Causes of Slightly Elevated Calprotectin
Slightly elevated fecal calprotectin (50-250 μg/g) is most commonly caused by NSAID use, colorectal neoplasia, infectious gastroenteritis, and untreated celiac disease, in addition to early or mild inflammatory bowel disease. 1, 2
Primary Non-IBD Causes to Consider
Medication-Related Causes
- NSAID use within the past 6 weeks is one of the most common causes of false elevation, including over-the-counter ibuprofen, naproxen, and aspirin at anti-inflammatory doses through direct mucosal injury. 2, 3
- Proton pump inhibitor (PPI) use is significantly associated with elevated calprotectin, with users having nearly 4-fold increased odds of elevated levels (adjusted OR: 3.843) compared to non-users. 3
- Acetylsalicylic acid use increases the odds of elevated calprotectin nearly 3-fold (adjusted OR: 2.934). 3
Structural and Neoplastic Causes
- Colorectal cancer and advanced adenomas elevate calprotectin and must be excluded, particularly in patients over age 50 or those with alarm symptoms like rectal bleeding. 1, 2, 4
- Hemorrhoids can cause false elevations due to local bleeding and inflammation, particularly when visible rectal bleeding is present. 2
Infectious and Inflammatory Causes
- Infectious gastroenteritis significantly elevates calprotectin during active infection and may remain mildly elevated during recovery. 1, 4, 5
- Untreated celiac disease causes intestinal inflammation that elevates calprotectin levels. 2
Physiologic Factors
- Age is independently associated with elevated calprotectin, with each year of age increasing odds by approximately 5% (adjusted OR: 1.051 per year). 3
Clinical Significance of Slightly Elevated Levels
The Indeterminate Range (50-250 μg/g)
- Values between 50-250 μg/g represent an indeterminate range with an 8% chance of developing IBD over 12 months, compared to only 1% in those with levels <50 μg/g. 1
- The British Society of Gastroenterology notes that this indeterminate range remains clinically challenging to interpret, as mild elevation may reflect non-specific low-grade inflammation. 1
Specificity Improves at Higher Thresholds
- Values >100 μg/g provide 78.2% specificity for endoscopically active disease. 6, 2
- Values >250 μg/g strongly suggest active inflammation with 82% specificity, correlating well with endoscopic inflammation. 1, 2
Diagnostic Approach to Slightly Elevated Calprotectin
Initial Assessment Steps
- Review all medications taken in the past 6 weeks, particularly NSAIDs, PPIs, and aspirin, and discontinue if clinically appropriate. 2, 3
- Ensure celiac serology (tissue transglutaminase antibodies) has been checked, as this is recommended by the British Society of Gastroenterology for all patients with chronic diarrhea. 1, 2
- Assess for recent infectious gastroenteritis, as calprotectin may remain elevated during recovery. 4, 5
When to Proceed to Colonoscopy
- Patients with alarm symptoms (rectal bleeding, abdominal pain) require cancer pathway referral regardless of calprotectin result, as calprotectin is not sensitive enough to exclude colorectal cancer. 7
- Values >250 μg/g strongly indicate need for urgent endoscopic assessment to evaluate for active inflammatory disease. 1, 7, 2
- For values 100-250 μg/g, consider routine gastroenterology referral with colonoscopy and biopsies to evaluate for microscopic colitis, colorectal neoplasia, and other mucosal abnormalities. 2
Alternative Strategy for Lower Elevations
- Repeat testing in 4-6 weeks may be reasonable before proceeding to colonoscopy if the value is in the 50-250 μg/g range and the patient has recently stopped NSAIDs or recovered from suspected infection. 2
Important Clinical Caveats
False Positive Considerations
- In asymptomatic patients with elevated calprotectin >150 μg/g, the false positive rate is 22.4%, meaning nearly one-quarter may not have significant endoscopic inflammation. 7, 2
- Calprotectin is highly sensitive (90.6%) but has lower specificity for IBD due to multiple other conditions that elevate this marker. 6, 2, 8