Why is my calprotectin level elevated despite negative tests for Inflammatory Bowel Disease (IBD) and absence of infectious pathogens?

Why Your Calprotectin Is Elevated Despite Negative IBD and Pathogen Testing

Elevated fecal calprotectin without confirmed IBD or infection most commonly indicates other sources of intestinal inflammation including NSAIDs, colorectal neoplasia, microscopic colitis, celiac disease, or hemorrhoids—and you need colonoscopy with biopsies to identify the underlying cause. 1, 2

Understanding What Calprotectin Actually Measures

Calprotectin is released when neutrophils degranulate during any inflammatory process in the intestinal tract, making it a sensitive but non-specific marker. 1 While it has 90.6% sensitivity for detecting IBD at cutoffs >50 μg/g, the specificity for IBD is lower than desirable because multiple other conditions elevate this marker. 1, 3

Common Non-IBD Causes of Elevated Calprotectin

Colorectal Cancer and Adenomas

• Colorectal neoplasia is a well-established cause of elevated calprotectin and must be excluded, particularly if you have alarm symptoms like rectal bleeding or are over age 50. 1, 2
• Cancer pathway referral is required regardless of calprotectin result if alarm symptoms are present, as calprotectin is not sensitive enough to exclude colorectal cancer. 2

NSAID Use

• Any NSAID use in the past 6 weeks can significantly elevate calprotectin levels through direct mucosal injury. 1, 3, 4
• This includes over-the-counter ibuprofen, naproxen, and aspirin at anti-inflammatory doses. 1

Infectious Gastroenteritis

• While your stool pathogen test was negative, calprotectin can remain elevated for weeks after acute infectious gastroenteritis even when pathogens are no longer detectable. 1, 5
• Standard stool cultures miss many pathogens, and recent infection may explain persistent elevation. 5

Microscopic Colitis

• This condition requires colonoscopy with biopsies for diagnosis and commonly presents with chronic diarrhea, normal-appearing mucosa on endoscopy, but elevated calprotectin. 1
• It is frequently missed without proper biopsies. 1

Celiac Disease

• Untreated celiac disease causes intestinal inflammation that elevates calprotectin. 1
• The British Society of Gastroenterology recommends screening with tissue transglutaminase or EMA antibodies in all patients with chronic diarrhea. 1

Hemorrhoids

• Local bleeding and inflammation from hemorrhoids can cause false elevations in fecal calprotectin. 3
• This is particularly relevant if you have visible rectal bleeding. 3

What Your Calprotectin Level Means

The interpretation depends on the actual value:

• Values 50-250 μg/g represent an indeterminate range with 8% chance of developing IBD over 12 months compared to 1% with levels <50 μg/g. 1
• Values >250 μg/g strongly suggest active inflammation requiring endoscopic assessment, with 82% specificity for active disease. 1, 2
• Values >150 μg/g have 78.2% specificity for endoscopically active disease. 1, 2

What You Need Next

Immediate Steps

1. Review all medications, particularly NSAIDs, taken in the past 6 weeks and discontinue if possible. 1, 3, 4
2. Ensure celiac serology (tissue transglutaminase antibodies) has been checked. 1
3. Proceed to colonoscopy with biopsies to evaluate for microscopic colitis, colorectal neoplasia, and other mucosal abnormalities not visible on standard endoscopy. 1, 2

Why Colonoscopy Is Essential

• High calprotectin concentration is a strong argument to perform colonoscopy to rule out organic pathology beyond IBD. 5
• Multiple conditions that elevate calprotectin require tissue diagnosis through biopsy. 1, 5
• The British Society of Gastroenterology states that endoscopic and histological assessment is necessary in most patients with chronic diarrhea and elevated inflammatory markers. 1

Important Caveats

False Positives in Asymptomatic Patients

• If you have minimal or no symptoms, elevated calprotectin >150 μg/g has a false positive rate of 22.4%, meaning nearly one-quarter of asymptomatic patients with elevated levels may not have significant endoscopic inflammation. 1, 3

Sample Collection Matters

• Use the first stool passed in the morning and ensure it's analyzed within 3 days at room temperature to avoid falsely elevated or degraded results. 1, 3, 4
• Variability exists between different stool samples from the same day. 1

Consider Repeat Testing

• If your value is in the 50-250 μg/g range and you've recently stopped NSAIDs or recovered from suspected infection, repeat testing in 4-6 weeks may be reasonable before proceeding to colonoscopy. 1
• However, if symptoms persist or worsen, proceed directly to endoscopic evaluation. 1, 2