What is calprotectin?

Calprotectin: A Biomarker of Intestinal Inflammation

Calprotectin is a sensitive and specific marker of intestinal inflammation that serves as a useful non-invasive biomarker for diagnosing and monitoring inflammatory bowel disease (IBD) and differentiating it from irritable bowel syndrome (IBS). 1

What is Calprotectin?

• Calprotectin is a heterodimeric calcium- and zinc-binding protein mainly derived from the cytoplasm of neutrophils that has direct antimicrobial functions and plays a role in regulating the innate immune response 2
• It is released during inflammatory processes due to the degranulation of neutrophil granulocytes 1
• When inflammation occurs within the intestinal tract, calprotectin is released into the intestinal lumen and remains stable enough to be measured in feces 1

Clinical Utility of Fecal Calprotectin

Differential Diagnosis of IBD vs IBS

• Fecal calprotectin has a very high negative predictive value for IBD, making it excellent for ruling out IBD in undiagnosed, symptomatic patients 1, 3
• Normal levels (defined as <50 μg/g stool) have a high negative predictive value for IBD 1
• Higher thresholds (between 100-250 μg/g stool) are recommended to trigger colonoscopy, which improves positive predictive value with minimal reduction in negative predictive value 1
• Used appropriately, fecal calprotectin can be a cost-effective measure to prevent unnecessary colonoscopies in patients where IBD is extremely unlikely 1

Assessment of Disease Activity in Known IBD

• Fecal calprotectin is a validated biomarker for endoscopic and histological disease activity in IBD 1
• It correlates well with endoscopic inflammation in both ulcerative colitis and Crohn's disease 1
• A meta-analysis found that a calprotectin cut-off of 50 μg/g had 90.6% sensitivity to detect endoscopically active disease, while levels >100 μg/g provided 78.2% specificity 1
• A threshold of 250 μg/g provides better specificity (82%) compared to thresholds of 100 μg/g (66%) and 50 μg/g (60%) in differentiating active IBD from remission 1

Monitoring Treatment Response

• Fecal calprotectin can be used to monitor intestinal inflammation and evaluate therapeutic responses 2
• It provides evidence of relapse or mucosal healing, which can guide decisions on treatment escalation or de-escalation 1, 2
• Clinically inactive disease but raised calprotectin levels can predict future relapse 1

Practical Considerations

Sample Collection and Processing

• The first stool passed in the morning should be routinely used for sampling 1
• Samples should be stored for no more than 3 days at room temperature before analysis 1
• Variability exists between different assays, in levels from different stool samples from one patient during a day, and in relation to the interval between stools being passed 1

Interpretation Challenges

• Fecal calprotectin is elevated in various inflammatory conditions beyond IBD, including infectious gastroenteritis and colorectal cancer 1, 2
• In acute diarrhea due to infection, calprotectin is likely to be raised and will not discriminate between IBD and gastroenteritis 1
• Fecal calprotectin is not sensitive enough to exclude advanced colorectal adenoma or colorectal carcinoma 1
• NSAID use in the past 6 weeks can affect calprotectin levels and should be considered when interpreting results 1

Diagnostic Thresholds and Topographical Considerations

• Different segments of the intestine show varying levels of calprotectin for similar levels of inflammation 4
• For a similar level of small bowel inflammatory activity, calprotectin levels incrementally increase from proximal to distal segments 4
• Calprotectin shows higher sensitivity for colonic inflammation compared to small bowel inflammation 4
• Local laboratory validation of specific cut-off values is recommended due to variability between assays 1

Clinical Applications in Practice

• For patients aged 16-40 with new lower gastrointestinal symptoms (>4 weeks) where IBD is suspected, fecal calprotectin measurement is recommended as part of the diagnostic pathway 1
• Levels <100 μg/g suggest IBS is likely 1
• Levels 100-250 μg/g warrant consideration of repeat testing or routine referral to gastroenterology 1
• Levels >250 μg/g indicate need for urgent referral to gastroenterology 1
• Interpretation should always consider the clinical context, including symptoms, history, and other diagnostic findings 2