What does the presence of eosinophilic protein X in a patient's stool indicate, particularly in relation to eosinophilic gastrointestinal disorders?

Eosinophil Protein X in Stool

Eosinophil protein X (EPX) in stool is a marker of eosinophil activation and degranulation in the gastrointestinal tract, indicating active intestinal inflammation from eosinophilic infiltration. 1

What EPX Represents

EPX (also called eosinophil-derived neurotoxin) is a cytotoxic granular protein released by activated eosinophils that accumulate in gastrointestinal tissues. 2, 1 When eosinophils degranulate in the gut mucosa, EPX is released and can be detected in stool samples as a non-invasive marker of intestinal eosinophilic inflammation. 1

Clinical Significance and Interpretation

Elevated fecal EPX levels indicate active mucosal eosinophilic inflammation and correlate with disease activity in eosinophilic gastrointestinal disorders. 1

Normal vs. Abnormal Levels

• Healthy controls: EPX levels range from 12-746 ng/g feces (median: 235 ng/g) 1
• Inflammatory conditions: EPX levels range from 10-33,225 ng/g feces (median: 803 ng/g) 1
• Particularly high concentrations occur in patients with active mucosal inflammation 1

Conditions Associated with Elevated Fecal EPX

Eosinophilic gastrointestinal disorders (EGIDs) are the primary conditions where fecal EPX measurement has diagnostic utility:

• Eosinophilic gastroenteritis: Characterized by pathologic eosinophilic infiltration of the stomach and/or small intestine causing organ dysfunction 2, 3, 4
• Eosinophilic enteritis and colitis: Eosinophilic infiltration of the small intestine or colon 3
• Inflammatory bowel disease: Both Crohn's disease and ulcerative colitis show elevated EPX levels 1
• Intestinal food allergy: Particularly in children, where food allergens trigger eosinophilic infiltration 2, 1

Diagnostic Context

EPX measurement should be interpreted alongside eosinophil cationic protein (ECP), which shows similar elevation patterns but with different concentration ranges. 1 In the same patient populations, ECP levels range from 0.4-1783 ng/g feces (median: 29 ng/g) in inflammatory conditions versus 0.5-55 ng/g (median: 1.5 ng/g) in healthy controls. 1

Important Distinction: Esophageal vs. Lower GI Disease

Eosinophilic esophagitis (EoE) is diagnosed by esophageal biopsy showing ≥15 eosinophils/hpf (~60 eos/mm²), not by stool testing. 5 Fecal EPX is not useful for diagnosing EoE because:

• EoE requires symptoms of esophageal dysfunction plus histologic confirmation from esophageal biopsies 5
• Gastric and duodenal biopsies have low yield for identifying other EGIDs in the absence of symptoms or endoscopic abnormalities 5
• Peripheral blood eosinophilia occurs in only 10-50% of adults with EoE 6

When to Consider Fecal EPX Testing

Fecal EPX measurement is most useful when evaluating suspected eosinophilic gastroenteritis, enteritis, or colitis in patients with:

• Abdominal pain, nausea, vomiting, early satiety, diarrhea, or weight loss 3
• Known inflammatory bowel disease requiring disease activity monitoring 1
• Suspected food allergy with gastrointestinal symptoms 2, 1
• Need for non-invasive monitoring of intestinal inflammation 1

Pathophysiology

Eosinophils release highly cytotoxic granular proteins including EPX that cause severe tissue damage characteristic of eosinophilic gastroenteritis. 2 The accumulation of eosinophils in gut tissue is regulated through a complex molecular network involving Th2 cells, cytokines (particularly IL-3, IL-5, and GM-CSF), and chemokines like eotaxin. 2, 7

Clinical Pitfalls to Avoid

• Do not use fecal EPX to diagnose EoE: Esophageal disease requires endoscopy with biopsy 5
• Do not interpret isolated EPX elevation without clinical context: EPX elevation occurs in multiple inflammatory conditions and requires correlation with symptoms, endoscopic findings, and histology 1
• Do not assume normal EPX excludes EGID: Eosinophilic infiltration may be patchy or involve layers of the bowel wall not reflected in stool markers 4