Primary (Addison) | Secondary (Pituitary/Hypothalamic) | |---------|-------------------|------------------------------------| | **ACTH** | **Markedly elevated** (>200 pg/mL) | Low or normal (<10 pg/mL) | | **Cortisol** | Low (<5 µg/dL) | Low (<5 µg/dL) | | **Sodium** | Low (wasting) | Normal or mildly low | | **Potassium** | High (retention) | Normal | | **Hyperpigmentation** | **Present** (ACTH-driven) | Absent | | **Aldosterone** | Low | Normal | **High-Yield:** In this patient, the **elevated ACTH with low cortisol** definitively excludes secondary and tertiary insufficiency, where ACTH would be low or absent. ### Etiology in India **Clinical Pearl:** Tuberculosis is the most common cause of Addison disease in India (accounting for ~70% of cases), followed by autoimmune adrenalitis. The insidious 3-month presentation with progressive symptoms is typical of TB-induced adrenal destruction. ### Diagnostic Confirmation 1. **Short Synacthen test** — 250 µg ACTH(1-24) IV; cortisol <18 µg/dL at 30 min confirms primary insufficiency. 2. **Imaging** — CT/MRI abdomen to assess adrenal size and look for TB (calcification, hypodensity) or autoimmune atrophy. 3. **Tuberculin skin test / GeneXpert MTB/RIF** — to confirm TB if suspected. **Mnemonic: ADDISON** — Adrenal, Darkening, Decreased sodium, Increased potassium, Shock, Orthostatic hypotension, Necrosis/destruction [cite:Harrison 21e Ch 375]