A 38-year-old woman from rural Maharashtra presents with a 6-month history of progressive dyspnea, dry cough, and constitutional symptoms (fever, weight loss, night sweats). Chest X-ray shows bilateral hilar lymphadenopathy with right upper lobe infiltrates. Serum calcium is 11.2 mg/dL (normal 8.5–10.5). ACE level is elevated at 68 U/L (normal <40). Transbronchial lung biopsy reveals non-caseating granulomas with multinucleated giant cells. Tuberculin skin test is negative. What is the most likely diagnosis?

Explanation

## Diagnosis: Sarcoidosis ### Clinical Features Supporting Sarcoidosis **Key Point:** Sarcoidosis is a multisystem granulomatous disease of unknown etiology characterized by non-caseating granulomas in multiple organs. ### Diagnostic Criteria Met | Feature | Finding | Significance | |---------|---------|---------------| | Pulmonary involvement | Bilateral hilar lymphadenopathy + infiltrates | Stage II sarcoidosis | | Histology | Non-caseating granulomas | Pathognomonic for sarcoidosis | | Hypercalcemia | Serum Ca 11.2 mg/dL | Due to 1α-hydroxylase in granulomas | | ACE level | Elevated (68 U/L) | Produced by epithelioid cells | | TST | Negative | Anergy in sarcoidosis | | TB exclusion | No caseating necrosis | Rules out tuberculosis | ### Pathophysiology of Hypercalcemia in Sarcoidosis 1. Activated macrophages in granulomas express **1α-hydroxylase** 2. Enzyme converts 25-OH vitamin D → active 1,25-dihydroxyvitamin D₃ 3. Increased intestinal calcium absorption → hypercalcemia and hypercalciuria 4. Can lead to nephrolithiasis and renal dysfunction if untreated **High-Yield:** Hypercalcemia in sarcoidosis is NOT PTH-mediated (PTH is suppressed); it is calcitriol-mediated. ### Differential Diagnosis of Non-Caseating Granulomas ```mermaid flowchart TD A[Non-caseating Granulomas]:::outcome --> B{Hypercalcemia present?}:::decision B -->|Yes| C{Negative TST?}:::decision B -->|No| D[Berylliosis, Crohn's, etc.] C -->|Yes + elevated ACE| E[Sarcoidosis]:::action C -->|No| F[TB or fungal disease] E --> G[Treat with corticosteroids]:::action ``` **Clinical Pearl:** Sarcoidosis commonly presents in young to middle-aged adults; higher incidence in African Americans and Northern Europeans. In India, it is less common than TB but must be excluded when caseation is absent. **Mnemonic for Sarcoidosis Manifestations — SARCOID:** - **S**kin (erythema nodosum, lupus pernio) - **A**rthritis (arthralgia, polyarthritis) - **R**espiratory (pulmonary infiltrates, hilar lymphadenopathy) - **C**ardiac (granulomatous myocarditis, conduction defects) - **O**cular (uveitis, iritis) - **I**ntestinal (rarely granulomas) - **D**iabetes insipidus (neurosarcoidosis, pituitary involvement) [cite:Robbins 10e Ch 5]