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 fine reticular opacities in the upper lobes. Serum calcium is elevated at 11.8 mg/dL (normal 8.5–10.5). ACE level is 65 U/L (normal <40). Transbronchial lung biopsy shows non-caseating granulomas with multinucleated giant cells. Tuberculin skin test is negative. What is the most likely diagnosis?

Explanation

## Diagnosis: Sarcoidosis ### Clinical Presentation **Key Point:** Sarcoidosis is a systemic granulomatous disease of unknown etiology that classically presents with bilateral hilar lymphadenopathy, pulmonary infiltrates, and constitutional symptoms. ### Diagnostic Criteria Met | Feature | Finding | Significance | |---------|---------|---------------| | **Chest imaging** | Bilateral hilar lymphadenopathy + upper lobe reticular opacities | Stage II sarcoidosis | | **Histology** | Non-caseating granulomas | Hallmark of sarcoidosis (NOT TB) | | **Hypercalcemia** | 11.8 mg/dL | Granulomas produce calcitriol (1,25-dihydroxyvitamin D) | | **Elevated ACE** | 65 U/L | Produced by epithelioid cells in granulomas | | **TST** | Negative | Anergy is common in sarcoidosis; rules out TB | | **Constitutional symptoms** | Fever, weight loss, night sweats | Systemic inflammatory response | ### Pathophysiology of Hypercalcemia 1. Epithelioid macrophages in granulomas express **1α-hydroxylase** 2. Converts 25-hydroxyvitamin D → **1,25-dihydroxyvitamin D (calcitriol)** 3. Increased intestinal calcium absorption → hypercalcemia 4. **Clinical Pearl:** Hypercalcemia in sarcoidosis is NOT PTH-mediated (PTH is suppressed) ### Why Non-Caseating Granulomas? **High-Yield:** The **absence of caseation** is the critical histologic distinction: - **Sarcoidosis:** Non-caseating granulomas (clean, well-formed) - **TB:** Caseating granulomas (central necrosis with "cheese-like" appearance) ### Mnemonic for Sarcoidosis Organs: **CHILL FM** - **C**ardiac (arrhythmias, cardiomyopathy) - **H**ypercalcemia / Hypercalciuria - **I**ntestinal (GI involvement rare) - **L**ung (most common, 90%) - **L**ymph nodes (hilar, mediastinal) - **F**acial (lupus pernio, erythema nodosum) - **M**ultisystem (CNS, renal, ocular) ### Diagnostic Workup **Key Point:** Diagnosis requires: 1. Compatible clinical/radiologic presentation 2. Histologic evidence of non-caseating granulomas 3. Exclusion of other granulomatous diseases (TB, fungal, berylliosis) ### Treatment Approach - **Asymptomatic:** Observation - **Symptomatic/Progressive:** Corticosteroids (first-line) - **Hypercalcemia:** Corticosteroids + hydration; avoid vitamin D and sun exposure [cite:Robbins 10e Ch 15]