What is fecal calprotectin?

What is Fecal Calprotectin?

Fecal calprotectin is a calcium- and zinc-binding protein derived primarily from neutrophil cytoplasm that serves as a highly sensitive, non-invasive biomarker of intestinal inflammation. 1, 2

Origin and Biological Basis

• Calprotectin is a member of the S-100 protein family found abundantly in neutrophils throughout the human body 2
• Its presence in stool results from neutrophil migration into gastrointestinal tissue during inflammatory processes 2
• The protein has direct antimicrobial functions and plays a role in regulating the innate immune response 3
• Fecal concentrations correlate directly with the level of mucosal inflammation 3

Primary Clinical Applications

Distinguishing IBD from IBS

• Fecal calprotectin has excellent negative predictive value for ruling out inflammatory bowel disease (IBD) in symptomatic patients with undiagnosed gastrointestinal complaints 1, 4
• Normal levels (<50 μg/g) effectively exclude IBD, making it particularly useful for differentiating IBD from irritable bowel syndrome (IBS) 1
• The European Society of Gastrointestinal Endoscopy recommends fecal calprotectin as a useful non-invasive biomarker for this differentiation 1

Monitoring Disease Activity in IBD

• Calprotectin correlates well with endoscopic inflammation in both ulcerative colitis and Crohn's disease 1, 4
• A meta-analysis demonstrated that calprotectin cutoff of 50 μg/g had 90.6% sensitivity to detect endoscopically active disease 1
• Levels >100 μg/g provided 78.2% specificity for active endoscopic inflammation 1
• The biomarker provides evidence of relapse or mucosal healing, guiding treatment escalation or de-escalation decisions 1

Predicting Disease Course

• Clinically inactive disease with raised calprotectin levels predicts future relapse 1
• Calprotectin successfully predicts relapses and detects pouchitis in IBD patients 4
• Serial monitoring at 3-6 month intervals facilitates early recognition of impending disease flares 1

Diagnostic Thresholds and Interpretation

Threshold Recommendations

• The American Gastroenterological Association recommends higher thresholds (100-250 μg/g) to trigger colonoscopy, which improves positive predictive value with minimal reduction in negative predictive value 1
• For patients with moderate to severe symptoms suggestive of IBD flare, calprotectin >150 μg/g reliably suggests moderate to severe endoscopic inflammation 1
• Levels <100 μg/g suggest IBS is likely in patients aged 16-40 with new lower gastrointestinal symptoms 1
• Levels 100-250 μg/g warrant consideration of repeat testing or routine gastroenterology referral 1
• Levels >250 μg/g indicate need for urgent gastroenterology referral 1

Correlation with Disease Severity

• Patients with clinically active Crohn's disease show higher calprotectin levels (405 μg/g) compared to those with quiescent disease (213 μg/g) 5
• In ulcerative colitis, active disease demonstrates levels of 327 μg/g versus 123 μg/g in quiescent disease 5
• Calprotectin demonstrates stronger correlation with extent of inflamed surface (r = 0.86) than region of maximal severity (r = 0.79) 6

Important Limitations and Caveats

Disease Location Affects Performance

• Performance is weaker for isolated proctitis (r = 0.54) compared with left-sided colitis (r = 0.75) or extensive colitis (r = 0.78) 6
• Fecal biomarkers may be less accurate in detecting endoscopic inflammation in patients with ulcerative proctitis or limited segmental disease 6
• Elevation is influenced by the extent and location of inflamed surface 6

Lack of Specificity

• Calprotectin is elevated in various inflammatory conditions beyond IBD, including infectious gastroenteritis, colorectal cancer, and microscopic colitis 1, 3
• The biomarker is not sensitive enough to exclude advanced colorectal adenoma or colorectal carcinoma 1
• NSAID use in the past 6 weeks can significantly elevate calprotectin levels through direct mucosal injury 1, 7
• Hemorrhoids can cause false elevations due to local bleeding and inflammation 1

Test Variability Issues

• Fecal calprotectin assays may not be interchangeable, and the same assay should be used for a given patient to compare results over time 6
• Five studies comparing different assays identified discrepancies ranging from 2.5- to 5-fold differences when testing the same stool sample 6
• Within-patient variability ranges from 13% to 114% using the same assay repeatedly with different stool samples 6
• Variation in results testing different regions of the same stool sample ranges from 3% to 31% 6
• If borderline or unexpected results occur, repeat fecal calprotectin testing or endoscopic evaluation for confirmation may be required 6

Detection Limitations

• Biomarkers may be suboptimal for detecting endoscopic remission (Mayo Endoscopic Score 0) or histologic remission 6
• Performance to distinguish endoscopic remission (MES 0) versus mild endoscopic activity (MES 1) is limited 6
• Test performance reflects ability to rule out moderate to severe endoscopic inflammation (MES 2 or 3) 6

Practical Testing Considerations

Sample Collection and Handling

• The British Society of Gastroenterology recommends using the first stool passed in the morning for sampling 1
• Samples should be stored for no more than 3 days at room temperature before analysis 1
• Proper collection technique is essential to avoid falsely elevated or degraded results 7

When to Order the Test

• For patients aged 16-40 with new lower gastrointestinal symptoms (>4 weeks) where IBD is suspected 1
• In patients with IBD in symptomatic remission, measure every 6-12 months 1
• For patients with IBD and mild symptoms with elevated calprotectin (>150 μg/g), endoscopic assessment is suggested rather than empiric treatment adjustment 1