What conditions, besides inflammatory bowel disease (IBD), can cause elevated fecal calprotectin levels?

What Other Conditions Raise Fecal Calprotectin?

Fecal calprotectin is elevated by any condition causing intestinal inflammation, including NSAIDs, colorectal neoplasia, infections, celiac disease, microscopic colitis, and even hemorrhoids with active bleeding—making it a sensitive but non-specific marker that requires clinical context for proper interpretation. 1, 2

Non-IBD Causes of Elevated Calprotectin

Medications and Direct Mucosal Injury

• NSAID use within the past 6 weeks is a major cause of false elevation through direct mucosal injury, including over-the-counter ibuprofen, naproxen, and aspirin at anti-inflammatory doses 1, 3
• You must specifically ask about and document any NSAID exposure before interpreting calprotectin results 1

Gastrointestinal Neoplasia

• Colorectal adenomas and colorectal cancer elevate calprotectin and must be excluded, particularly in patients over age 50 or those with alarm symptoms like rectal bleeding 1, 2
• Calprotectin is not sensitive enough to exclude advanced colorectal adenoma or colorectal carcinoma, so cancer pathway referral should proceed based on clinical features regardless of calprotectin level 4, 3

Other Inflammatory Conditions

• Untreated celiac disease causes intestinal inflammation that elevates calprotectin, and the British Society of Gastroenterology recommends screening with tissue transglutaminase or EMA antibodies in all patients with chronic diarrhea 1
• Microscopic colitis (including collagenous and lymphocytic colitis) elevates calprotectin and requires colonoscopy with biopsies for diagnosis 1, 2
• Eosinophilic colitis produces calprotectin elevation through eosinophilic infiltration 2

Infectious Causes

• Infectious gastroenteritis and infective colitis significantly elevate calprotectin during active infection 3, 2
• Calprotectin levels typically normalize after resolution of infection 2

Local Bleeding Sources

• Hemorrhoids with active bleeding can cause false elevations due to local inflammation and blood contamination of stool samples 1, 3
• This is particularly relevant when visible rectal bleeding is present 1

Clinical Approach to Elevated Calprotectin

Immediate Medication Review

• Stop all NSAIDs if clinically feasible and consider repeat testing in 4-6 weeks if initial values are in the 50-250 μg/g range 1
• Document timing of last NSAID use relative to stool collection 1, 3

Essential Screening Tests

• Check celiac serology (tissue transglutaminase antibodies) in all patients with elevated calprotectin and chronic diarrhea 1
• This is a British Society of Gastroenterology recommendation for the chronic diarrhea workup 1

Endoscopic Evaluation

• Proceed to colonoscopy with biopsies to evaluate for microscopic colitis, colorectal neoplasia, and other mucosal abnormalities not visible on standard endoscopy 1
• The British Society of Gastroenterology states that endoscopic and histological assessment is necessary in most patients with chronic diarrhea and elevated inflammatory markers 1

Interpretation Caveats by Calprotectin Level

Values 50-250 μg/g (Indeterminate Range)

• This range carries an 8% chance of developing IBD over 12 months compared to 1% with levels <50 μg/g 1
• Consider repeat testing in 4-6 weeks after stopping NSAIDs or recovering from suspected infection before proceeding to colonoscopy 1

Values >150 μg/g

• These levels have 78.2% specificity for endoscopically active disease 4, 1
• In asymptomatic patients, the false positive rate is 22.4%, meaning nearly one-quarter may not have significant endoscopic inflammation 1, 5

Values >250 μg/g

• These strongly suggest active inflammation requiring endoscopic assessment, with 82% specificity for active disease 4, 1
• This threshold provides better specificity than lower cutoffs 4

Critical Pitfalls to Avoid

Sample Collection Issues

• Use the first stool passed in the morning and ensure analysis within 3 days at room temperature to avoid falsely elevated or degraded results 1, 3
• Variability exists between different assays and in different stool samples from the same patient during one day 4

Alarm Symptoms Override Calprotectin

• In patients with rectal bleeding, abdominal pain, change in bowel habit, weight loss, or iron-deficiency anemia, cancer pathway referral should proceed regardless of calprotectin result 4, 5
• Calprotectin cannot reliably exclude colorectal cancer 4, 3

Non-Pathological Factors

• Individual, environmental, and method-related factors can affect FC measurement and clinical interpretation 2
• Age, diet, and other physiological variables may influence baseline levels 2