Pathophysiology of Sarcoidosis
Sarcoidosis is fundamentally a T-cell mediated inflammatory disorder characterized by the formation of compact, non-caseating granulomas that result from an exaggerated immune response to unidentified antigens in genetically susceptible individuals. 1
Core Immunologic Mechanism
The pathophysiology centers on abnormal cellular immune activation with accumulation of CD4+ T helper cells at sites of disease activity 1, 2. This process unfolds through the following sequence:
- CD4+ T cells accumulate and release pro-inflammatory cytokines, particularly IL-2 and TNF-alpha, which drive the inflammatory cascade 1, 2
- Macrophage chemotactic factors produced by activated T-helper cells recruit additional immune cells to affected tissues 3
- Pro-inflammatory cytokines stimulate bone marrow and perpetuate chronic inflammation, which can lead to systemic manifestations including reactive thrombocytosis and anemia of chronic disease 1
Granuloma Formation and Characteristics
The hallmark pathologic feature is the formation of well-organized, non-caseating granulomas with distinctive architecture 1:
- Central core consists of tightly packed epithelioid histiocytes and multinucleated giant cells arranged in compact collections 4
- Peripheral zone contains loosely organized lymphocytes with sparse surrounding inflammatory infiltrate 4
- Granulomas remain discrete and non-necrotic, though focal minimal ischemic necrosis may occur 4
- Fibrosis begins at the granuloma periphery and extends centrally, with or without calcification, representing the healing phase 4
Anatomic Distribution Pattern
Granulomas follow a characteristic perilymphatic distribution 4:
- Located around bronchovascular bundles and fibrous septa containing pulmonary veins 4
- Concentrated near visceral pleura 4
- In necrotizing variants, granulomatous angiitis with vascular wall invasion may occur 4
Etiologic Hypothesis
While the precise cause remains unknown, the prevailing hypothesis suggests that poorly degradable antigens of infectious or environmental origin trigger exaggerated immune reactions in genetically susceptible hosts 5, 6. This explains:
- Geographic and ethnic variations in prevalence, with higher rates in African Americans and Scandinavians 1, 5, 7
- Variable clinical presentations and disease courses across different populations 2, 7
- Age predilection for adults 30-50 years, particularly women who experience higher morbidity and mortality 1, 7
Metabolic Consequences
Abnormal vitamin D metabolism occurs within granulomatous lesions 1, 5:
- Granulomas produce elevated 1,25-dihydroxyvitamin D levels 4
- This leads to hypercalcemia and hypercalciuria in affected patients 4, 5
- Parathyroid hormone levels remain normal to low despite calcium abnormalities 4
Clinical Pitfalls
A critical caveat: extensive necrosis, palisading granulomas, or robust surrounding inflammatory infiltrates argue against sarcoidosis and should prompt consideration of alternative diagnoses including infections, vasculitis, or malignancy 4. The presence of positive microorganism stains or cultures definitively excludes sarcoidosis 4.