Pathophysiology of Eosinophilic Gastrointestinal Disorders (EGID)
Eosinophilic gastrointestinal disorders (EGIDs) are primarily driven by an aberrant Th2 inflammatory immune response involving interleukins IL-4, IL-5, and IL-13, leading to eosinophil recruitment and activation in the gastrointestinal tract with resultant tissue damage and organ dysfunction. 1
Core Immunopathologic Mechanisms
Allergic/Immune-Mediated Inflammation
- Th2-predominant response: EGIDs are characterized by an abnormal immune-mediated response to food antigens with overexpression of Th2 cytokines 1
- Key cytokines involved:
- IL-5: Promotes eosinophil development, activation, and survival
- IL-13: Induces tissue remodeling and epithelial barrier dysfunction
- IL-4: Promotes IgE production and Th2 differentiation
- TSLP (thymic stromal lymphopoietin): Activates dendritic cells to promote Th2 responses 1
Eosinophil Recruitment and Activation
- Chemokine production: Local production of CCL26 (eotaxin-3) specifically attracts eosinophils to the gastrointestinal mucosa 1
- Eosinophil infiltration patterns:
Tissue Damage Mechanisms
- Eosinophil-mediated damage: Activated eosinophils release:
- Major basic protein (MBP)
- Eosinophil cationic protein (ECP)
- Eosinophil-derived neurotoxin (EDN)
- Eosinophil peroxidase (EPO) 1
- Mast cell involvement: Increased mast cells and tryptase expression contribute to inflammation and fibrosis 1
Tissue Remodeling and Fibrosis
- Epithelial barrier dysfunction: Decreased expression of barrier molecules (desmoglein DSG1, CDH26, FLG) 1
- Tissue remodeling: Overexpression of periostin (POSTN) and other fibrosis markers (KRT13) 1
- Lamina propria fibrosis: Progressive fibrotic remodeling leads to stricture formation, particularly in EoE 1
- Basal cell hyperplasia and papillary elongation: Common histologic features in affected tissues 1
Disease-Specific Pathophysiology
Eosinophilic Esophagitis (EoE)
- Most well-characterized EGID with diagnostic threshold of ≥15 eosinophils/HPF 1
- Molecular EoE diagnostic panel (EDP) of 94 genes distinguishes EoE from GERD 1
- Transcriptome nearly completely overlaps with PPI-responsive esophageal eosinophilia (PPI-REE) 1
Non-Esophageal EGIDs
- Can affect any segment of GI tract (stomach, small intestine, colon) 2, 3
- Symptoms depend on location and depth of bowel wall involvement 2
- May involve multiple locations simultaneously or sequentially 3
Role of Allergic Sensitization
- Food allergen triggers: Strong link between food allergens and EGID development 2, 4
- Atopic comorbidity: 50-80% of patients have concurrent atopic conditions (asthma, allergic rhinitis, eczema) 1
- Seasonal variations: Some patients show seasonal changes in symptoms and eosinophil levels 1
Systemic Considerations
Differentiation from Systemic Eosinophilic Disorders
- Hypereosinophilic syndrome (HES): Distinguished by peripheral eosinophilia >1500 cells/μL and multi-organ involvement 1, 5
- Eosinophilic granulomatosis with polyangiitis (EGPA): Characterized by asthma, peripheral eosinophilia, and small-to-medium vessel vasculitis 1
Clinical Implications
- Disease progression: Untreated disease may lead to fibrostenotic complications, particularly in EoE 1
- Treatment response: PPI therapy can reverse Th2 inflammatory signatures in some patients 1
- Therapeutic targets: IL-4/IL-13 (dupilumab) and IL-5 (mepolizumab) pathway inhibition shows promise in treating EGIDs 1, 4
Diagnostic Considerations
- Diagnosis requires ruling out secondary causes of eosinophilia (GERD, parasitic infections, drug reactions) 1, 3
- Endoscopic and histologic evaluation is essential, with biopsies from affected areas 3
- Molecular and genetic markers are emerging as diagnostic tools 1
The pathophysiology of EGIDs represents a complex interplay between genetic predisposition, environmental triggers (particularly food allergens), and aberrant immune responses, ultimately leading to eosinophil-mediated tissue damage and remodeling in the gastrointestinal tract.